[Federal Register Volume 80, Number 173 (Tuesday, September 8, 2015)]
[Proposed Rules]
[Pages 53931-54061]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2015-21756]
[[Page 53931]]
Vol. 80
Tuesday,
No. 173
September 8, 2015
Part II
Department of Homeland Security
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6 CFR Part 46
Department of Agriculture
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7 CFR Part 1c
Department of Energy
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10 CFR Part 745
National Aeronautics and Space Administration
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14 CFR Part 1230
Department of Commerce
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15 CFR Part 27
Social Security Administration
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20 CFR Part 431
Agency for International Development
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22 CFR Part 225
Department of Justice
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28 CFR Part 46
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Department of Labor
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29 CFR Part 21
Department of Defense
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32 CFR Part 219
Department of Education
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34 CFR Part 97
Department of Veterans Affairs
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38 CFR Part 16
Environmental Protection Agency
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40 CFR Part 26
Department of Health and Human Services
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45 CFR Part 46
National Science Foundation
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45 CFR Part 690
Department of Transportation
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49 CFR Part 11
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Federal Policy for the Protection of Human Subjects; Proposed Rules
Federal Register / Vol. 80 , No. 173 / Tuesday, September 8, 2015 /
Proposed Rules
[[Page 53933]]
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DEPARTMENT OF HOMELAND SECURITY
6 CFR Part 46
DEPARTMENT OF AGRICULTURE
7 CFR Part 1c
DEPARTMENT OF ENERGY
10 CFR Part 745
NATIONAL AERONAUTICS AND SPACE ADMINISTRATION
14 CFR Part 1230
DEPARTMENT OF COMMERCE
15 CFR Part 27
SOCIAL SECURITY ADMINISTRATION
20 CFR Part 431
AGENCY FOR INTERNATIONAL DEVELOPMENT
22 CFR Part 225
DEPARTMENT OF JUSTICE
28 CFR Part 46
DEPARTMENT OF LABOR
29 CFR Part 21
DEPARTMENT OF DEFENSE
32 CFR Part 219
DEPARTMENT OF EDUCATION
34 CFR Part 97
DEPARTMENT OF VETERANS AFFAIRS
38 CFR Part 16
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 26
DEPARTMENT OF HEALTH AND HUMAN SERVICES
45 CFR Part 46
RIN 0937-AA02
NATIONAL SCIENCE FOUNDATION
45 CFR Part 690
DEPARTMENT OF TRANSPORTATION
49 CFR Part 11
Federal Policy for the Protection of Human Subjects
AGENCY: Department of Homeland Security; Department of Agriculture;
Department of Energy; National Aeronautics and Space Administration;
Department of Commerce; Social Security Administration; Agency for
International Development; Department of Justice; Department of Labor;
Department of Defense; Department of Education; Department of Veterans
Affairs; Environmental Protection Agency; Department of Health and
Human Services; National Science Foundation; and Department of
Transportation.
ACTION: Notice of proposed rulemaking.
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SUMMARY: The departments and agencies listed in this document propose
revisions to modernize, strengthen, and make more effective the Federal
Policy for the Protection of Human Subjects that was promulgated as a
Common Rule in 1991. This NPRM seeks comment on proposals to better
protect human subjects involved in research, while facilitating
valuable research and reducing burden, delay, and ambiguity for
investigators. This proposed rule is an effort to modernize, simplify,
and enhance the current system of oversight. The participating
departments and agencies propose these revisions to the human subjects
regulations because they believe these changes would strengthen
protections for research subjects while facilitating important
research.
DATES: To be assured consideration, comments must be received at one of
the addresses provided below, no later than 5 p.m. on December 7, 2015.
ADDRESSES: You may submit comments, identified by docket ID number HHS-
OPHS-2015-0008, by one of the following methods:
Federal eRulemaking Portal:http://www.regulations.gov.
Enter the above docket ID number in the ``Enter Keyword or ID'' field
and click on ``Search.'' On the next Web page, click on ``Submit a
Comment'' action and follow the instructions.
Mail/Hand delivery/Courier [For paper, disk, or CD-ROM
submissions] to: Jerry Menikoff, M.D., J.D., OHRP, 1101 Wootton
Parkway, Suite 200, Rockville, MD 20852.
Comments received, including any personal information, will be
posted without change to http://www.regulations.gov.
FOR FURTHER INFORMATION CONTACT: Jerry Menikoff, M.D., J.D., Office for
Human Research Protections (OHRP), Department of Health and Human
Services, 1101 Wootton Parkway, Suite 200, Rockville, MD 20852;
telephone: 240-453-6900 or 1-866-447-4777; facsimile: 301-402-2071;
email: jerry.menikoff@hhs.gov.
SUPPLEMENTARY INFORMATION:
Executive Summary
Purpose of the Regulatory Action
Summary of the Major Provisions of the Proposed Regulatory Actions
Estimated Costs and Benefits
I. The Rationale for Modernizing the Common Rule
A. The Changing Nature of Research
B. Public Comments, Expert Advice, Stakeholder Dialogue
C. Guiding Principles for Proposed Changes
1. Question for Public Comment
D. Organization of the NPRM
II. Major Proposals To Modernize the Common Rule
A. Proposed Changes to the Scope and Applicability of the
Regulations
1. Expanding the Definition of Human Subject to Cover Research
With Non-identified Biospecimens (NPRM at Sec. Sec. __.102(e) and
__.101(b)(3)(i))
a. NPRM Goals
b. Current Rule
c. ANPRM Discussion
d. NPRM Proposal
i. Alternative Proposals
e. What would change in the definition of ``human subject''
under the primary proposal?
f. Questions for Public Comment
2. Explicit Exclusion of Activities From the Common Rule
a. Exclusion of Activities That Are Deemed Not Research (NPRM at
Sec. __.101(b)(1))
i. Program Improvement Activities (NPRM at Sec.
__.101(b)(1)(i))
(1) NPRM Proposal
(2) Questions for Public Comment
ii. Oral History, Journalism, Biography, and Historical
Scholarship Activities (NPRM at Sec. __.101(b)(1)(ii))
(1) ANPRM Discussion
(2) NPRM Proposal
iii. Criminal Justice Activities (NPRM at Sec.
__.101(b)(1)(iii))
(1) NPRM Proposal
iv. Quality Assurance and Quality Improvement Activities (NPRM
at Sec. __.101(b)(1)(iv))
(1) NPRM Proposal
v. Public Health Surveillance (NPRM at Sec. __.101(b)(1)(v))
(1) NPRM Proposal
(2) Question for Public Comment
vi. Intelligence Surveillance Activities (NPRM at Sec.
__.101(b)(1)(vi))
(1) NPRM Proposal
b. Exclusion of Activities That Are Low-Risk and Already Subject
to Independent Controls (NPRM at Sec. __.101(b)(2))
i. NPRM Goals
ii. ANPRM Discussion
iii. Educational Tests, Survey Procedures, Interview Procedures,
or Observation of Public Behaviors (NPRM at Sec. __.101(b)(2)(i))
(1) NPRM Proposal
(2) Questions for Public Comment
iv. Research Involving the Collection or Study of Information
That Has Been or
[[Page 53934]]
Will Be Collected (NPRM at Sec. __.101(b)(2)(ii))
(1) Current Rule
(2) ANPRM Discussion
(3) NPRM Proposal
(4) Questions for Public Comment
v. Research Conducted by a Government Agency Using Government-
Generated or Government-Collected Data (NPRM at Sec.
__.101(b)(2)(iii))
(1) NPRM Proposal
(2) Questions for Public Comment
vi. Certain Activities Covered by HIPAA (NPRM at Sec.
__.101(b)(2)(iv))
(1) ANPRM Discussion
(2) NPRM Proposal
(3) Questions for Public Comment
c. Applicability of Exclusions to the Subparts
i. Current Rule
ii. NPRM Proposals
iii. Questions for Public Comment
3. Proposed Exemptions (NPRM at Sec. __.104)
a. Making Exempt Research Determinations (NPRM at Sec.
__.104(c))
i. NPRM Goal
ii. Current Rule
iii. ANPRM Discussion
iv. NPRM Proposal
v. Questions for Public Comment
b. Exemptions Subject to the Documentation Requirements of Sec.
__.104(c) and No Other Section of the Proposed Rule
i. Research Conducted in Established or Commonly Accepted
Educational Settings (NPRM at Sec. __.104(d)(1); current Rule at
Sec. __.101(b)(1))
(1) NPRM Goal
(2) Current Rule
(3) NPRM Proposal
(4) Questions for Public Comment
ii. Research and Demonstration Projects Conducted or Supported
by a Federal Department or Agency (NPRM at Sec. __.104(d)(2);
Current Rule at Sec. __.101(b)(5))
(1) NPRM Goal
(2) Current Rule
(3) ANPRM Discussion
(4) NPRM Proposal
(5) Questions for Public Comment
iii. Research Involving Benign Interventions in Conjunction With
the Collection of Data fFrom an Adult Subject (NPRM at Sec.
__.104(d)(3))
(1) NPRM Goal
(2) Current Rule
(3) ANPRM Discussion
(4) NPRM Proposal
(5) Questions for Public Comment
iv. Taste and Food Quality Evaluation and Consumer Acceptance
Studies (NPRM at Sec. __.104(d)(4); Current Rule at Sec.
__.101(b)(6))
(1) Question for Public Comment
c. Exemptions Subject to the Documentation Requirements of Sec.
__.104(c) and the Privacy Safeguards Described in Sec. __.105
i. Questions for Public Comment
ii. Research Involving Educational Tests, Surveys, Interviews,
or Observation of Public Behavior if the Information Is Recorded
With Identifiers and Even if the Information Is Sensitive (NPRM at
Sec. __.104(e)(1))
(1) NPRM Goals
(2) Current Rule
(3) ANPRM Discussion
(4) NPRM Proposal
(5). Questions for Public Comment
iii. Secondary Research Use of Identifiable Private Information
(NPRM at Sec. __.104(e)(2))
(1) NPRM Goal
(2) Current Rule
(3) ANPRM Discussion
(4) NPRM Proposal
(5) Questions for Public Comment
d. Exemptions Subject to the Documentation Requirements of Sec.
__.104(c), the Privacy Safeguards Described in Sec. __.105, Limited
IRB Review as Described in Sec. __.111(a)(9), and Broad Consent in
Accordance With Sec. __.116(c)
i. NPRM Goals
ii. Current Rule
iii. ANPRM Discussion
iv. NPRM Proposals
(1) Exemption for the Storage or Maintenance of Biospecimens or
Identifiable Private Information for Secondary Research Use (NPRM at
Sec. __.104(f)(1))
(2) Exemption for Secondary Research Use of Biospecimens or
Identifiable Private Information Where Broad Consent Has Been Sought
and Obtained (NPRM at Sec. __.104(f)(2))
v. Questions for Public Comment
e. Applicability of Exemptions to the Subparts (NPRM at Sec.
__.104(b); Current Rule at Footnote 1)
i. Current Rule
ii. NPRM Proposals
ii. Questions for Public Comment
f. What would change in the exemptions?
B. Proposed Changes To Obtaining, Waiving, and Documenting
Informed Consent (Sec. Sec. __.116 and__.117)
1. Required Elements of Informed Consent (NPRM at Sec.
__.116(a), (b))
a. NPRM Goal
b. Current Rule
c. ANPRM Discussion
d. NPRM Proposals
e. What would change?
f. Question for Public Comment
2. Broad Consent to the Storage, Maintenance and Secondary
Research Use of Biospecimens and Identifiable Private Information
(NPRM at Sec. __.116(c), (d))
a. NPRM Goal
b. Current Rule
c. ANPRM Discussion
d. NPRM Proposal
e. What would change?
f. Questions for Public Comment
3. Waiver of Informed Consent or Documentation of Informed
Consent (NPRM at Sec. Sec. __.116(e), (f) and __.117)
a. NPRM Goals
b. Current Rule
c. ANPRM Discussion
d. NPRM Proposals
e. What would change?
f. Questions for Public Comment
4. Posting of Consent Forms
a. NPRM Goals
b. NPRM Proposal
c. What would change?
C. Proposed Changes To Protect Information and Biospecimens
(NPRM at Sec. __.105)
1. NPRM Goal
2. Current Rule and Other Regulatory or Statutory Requirements
3. ANPRM Discussion
4. NPRM Proposals
5. What would change?
6. Questions for Public Comment
D. Harmonization of Agency Guidance (NPRM at Sec. __.101(j))
1. NPRM Goal
2. Current Rule
3. ANPRM Discussion
4. NPRM Proposal
5. What would change?
6. Question for Public Comment
E. Cooperative Research (NPRM and Current Rule at Sec. __.114)
and Proposal To Cover Unaffiliated IRBs Not Operated by an
Institution Holding a Federalwide Assurance (NPRM at Sec.
__.101(a))
1. NPRM Goal
2. Current Rule
3. Relevant Prior Proposals and Discussions
4. NPRM Proposals
5. What would change?
6. Questions for Public Comment
F. Changes To Promote Effectiveness and Efficiency in IRB
Operations
1. Continuing Review of Research (NPRM at Sec. __.109(f);
Current Rule at Sec. __.109(e))
a. NPRM Goal
b. Current Rule
c. ANPRM Discussion
d. NPRM Proposals
e. What would change?
2. Expedited Review Procedures and the Definition of ``Minimal
Risk'' (NPRM at Sec. Sec. __.110 and __.102(j))
a. NPRM Goal
b. Current Rule
c. ANPRM Discussion
d. NPRM Proposal
e. What would change?
f. Questions for Public Comment
G. Proposed Changes to IRB Operational Requirements
1. Proposed Criteria for IRB Approval of Research (NPRM at Sec.
__.111)
a. NPRM Goals
b. Current Rule
c. ANPRM Discussion
d. NPRM Proposals
e. What would change?
f. Questions for Public Comment
2. Proposed Revisions To IRB Operations, Functions, and
Membership Requirements
a. NPRM Goal
b. Current Rule
c. NPRM Proposal
d. What would change?
e. Question for Public Comment
H. Other Proposed Changes
1. Proposal To Extend the Common Rule to All Clinical Trials
(With Exceptions) (NPRM at Sec. __.101(a)(1))
a. NPRM Goals
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b. Current Rule
c. ANPRM Discussion
d. NPRM Proposal
e. What Would Change?
f. Questions for Public Comment
2. Changes to the Assurance Process (NPRM at Sec. Sec. __.103
and __.108; Current Rule at Sec. __.103)
a. NPRM Goal
b. Current Rule
c. NPRM Proposals
d. What would change?
e. Question for Public Comment
3. Department or Agency Discretion About Applicability of the
Policy (NPRM at Sec. __.101(c), (d), (i)) and Discretion Regarding
Additional Requirements Imposed by the Conducting or Supporting
Department or Agency (NPRM and Current Rule at Sec. __.124)
a. NPRM Goals
b. Current Rule
c. NPRM Proposals
4. Research Covered by This Policy Conducted in Foreign
Countries (NPRM at Sec. __.101(h))
I. Effective and Compliance Dates of New Rule (NPRM at Sec.
__.101(k))
1. Effective Dates
2. Transition Provisions
a. Research Initiated Prior to the Effective Date of This
Subpart (NPRM at Sec. __.101(k)(1))
b. Use of Prior Collections of Biospecimens (NPRM at Sec.
__.101(k)(2))
III. Regulatory Impact Analyses
IV. Environmental Impact
V. Paperwork Reduction Act
VI. Summary of Comments Received on the 2011 Common Rule ANPRM
VII. Regulatory Text
Executive Summary
Purpose of the Regulatory Action
Individuals who are the subjects of research may be asked to
contribute their time and assume risk to advance the research
enterprise, which benefits society at large. U.S. federal regulations
governing the protection of human subjects in research have been in
existence for more than three decades. The Department of Health,
Education, and Welfare (HEW) first published regulations for the
protection of human subjects in 1974, and the Department of Health and
Human Services (HHS) revised them in the early 1980s. During the 1980s,
HHS began a process that eventually led to the adoption of a revised
version of the regulations by 15 U.S. federal departments and agencies
in 1991. The purpose of this effort was to promote uniformity,
understanding, and compliance with human subject protections as well as
to create a uniform body of regulations across Federal departments and
agencies (subpart A of 45 CFR part 46), often referred to as the
``Common Rule'' for the Protection of Human Subjects.
Since the Common Rule was promulgated, the volume and landscape of
research involving human subjects have changed considerably. Research
with human subjects has grown in scale and become more diverse.
Examples of developments include: An expansion in the number and type
of clinical trials, as well as observational studies and cohort
studies; a diversification of the types of social and behavioral
research being used in human subjects research; increased use of
sophisticated analytic techniques for use with human biospecimens; and
the growing use of electronic health data and other digital records to
enable very large data sets to be analyzed and combined in novel ways.
Yet these developments have not been accompanied by major change in the
human subjects research oversight system, which has remained largely
unchanged over the last two decades.
The regulations are codified in each department or agency's title
or chapter of the Code of Federal Regulations (CFR). The Common Rule
was based on HHS' regulations, 45 CFR part 46, subpart A, and includes
identical language in the separate regulations of each department and
agency.
Although they have not issued the Common Rule in regulations, three
departments and agencies currently comply with all subparts of the HHS
protection of human subjects regulations at 45 CFR part 46. These are
the Central Intelligence Agency (CIA), the Department of Homeland
Security (DHS), and the Social Security Administration (SSA). DHS, and
SSA are joining this proposed rulemaking with the intent of codifying
the final rule in their own agency regulations.
Pursuant to Executive Order 12333 of December 4, 1981, as amended,
elements of the Intelligence Community must comply with the guidelines
issued by the Department of Health and Human Services regarding
research on human subjects found in 45 CFR part 46. This proposed
rulemaking does not supersede the Executive Order. The Office of the
Director of National Intelligence and the CIA will continue to adhere
to the HHS guidelines, pursuant to the Executive Order, when the final
rule is implemented.
DHS, created after issuance of the Common Rule, is required by
statute (Pub. L. 108-458, title VIII, section 8306) to comply with 45
CFR part 46, or with equivalent regulations promulgated by the
Secretary of Homeland Security or his designee. This proposed
rulemaking initiates the process of promulgating equivalent
regulations, consistent with statute. Once DHS executes a final rule,
DHS will comply with the DHS regulations as the requirements will be
equivalent to compliance with HHS regulations at 45 CFR part 46,
subpart A.
SSA was separated from HHS in 1995 and, pursuant to the transition
rules provided in Section 106 of title 1 of Public Law 103-296, must
apply all regulations that applied to SSA before the separation, absent
action by the Commissioner. Once the final rule is codified in SSA
regulations, SSA will follow the SSA regulations instead of HHS
regulations at 45 CFR part 46, subpart A. See Public Law 103-296 Sec.
106(b), 108 Stat. 1464, 1476.
Another department is joining this proposed rulemaking. The
Department of Labor (DOL) is not a signatory to the current Common
Rule, and is joining this proposed rulemaking in order to promulgate
the Common Rule in DOL regulations and to apply the regulations to
human subjects research that DOL may conduct or support, pending the
scope of the final rule.
Finally, note that there are two current Common Rule agencies that
are not listed as part of this proposed rulemaking. The Department of
Housing and Urban Development (HUD) supports this proposal, but due to
certain statutory prepublication requirements governing HUD rules, HUD
will adopt this proposal through a separate rulemaking. The Consumer
Product Safety Commission (CPSC), subject to Commission vote, also
intends to adopt this proposed rule through a separate rulemaking.
On July 26, 2011, the Office of the Secretary of HHS, in
coordination with the Executive Office of the President's Office of
Science and Technology Policy (OSTP), published an advanced notice of
public rulemaking (ANPRM) to request comment on how current regulations
for protecting human subjects who participate in research might be
modernized and revised to be more effective.\1\ The ANPRM sought
comment on how to better protect human subjects who are involved in
research while facilitating valuable research and reducing burden,
delay, and ambiguity for investigators.
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\1\ 76 FR 44512 (Jul. 26, 2011).
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Since the publication of the ANPRM, science has continued to
advance, as has the dialogue regarding the changing nature of research
and the preferred balance of protections for research participants
among the principles of respect for persons, beneficence, and justice.
Important elements of that debate have centered on the appropriate
level of transparency in government and medicine and how patient and
research participant expectations should be incorporated into
government policies.
[[Page 53936]]
These factors have helped shape the development of the regulatory
actions proposed in this NPRM.
The proposal also benefits from public comments submitted in
response to more recent policy proposals regarding specific topics such
as informed consent through the Office for Human Research Protection
(OHRP)'s Draft Guidance on Disclosing Reasonably Foreseeable Risks in
Research Evaluating Standards of Care \2\ and the use of a single
institutional review board (IRB) for multi-site research studies
through the National Institutes of Health (NIH)'s Draft Policy on the
Use of a Single Institutional Review Board for Multi-Site Research.\3\
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\2\ 79 FR 63630 (Oct. 24, 2014).
\3\ National Institutes of Health. (2014, December 14). Request
for Comments on the Draft NIH Policy on the Use of a Single
Institutional Review Board for Multi-Site Research. See more at:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-026.html#sthash.fmjlNRi6.dpuf. Retrieved from National Institutes of
Health, Office of Extramural Research: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-026.html.
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Finally, the NPRM more thoroughly addresses behavioral and social
science research perspectives and the broader types of research
conducted or otherwise supported by the other Common Rule agencies.
Similarly, the proposal benefits from continuing efforts at HHS to
harmonize human subjects policies, particularly between OHRP and the
U.S. Food and Drug Administration (FDA).
Summary of the Major Provisions of the Proposed Regulatory Action
The goals of the NPRM are to increase human subjects' ability and
opportunity to make informed decisions; reduce potential for harm and
increase justice by increasing the uniformity of human subject
protections in areas such as information disclosure risk, coverage of
clinical trials, and coverage of IRBs; and facilitate current and
evolving types of research that offer promising approaches to treating
and preventing medical and societal problems through reduced ambiguity
in interpretation of the regulations, increased efficiencies in the
performance of the review system, and reduced burdens on researchers
that do not appear to provide commensurate protections to human
subjects. It is hoped that these changes will also build public trust
in the research system.
An example of some major changes being proposed that will better
protect research subjects and help build public trust are the rules
relating to informed consent. With regard to informed consent in
general (such as consent to participating in clinical trials), the
rules would be significantly tightened to make sure that the process
becomes more meaningful. Consent forms would no longer be able to be
unduly long documents, with the most important information often buried
and hard to find. They would need to give appropriate details about the
research that is most relevant to a person's decision to participate in
the study, such as information a reasonable person would want to know,
and present that information in a way that highlights the key
information. In addition, to assure that these rules do indeed change
current practices, there will be a one-time posting requirement for the
consent forms for clinical trials, so that anyone drafting a consent
form will do so knowing that it will eventually be subject to public
scrutiny.
In addition, informed consent would generally be required for
secondary research with a biospecimen (for example, part of a blood
sample that is left over after being drawn for clinical purposes), even
if the investigator is not being given information that would enable
him or her to identify whose biospecimen it is. Such consent would not
need to be obtained for each specific research use of the biospecimen,
but rather could be obtained using a ``broad'' consent form in which a
person would give consent to future unspecified research uses.
The NPRM also attempts to strengthen the effectiveness and
efficiency of the oversight system by making the level of review more
proportional to the seriousness of the harm or danger to be avoided.
Research that poses greater risk to subjects should receive more
oversight and deliberation than less risky research. The NPRM seeks to
avoid requirements that do not enhance protection and impose burden,
which can decrease efficiency, waste resources, erode trust, and
obscure the true ethical challenges that require careful deliberation
and stakeholder input. Cumbersome and outdated regulatory standards
overwhelm and distract institutions, IRBs, and investigators in ways
that stymie efforts to appropriately address the real risks and
benefits of research.
The result of these types of changes, as the NPRM proposes to
implement them, is that some studies that currently require IRB review
would now become exempt. Some that are currently exempt would
specifically be declared as outside the scope of the regulations
(``excluded''), and thus would not require any administrative or IRB
review. Further, in terms of determining when a study is exempt, a web-
based ``decision tool'' will be created. That decision tool will
provide a determination of whether or not a study is exempt. That
result, so long as the tool was provided with accurate information,
will be presumed by the Common Rule agencies to be an appropriate
determination of exempt status. Thus, it is expected that in many
instances the tool would be used by the investigators themselves, thus
obviating both the need for further review and the concern that the
institution might be subjecting itself to future liability by allowing
investigators to use the tool. For all of the excluded and exempt
research activities, this NPRM also affirms the importance of applying
the ethical principle of respect for persons, in addition to the
importance of abiding by this principle in fully regulated non-exempt
research involving human subjects.
The following list encompasses the most significant changes to the
Common Rule proposed in the NPRM:
(1) Improve informed consent by increasing transparency and by
imposing stricter new requirements regarding the information that must
be given to prospective subjects, and the manner in which it is given
to them, to better assure that subjects are appropriately informed
before they decide to enroll in a research study.
(2) Generally require informed consent for the use of stored
biospecimens in secondary research (for example, part of a blood sample
that is left over after being drawn for clinical purposes), even if the
investigator is not being given information that would enable him or
her to identify whose biospecimen it is. That consent would generally
be obtained by means of broad consent (i.e., consent for future,
unspecified research studies) to the storage and eventual research use
of biospecimens.
(3) Exclude from coverage under the Common Rule certain categories
of activities that should be deemed not to be research, are inherently
low risk, or where protections similar to those usually provided by IRB
review are separately mandated.
(4) Add additional categories of exempt research to accommodate
changes in the scientific landscape and to better calibrate the level
of review to the level of risk involved in the research. A new process
would allow studies to be determined to be exempt without requiring any
administrative or IRB review. Certain exempt and all non-exempt
research would be required to provide privacy safeguards for
biospecimens and identifiable private information. New categories
include:
a. certain research involving benign interventions with adult
subjects;
[[Page 53937]]
b. research involving educational tests, surveys, interviews or
observations of public behavior when sensitive information may be
collected, provided that data security and information privacy
protections policies are followed;
c. secondary research use of identifiable private information
originally collected as part of a non-research activity, where notice
of such possible use was given;
d. storing or maintaining biospecimens and identifiable private
information for future, unspecified secondary research studies, or
conducting such studies, when a broad consent template to be
promulgated by the Secretary of HHS is used, information and
biospecimen privacy safeguards are followed, and limited IRB approval
of the consent process used is obtained.
(5) Change the conditions and requirements for waiver or alteration
of consent such that waiver of consent for research involving
biospecimens (regardless of identifiability) will occur only in very
rare circumstances.
(6) Mandate that U.S. institutions engaged in cooperative research
rely on a single IRB for that portion of the research that takes place
within the United States, with certain exceptions. To encourage the use
of IRBs that are otherwise not affiliated with or operated by an
assurance-holding institution (``unaffiliated IRBs''), this NPRM also
includes a proposal that would hold such IRBs directly responsible for
compliance with the Common Rule.
(7) Eliminate the continuing review requirement for studies that
undergo expedited review and for studies that have completed study
interventions and are merely analyzing data or involve only
observational follow-up in conjunction with standard clinical care.
(8) Extend the scope of the policy to cover all clinical trials,
regardless of funding source, conducted at a U.S. institution that
receives federal funding for non-exempt human subjects research.
In sum, the proposed modifications described above are designed to
continue to uphold the ethical principles upon which the Common Rule is
based, as applied to the current social, cultural, and technological
environment.
The legal authority for the departments and agencies that are
signatories to this action is as follows:
Department of Homeland Security, 5 U.S.C. 301; Public Law 107-296,
sec. 102, 306(c); Public Law 108-458, sec. 8306. Department of
Agriculture, 5 U.S.C. 301. Department of Energy, 5 U.S.C. 301; 42
U.S.C. 7254. National Aeronautics and Space Administration, 5 U.S.C.
301. Department of Commerce, 5 U.S.C. 301. Social Security
Administration, 5 U.S.C. 301; 42 U.S.C. 289(a). Agency for
International Development, 5 U.S.C. 301. Department of Justice, 5
U.S.C. 301; 28 U.S.C. 509-510. Department of Labor, 5 U.S.C. 301; 29
U.S.C. 551. Department of Defense, 5 U.S.C. 301. Department of
Education, 5 U.S.C. 301; 20 U.S.C. 1221e-3, 3474. Department of
Veterans Affairs, 5 U.S.C. 301; 38 U.S.C. 501, 7331, 7334.
Environmental Protection Agency, 5 U.S.C. 301. Department of Health and
Human Services, 5 U.S.C. 301; 42 U.S.C. 289. National Science
Foundation, 5 U.S.C. 301. Department of Transportation, 5 U.S.C. 301.
Estimated Costs and Benefits
Table 1 summarizes the quantified and non-quantified benefits and
costs of all proposed changes to the Common Rule. Over the 2016-2025
period, present value benefits of $2,629 million and annualized
benefits of $308 million are estimated using a 3 percent discount rate;
present value benefits of $2,047 million and annualized benefits of
$291 million are estimated using a 7 percent discount rate. Present
value costs of $13,342 million and annualized costs of $1,564 million
are estimated using a 3 percent discount rate; present value costs of
$9,605 million and annualized costs of $1,367 million are estimated
using a 7 percent discount rate. Non-quantified benefits include
improved human subjects protections in clinical trials and biospecimen
research not currently subject to oversight; enhanced oversight of
research reviewed by unaffiliated IRBs; increased uniformity in
regulatory requirements among Common Rule agencies; standardization of
human subjects protections when variation among review IRBs is not
warranted; revised informed consent forms and processes; improved
protection of biospecimens and individually identifiable private
information; and increased transparency of Common Rule agency-supported
clinical trials to inform the development of new consent forms. Non-
quantified costs include the time needed for consultation among Common
Rule agencies before federal guidance is issued; and the time needed by
investigators to obtain, document, and track the permissible uses of
biospecimens and identifiable private information for secondary
research use.
Table 1--Accounting Table of Benefits and Costs of All Proposed Changes
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits..................... 2,629 2,047 308 291
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Improved human subjects protections in clinical trials and biospecimen research not currently subject to
oversight; enhanced oversight in research reviewed by unaffiliated IRBs; increased uniformity in regulatory
requirements among Common Rule agencies; ethical benefit of respecting an individual's wishes in how his or
her biospecimens are used in future research; standardization of human subjects protections when variation
among review IRBs is not warranted; improved informed consent forms and processes; improved protection of
biospecimens and individually identifiable private information; better ensuring availability of
biospecimens for future research activities; and increased transparency of Common Rule-supported clinical
trials to inform the development of new consent forms......................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs 13,342 9,605 1,564 1,367
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
Time for consultation among Common Rule agencies before federal guidance is issued; time for investigators
to obtain consent for secondary use of biospecimens or identifiable private information....................
----------------------------------------------------------------------------------------------------------------
[[Page 53938]]
I. The Rationale for Modernizing the Common Rule
A. The Changing Nature of Research
In the last two decades there has been a paradigm shift in how
research is conducted. Evolving technologies, including imaging, mobile
technologies, and the growth in computing power have changed the scale
of information collected in many disciplines. Computer scientists,
engineers, and social scientists are developing techniques to integrate
different types of data so they can be combined, mined, analyzed, and
shared. Research has also increased, evolved, and diversified in other
areas, such as national security, crime and crime prevention,
economics, education, and the environment, using a wide array of
methodologies in the social sciences and multidisciplinary fields. The
advent of sophisticated computer software programs, the internet, and
mobile technology has created new areas of research activity,
particularly within the social and behavioral sciences. In biomedical
science, the Human Genome Project laid the foundation for precision
medicine and promoted an environment of data sharing and innovation in
analytics and technology, and drew attention to the need for policies
that support a changing research landscape. New technologies, including
genomic sequencing, have quickly led to exponential growth in the data
to which investigators have access. The sheer volume of data that can
be generated in research, the ease with which it can be shared, and the
ways in which it can be used to identify individuals were simply not
possible, or even imaginable, when the Common Rule was first adopted.
Research settings are also shifting. While much biomedical research
continues to be conducted in academic medical centers, more research is
being conducted in clinical care settings, thus combining research and
medical data. Biospecimen repositories and large databases have made it
easier to do research on existing biospecimens and data. Clinical
research networks connected through electronic health records (EHRs)
have developed methods for extracting clinical data for research
purposes and are working toward integration of research data into EHRs
in a meaningful way. The overall volume of research has increased
across the board, with growing reliance on research networks and multi-
site studies. Large cohort studies number well into the hundreds in the
United States alone and many collect biospecimens and data on the same
people over many years. Recent trends clearly show that the scientific
community recognizes the value of data sharing and open-source
resources and understands that pooling intellectual resources and
capitalizing on efficient uses of data and technology represent the
best ways to advance knowledge.
At the same time, the level of public engagement in the research
enterprise has changed; more people want to play an active role in
research, particularly related to health, and they have different
expectations than when the Common Rule was first established. A more
participatory research model is emerging in social, behavioral, and
biomedical research, one in which potential research subjects and
communities express their views about the value and acceptability of
research studies. This participatory model has emerged alongside a
broader trend in American society, facilitated by the widespread use of
social media, in which Americans are increasingly sharing identifiable
personal information and expect to be involved in decisions about how
to further share the personal information, including health-related
information that they have voluntarily chosen to provide. In many ways,
these changes are extensions of the fact that over the past half-
century, rather than being passive recipients of health advice and
treatment, patients have gradually become more active in decisions
about their health and health care. The shift from a paternalistic
research environment to one where participants are active partners in
biomedical and behavioral research is a critical development in human
subjects research.
As technology evolves, so does the nature of the risks and benefits
of participating in certain types of research. Many studies do not
involve interaction with research subjects, but instead involve, for
example, analyzing information obtained from medical records,
administrative claims data, education records, criminal justice
records, research data shared through data repositories, and existing
biospecimens stored in repositories. Risks related to these types of
research studies are largely informational, not physical; that is,
harms could result primarily from the inappropriate release of
information and not from the research interventions themselves.
Nonetheless, those harms can be significant.
New methods, more powerful computers, and easy access to large
administrative datasets produced by local, state, and federal
governments have meant that some types of data that formerly were
treated as non-identified can now be re-identified through combining
large amounts of information from multiple sources. In 2013, scientists
demonstrated that the identity of individual research subjects could be
ascertained by collating and analyzing certain types of genomic data,
including genomic data from publicly available information sources.\4\
Thus, the possibility of fully identifying biospecimens and some types
of data from which direct identifiers had been stripped or did not
originally include direct identifiers has grown, requiring vigilance to
ensure that such research be subject to appropriate oversight. Most
importantly, people want to be asked for their permission. A growing
body of survey data show that many prospective participants want to be
asked for their consent before their biospecimens are used in
research.5 6 7 8
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\4\ Gymrek M et al. ``Identifying personal genomes by surname
inference''. Science 339.6117(2013) 0: 321-324.
\5\ Kaufman DJ et al. Public opinion about the importance of
privacy in biobank research. American Journal of Human Genetics 2009
Nov;85(5):643-654.
\6\ Vermeulen E et al. A trial of consent procedures for future
research with clinically derived biological samples. British Journal
of Cancer 2009 Nov 3;101(9):1505-1512.
\7\ Trinidad SB et al. Research practice and participant
preferences: The growing gulf. Science 2011 Jan 21; 331(6015):287-
288.
\8\ Simon CM et al. Active choice but not too active: Public
perspectives on biobank consent models. Genetics in Medicine. 2011
Sep;13(9):821-831.
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Because of these shifts in science, technology, and public
engagement expectations, a wide range of stakeholders have raised
concerns about the limitations of the existing framework, arguing for a
re-evaluation of how the fundamental principles that underlie the
Common Rule --respect for persons, beneficence, and justice--are
applied in practice to the myriad new contexts in which U.S. research
is conducted in the 21st century.9 10 Dialogue focuses
around whether the current system:
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\9\ Emanuel EJ, Wood A, Fleischman A, et al. Oversight of human
participants research: Identifying problems to evaluate reform
proposals. Annals of Internal Medicine 2004;141(4):282-291.
\10\ Maschke K. Human research protections: Time for regulatory
reform? Hastings Center Report. 2008 Mar-Apr; 38(2):19-22.
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Is sufficiently supportive of a participant-centered
research model that adequately respects participants as partners;
is not sufficiently risk-based, resulting in both over-
and under-regulation of research activities; 11 12 13
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\11\ Kim S, Ubel P, De Vries R. Pruning the regulatory tree.
Nature 2009 Jan 29;457(7229):534-535.
\12\ Wendler D, Varma S. Minimal risk in pediatric research.
Journal of Pediatrics. 2006 Dec;149(6):855-861.
\13\ Infectious Disease Society of America. Grinding to a halt:
The effects of the increasing regulatory burden on research and
quality improvement efforts. Clinical Infectious Diseases 2009 Aug
1;49(3):328-335.
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[[Page 53939]]
is sufficiently tailored to new and emerging areas of
research, including social and behavioral research and research
involving the collection and use of genetic information;
14 15 16 17 18 19
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\14\ National Research Council. Protecting Participants and
Facilitating Social and Behavioral Sciences Research. Washington,
DC: National Academies Press, 2003.
\15\ Anderlik M. Commercial biobanks and genetic research:
Ethical and legal issues. American Journal of Pharmacogenomics
2003;3(3):203-215.
\16\ Schrag ZM. How talking became human subjects research: The
Federal regulation of the social sciences, 1965-1991. Journal of
Policy History 2009 January; 21(01):3-37.
\17\ Hansson MG et al. Should donors be allowed to give broad
consent to future biobank research? Lancet Oncology 2006 Mar;
7(3):266-269.
\18\ Murphy J et al. Public perspectives on informed consent for
biobanking. American Journal of Public Health 2009 December;
99(12):2128-2134.
\19\ Kaufman DJ et al. Public opinion about the importance of
privacy in biobank research. American Journal of Human Genetics 2009
Nov; 85(5):643-654.
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effectively informs subjects of psychological,
informational, or privacy risks; 20 21 22
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\20\ Paasche-Orlow MK, Taylor HA, Brancati F. Readability
standards for informed-consent forms as compared with actual
readability. New England Journal of Medicine 2003 Feb 20;
348(8):721-726.
\21\ Schneider CE. The Hydra. Hastings Center Report 2010 Jul-
Aug; 40(4):9-11.
\22\ Albala I, Doyle M, Appelbaum PS. The evolution of consent
forms for research: A quarter century of changes. IRB Ethics & Human
Research 2010 May-June; 32(3):7-11.
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adequately accounts for the needs of a ``learning''
healthcare system for continual quality improvement;
23 24 25
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\23\ Faden RR, Beauchamp TL, Kass NE. Informed consent,
comparative effectiveness, and learning health care. New England
Journal of Medicine 2014 Feb 20;370(8):766-768.
\24\ Dziak K et al. Variations among institutional review board
reviews in a multisite health services research study. Health
Services Research 2005 Feb; 40(1):279-290.
\25\ Lynn J et al. The ethics of using quality improvement
methods in health care. Annals of Internal Medicine 2007 May
1;146(9):666-673.
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provides sufficient mechanisms to ensure the consistency,
quality, and accountability of IRB decision-
making.26 27 28 29
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\26\ Heimer CA et al. Regulating creativity: Research and
survival in the IRB iron cage. Northwestern University Law Review
2007; 101:593-641.
\27\ Green LA et al. Impact of institutional review board
practice variation on observational health services research. Health
Services Research 2006 Feb; 41(1):214-230.
\28\ Jansen LA. Local IRBs, multicenter trials, and the ethics
of internal amendments. IRB 2005 Jul-Aug;27(4):7-11.
\29\ Schrag Z. Ethical Imperialism. Baltimore, MD: Johns Hopkins
University Press, 2010.
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B. Public Comments, Expert Advice, Stakeholder Dialogue
The revisions to the Common Rule proposed here are based upon a
variety of sources of public, stakeholder, and expert comments and
advice. First, the NPRM more thoroughly addresses social science and
behavioral research perspectives, benefiting from guidance provided by
a National Research Council's consensus report entitled ``Proposed
Revisions to the Common Rule for the Protection of Human Subjects in
the Behavioral and Social Sciences.'' \30\ The Report was commissioned
to ensure that the issues related to research involving human subjects
in social and behavioral research would be addressed appropriately, in
view of what had been said in the ANPRM. The Panel made numerous
recommendations, including recommendations about what research studies
should not undergo review, about calibrating the level of IRB review to
the level of risk, about the desirability of privacy and
confidentiality protections in social and behavioral research other
than those of the Health Insurance Portability and Accountability Act
of 1996 (HIPAA), and about improving informed consent by placing
greater emphasis on the process of consent. The NPRM revises some of
the ANPRM proposals in light of those recommendations.
---------------------------------------------------------------------------
\30\ National Research Council of the National Academies.
(2014). Proposes Revisions to the Common Rule for the Protections of
Human Subjects in the Behavioral and Social Science. The National
Academies Press, 13-168. Retrieved from http://www.nap.edu/catalog/18614/proposed-revisions-to-the-common-rule-for-the-protection-of-human-subjects-in-the-behavioral-and-social-sciences.
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Second, since the publication of the ANPRM, HHS has continued to
solicit public comment on a variety of human subjects related issues,
including consent, the use of a single IRB for multi-site studies, and
sharing of genomic data. Although these policies were more specific
than the issues raised in the ANPRM, the responses received from public
comments provide insight for refining the proposals initially put
forward in the ANPRM. Of particular interest:
NIH's proposal that it expects the use of a single IRB for
all multi-site research studies funded or conducted by the NIH.\31\
Under that proposal, all domestic sites of a multi-site study would be
expected, as a condition of NIH funding, to use a single IRB of record.
In response to this proposal, NIH received 165 comments from a range of
stakeholders, including investigators, IRB members, and members of the
public. The majority of respondents were supportive; however concerns
were raised that it would be expensive and time-consuming to identify a
single IRB for each new multi-site study.
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\31\ National Institutes of Health. (2014, December 14). Request
for Comments on the Draft NIH Policy on the Use of a Single
Institutional Review Board for Multi-Site Research. See more at:
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-026.html#sthash.fmjlNRi6.dpuf. Retrieved from National Institutes of
Health, Office of Extramural Research: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-026.html.
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OHRP's draft guidance discussing the required content of
consent language for research done within the standard of care.\32\ In
August of 2013, prior to the publication of the draft guidance
document, HHS held a public meeting to hear from the community on
issues raised during the debate surrounding the SUPPORT study.\33\ The
public meeting and the draft guidance document spurred a significant
public discussion about the nature of the information included in
informed consent forms, specifically how investigators should
communicate the risks of research studies done within the standard of
care. A total of 93 comments were received from bioethicists,
investigators and research institutions, hospitals and physicians, IRB
members, patient advocates, and industry.
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\32\ 79 FR 63630 (Oct. 24, 2014).
\33\ 78 FR 48163 (Aug 7, 2013).
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To enhance human subject protections and reduce regulatory
burden, OHRP and FDA have been actively working to harmonize the
agencies' regulatory requirements and guidance for human subject
research, and the FDA's draft guidance, ``Use of Electronic Informed
Consent in Clinical Investigations'' was developed as part of these
efforts. The draft guidance was issued in conjunction with an OHRP
Federal Register notice soliciting comment on the whether joint final
guidance would be useful for the regulated community, and whether FDA's
draft guidance would be appropriate for all research regulated under 45
CFR part 46, such as social and behavioral research studies. Comments
were received largely favoring joint guidance, but with separate
sections addressing research regulated solely by 45 CFR part 46.
NIH's proposal to promote sharing of large-scale human
genomic data generated from studies funded or conducted by NIH.\34\ The
policy lays out an expectation that investigators generating genomic
data get consent for future research use of those data. The NIH
received 107 comments on the policy, including many that addressed
[[Page 53940]]
the concept of broad consent for unspecified future research use.
---------------------------------------------------------------------------
\34\ 79 FR 51345 (Aug. 28, 2014).
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There have also been developments on the legislative front that
have informed the discussions leading up to this NPRM. In December of
2014, the Newborn Screening Saves Lives Reauthorization Act of 2014
(Pub. L. 113-240), was signed into law. The new law makes a number of
changes relevant to the HHS regulations for protecting research
subjects, including declaring that research with newborn dried blood
spots that is federally funded pursuant to the Public Health Service
Act is to be considered research with human subjects, and the
provisions allowing IRBs to waive consent will not apply. These changes
will be effective until updates to the Common Rule are promulgated. In
addition, in April of 2015, the Medicare Access and CHIP
Reauthorization Act of 2015 (Pub. L. 114-10) was passed. That law
requires HHS to issue a clarification or modification of the Common
Rule with regard to how they apply to activities involving clinical
data registries.
Most recently, with the launch of the President's Precision
Medicine Initiative (PMI),35 36 the Federal Government is
proposing a new research cohort based on a model that puts participants
at the center.\37\ To understand participant preferences the White
House and PMI agencies have been hosting a series of roundtables and
public workshops about public expectations for how participants want to
engage in research today. These discussions have included individuals
from many sectors, including prospective research participants,
patients and patient advocates, privacy experts, bioethicists, academic
and industry investigators, data scientists, technology innovators,
healthcare institutions and providers. The government has heard many
perspectives, with much alignment around the central tenet that
participants should be active partners in research, and not merely
passive subjects of research studies. Many are seeking a research
environment where they can contribute to the greater good and have
transparency into the research being conducted using their specimens
and data. The conversations have focused on promoting the ethical
principles of respect for persons, beneficence, and justice, as well as
promoting other protections, such as data security and privacy.
---------------------------------------------------------------------------
\35\ The White House, Office of the Press Secretary. (2015,
January 30). Fact Sheets: President Obama's Precision Medicine
Initiative. Retrieved from The White House: https://www.whitehouse.gov/the-press-office/2015/01/30/fact-sheet-president-obama-s-precision-medicine-initiative.
\36\ Collins FS, Varmus H. A New Initiative on Precision
Medicine. N Engl J Med 2015 Feb; 372:793-795.
\37\ See also http://www.scientificamerican.com/article/big-precision-medicine-plan-raises-patient-privacy-concerns/, http://www.nih.gov/precisionmedicine/, and http://www.nih.gov/precisionmedicine/.
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C. Guiding Principles for Proposed Changes
In 1979, the Belmont Report \38\ was predicated on three principles
that were felt to be central to shaping an ethical framework for the
conduct of research with human subjects. The three ethical principles
are respect for persons, beneficence, and justice. Interpretation of,
and balancing among, these three principles played a major role in
shaping what became the development the federal regulations that have
become known as the Common Rule. The preamble to the proposal considers
whether and how the interpretation of these fundamental principles
might be updated within the context of the current technological,
social, cultural, and ethical environment. That consideration involves
explicitly identifying the interplay among the principles. The Common
Rule provides a framework for how researchers and IRBs weigh the often
conflicting implications of these three principles.
---------------------------------------------------------------------------
\38\ National Commission for the Protection of Human Subjects of
Biomedical and Behavioral Research. (1979). Belmont Report.
Washington, DC: U.S. Department of Health & Human Services.
Available at: http://www.hhs.gov/ohrp/humansubjects/guidance/belmont.html.
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Beneficence: Individuals who participate in research contribute
their time and may assume significant risks to advance the research
enterprise. Their valuable contributions produce knowledge that
benefits society at large. The Belmont Report describes the principle
of beneficence as the goal of maximizing possible benefits of research
and minimizing possible harms. This principle has been interpreted to,
in part, emphasize the benefit associated with the knowledge that might
be generated by a research study. Evaluating beneficence requires
examining the likelihood that knowledge would be generated, and how
important or useful that knowledge might be to the population. When
more weight is given to research that has the potential to generate a
great deal of knowledge, particularly knowledge that could be very
useful to society (such as how to treat serious diseases that are
currently untreatable), policies would lean in favor of encouraging and
facilitating more of that type of research.
A distinct aspect of the principle of beneficence concerns the
benefits and risks to the specific persons who would be participating
in a particular research study. In the example of a randomized clinical
trial comparing two treatments for a disease, the benefits and risks to
the subjects in the trial are distinct from the possible benefits to
society as a whole from learning which of the two treatments is better.
This aspect of beneficence assumes that there are limits on the risks
to which people should be subject, even if they are willing to undergo
those risks.
Society is in an information age. In all facets of one's life
information about that person is generated, stored, shared, analyzed,
and often provides tremendous societal value. People share information
about themselves with large numbers of people with the click of a
button, and this trend of rapid and widespread sharing is only likely
to grow. The increase in concern about unauthorized and inadvertent
information disclosure, in combination with newer research techniques
that increase the volume and nature of identifiable data suggest the
need for the Common Rule to more explicitly address data security and
privacy protection.
Of particular interest for this proposal is addressing risks from
inappropriate disclosure of information generated from biospecimens.
One way to protect subjects from such risks is to bring under oversight
research for which risks are greater of subjects being identified and
information being inappropriately disclosed. Although it may be
difficult to identify individuals from their non-identified
biospecimens at present, and most investigators would have no need to
do so unless they were seeking additional associated phenotypic
information, certain technologies and methods can be used to generate
data that are unique to the individual who provides the biospecimen,
and those data can sometimes be combined with other data sources to
identify the individual. In the future, technologies will facilitate
the use and analysis of greater variety and volumes of information, and
there is a possibility that it will be increasingly difficult, if not
impossible, to make biospecimens fully non-identified. In fact, a
number of reports have already demonstrated the ability to re-identify
individuals from biospecimens or data that lack direct
identifiers.39 40 As analytic techniques become more
sophisticated and large
[[Page 53941]]
datasets become more accessible, it will not be possible to guarantee
that an individual could never be identified from a biospecimen or
combination or data sources, particularly if whole genome sequencing is
conducted.
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\39\ Rothstein MA. Is deidentification sufficient to protect
health privacy in research? American Journal of Bioethics Sep 2010;
10(9): 3-11.
\40\ El Emam K et al. A systematic review of re-identification
attacks on health data. PLoS One 2011; 6(12):e28071.
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Respect for Persons: The Belmont Report describes this concept as
the notion of treating people as autonomous agents, and allowing them
to make choices based on their own judgments and opinions. Inherent in
the principle of autonomy is the concept of transparency--clearly
providing the information necessary for the research participant to
make such judgments. Transparency requires a clear articulation of
risks, potential benefits, and alternatives to participating in a
research study, as well as the purpose of the research. The principle
of autonomy encompasses the value ascribed to an individual's right to
know how one's data is being used and who will have access to it. As
such autonomy also covers the paired concept of protecting those
persons who lack the capability to make such decisions. There are a
variety of different ways of demonstrating respect for persons.
Obtaining informed consent from human subjects for the collection
and analysis of information about them is one means of implementation
of respect for persons in the research context. Informed consent is
designed to ensure that each individual approached to participate in a
research study fully understands the risks and potential benefits of
the study so that they have sufficient information to make an
individualized calculation as to whether or not the tradeoffs inherent
in participation are worth it for them to agree to participate. Both
the potential harms and benefits tend to be greater in the context of a
clinical trial where subjects are randomized to one or another of two
possible treatments with significantly different suspected risks than
in situations where subjects are simply asked to provide, for instance,
a urine sample.
Notice, in which individuals are informed about how data will be
used, but explicit consent is not obtained, is another means of
facilitating transparency. Notice is sometimes used in the context of
informing people about how data collected for non-research purposes
(e.g., when providing information in the context of applying for public
benefits) might be used for either general or specific research
purposes. Another method for showing respect for persons with regard to
using data about them for research could be providing them with a right
to opt out of such research, by, for example, filing a form stating
such a wish with the holder of the data.
Related, implicit consent might be obtained when a research subject
completes a questionnaire. If they did not wish to provide the
information, presumably they would not be answering the questions. The
NPRM contains a number of provisions that are designed to further
promote respect for participants through increases in both transparency
and opportunities for consent.
Justice: The Belmont Report describes this principle as being about
fairness in terms of who receives the benefits from research and who
bears its burdens. One of the most direct applications of the principle
of justice to the Common Rule relates to determining who is studied and
how subjects are selected. This principle also is relevant to
protection of vulnerable populations. In addition, the idea of justice
is relevant to one of core goals of this NPRM: Clarifying important
aspects of the Common Rule where there has been ambiguity in
interpretation. To the extent that IRBs and others interpret the
regulations in significantly different ways, the result is that
participants in research can end up being treated in very different
ways, even when they are participating in the same study. Thus this
idea is embedded in all of the NPRM's attempts to make sure that these
rules are applied in a more uniform and consistent manner.
The three ethical principles of the Belmont Report often cannot all
be fulfilled at the same time. In many cases, it will be necessary to
choose which of those principles will deserve the greatest adherence.
This NPRM, at its heart, represents an attempt to evaluate the weights
to be applied to each of these three core principles in a variety of
specific contexts. Giving greater weight to one of the principles will
frequently mean a decreased ability to fulfill one of the other
principles. By necessity, value judgments, influenced by the social
norms of the time, drive the implementation of the broad principles
underlying the Belmont Report. The efficacy of the oversight system
also requires proportionality in weighing the application of these
three principles. This is reflected in the analysis that follows, in
terms of evaluating the specific aspects of beneficence, respect for
persons, and justice that relate to a particular issue, and weighing
those aspects against one another. Research that poses greater risk
should receive more attention and deliberation than less risky
research, and the degree and type of oversight should be commensurate
with the level of risk. In addition, requirements that do not enhance
protection but that impose burden can increase inefficiency, waste
resources, erode trust, and obscure the ethical challenges that require
careful deliberation and stakeholder input. Cumbersome and outdated
regulatory standards overwhelm and distract oversight bodies and other
stakeholders from appropriately addressing the real risks and benefits
of research.
There is tremendous support for research in this country. American
society values advances in knowledge and has reaped the reward of many
key insights that have led to increases in quality of life and a
doubling of our life expectancy in the last century. There would not
have been such strides in medical and behavioral research without the
willingness of individuals to join research studies. Participants are
told that they are not likely to benefit directly from any given study,
yet they choose to participate for the greater good. Beneficence is a
powerful driver. On the other hand, members of the public deserve, and
indeed now expect, to know how publicly-funded research is being
conducted and overseen, and need to have confidence that the interests
of research participants are adequately protected. Transparency is key
for developing trust, especially between investigators, funders,
regulators, and the public.
Our reassessment of these ethical principles in the context of
current technology and social norms suggests the need for changes to
the Common Rule that: (1) Increase subject autonomy by increasing human
subjects' ability and opportunity to make informed decisions; (2)
reduce potential for harm and increase justice by increasing the
uniformity of human subject protections in areas such as information
disclosure risk, coverage of clinical trials, and coverage of IRBs; and
(3) increase beneficence by facilitating current and evolving types of
research that offer promising approaches to treating and preventing
medical and societal problems though reduced ambiguity in
interpretation of the regulations, increased efficiencies in the
performance of the review system, and reduced burdens on researchers
that do not appear to provide commensurate protections to human
subjects. If a reasonable balance is struck between protecting human
research subjects, minimizing the administrative burden of the system,
and engendering public trust, this should maximize beneficence and
raise all ships.
Public comment is sought not only on the provisions outlined below,
but on whether the proposals strike a reasonable balance among the core
[[Page 53942]]
ethical principles. A better balance among the core principles should
increase the strength of the partnership between the research
enterprise and the public, and even greater scientific understanding
and innovation will be fostered.
Finally, it is important to note that, to the extent appropriate,
the intent is to eventually amend the other subparts of the HHS human
subjects protection regulations in 45 CFR part 46 (subparts B, C, D,
and E), and consider the need for updates to FDA regulations and other
relevant Federal departmental or agency regulations with overlapping
scope.
1. Question for Public Comment
1. Public comment is sought on whether the proposed changes will
achieve the objectives of (i) decreasing administrative burden, delay
and ambiguity for investigators, institutions, and IRBs, and (ii)
strengthening, modernizing, and making the regulations more effective
in protecting research subjects.
D. Organization of the NPRM
Section II of the NPRM, which immediately follows, describes in
detail the major proposals for revisions to the Common Rule. In
general, the changes that are likely to be of greatest significance are
discussed in the earlier parts of section II of this preamble. Section
II.A is devoted to changes that affect which activities are subject to
the Common Rule. Following that section are discussions devoted to
changes relating to informed consent (section II.B), changes relating
to privacy safeguards for the research use of information and
biospecimens (section II.C), and a proposal to encourage greater
harmonization of guidance across the agencies that adhere to the Common
Rule (section II.D). Discussions of changes relating to how IRBs
operate, including a proposal to reduce the number of reviews by
different IRBs that take place for multi-site studies, are in the
several sections that follow (sections II.E, F and G). The final
section (section II.H) collects a variety of other changes, including
expanding the scope of the rule to cover clinical trials that are not
federally funded but are conducted at institutions that received some
federal funding for research with human subjects.
The three sections that follow then discuss various administrative
review requirements: Regulatory Impact Analyses (section III),
Environmental Impact (section IV), and Paperwork Reduction Act (section
V). The final section of the document (section VII) provides the full
regulatory text of the proposed changes to the Common Rule. Section VI
provides a comprehensive summary of responses received to the 2011
Common Rule ANPRM.
II. Major Proposals To Modernize the Common Rule
A. Proposed Changes to the Scope and Applicability of the Regulations
1. Expanding the Definition of Human Subject to Cover Research with
Non-identified Biospecimens (NPRM at Sec. Sec. __.102(e) and
__.101(b)(3)(i))
This section focuses on the ethical principles associated with the
secondary research use of biospecimens. These biospecimens may have
been originally collected from either research or non-research settings
(e.g., leftover portion of tissue from a clinical biopsy).
a. NPRM Goals
One of the goals of this NPRM is facilitating cutting edge research
in genomics and other `omics' such as the transcriptome and the
microbiome, which generate a wealth of data from biospecimens designed
to inform the development of treatments and preventative measures for
chronic diseases such as cancer. Facilitating such research, however,
requires navigating complex ethical issues. The key question is, under
what circumstances should the Common Rule govern what research
investigators are able to do with biospecimens that have been collected
for some other (e.g., clinical) purpose? (Note that if a researcher
interacted with an individual to actually collect a biospecimen for
research purposes--for example, obtaining a saliva sample--that
``primary'' research activity is already covered under the current
regulations, and is not the focus of the change discussed in this
section.) In this case, maximizing the societal value of research would
mean reducing barriers to the secondary use of biospecimens to the
extent possible.
However, there is a growing recognition that many people want to
have some degree of control over the circumstances in which an
investigator can derive information about them, above and apart from
their interest in whether or not that information might be
inappropriately disclosed. More specifically, a growing body of
literature shows that in general people prefer to have the opportunity
to consent (or refuse to consent) to research involving their own
biological materials.\41\ Furthermore, in 2012, the Presidential
Commission for the Study of Bioethical Issues highlighted the ethical
importance of obtaining consent for genomics research and recommended
that ``unauthorized whole genome sequencing without the consent of the
individual from whom the sample came'' be prohibited.\42\ Their
rationale for reaching this conclusion was based on concerns relating
to privacy as well as autonomy.
---------------------------------------------------------------------------
\41\ See supra notes 5-8.
\42\ Presidential Commission for the Study of Bioethical Issues.
(2012). Privacy and Progress in Whole Genome Sequencing. Washington,
DC: Presidential Commission for the Study of Bioethical Issues.
Retrieved from http://bioethics.gov/sites/default/files/PrivacyProgress508_1.pdf.
---------------------------------------------------------------------------
In assigning weights to the principles of beneficence and respect
for persons in the context of research with biospecimens, strong
consideration was given to the fact that failure to acknowledge and
give appropriate weight to this distinct autonomy interest in research
using biospecimens could, in the end, diminish public support for such
research, and ultimately jeopardize our ability to be able to conduct
the appropriate amount of future research with biospecimens. To that
end, the proposals given below are designed to meet the goals of
increasing transparency in when and how biospecimens collected in a
variety of circumstances will be used for research purposes and
increasing opportunities for consent. Various ways in which these goals
might be achieved are the subject of alternative proposals discussed
below.
b. Current Rule
The application of the current regulations to secondary research
use of a biospecimen is tied to the identifiability of the biospecimen
in the hands of the researcher. In particular, the definition of human
subject in the current Common Rule at Sec. __.102(f) states that a
human subject is a living individual about whom an investigator
(whether professional or student) conducting research obtains data
through intervention or interaction with the individual, or
identifiable private information. Private information is described as
information that is individually identifiable (i.e., the identity of
the subject is or may readily be ascertained by the investigator or
associated with the information) in order for obtaining the information
to constitute research involving human subjects.
Consistent with historical interpretation of identifiable private
information under the Common Rule, the terms ``non-identified'' or
``non-identifiable'' are used throughout this
[[Page 53943]]
NPRM to signify biospecimens or data that have been stripped of
identifiers such that an investigator cannot readily ascertain a human
subject's identity. Re-identification of non-identified or non-
identifiable biospecimens or information may be possible, depending on
the circumstances. The term ``de-identified'' is distinct; it is only
used in this proposal to refer specifically to the HIPAA standard of
non-identifiability.
Thus, where there is no intervention or interaction with an
individual, central to determining whether human subjects are involved
in a research activity covered by the current Common Rule is
determining the meaning of ``identifiable.'' Under the current Rule,
provided the biospecimens and data were collected for purposes other
than the currently proposed research, it is permissible for
investigators to conduct research on biospecimens and data that have
been stripped of all identifiers without obtaining consent because the
non-identified biospecimens and data do not meet the regulatory
definition of human subject.
It is, however, worth noting that although informed consent is not
strictly required by the current regulations when research takes place
using non-identified biospecimens, some IRBs have indicated that they
are requiring that investigators explicitly obtain consent for future
analysis of biospecimens collected in the research setting, and some
are refusing to waive consent for use of biospecimens collected in non-
research contexts.
c. ANPRM Discussion
The ANPRM asked whether consent should be required before an
investigator could conduct research on a non-identified biospecimen. It
further asked, if consent were to be required, could such consent be
obtained by having a person provide consent for unspecified future
research with the biospecimen, instead of requiring that specific
consent be obtained each time that the biospecimen would actually be
used in a research study.
Although HHS does not consider whole genome analysis to produce
identifiable private information unless additional information is
available to the investigator that would enable the investigator to
``readily ascertain'' the identity of the individual, it is
acknowledged that a time when investigators will be able readily
ascertain the identity of individuals from their genetic information
may not be far away. The ANPRM suggested that, regardless of what
information is removed, it is theoretically possible to extract DNA
from a biospecimen itself and potentially link it to otherwise
available data to identify individuals. In addition, irrespective of
whether biospecimens are considered individually identifiable, the
ANPRM sought comment on whether the regulations should be changed to
allow human subjects to decide whether their biospecimens would be
available for research.
The ANPRM asked whether some types of genomic data should be
considered identifiable and, if so, which types (e.g., genome-wide
single nucleotide polymorphism [SNP] analyses or whole genome
sequences). It also asked whether a human biospecimen should be
considered inherently identifiable.
The ANPRM also suggested that the definition of identifiability in
the Common Rule be modified to better harmonize it with other
regulatory definitions of identifiability within HHS. The ANPRM
considered adopting the HIPAA Privacy Rule's standards of what
constitutes individually identifiable information, a limited data set,
and de-identified information (as defined under HIPAA), in order to
address inconsistencies regarding these definitions and concepts
between the HIPAA Privacy Rule and the Common Rule.
More specifically, as described above, private information is not
considered to be identifiable under the current Rule if the identity of
the subject is not or may not be ``readily ascertained'' by the
investigator from the information or associated with the information.
In contrast, under the HIPAA Privacy Rule, health information is de-
identified and thus exempt from that rule only if it neither identifies
nor provides a reasonable basis to believe that the information can be
used to identify an individual. The HIPAA Privacy Rule provides two
ways to de-identify information: (1) A formal determination by a
qualified expert that the risk is very small that an individual could
be identified; or (2) the removal of all 18 specified identifiers of
the individual and of the individual's relatives, household members,
and employers, as long as the covered entity has no actual knowledge
that the remaining information could be used to identify the individual
(45 CFR 164.514(b)).
The HIPAA Privacy Rule addresses some informational risks by
imposing restrictions on how individually identifiable health
information collected by health plans, health care clearinghouses, and
most health care providers (``covered entities'') may be used and
disclosed, including for research. In addition, the HIPAA Security Rule
(45 CFR parts 160 and, subparts A and C of part 164) requires that
these entities implement certain administrative, physical, and
technical safeguards to protect this information, when in electronic
form, from unauthorized use or disclosure. However, the HIPAA Rules
apply only to covered entities (and in certain situations to their
business associates), and thus not all investigators are part of a
covered entity and required to comply with those rules. Moreover, the
HIPAA Rules do not apply specifically to biospecimens in and of
themselves.
Public comments in response to the 2011 ANPRM regarding covering
all biospecimens raised a series of important concerns. A majority of
the commenters opposed the ANPRM's suggested requirement of consent for
research use of all biospecimens, regardless of identifiability,
particularly if applied to samples collected before the effective date
of the regulation. Some commenters cited lack of convincing evidence of
harm caused by research use of non-identified clinical biospecimens
without consent; they noted that they were not convinced that the
principle of autonomy outweighs or trumps the principle of beneficence.
They expressed concern that doing so would significantly slow advances
in research and human health.
Others acknowledged the erosion of public trust that can result
from high-profile disputes involving the use of non-identified
biospecimens collected during research.\43\ Commenters cited the costs
to collect, log, and track consent status of data and biospecimens
collected in a clinical setting to ensure that any restrictions on the
research use of such resources were honored. However, it is important
to note that it appears that many commenters were reacting to concerns
that any change in the Common Rule with respect to consent for use of
biospecimens would be applied retroactively--that is, to samples
already collected.
---------------------------------------------------------------------------
\43\ National Congress of American Indians. Havasupai Tribe and
the lawsuit settlement aftermath. Retrieved on November 17, 2014,
from http://genetics.ncai.org/case-study/havasupai-Tribe.cfm.
---------------------------------------------------------------------------
Some patient advocacy organizations also expressed concerns about
the consequences of requiring consent for the use of non-identified
biospecimens. Other commenters noted that the recommendation to require
consent might inappropriately give greater weight to the Belmont
Report's principle of autonomy over the principle of justice, because
requiring consent could result in lower participation rates in research
by
[[Page 53944]]
minority groups and marginalized members of society. Yet, most of the
comments from individual members of the public strongly supported
consent requirements for use of their biospecimens, regardless of
identifiability.
Many commenters expressed the opinion that the existing regulatory
framework is adequate and that current practices should be maintained,
stressing that the research use of non-identified data or biospecimens
does not involve risk to the research participant. Furthermore, several
commenters noted that, although it is theoretically plausible to
identify a person based on their biospecimen, the likelihood remains
remote enough to argue against the presumption that the sources of all
biospecimens are identifiable and cited a study showing that the risk
of re-identification from a system intrusion of databases was only
0.22%.\44\ In contrast, some commenters supported the idea of requiring
consent for research use of all biospecimens, with one commenter noting
simply that ``research use of data initially collected for non-research
purposes should always require informed consent.''
---------------------------------------------------------------------------
\44\ Kwok P et al. Harder Than You Think: A Case Study of Re-
Identification Risk of HIPAA-Compliant Records. NORC at The
University of Chicago and Office of the National Coordinator for
Health Information Technology. 2011. http://www.amstat.org/meetings/jsm/2011/onlineprogram/AbstractDetails.cfm?abstractid=302255.
---------------------------------------------------------------------------
Several commenters stated that if the Common Rule were modified
such that all biospecimens were covered under the rule regardless of
identifiability there still might be some activities involving
biospecimens that should be considered exempt or excluded from
coverage. Suggestions included:
Identifying markers for cancer prognosis or prediction of
response to cancer therapy, or identifying cancer molecular targets
(molecular research)
Basic science research (including analysis of biological
processes)
Research on rare conditions and diseases
Pediatric research
Research with samples that lack potentially identifying
information, such as serum or plasma not containing DNA
Biospecimens lacking nucleic acids (such as certain red blood
cells, expiratory gases)
Blood culture bacteria
Bacterial and viral specimens (this was listed in a comment as
a public health issue)
Protein analysis
Statistical method development (to the extent that this
development is related to biospecimens)
New molecular methods to detect infectious agents
Use of specimens to develop and validate new assays for
infectious agents
Archival paraffin blocks
With respect to the 2011 proposal to adopt the HIPAA Privacy Rule's
definition of identifiability, a majority of the public commenters
strongly opposed the idea. They indicated that the HIPAA Privacy Rule's
standard of identifiability would expand what is considered
identifiable for purposes of the Common Rule and thus greatly impede
relatively low-risk research without adding meaningful protections for
human subjects. In particular, they asserted that the HIPAA standards
were created to protect against disclosure of health information
contained in medical records. As such, commenters argued, they are not
appropriate for many types of research that would be covered by the
Common Rule (e.g., behavioral and social science research). Others said
this would be an extreme change in response to an as yet unidentified
or clear problem. Commenters said that the information most at risk for
inappropriate disclosure is the type of private health information that
is already protected under the HIPAA Rules. Commenters feared that such
a change in policy, while ``harmonizing'' the Common Rule to certain
HIPAA standards, would create inordinate burdens in terms of new
documentation requirements and result in a requirement to apply the
HIPAA standards to all types of research, regardless of the level of
risk.
d. NPRM Proposal
Regardless of the scale on which harms may have occurred in the
past, continuing to allow secondary research with biospecimens
collected without consent for research places the publicly-funded
research enterprise in an increasingly untenable position because it is
not consistent with the majority of the public's wishes, which reflect
legitimate autonomy interests. As such, one of the most fundamental
changes proposed in this NPRM is to the definition of human subject
(proposed Sec. __.102(e)). The proposal is for the obtaining, use,
study, or analysis of biospecimens to be covered under the Common Rule,
regardless of identifiability. Covering biospecimens regardless of
identifiability avoids codifying any given interpretation of the
quickly evolving debates regarding whether certain analytic results
(e.g., decoding the whole genome) should be considered to yield
identifiable data. (Accompanying this proposal are some minor wording
changes to other portions of that definition that are merely intended
to clarify how the word ``obtains'' is currently interpreted by OHRP.)
Thus, the focus of this proposal is to require informed consent for
research involving biospecimens in all but a limited number of
circumstances. The consent would not need to be obtained for each
specific study using the biospecimen, but could instead be obtained
through broad consent for future unspecified research (described in
more detail in sections II.A.3.d and II.B of this preamble).
An increase in trust and partnership is likely to increase
participation rates in research; using individuals' samples and data
without permission will hinder true partnership. Better communication
and community engagement with patients, particularly in geographic
areas and for population subgroups where consent rates are lower than
average, should be a priority for the research community.
In response to comments received about the 2011 ANPRM, the NPRM
proposes to have the new definition of human subject apply
prospectively, that is, it will only apply to research involving
biospecimens that will be collected in the future. Additionally, in
recognizing that this proposal will have major implications for the
operational functioning of the research enterprise, compliance with
this provision would be delayed until three years after publication of
a final rule.
Also consistent with comments received on the ANPRM, it is proposed
that a subset of secondary research on stored biospecimens would be
allowed without consent. Specifically, research designed to only
generate information about the person that is already known would be
considered outside of the scope of the Common Rule. This exclusion
would include but not be limited to the development and validation of
certain tests and assays (such as research to develop a diagnostic test
for a condition using specimens from individuals known to have the
condition and those known not to have the condition), quality assurance
and control activities, and proficiency testing. This provision would
be implemented through a new exclusion from the regulations at Sec.
__.101(b)(3)(i), which has specifically been designed to reflect the
underlying ethical principles.
If the research is designed not to generate any new information
about the
[[Page 53945]]
person, but only confirm something about them that is already known,
then the interest in respecting the person's autonomy would appear to
be relatively weak. As an example, imagine that a person is known to
have a particular genetic disease, and the research involves evaluating
a new product that might in a few minutes, at low cost, produce a
result showing whether a person has that disease. The person's autonomy
interest in whether or not such a study could take place would seem
little different from that of anyone in a study that involved secondary
use of identifiable information about them.
In addition, the proposal permits IRBs to waive the requirement for
informed consent, but the requirements for approval of such waivers
would be very strict, and such waivers will only occur in rare
circumstances. Note also that the exclusions proposed in Sec.
;____.101(b)(1)(i), (iii)-(vi) would also allow for the use of
biospecimens without consent in certain limited circumstances; these
additional exclusions are discussed in section II.A.2 of this preamble,
below.
This proposal would not modify the Common Rule standard of
identifiability (in contrast to what was discussed in the 2011 ANPRM).
That is, the standard for determining when an investigator has
sufficient information to readily ascertain the identity of an
individual is not being changed under this proposal. Thus, coverage of
information derived from biospecimens (whether or not the biospecimen
was initially collected in the research or non-research context), or
indeed any other type of information, would be the same under this
proposal as is the case under the current Common Rule.
i. Alternative Proposals
In this section, we discuss two alternative proposals, both of
which maintain ``identifiability'' as the lynchpin for determining
applicability of the Common Rule to biospecimens. These models increase
transparency and opportunities for consent over and above what is
provided for in the current Common Rule, but in a smaller set of
circumstances than provided for under the primary proposal discussed
above.
Alternative Proposal A: Expand the Definition of ``Human Subject'' To
Include Whole Genome Sequencing (WGS)
Rather than consider all research using biospecimens as
constituting human subjects research, this alternative proposal would
expand the definition of human subjects to include only specifically
whole genome sequencing data, or any part of the data generated as a
consequence of whole genome sequencing, regardless of the individual
identifiability of biospecimens used to generate such data. Under this
alternative, whole genome sequencing would be considered the sequencing
of a human germline or somatic biospecimen with the intent to generate
the genome or exome sequence of that biospecimen.
Thus, under this alternative, the regulations would then apply both
to research that would generate whole genome sequencing data, the use
of any part of the generated data, and to research involving secondary
use of any part of whole genome sequencing data that was originally
generated for other purposes than the proposed research. Investigators
conducting whole genome sequencing research could not avoid the need to
comply with the Common Rule by removing identifiers from biospecimens
or data, because whole genome sequence data in and of itself would meet
the definition of human subject. Under this alternative, a new
exemption would also be created that would allow such research to be
considered exempt if consent to secondary future research use were
obtained in accordance with proposed new requirements at Sec.
__.116(c) and standards were met for protecting information and
biospecimens as proposed at Sec. __.105. A waiver of consent would be
permitted, but would be modeled on the more stringent waiver criteria
proposed for research involving biospecimens at Sec. __.116(f)(2).
Explicit consent to conduct research using whole genome sequencing
data can be considered ethically important because such data can
provide important insights into the health of individuals as well as
their relatives. Moreover, whole genome sequence data gathered for one
purpose may reveal important information, perhaps unanticipated and
unplanned for, years later. Finally, whole genome sequence data are
unique for each individual, or at the very least, highly unlikely to be
the same as any other individual. Thus, the current allowable practice
of removing identifiers from biospecimens and data to conduct whole
genome sequencing research without consent might not sufficiently
protect both the privacy and autonomy interests of the subject.
As is currently the case, under this alternative, investigators'
use of individually identifiable biospecimens, collected for purposes
other than the currently proposed research study, would continue to be
considered human subjects research. However, the secondary research use
of non-identified information or non-identified biospecimens would
continue to fall outside of the scope of the Common Rule, with the
exception of whole genome sequence data as described above.
One of the less obvious differences in scope between the primary
proposal and this Alternative A relates to what research could be done
with the data generated from whole genome sequencing that had taken
place for clinical purposes. Under the primary proposal, the data
produced by such sequencing could continue to be used for research,
without additional consent, so long as it did not meet the definition
of being identifiable private information. (HHS does not currently
consider whole genome sequencing data to meet that definition for
purposes of the Common Rule.) Under this Alternative A, consent would
be required before using that data for research purposes.
In contrast with the primary proposal in this NPRM, this
Alternative Proposal A could be viewed as giving greater weight to the
principle of beneficence, while giving less weight to the principle of
respecting the autonomy of persons. It would require consent only for
the type of studies that many people seem most concerned about (genomic
research, including secondary use of genomic information that was
produced for clinical purposes). And given that at the moment there is
relatively little whole genome sequencing research taking place (in
comparison to other types of biospecimen research; see section III.F of
this preamble for more information), it would appear to currently
impose a somewhat lesser burden in terms of obtaining and tracking
consent than the main NPRM proposal.
The major concern with this alternative proposal is that it would
codify only a single technology as producing information that would be
subject to the Common Rule, necessitating a re-evaluation of the scope
of the Rule when technologies now in development to study, for
instance, other ``omics,'' become more widespread.
Alternative Proposal B: Classifying Certain Biospecimens Used in
Particular Technologies as Meeting the Criteria for ``Human Subject''
This Alternative Proposal B would expand the definition of human
subjects to include the research use of information that was produced
using a
[[Page 53946]]
technology applied to a biospecimen that generates information unique
to an individual such that it is foreseeable that, when used in
combination with publicly available information, the individual could
be identified. Information that met this standard would be referred to
as bio-unique information. This proposal is conceptually very similar
to Alternative Proposal A. The main difference is that the scope is
somewhat broader: Whereas Alternative A requires consent for whole
genome sequencing, Alternative B would require consent for genomic
sequencing of even small portions of a person's genome, and also
require consent for the use of other technologies that might be
developed that similarly can generate information unique to a person.
There are three separate conditions that would all need to be met
before information would constitute bio-unique information: (1) It
would have to have been produced by applying to a biospecimen a
technology that is capable of producing information that is unique to
an individual; (2) The technology would have to be used to produce
enough information such that the information produced is likely to be
unique to an individual; and (3) There would need to be publicly
available information that, when combined with the information produced
by the use of the technology, would create the possibility that some of
the individuals whose biospecimens were analyzed using the technologies
could be identified.
The major concern with this alternative proposal is that, in order
to make such a requirement responsive to scientific and technological
developments, HHS would have to continually evaluate new technologies
and the nature and amount of information produced using such
technologies. Not only would this involve resources and expertise that
may not be available to Federal departments and agencies, it would
introduce ongoing uncertainty that may actually increase delays in
important research.
e. What would change in the definition of ``human subject'' under the
primary proposal?
It is anticipated that the compliance date for the
proposed expansion of the definition would be three years after the
publication date. The main consequence of this change would be that
informed consent (which could be broad, as described in sections
II.A.3.d and II.B of this preamble) would generally be required before
research use of biospecimens not covered by an exclusion.
All biospecimens used for research purposes that do not
fall under an exclusion (see proposed Sec. __.101(b)(3)(i), and also
Sec. __.101(b)(1)(i), (iii)-(vi)) and are collected after the
compliance date would be subject to the requirements of this rule,
regardless of identifiability.
f. Questions for Public Comment
2. Would providing a definition of biospecimen be helpful in
implementing this provision? If so, how might the definition draw a
line between when a biospecimen is covered by the Common Rule, and when
processing of biological materials (e.g., to create a commercial
product used for treatment purposes) has sufficiently altered the
materials so that they should not be subject to the regulations? Would
only covering biospecimens that include nucleic acids draw an
appropriate line?
3. To what extent do the issues raised in this discussion suggest
the need to be clearer and more direct about the definition of
identifiable private information? How useful and appropriate is the
current modifier ``may be readily ascertained'' in the context of
modern genomic technology, widespread data sharing, and high speed
computing? One alternative is to replace the term ``identifiable
private information'' with the term used across the Federal Government:
Personally identifiable information (PII). The Office of Management and
Budget's \45\ concept of PII refers to information that can be used to
distinguish or trace an individual's identity (such as their name,
social security number, biometric records, etc.) alone, or when
combined with other personal or identifying information which is linked
or linkable to a specific individual, such as date and place of birth,
mother's maiden name, etc. It is acknowledged that replacing
``identifiable private information'' with ``PII'' would increase the
scope of what is subject to the Common Rule. However, the practical
implications of such an expansion, other than the need to ensure that
the data are security stored and otherwise protected against
disclosure, may be minimal. Public comment is requested on the
advantages and disadvantages of such a change.
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\45\ Executive Office of the President, Office of Management and
Budget. (2007). Memorandum for the Heads of Executive Departments
and Agencies. Retrieved from The White House: https://www.whitehouse.gov/sites/default/files/omb/memoranda/fy2007/m07-16.pdf.
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4. Which of the three proposals regarding the definition of human
subject achieves the most reasonable tradeoff between the principles of
autonomy (including transparency and level of trust) versus beneficence
(as measured by facilitating valuable research)?
5. Public comment is sought regarding any concerns that you have
about each of the three proposals, including concerns about
implementation or burden to investigators and institutions.
2. Explicit Exclusion of Activities From the Common Rule
The NPRM creates a new section in the regulations referred to as
``exclusions.'' This section outlines eleven specific types of
activities that will be outside the scope of the regulations. These
activities will therefore not have to satisfy any regulatory
requirements, nor is it expected (unlike exempt research) that they
will undergo any type of review process to determine this status. The
exclusions will eliminate uncertainty regarding some activities that
are not research, and identify some activities that arguably might be
judged to be research, but whose contribution to public welfare is so
imperative that they should proceed without having to satisfy the
regulatory requirements. The exclusions also identify certain research
activities that are sufficiently low-risk and nonintrusive that the
protections provided by the regulations are an unnecessary use of time
and resources, whereas the potential benefits of the research are
substantial.
The Common Rule has been criticized for not being clear about how
to interpret what activities are covered by the policy and for
inappropriately being applied to and inhibiting certain activities. The
first six exclusion categories are for activities that are deemed not
to be research for the purposes of this policy, without needing to
consider whether the regulatory definition applies. The definition of
research does not provide such a clear and precise way of
distinguishing among similar activities that it is immediately obvious
which activities fall under the definition and which do not. By
creating exclusion categories that are deemed not research, these
activities are more clearly distinguished as not having to satisfy the
regulatory requirements.
Three of the exclusions seek to eliminate any uncertainty about
whether certain internal program improvement activities, historical or
journalistic inquiries, or quality assurance or improvement activities
satisfy the definition of research. The other three exclusions include
some
[[Page 53947]]
activities that fall into to a gray area that encompasses some
activities that arguably might be judged to be research, but that are
part of inherently governmental functions that have purposes other than
research, such as responsibilities to protect public health and welfare
(see exclusions for criminal investigations, public healthy
surveillance, and intelligence surveillance). These activities promote
recognized specific goods that are crucial to the public welfare, and
should be carried out without any hindrances that satisfying regulatory
requirements might impose. For these activities, the principles of
beneficence and justice outweigh any intrusions on individual autonomy
that the regulations might have prevented.
The next four categories of proposed exclusions are for activities
that are considered low-risk either in themselves or because there are
appropriate safeguards already in place independent of the Common Rule.
Here the level of risk, the potential benefits, and the nature of human
participation in this research are such that the principle of
beneficence determines that the research activities may go forward
without the need to impose the protections of the Common Rule.
The last exclusion applies to research involving the secondary use
of non-identified biospecimens when the research is limited to
generating information about the subject that is already known. As
such, this research does not need any additional protections provided
by these regulations and the potential benefits of this research
justify it under the principle of beneficence. Because this exclusion
directly relates to the proposed changes in the definition of ``human
subject'' to include all biospecimens, it is discussed above in section
II.A.1 of this preamble.
It should be noted that the fact that the NPRM now specifically
includes a list of certain excluded activities should not be seen as
altering the fact that many other activities that do not meet the
criteria for being subject to the Common Rule remain outside the scope
of the rule. For example, an activity that does not meet the regulatory
definition of research, or does not involve human subjects, would still
not be subject to these regulations.
Currently, the Common Rule excludes from coverage (1) activities
that do not meet the definition of research (Sec. __.102(d) of the
current Rule); (2) activities that are not described as research
subject to regulation (Sec. __.102(e) of the current Rule); and (3)
activities that do not involve a human subject (Sec. __.102(f) of the
current Rule).
The ANPRM asked questions about the definition of research and
whether various activities should be excluded from the Common Rule,
either by changing the definition of research or by adding exemptions,
or both. The ANPRM sought comment on whether and, if so, how, the
Common Rule should be changed to clarify whether quality improvement
activities, program evaluation studies, or public health activities are
covered. It also asked whether there are specific types of studies for
which the existing rules are inappropriate. If so, comments were sought
on whether this problem should be addressed through modifications to
the exemption categories, or by changing the definition of ``research''
used in the Common Rule to exclude some of these studies, or a
combination of both.
If the definition of research were to be changed, public comment
was sought on how excluded activities should be defined (e.g.,
``quality improvement'' or ``program evaluation''). With regard to
quality improvement activities, the public was asked to comment on
whether it might be useful to adopt the distinction made by the HIPAA
Privacy Rule, which distinguishes between ``health care operations''
and ``research'' activities, defining ``health care operations'' to
include, among other activities, ``conducting quality assessment and
improvement activities, including outcomes evaluation and development
of clinical guidelines, provided that the obtaining of generalizable
knowledge is not the primary purpose of any studies resulting from such
activities.''
a. Exclusion of Activities that are Deemed Not Research (NPRM at Sec.
__.101(b)(1))
The first set of six exclusions involve activities that will be
excluded from the regulations because they will be deemed to not
involve research. Three of the first six exclusions (discussed in
sections II.A.1.a.i, ii, and iv, below) provide clarity regarding the
applicability of the Common Rule to activities about which institutions
have raised questions in the past as to whether these activities meet
the regulatory definition of research. These exclusions aim to reduce
the time and effort involved trying to determine whether the
regulations apply, and in unnecessary reviews of these activities.
The other three of these exclusions (discussed in sections
II.A.1.iii, v, and vi below) apply to activities that are largely
inherently government functions that have purposes other than research,
and, when conducted by a government employee or contractor, are subject
to a variety of other statutes, regulations, and polices that are
designed to protect individual privacy and data security, as well as
provide notice to those providing the information as to the uses to
which the information will be put (see, for example, the Privacy Act of
1974). These activities promote recognized specific goods that are
crucial to the public welfare, and because of this they should be
carried out without any hindrances that satisfying the Common Rule
regulatory requirements might impose. For these activities, the
principle of beneficence outweighs any intrusions on individual
autonomy that the regulations might have prevented, and this allows
these important activities to proceed without delay.
The ANPRM asked whether various activities such as quality
improvement, public health activities, or program evaluations studies
should be excluded from the rule.
i. Program Improvement Activities (NPRM at Sec. __.101(b)(1)(i))
(1) NPRM Proposal
The first exclusion, proposed in the NPRM at Sec. __.101(b)(1)(i),
is for data collection and analysis, including the use of biospecimens,
for an institution's own internal operational monitoring and program
improvement purposes, if the data collection and analysis is limited to
the use of data or biospecimens originally collected for any purpose
other than the currently proposed activity, or is obtained through oral
or written communications with individuals (e.g., surveys or
interviews). This category is excluded because these activities are
designed for various administrative purposes related to using
information to improve the quality of services provided by a specific
institution, and are not designed to produce generalizable knowledge. A
majority of commenters to the 2011 ANPRM supported excluding program
evaluation activities from the scope of the Common Rule. Many of these
commenters argued that the public benefits resulting from this type of
activity justified its practice, particularly given the generally low-
risk involved.
An example of an activity that would satisfy this exclusion is a
survey of hospital patients to evaluate and improve the quality of
meals delivered to hospital patients. An example of an activity that
would not satisfy this exclusion is a prospective observational
[[Page 53948]]
study of patient treatments to analyze the comparative effectiveness of
two different standard of care treatments frequently used to treat the
same medical condition.
(2) Questions for Public Comment
6. Public comment is sought for whether this excluded activity
should simply be discussed in the text of the final rule's preamble,
and guidance produced to assist investigators in making such a
determination, or whether any other similar exclusions should be
addressed.
7. Public comment is sought for whether biospecimens should not be
included in any of these exclusion categories, and if so, which ones.
ii. Oral History, Journalism, Biography, and Historical Scholarship
Activities (NPRM at Sec. __.101(b)(1)(ii))
(1) ANPRM Discussion
The ANPRM asked whether there were any fields of study (such as
classics, history, languages, literature, and journalism) whose usual
methods of inquiry were not intended to or should not be covered by the
Common Rule.
(2) NPRM Proposal
The second proposed exclusion, in the NPRM at Sec.
__.101(b)(1)(ii) is for oral history, journalism, biography and
historical scholarship activities that focus directly on the specific
individuals about whom the information is collected.
The overwhelming majority of public comments to the 2011 ANPRM
responding to the question about excluding specific fields of study
from the regulatory requirements of the Common Rule supported
explicitly excluding certain activities from the definition of research
versus modifying the exemption categories. The overwhelming majority of
these comments focused on oral history. Some of the comments were
virtually identical and appear to have been coordinated. Many of the
comments reflected the view that the Common Rule was not designed or
intended to include oral history activities, and that the ethical codes
pertaining to oral history procedures are not consistent with the
application of the ethical principles reflected in the Common Rule.
A smaller number of similar comments were submitted with respect to
various humanities disciplines and journalism. A significant minority
of commenters opposed the exclusion of any fields of study, arguing
that the activity itself rather than the academic discipline or
training of the investigator should be the basis for the assessment of
whether the activity should be excluded. Some of the commenters
recommended that the definition of research be focused more explicitly
by being limited to ``biomedical and behavioral research,'' in
accordance with the statutory provision underlying the Common Rule. A
significant number of commenters recommended that guidance should be
issued to clarify how the definition of research should be applied,
with cases and explanations.
While the NPRM does not propose to modify the definition of
``research'', it does propose to explicitly exclude oral history,
journalism, biography, and historical scholarship activities that focus
directly on the specific individuals about whom the information or
biospecimens is collected. In the kinds of activities referred to here,
the ethical requirement is to provide an accurate and evidence-based
portrayal of the individuals involved, and not to protect them from
public scrutiny. Therefore, the protections afforded to individuals by
the Common Rule seem unhelpful in furthering the aforementioned ethical
goal in this context. Additionally, these fields of research have their
own codes of ethics, according to which, for example, consent is
obtained for oral histories. It is believed that because of these
reasons, explicit exclusion of these activities from the scope of the
Common Rule is appropriate.
iii. Criminal Justice Activities (NPRM at Sec. __.101(b)(1)(iii))
(1) NPRM Proposal
The third category of activities that the NPRM excludes from the
proposed rule encompasses data collection and analysis that enables the
uniform delivery of criminal justice. The scope of this exclusion is
collection and analysis of data, biospecimens, or records by or for a
criminal justice agency for activities authorized by law or court order
solely for criminal justice or criminal investigative purposes. The
activities excluded are necessary for the operation and implementation
of the criminal justice system.
The provision would essentially codify current Federal
interpretation that such activities are not deemed to be research under
the Common Rule. The addition of this provision is designed to avoid
the imposition of disparate requirements by IRBs with overlapping
jurisdiction when a data collection or analysis activity encompasses
the development of methods required by law or court order for criminal
justice or criminal investigative purposes. For example, the Federal
Bureau of Investigation (FBI) is charged by law with setting standards
governing the collection and processing of DNA biospecimens and
information taken (forcibly if necessary) from certain federal and
state criminal offenders incident to their arrest or conviction for
prescribed offenses under the National DNA Identification Act of 1994
and other acts. Similarly, the FBI is charged by law with setting
standards governing the collection and processing of fingerprints and
related biographical information taken from federal and state criminal
offenders and certain sensitive civil employment applicants. At the
same time, through its Laboratory Division and other components the FBI
routinely collects human biospecimens at crime scenes from or relating
to victims and offenders both known and unknown. Incident to these
activities, the FBI is also charged with maintaining, and
authenticating through identification processes, the criminal record
history information of criminal offenders for the Federal Government
and for the overwhelming majority of state governments who elect to
participate and share information through those FBI systems.
iv. Quality Assurance and Quality Improvement Activities (NPRM at Sec.
__.101(b)(1)(iv))
(1) NPRM Proposal
The fourth category of excluded activities covers quality assurance
or improvement activities involving the implementation of an accepted
practice to improve the delivery or quality of care or services
(including, but not limited to, education, training, and changing
procedures related to care or services) if the purposes are limited to
altering the utilization of the accepted practice and collecting data
or biospecimens to evaluate the effects on the utilization of the
practice. This exclusion does not cover the evaluation of an accepted
practice itself.
As an example of an activity that would satisfy this exclusion,
assume that there is an accepted practice that is known to reduce the
likelihood of an infection after the insertion of a central line. A
randomized study in which half the participating institutions would be
assigned to have the staff undergo an educational intervention about
the need to use that accepted practice, and the other half would not
undergo that intervention, would satisfy this exclusion, since it would
only be intended to see if the intervention resulted in greater use of
the accepted practice. In contrast, imagine a different study that was
designed to determine
[[Page 53949]]
how well that accepted practice, when it is used, reduces infections.
That study would not satisfy this exclusion, since it would be studying
the effectiveness of the practice itself, in contrast to studying an
effort to increase use of the practice.
Over the past several years, including in response to the 2011
ANPRM, OHRP has received comments from many individuals and
organizations expressing concern that some readings of the definition
of ``research'' would imply that the regulations apply to quality
improvement activities, thereby potentially interfering with the
ability of health care and other professionals to enhance the delivery
or quality of care or services involving the use of accepted practices.
Indeed, a majority of commenters to the 2011 ANPRM supported excluding
quality improvement activities from the scope of the Common Rule. These
quality improvement activities are in many instances conducted by
health care and other organizations under clear legal authority to
change internal operating procedures to increase safety or otherwise
improve performance, often without the consent of staff or clients,
followed by monitoring or evaluation of the effects. These activities
are generally conducted in circumstances where independent privacy,
confidentiality, and security safeguards are in place, minimizing the
chances of harm. These efforts, some of which could be judged to be
research, should be carried out because of the recognized public good
they achieve. This exclusion is intended to avoid impeding such efforts
where the Common Rule's requirements might have a chilling effect on
the ability to learn from, and conduct, important types of innovation.
Recognizing that some quality improvement efforts should not be
considered to involve research as it is defined in the Common Rule can
allay many of these concerns. Thus, this exclusion is being proposed to
deal with quality improvement activities that are aimed at implementing
practices that are already accepted, with the goal of improving the
delivery or quality of treatments or services. This exclusion would
permit measuring and reporting provider performance data for practice
management, clinical, or administrative uses. As proposed, this
exclusion does not include evaluations of different accepted practices
themselves, however, such as activities designed to determine whether a
particular accepted medical treatment is or is not more effective than
another.
This provision also covers quality improvement activities that are
not related to delivery of patient care, but rather involve the
delivery or quality of other public benefit or social services. For
example, institutions and other entities may provide social services,
educational offerings, or other beneficial activities where there is
empirical evidence of the value of those efforts, and they may wish to
evaluate different ways of enhancing the delivery or quality of those
existing services. This exclusion has been written broadly to include
such activities.
The rationale for this excluded category is that these activities
are designed only to improve the implementation of a practice that is
already accepted, not to evaluate the effectiveness and value of the
accepted practice itself, and thus would generally be expected to pose
little if any risks to the recipients of those practices, and are
directly aimed at improving the practical use of those practices. This
does not include quality improvement activities designed with a
research purpose relating to the safety and efficacy of the accepted
practice. It is accordingly important to note that activities that do
involve such research--for example, assigning patients to different
versions of treatments that are within the standard of care in order to
evaluate the differences between those treatments in terms of
effectiveness or risks--would not come within this exclusion. In the
educational context, for example, activities where students are
assigned to experimental and control groups to determine the
effectiveness of experimental teaching methodologies would also not
come within this exclusion. Furthermore, that type of activity would
also not meet a separate requirement of this exclusion--that the
activity be related to the delivery of (i.e., implementing) an accepted
form of care, and not an attempt to evaluate the efficacy or risks of
that form of care.
v. Public Health Surveillance (NPRM at Sec. __.101(b)(1)(v))
(1) NPRM Proposal
The fifth category of excluded activities involves public health
surveillance activities, including the collection and testing of
biospecimens, conducted, supported, requested, ordered, required, or
authorized by a public health authority and limited to those necessary
to allow the public health authority to identify, monitor, assess, or
investigate potential public health signals or the onset of a disease
outbreak, including trends, or signals, and patterns in diseases, or
sudden increase in injuries from using a consumer product, or
conditions of public health importance, from data, and including those
associated with providing timely situational awareness and priority
setting during the course of an event or crisis that threatens public
health, including natural or man-made disasters. A majority of
commenters to the 2011 ANPRM supported excluding public health
activities from the scope of the Common Rule.
The rationale for excluding some public health surveillance
activities is that when a public health authority conducts public
health surveillance activities to fulfill its legal mandate to protect
and maintain the health and welfare of the populations it oversees, the
regulatory protections of the Common Rule should not impede its ability
to accomplish its mandated mission of promoting this recognized public
good, in keeping with the principle of beneficence. Other protections
independent of the Common Rule exist that serve to protect the rights
and welfare of individuals participating in such activities, including
privacy, confidentiality and security safeguards for the information
collected.
Public health surveillance refers to the collection, analysis, and
use of data to target public health prevention. It is the foundation of
public health practice. Surveillance uses data from a variety of
sources, including mandatory reporting of certain conditions, routine
monitoring, vital records, medical billing records, and public health
investigations in response to reports of potential outbreaks. The line
between public health surveillance and epidemiological research can be
difficult to draw, as the same techniques may be used in both.
Generally, the difference between the activities is the purpose or
context in which the investigation is being conducted and the role of
the public health authority.
The following are examples of activities that meet the public
health surveillance exclusion:
Safety and injury surveillance activities designed to
enable a public health authority to identify, monitor, assess, and
investigate potential safety signals for a specific product or class of
products (for example, the surveillance activities of the FDA's Adverse
Event Reporting System (AERS), the Vaccine Adverse Event Reporting
System (VAERS), Manufacturer and User Facility Device Experience
(MAUDE) database, the Medical Product Safety Network (MedSun), and the
Sentinel Initiative);
Surveillance activities designed to enable a public health
authority to identify unexpected changes in the
[[Page 53950]]
incidence or prevalence of a certain disease in a defined geographic
region where specific public health concerns have been raised (e.g.,
the U.S. influenza surveillance system, which allows CDC to find out
when and where influenza activity is occurring, track influenza-related
illness, determine what influenza viruses are circulating, detect
changes in influenza viruses, and measure the impact influenza is
having on hospitalizations and deaths in the United States);
Surveillance activities designed to enable a public health
authority to identify the prevalence of known risk factors associated
with a health problem in the context of a domestic or international
public health emergency;
Surveillance activities designed to enable a public health
authority to locate the range and source of a disease outbreak or to
identify cases of a disease outbreak;
Surveillance activities designed to enable a public health
authority to detect the onset of disease outbreaks or provide timely
situational awareness during the course of an event or crisis that
threatens the public health, such as a natural or man-made disaster.
On the other hand, subsequent research using information collected
during a public health surveillance activity, for instance genetic
analysis of biospecimens, would not fall under this exclusion, but
would likely be covered under one or more of the other exclusions for
low-risk research or exemptions.
Additional examples of activities that would not fall under the
exclusion include: Exploratory studies designed to better understand
risk factors, including genetic predisposition, for chronic diseases;
exploratory studies designed elucidate the relationships between
biomarkers of exposure and biomarkers of disease; exploratory studies
of potential relationships between behavioral factors (e.g., diet) and
indicators of environmental exposures. These types of activities would
be considered research, and thus subject to the Common Rule, even if
conducted by a Federal agency with a public health mandate. To clarify
this proposed exclusion the NPRM also proposes a new regulatory
definition of public health authority proposed in Sec. __.102(k).
(2) Question for Public Comment
8. Public comment is requested on whether the parameters of the
exclusions are sufficiently clear to provide the necessary operational
guidance, or whether any additional criteria or parameters should be
applied to clarify or narrow any of these exclusions.
vi. Intelligence Surveillance Activities (NPRM at Sec.
__.101(b)(1)(vi))
(1) NPRM Proposal
The sixth category of excluded activities that will not be
considered research involves surveys, interviews, surveillance
activities and related analyses, or the collection and use of
biospecimens where these activities are conducted by a defense,
national security, or homeland security authority solely for authorized
intelligence, homeland security, defense, or other national security
purposes.
The rationale for excluding the defense or national security-
related activities is similar to that described above regarding public
health surveillance activities. The lawful conduct of the departments'
and agencies' mandated missions for actively protecting national
security, homeland security, and homeland defense are fundamentally not
research. These activities may incorporate the collection and analysis
of identifiable information, but they are not designed to develop or
contribute to generalizable knowledge; rather, they are solely
conducted to fulfill a department or agency's legal mandate to ensure
the safety and protection of the United States, its people, and its
national security interests. This exclusion codifies the current
interpretation of the Common Rule. Research conducted or sponsored by
Federal departments and agencies using this exclusion will continue to
be subject to this regulation.
b. Exclusion of Activities That Are Low-Risk and Already Subject to
Independent Controls (NPRM at Sec. __.101(b)(2))
i. NPRM Goals
The NPRM proposes to exclude four categories of research activities
that do not entail physical risk and are non-intrusive, either in
themselves or because they are subject to policies that provide
oversight independent of the Common Rule. Although the activities are
research, they will not be required to receive any form of
determination or IRB approval--including expedited review.
Additionally, statements of purpose, benefit, and voluntariness as well
as consent are not required unless the entity conducting the research,
collecting data, or providing data is also subject to separate statutes
and regulations requiring such statements. Some of the activities
proposed for exclusion are categories that appear as exemptions in the
current Rule. It is proposed that the marginal protections provided by
the Common Rule are not consistent with the amount of researcher time
and institutional resources that they currently draw.
By reclassifying certain research activities from being exempt to
being excluded, the proposed rule would eliminate the need for any
administrative or IRB review. All investigators performing excluded
studies are expected to act in a way that is consistent with the
principles outlined in the Belmont Report, even if the Common Rule does
not impose requirements on excluded work. For instance, consistent with
the spirit of respect for persons, investigators should tell
prospective subjects the purpose of the information collection and,
where appropriate, that they can choose to participate or not in these
activities, although investigators are not explicitly required to do
so.
Designating certain research fully outside of the bounds of the
Common Rule means that investigators are self-determining whether their
own research is covered by the law. As such, the proposal to add these
categories is based on the assumption that all investigators will be
accurately determining whether their proposed activity is outside the
scope of the Common Rule. There is no current proposal outlining how
decisions will be made for determining whether a research activity is
eligible for exclusion and by whom or how differences among
collaborators would be handled. As readers review each of the exclusion
categories below, please consider whether the benefits associated with
reducing the delay for researchers are countervailed by potential
increases in risk of harm.
Throughout this NPRM, the term ``low-risk'' is used to denote
research activities that do not entail physical risk, and where both
the probability and magnitude of other risks, once required protections
are applied, are hypothesized to be low. Public comment is sought on
whether there are instances in the regulatory text where the term
``low-risk'' is used, but these conditions do not apply, and whether
there is a better way to characterize this category of risk.
ii. ANPRM Discussion
The ANPRM discussed criticisms of the current rule that it does not
adequately calibrate the review process to the level of risk of the
research, particularly in social and behavioral research. It also
discussed whether answering questions should be sufficient indication
of willingness to participate in survey or interview
[[Page 53951]]
research. It distinguished between informational or psychological risks
and physical risks, and raised questions about how effectively IRB
review provides protections from informational or psychological risks.
iii. Educational Tests, Survey Procedures, Interview Procedures, or
Observation of Public Behaviors (NPRM at Sec. __.101(b)(2)(i))
(1) NPRM Proposal
The exclusion at Sec. __.101(b)(2)(i) is for research, not
including interventions, that involves the use of educational tests
(cognitive, diagnostic, aptitude, achievement), survey procedures,
interview procedures, or observation of public behavior (including
visual or auditory recording) uninfluenced by the investigators, if at
least one of the following is met:
The information is recorded by the investigator in such a
manner that human subjects cannot be identified, directly or through
identifiers linked to the subjects; or
Any disclosure of the human subjects' responses outside
the research would not reasonably place the subjects at risk of
criminal or civil liability or be damaging to the subjects' financial
standing, employability, educational advancement, or reputation; or
The research will involve a collection of information
subject to the Paperwork Reduction Act of 1995, 44 U.S.C. 3501 et seq.,
research information will be maintained on information technology that
is subject to and in compliance with section 208(b) of the E-Government
Act of 2002, 44 U.S.C. 3501 note, and all of the information collected,
used, or generated as part of the research will be maintained in a
system or systems of records subject to the Privacy Act of 1974, 5
U.S.C. 552a.
The exclusion does not include research activities in which any
sort of intervention is used, in addition to the specified methods of
information collection. Also, the term ``survey'' as used here refers
to information collected about individuals via questionnaire or similar
procedures (e.g., the Current Population Survey conducted by the
Census). ``Human subjects'' do not include organizations or businesses.
``Survey,'' as used here, does not include the collection of
biospecimens or other types of information collection that might
involve invasive procedures. Thus, a survey that included information
collections in addition to verbal or written responses, including the
collection of a biospecimen or the use of some other physically
invasive procedures (e.g., a diagnostic test and blood spot or buccal
swab) could not use this exclusion.
This exclusion includes the research activities in current
exemption category 2 in the (current Common Rule at Sec.
__.101(b)(2)), and some additional government information collection
research activities using the same methods. As in the current exemption
category 2, this proposed exclusion includes research studies whose
methods consist of the use of educational tests, survey procedures or
interview procedures, or observation of public behavior uninfluenced by
the investigators, if the data are recorded anonymously, or the
information is recorded with identifiers, but is not sensitive such
that its disclosure could result in harm to the subjects. The exclusion
provides a list of the specific harms that must be considered, which is
the same as in the current exemption category, with the addition of the
specific harm of being damaging to the subjects' educational
advancement. This potential harm has been added because of the obvious
relevance to the effects of the disclosure of responses in research
involving educational tests.
This proposed exclusion does not include the first element in the
current exemption category at Sec. __.101(b)(3)(i), which is the
element pertaining to research involving the use of educational tests,
survey procedures, interview procedures, or observation of public
behavior if the human subjects are elected or appointed public
officials or candidates for public office. The rationale for this
change in the proposed NPRM is that it does not seem appropriate to
single out this category of subjects for different treatment in this
way.
The third element of this proposed exclusion covers research
activities using the same methods identified above even when the data
are recorded with identifiers and the information recorded may be
personally sensitive or private but not explicitly damaging to an
individual, if the research is subject to specified federal statutes
and regulations that require data security and subject privacy
protections. Under this proposal, the preponderance of research
conducted by Federal employees and contractors that collects
information exclusively through educational tests, questionnaires, or
observations of behavior would no longer be subject to the Common Rule
because most such collections would be subject to the Paperwork
Reduction Act of 1995, would be maintained on information technology
that is subject to and in compliance with section 208(b) of the E-
Government Act of 2002, and all of the information collected, used, or
generated as part of the research would be maintained in a system or
systems of records subject to the Privacy Act of 1974. Furthermore,
consistent with these laws, OMB's Standard 2.2 in its ``Standards and
Guidelines for Statistical Surveys'' \46\ identifies the required
notifications to potential survey respondents.
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\46\ Executive Office of the President, OMB. (Sept. 2006).
Standards and Guidelines for Statistical Surveys. Retrieved from The
White House: https://www.whitehouse.gov/sites/default/files/omb/inforeg/statpolicy/standards_stat_surveys.pdf.
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Specifically, Standard 2.2 states that Federal agencies must ensure
that each information collection instrument clearly states the reasons
the information is planned to be collected; the way such information is
planned to be used to further the proper performance of the functions
of the agency; whether responses to the collection of information are
voluntary or mandatory (citing authority); the nature and extent of
confidentiality to be provided, if any (citing authority); an estimate
of the average respondent burden together with a request that the
public direct to the agency any comments concerning the accuracy of
this burden estimate and any suggestions for reducing this burden; the
OMB control number; and a statement that an agency may not conduct and
a person is not required to respond to an information collection
request unless it displays a currently valid OMB control number. These
policies are rooted in the Fair Information Practice Principles that
cover the following concepts: Individual participation, transparency,
authority, purpose specification and use limitation, minimization,
access and amendment, redress, quality and integrity, security,
training, integration, and accountability. It is proposed that the
information risk protections afforded by these laws and their
implementing regulations are generally stronger than the privacy
protections that result from IRB review, and would result in affording
more uniform protections to participants.
The rationale for excluding these research activities from the
Common Rule, even when the research is not otherwise subject to
additional federal controls, is that consent is inherent to
participation and that the risks most likely to be experienced by
subjects are related to disclosure of anonymous, non-sensitive
information and are thus categorized as ``low.'' Said another way, all
individuals, including vulnerable populations, would understand that
actively providing response to
[[Page 53952]]
educational tests, surveys, or interview procedures constitutes consent
to participate and that the risk associated with such participation
would be related to disclosure of the information they provided. The
exclusion of this type of activity rests in large part on the idea that
all individuals, regardless of the setting or context in which the
activity will take place, are generally familiar with common forms of
educational tests, survey and interview procedures which they
experience in their daily lives, and do not need additional measures to
protect themselves and their privacy from investigators who seek their
involvement in research activities involving these procedures.
This exclusion is based on the assumption that the activities
covered by this category are largely informational, and thus the most
important role that an IRB might play with respect to reducing
potential harms is to ensure data security and privacy protections.
Under this assumption, the proposed exclusion is consistent with the
principle of respect for persons and the preservation of autonomy. In
the case of observation of public behavior, even if the subject does
not know that an investigator is watching his or her actions, the
subject's behavior is public and could be observed by others and thus
the research observation is not inappropriately intrusive. However,
there are situations in which this assumption would not always hold.
For instance, administration of a questionnaire or participation in a
focus group on a sensitive topic may induce significant stress in some
individuals, or individuals approached about taking a survey may feel
compelled to participate. Whether and how the exclusion should be
bounded so that the final rule achieves a balance among the principles
of beneficence, autonomy, and justice is the subject of the request for
comment on this proposed exclusion.
In addition, this exclusion is in keeping with one of the goals of
this NPRM, namely to reduce burden on research that includes sufficient
protections to research subjects. By proposing that this exclusion
could be satisfied if the information to be collected is subject to the
Paperwork Reduction Act of 1995, would be maintained on information
technology that is subject to and in compliance with section 208(b) of
the E-Government Act of 2002, and all of the information collected,
used, or generated as part of the research would be maintained in a
system or systems of records subject to the Privacy Act of 1974, the
NPRM notes that the privacy protections afforded by these laws are
generally comparable, if not stronger, than the privacy protections
that result from IRB review.
(2) Questions for Public Comment
9. Public comment is requested on the extent to which covering any
of these activities under the Common Rule would substantially add to
the protections provided to human research subjects.
10. Public comment is sought on whether this exclusion should only
apply to research activities in which notice is given to prospective
subjects or their legally authorized representatives as a regulatory
requirement. If so, please comment on what kind of information should
be included in the notice such as the research purpose, privacy
safeguards, contact information, ability to opt-out, etc. Would
requiring notice as a condition of this exempt research strike a good
balance between autonomy and beneficence?
11. Public comment is sought regarding whether it is reasonable to
rely on investigators to make self-determinations for the types of
research activities covered in this particular exclusion category. If
so, should documentation of any kind be generated and retained?
12. Public comment is sought regarding whether some or all of these
activities should be exemptions rather than exclusions.
13. Public comment is sought regarding whether these exclusions
should be narrowed such that studies with the potential for
psychological risk are not included. Are there certain topic areas of
sensitive information that should not be covered by this exclusion? If
so, please provide exemplary language to characterize such topic areas
in a manner that would provide clarity for implementing the Rule.
14. For activities captured under the third element of this
exclusion, do the statutory, regulatory, and other policy requirements
cited provide enough oversight and protection that being subject to
expedited review under the Common Rule would produce minimal additional
subject protections? If so, should the exclusion be broadened to also
cover secondary analysis of information collected pursuant to such
activities?
15. Public comment is requested on the extent to which excluding
any of these research activities from the Common Rule could result an
actual or perceived reduction or alteration of existing rights or
protections provided to human research subjects. Are there any risks to
scientific integrity or public trust that may result from excluding
these research activities from the Common Rule?
iv. Research Involving the Collection or Study of Information that has
been or will be Collected (NPRM at Sec. __.101(b)(2)(ii))
(1) Current Rule
This exclusion appears in the current Common Rule as exemption
category 4 (current Rule at Sec. __.101(b)(4)). This exemption
currently applies to research involving the use of existing data,
documents, records, and pathological or diagnostic specimens, but only
if the sources are publicly available or if the information is recorded
by investigators in such a manner that subjects cannot be identified,
directly or through identifiers linked to them.
(2) ANPRM Discussion
The ANPRM proposed retaining this exemption as an exemption (not an
exclusion). The ANPRM asked questions about whether the current
limitations specified in exempt category 4 (research involving the use
of existing information or biospecimens, Sec. __.101(b)(4) in the
current Rule) should be eliminated. Specifically, the ANPRM suggested
that the category would be revised to eliminate the word ``existing.''
With this elimination, the exemption would be broadened to cover the
use of information or biospecimens that were or will be collected for
purposes other than the suggested research, rather than requiring that
all of the information or biospecimens already exist at the time the
study is suggested for exemption.
(3) NPRM Proposal
The second category of low-risk research activities excluded from
the proposed rule is a revised version of the current Rule's exemption
category 4 (current Rule at Sec. __.101(b)(4)). The NPRM proposal is
that the excluded category at Sec. __.101(b)(2)(ii) includes research
involving the collection or study of information that has been or will
be acquired solely for non-research activities or was acquired for
research studies other than the proposed research study when the
sources are publicly available, or the information is recorded by the
investigator in such a manner that human subjects cannot be identified,
directly or through identifiers linked to the subjects, the
investigator does not contact the subjects, and the investigator will
not re-identify subjects or otherwise conduct an analysis that could
lead to
[[Page 53953]]
creating individually identifiable private information.
In light of the proposed expansion of the rule to cover certain
biospecimens regardless of identifiability, this category has been
modified such that it does not include secondary research use of
biospecimens. Many of the comments supported the discussion in the
ANPRM of eliminating the requirement that the information be
``existing'' at the time the study was suggested for exemption. Thus,
in addition to changing this category of activities from being exempted
to being excluded, the proposed exclusion does not require that the
data exist as of the time that the study commences, but rather is
expanded to include the secondary research use of data collected in the
future for research or non-research purposes. The underlying logic
behind the exclusion in proposed Sec. __.101(b)(2)(ii) is that such
research involves no direct interaction or intervention with human
subjects, and any research use of the information does not impose any
additional personal or informational risk to the subjects, because (1)
the information is already available to the public, and so any risk it
may include exists already, or (2) the information recorded by the
investigator cannot be identified, and no connection to or involvement
of the subjects is contemplated. Any requirements of the Common Rule
would not provide additional protections to subjects, and could add
substantial administrative burden on IRBs, institutions, and
investigators. Creating this excluded category avoids that problem.
(4) Questions for Public Comment
16. Public comment is sought regarding whether it is reasonable to
rely on investigators to make self-determinations for the types of
research activities covered in this particular exclusion category. If
so, should documentation of any kind be generated and retained?
17. Public comment is requested on the extent to which covering any
of these activities under the Common Rule would substantially add to
the protections provided to human research subjects. Is there a way in
which this exclusion should be narrowed? Public comment is also sought
regarding whether activities described here should appear as an
exclusion or as an exemption.
v. Research Conducted by a Government Agency using Government-Generated
or Government-Collected Data (NPRM at Sec. __.101(b)(2)(iii))
(1) NPRM Proposal
The third category of low-risk research activities excluded from
the proposed rule at Sec. __.101(b)(2)(iii) is research conducted by a
federal department or agency using government-generated or government-
collected information obtained for non-research purposes (including
criminal history data), if the information originally involved a
collection of information subject to the Paperwork Reduction Act of
1995, 44 U.S.C. 3501 et seq., the information is maintained on
information technology that is subject to and in compliance with
section 208(b) of the E-Government Act of 2002, 44 U.S.C. 3501 note,
and all of the information collected, used, or generated as part of the
research is maintained in a system or systems of records subject to the
Privacy Act of 1974, 5 U.S.C. 552a. This proposed exclusion is
consistent with the Federal Government's emphasis on minimizing the
burden on the public and maximizing the value of the information
collected by the Federal Government, while protecting participant
privacy and data security.\47\ This exclusion is proposed for
situations in which both the original data collection and the
subsequent (secondary) analysis are subject to data security,
participant privacy, and notice requirements associated with the named
federal statutes and regulations. As such, it does not seem that the
delay imposed by obtaining a determination as ``exempt'' or
``expedited'' is likely to increase the protections provided to those
who have already provided the government with information for other
purposes. Public comment is requested on the extent to which covering
any these activities under the Common Rule would substantially add to
the protections provided to human research subjects.
---------------------------------------------------------------------------
\47\ United States Office of Management and Budget, February 14,
2014, Memorandum to Heads of Executive Departments and Agencies;
Guidance for Providing and Using Administrative Data for Statistical
Purposes https://www.whitehouse.gov/sites/default/files/omb/memoranda/2014/m-14-06.pdf. This guidance builds on three previously
issued OMB memoranda designed to increase the value of existing
data: Sharing Data While Protecting Privacy (M-11-02 of November 3,
2010), Open Data Policy-Managing Information as an Asset (M-13-13 of
May 9, 2013), and Next Steps in the Evidence and Innovation Agenda
(M-13-17 of July 26, 2013).
---------------------------------------------------------------------------
(2) Questions for Public Comment
18. Public comment is sought on whether this or a separate
exclusion should also include research involving information collected
for non-research purposes by non-federal entities where there are
comparable privacy safeguards established by state laws and
regulations, or whether such non-federally conducted research would be
covered by the proposed exemption at Sec. __.104(e)(2).
19. Public comment is requested on the extent to which covering any
of these activities under the Common Rule would substantially add to
the protections provided to human research subjects.
20. Public comment is sought regarding whether it is reasonable to
rely on investigators to make self-determinations for the types of
research activities covered in this particular exclusion category. If
so, should documentation of any kind be generated and retained?
21. Public comment is sought regarding whether some or all of these
activities should be exemptions rather than exclusions.
vi. Certain Activities Covered by HIPAA (NPRM at Sec.
__.101(b)(2)(iv))
(1) ANPRM Discussion
The public was asked to comment on whether it might be useful to
adopt the distinction made by the HIPAA Privacy Rule, which
distinguishes between ``health care operations'' and ``research''
activities, defining ``health care operations'' to include, among other
activities, ``conducting quality assessment and improvement activities,
including outcomes evaluation and development of clinical guidelines,
provided that the obtaining of generalizable knowledge is not the
primary purpose of any studies resulting from such activities.'' The
public was asked to comment about this specifically in the context of
quality improvement activities.
(2) NPRM Proposal
The fourth category of low-risk research activities excluded from
the proposed rule, found at Sec. __.101(b)(2)(iv), covers activities
that are regulated under the HIPAA Privacy Rule (i.e., covered
entities). These are activities whose risks relate only to privacy and
confidentiality, and are already subject to independent controls
provided by HIPAA. Specifically, it is proposed that research, as it is
defined in this proposed rule, that involves the use of protected
health information by a HIPAA covered entity for ``health care
operations,'' ``public health activities,'' or ``research,'' as those
three terms are defined under the HIPAA Rules, would
[[Page 53954]]
be excluded from the Common Rule. This proposed exclusion would not
apply if the investigator that receives and uses individually
identifiable health information for a research study was not covered by
the HIPAA Rules, even if the entity disclosing the individually
identifiable health information to the investigator was covered by the
HIPAA Rules. The exclusion is limited in this way to ensure that it
only applies to research studies and information that are already
subject to independent privacy, confidentiality, and security
protections.
A majority of comments on the 2011 ANPRM favored distinguishing
between research and health care operations, as such terms are defined
in the HIPAA Privacy Rule and the Health Information Technology for
Economic and Clinical Health (HITECH) Act, and excluding the latter
from the policy. Some commenters noted that people involved in these
various activities are protected in other ways, and alluded to the
sorts of measures that provide protection. Others suggested that any
exclusions should be limited to data collection and analysis
activities, or to activities below a certain threshold of risk (i.e.,
minimal risk). A minority of comments objected to these exclusions,
arguing that these activities represent encroachments on their
individual rights and privacy, and that oversight in accordance with
the Common Rule requirements would be more protective. The proposed
exclusion excludes only certain activities that involve data collection
and analysis, where privacy safeguards are in place.
(3) Questions for Public Comment
22. Public comment is requested on whether the protections provided
by the HIPAA Rules for identifiable health information used for health
care operations, public health activities, and research activities are
sufficient to protect human subjects involved in such activities, and
whether the current process of seeking IRB approval meaningfully adds
to the protection of human subjects involved in such research studies.
23. Public comment is sought regarding to what extent the HIPAA
Rules and HITECH adequately address the beneficence, autonomy, and
justice aspects for the collection of new information (versus
information collected or generated in the course of clinical practice,
e.g., examination, treatment, and prevention). Should this exclusion be
limited to data collected or generated in the course of clinical
practice? If additional data collection is allowable, should it be
limited to what is on the proposed Secretary's list of minimal risk
activities (discussed in more detail below in II.F.2 of this preamble)?
24. Public comment is requested on whether additional or fewer
activities regulated under the HIPAA Privacy Rule should be included in
this exclusion.
c. Applicability of Exclusions to the Subparts
i. Current Rule
The current Common Rule does not contain exclusion categories,
though as discussed above, some of the proposed exclusions are similar
to activities that are exempt under the current regulations, which
therefore might provide a basis for comparison.
All of the current exemption categories can be applied to research
that is subject to subpart B. None of the current exemption categories
can be applied to research that is subject to subpart C.
The exemptions in the current Rule generally apply to subpart D.
However, the exemption at Sec. __.101(b)(2), for research involving
educational tests, survey or interview procedures, or observation of
public behavior does not apply to subpart D except for research
involving educational tests or observations of public behavior when the
investigators do not participate in the activities being observed.
ii. NPRM Proposals
Language specifying the application of the exclusions to the
subparts can be found in the NPRM at Sec. __.101(b)(2) and (3).
It is proposed that all of the exclusion categories in Sec.
__.101(b)(2) and (3) apply to research that is subject to subpart B,
and therefore the requirements imposed by subpart B would not need to
be met.
It is similarly proposed that all of the exclusion categories in
Sec. __.101(b)(2) and (3) apply to research involving prisoners,
therefore the requirements of subpart C would not need to be met. This
would narrow the scope of research currently requiring subpart C review
and certification to OHRP. Considerations in favor of this conclusion
include the preponderance of low-risk socio-behavioral research
designed to improve prisoner welfare, including studies that focus on
substance abuse treatment, community reintegration, and services
utilization; the occurrence of prisoner-subjects in research not
targeting prisoner populations; the occurrence of prisoner-subjects in
databases or registries; and the broad regulatory interpretation of the
subpart C ``prisoner'' definition. Public comment is requested on
whether the application of these exclusions to research involving
prisoners is appropriate and acceptable.
It is proposed that all of the exclusion categories in Sec.
__.101(b)(2) apply to research subject to subpart D, with the exception
that the exclusion proposed under Sec. __.101(b)(2)(i) would only
apply to research involving educational tests or observations of public
behavior when the investigator does not participate in the activities
being observed. This limitation would maintain the protection currently
provided by the similar application of the current exemption Sec.
__.101(b)(2) to research involving children, and would continue to
require IRB review under the Common Rule and additional IRB review
under subpart D of 45 CFR part 46 when the research involves surveys or
interview procedures with children or observation of public behavior
when the investigator participates in the activities being observed.
iii. Questions for Public Comment
25. Should research involving prisoners be allowed to use any or
all of the exclusions found at Sec. __.101(b)(2) and (3), as currently
proposed?
26. Are there certain provisions within the broader categories
proposed at Sec. __.101(b)(2) and (3) to which the subparts should or
should not apply?
3. Proposed Exemptions (NPRM at Sec. __.104)
The Common Rule has been criticized for inadequately calibrating
the review process to the risk of research. Some have argued that,
particularly given the paucity of information suggesting significant
risks to subjects in certain types of survey and interview-based
research, the current system overregulates such research. Further, many
critics see little evidence that most IRB review of social and
behavioral research effectively protects subjects from psychological or
informational risks. Overregulating social and behavioral research in
general may serve to distract attention from identification of social
and behavioral research studies that do pose ethical challenges and
thus merit significant oversight.
The proposed exemption categories and attendant policies and
procedures related to exemptions appear in the NPRM at Sec. __.104,
and are guided by the following policy goals:
[[Page 53955]]
To create procedural efficiencies for IRBs, administrators
and investigators in making and receiving exemption determinations,
thereby reducing the overall IRB workload and the wait time for
investigators to begin their work.
To ensure that reasonable safeguards are in place for
certain lower risk research activities not fully excluded under the
current Common Rule by requiring that research in certain exemption
categories follow elements of the proposed rule, but not be required to
undergo full IRB review according to the full set of criteria at Sec.
__.111(a)(1)-(8) and other regulatory requirements of the Common Rule .
Note that all of the exemption categories in the current Rule have
been carried over to the proposed Rule in one or another form. In
particular, some of the current Rule's exemptions have now become
exclusions under the NPRM (and thus subject to no administrative or IRB
review), while some remain in the NPRM's exempt categories section.
Under the current Common Rule, research may qualify for exemption
from the regulatory policy if it falls into one of the six current
categories at Sec. __.101(b)(1)-(6). Such studies are fully exempt
from the regulations. The current regulations do not specify who at an
institution may determine that research is exempt under Sec.
__.101(b). However, in the past OHRP has recommended that because of
the potential for conflict of interest, investigators not be given the
authority to make an independent determination that human subjects
research is exempt. OHRP has recommended that institutions should
implement exemption policies that most effectively address the local
setting and programs of research. OHRP has recognized that this may
result in a variety of configurations of exemption authority, any of
which are acceptable assuming compliance with applicable regulations.
The NPRM proposes to retain the term ``exempt,'' (rather than
``excused,'' as suggested in the ANPRM) but require that exempt
research comply with certain provisions of the proposed rule such as
proposed privacy safeguards at Sec. __.105 (discussed below). This
policy retains and, in important respects (through a new safe harbor
provision), expands the current flexibility of institutions to develop
a system in which someone at the institution--including the
investigator, unless prohibited by law--uses an exemption decision tool
to make the exemption determination.
It is important to recognize that while in some cases there are new
requirements that have been imposed on the exemption categories that do
not exist in the current version of the exemption categories, this
usually does not actually represent a tightening of the rules for those
exemptions. To the contrary, these changes are generally being made to
allow the exemption in question to be expanded to cover activities that
are not currently exempt. For example, adherence to new privacy
standards is a new requirement in order for certain surveys to be
exempt, but these are surveys that under the current Common Rule would
require IRB review.
The proposed eight exemptions are divided into three groupings
according to the kind of risk characteristically involved and what
protections are called for: (1) Low-risk interventions that do not
require application of standards for information and biospecimen
protection; (2) research that may involve sensitive information that
requires application of standards for information and biospecimen
protection described in proposed Sec. __.105; and (3) secondary
research involving biospecimens and identifiable private information
that requires application of privacy safeguards discussed at proposed
Sec. __.105, broad consent as discussed in proposed Sec. __.116(c),
and limited IRB review as discussed in proposed Sec. __.111(a)(9).
a. Making Exempt Research Determinations (NPRM at Sec. __.104(c))
i. NPRM Goal
The goal of this NPRM proposal is to create procedures for
appropriate exemption determinations in a manner that does not waste
time and effort.
ii. Current Rule
In developing policies and procedures addressing the exemptions,
OHRP currently recommends that when an exemption determination is made,
the specific exemption category or categories should be included in the
record of the material supplied to the IRB and this information should
be available for oversight purposes. In addition, OHRP guidance has
said that institutional policies and procedures should identify clearly
who is responsible for making exemption decisions. OHRP notes that
under current policy a Common Rule Department or Agency retains final
authority as to whether a particular human subjects research study
conducted or supported by that Department or Agency is exempt from the
Common Rule (Sec. __.101(c)) and that authority continues under the
proposed regulations.
iii. ANPRM Discussion
The ANPRM discussed a mechanism to (1) register exempt research,
and (2) audit a small but appropriate portion of such research, which
would still be subject to other regulatory protections such as the
suggested data security and information protection standards and
certain consent requirements.
The ANPRM discussed a tracking mechanism to enable institutions to
assure that such research meets the criteria for inclusion in the
suggested ``excused'' categories. The original recommendations would
require investigators to register their study with an institutional
office by completing a brief form, thus eliminating the current
practice of not allowing investigators to begin conducting such studies
until a reviewer had determined it meets the criteria for excused
research. This would make the institution aware of key information
about the research (such as the purpose of the research and the name of
the study's principal investigator), without also requiring that the
activity undergo a review that, if not done in a timely manner, could
slow the research without adding any significant protection to
subjects. In addition, the institution could choose to review some of
the submissions at the time they are filed and, if deemed appropriate,
require that the study be sent for expedited review or, in rare cases,
convened IRB review. It would be made clear that the regulations would
not require, and in fact, would discourage, having each of these
registration forms undergo a comprehensive administrative or IRB review
prior to commencing the study or even afterward.
The auditing requirement was intended to encourage institutions to
use the regulatory flexibility suggested for the exempt categories of
research. The auditing requirement would have provided institutions
with information needed to assess their compliance with the new
``excused'' categories without unnecessarily subjecting all such
research to either prospective review, or even routine review sometime
after the study is begun. Note that currently, OHRP recommends that
there be some type of review by someone other than the investigator to
confirm that a study qualifies as exempt, and many institutions do
impose such a requirement even though such a requirement is extra-
regulatory.\48\
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\48\ Office for Human Research Protections. (2011, January 20).
Exempt Research Determination FAQs. Retrieved from Frequently Asked
Questions About Human Research: http://www.hhs.gov/ohrp/policy/faq/index.html.
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[[Page 53956]]
The ANPRM also asked whether it was acceptable for investigators to
independently determine whether their research was exempt, whether
review of all registrations should be required, and whether there
should be a time limitation or waiting period before excused research
could begin.
The ANPRM also asked whether it was appropriate to require
institutions holding a Federalwide assurance (FWA) to conduct
retrospective audits of a percentage of the excused studies to make
sure they qualify for inclusion in an excused category, and if so, how
such audits should be conducted.
iv. NPRM Proposal
The NPRM proposes to adopt an exemption determination documentation
requirement which is somewhat different from the registration system
suggested in the 2011 ANPRM. To assist investigators and institutions
in making a timely and accurate determination of exemption status the
NPRM at Sec. __.104(c) states that federal departments or agencies
will develop one or more exemption determination tools. Federal
departments or agencies may create their own tool, or rely on a tool
created by another department or agency (including the web-based tool
created by HHS). The tool, which has not yet been developed, will be
designed in such a way that if the person using the tool inputs
accurate information about the study, the tool will produce an outcome
which is the determination as to whether the study is exempt or not.
Institutions may rely on use of the federally developed tool by
investigators as a ``safe harbor'' for this determination: So long as
the information that was provided to the tool was accurate, result of
the application of the tool will be presumed by the federal departments
or agencies to be an appropriate determination of exempt status. Use of
the tool will be voluntary; each institution and agency would determine
whether to rely on the decision tool for their determinations, and if
so, who would be allowed to operate it. Institutions, if they so
choose, could continue to have such determinations made by an
individual who is knowledgeable about the exemption categories and who
has access to sufficient information to make an informed and reasonable
determination. In general, it is expected that investigators would not
be allowed to make exemption determinations for themselves without the
use of the decision tool, due to considerations of a conflict of
interest. It should also be noted that for FDA-regulated device studies
IRB review is required by statute.
The NPRM also proposes that the institution or IRB be required to
maintain records of exemption determinations, which records must
include, at a minimum, the name of the research study, the name of the
investigator, and the exemption category applied to the research study.
Maintenance of the output of the completed decision tool would fulfill
this recordkeeping requirement.
In general, commenters to the 2011 ANPRM were not necessarily
opposed to the concept of registration but sought further information
on what this process would entail. Public commenters also expressed
concerns about allowing an investigator to independently make the
determination that his or her research is exempt. Other commenters
suggested that this practice would be acceptable for some
investigators, whose research is well known to IRB members, and is
clearly within an exempt category. The ANPRM noted concerns that some
exempt research was unnecessarily delayed by requirements of some
institutions to review the research to make an exemption decision.
Several institutions reported that they already as a matter of
policy require investigators to submit exempt studies to the IRB, not
necessarily for full board review, but to ensure that the exempt
determination is valid. These decisions typically are made by the IRB
administrator and never involve full review unless there is concern
about the exemption status. Thus, they felt the registration
requirement was unnecessary and would add new administrative burdens
for research already considered low-risk.
Other commenters, such as investigators conducting research
currently considered exempt, were strongly opposed to a registration
requirement because it would add a new burden to conducting less than
minimal risk and exempt research. In addition, commenters raised
concerns about the administrative burden and need for a retrospective
audit system of registered research.
This NPRM proposal is anticipated to provide more flexibility than
the registration requirement originally proposed, while helping to
ensure that correct determinations of exempt status are made. The
existence of a ``safe harbor'' mechanism will hopefully encourage
institutions to create policies that allow investigators to use the
tool, and thus to be able to more quickly commence their research
without needing additional administrative or IRB reviews for these
types of studies. Other people at the institution who have access to
accurate information about a proposed study may also utilize the tool,
which will also allow research to go forward unimpeded.
In addition, it is proposed that a change to Sec. __.109(a) be
made to clarify that the Common Rule does not give IRBs the authority
to review or approve, require modification in or disapprove research
that qualifies for exemption under Sec. __.104(d), (e), or (f)(2).
There is no auditing requirement in this NPRM proposal.
Consequently, it does not address concerns raised at the ANPRM stage
regarding potential conflict of interest if the investigator is
providing the information to operate the decision tool. Public comment
is sought on this idea regarding the operational details for further
development of this proposal. Depending upon the comments received on
this proposal, additional operational details regarding the proposed
federally sponsored decision tool would be developed and subject to
public comment. It should also be noted that the lack of an auditing
requirement would not prohibit an institution from performing post-
approval monitoring of exemption determinations according to the
institution's standard operating procedure.
v. Questions for Public Comment
27. Public comment is sought regarding how likely it would be that
institutions would allow an investigator to independently make an
exempt determination for his or her own research without additional
review by an individual who is not involved in the research and
immersed in human research protection e.g., a member of the IRB Staff.
28. Public comment is sought regarding whether an investigator
would be able to contrive his or her responses to the automated
exemption decision tool in order to receive a desired result i.e., an
exempt determination, even if it does not accurately reflect the
research activities.
29. Public comment is sought on whether it would be more
appropriate for some of the exempt categories than others to rely on
the exemption determination produced by the decision tool where
investigators themselves input the data into the tool, or whether there
should be further administrative review in such circumstances.
30. Public comment is sought regarding whether relying on the
exemption determination produced by the decision tool where
investigators themselves input the data into the tool
[[Page 53957]]
as proposed would reduce public trust in research.
31. Public comment is sought regarding how likely it would be that
institutions would rely on such a decision tool to provide a safe
harbor for an investigator making a determination that the proposed
research qualifies for an exemption, or whether developing such a tool
would not be worthwhile, and whether institutions would be able to
adequately manage exemption determinations without the use of the
decision tool.
32. Public comment is sought regarding what additional information
should be required to be kept as a record other than the information
submitted into the decision tool, for example, a study abstract, the
privacy safeguards to be employed, or any notice or consent document
that will be provided.
33. Public comment is sought regarding the value of adding an
auditing requirement.
b. Exemptions Subject to the Documentation Requirements of Sec.
__.104(c) and No Other Section of the Proposed Rule
Four exemptions are proposed that will not be subject to any
additional requirements apart from the need to keep a record of the
determination that the study was exempt. Three of these four exemptions
in proposed Sec. __.104(d) are versions of exemptions found in the
current rule. A revised version of exemption category 1 in the current
Common Rule (research conducted in established or commonly accepted
educational settings) is found at proposed Sec. __.104(d)(1) in the
NPRM. A revised version of the current exemption category 5 (research
and demonstration projects) is found at proposed Sec. __.104(d)(2).
Exemption category 6 in the current Common Rule (taste and food quality
evaluations) is found in the NPRM at Sec. __.104(d)(4), and is
unchanged.
i. Research Conducted in Established or Commonly Accepted Educational
Settings (NPRM at Sec. __.104(d)(1); Current Rule at Sec.
__.101(b)(1))
(1) NPRM Goal
The goal is to retain an exemption for a considerable portion of
education research, but to provide for review if the research might
adversely affect students' opportunity to learn required educational
content, or the assessment of educators.
(2) Current Rule
The current exemption category 1 (Sec. __.101(b)(1) in the current
Rule) is for research conducted in established or commonly accepted
educational settings, involving normal educational practices, such as
(i) research on regular and special education instructional strategies,
or (ii) research on the effectiveness of or the comparison among
instructional techniques, curricula, or classroom management methods.
(3) NPRM Proposal
The first exemption category is for research conducted in
established or commonly accepted educational settings when it
specifically involves normal educational practices. This includes most
research on regular and special education instructional strategies, and
research on the effectiveness of, or the comparison among,
instructional techniques, curricula, or classroom management methods,
so long as the research is not likely to adversely impact students'
opportunity to learn required educational content in that educational
setting or the assessment of educators who provide instruction.
This exemption category is a revised version of the first exemption
category in the current Common Rule. The rationale for the revision is
that there are concerns about whether the conduct of some research
projects of this type might draw sufficient time and attention away
from the delivery of the regular educational curriculum, and thereby
have a detrimental effect on student achievement. The current education
system places a strong emphasis on student performance on tests in core
curriculum areas such as reading, science, and mathematics, which have
a significant effect on such things as grade promotion and student
assignment to different courses, and cumulatively influence student
attainment and achievement. It could also have a negative effect on
teachers being evaluated on the basis of student performance. The
exemption category is designed to not include such research projects.
Otherwise, the exemption is retained in order to allow for the conduct
of education research that may contribute to the important public good
of improving education, consistent with the principle of beneficence.
(4) Questions for Public Comment
34. Public comment is sought on whether this exemption category
should only apply to research activities in which notice that the
information collected will be used for research purposes is given to
prospective subjects or their legally authorized representatives as a
regulatory requirement, when not already required under the Privacy Act
of 1974. If so, comment is sought on what kind of information should be
included in the notice, such as the research purpose, privacy
safeguards, contact information, etc. Comment is also sought on how
such a notice should be delivered, e.g., publication in a newspaper or
posting in a public place such as the school where the research is
taking place, or by individual email or postal delivery. Note that
other requirements, such as those of the Family Educational Rights and
Privacy Act (FERPA) or the Protection of Pupil Rights Amendment, may
also apply. Would requiring notice as a condition of this exempt
research strike a good balance between autonomy and beneficence?
35. Public comment is sought on whether the privacy safeguards of
Sec. __.105 should apply to the research included in Sec.
__.104(d)(1), given that such research may involve risk of disclosure
of identifiable private information.
ii. Research and Demonstration Projects Conducted or Supported by a
Federal Department or Agency (NPRM at Sec. __.104(d)(2); Current Rule
at Sec. __.101(b)(5))
(1) NPRM Goal
The NPRM exemption proposed at Sec. __.104(d)(2) is for research
and demonstration projects involving public benefit or service
programs, and is a slightly revised version of exemption 5 in the
current Common Rule.
The proposed regulatory revision and change in interpretation of
the exemption is designed to clarify the scope of the exemption so that
more research studies would be exempt. It is believed that these
changes would make the exemptions easier to apply. It is also designed
to allow the Federal Government to carry out important evaluations of
its public benefit and service programs to ensure that those programs
are cost effective and deliver social goods, consistent with the
principle of beneficence.
(2) Current Rule
The current version of this exemption category was originally
created based on the recognition that alternative processes are in
place in which ethical issues raised by research in public benefit or
service programs are be addressed by the officials who are familiar
with the programs and responsible for their successful operation under
state and federal laws. These alternative processes implicitly consider
risk, but there is not a predefined scope for the likelihood or
[[Page 53958]]
magnitude of risk in these research activities. In fact, the Secretary
of HHS noted in 1983 that these demonstration and service projects are
already subject to procedures which provide for extensive review by
high level officials in various program administration offices. The
Secretary further noted that review by an IRB would be duplicative and
burdensome to state and local agencies and to other entities
participating in demonstration projects. It was thought that removal of
this unnecessary layer of review would not only reduce the cost of the
projects but also help avoid unnecessary delays in project
implementation.\49\
---------------------------------------------------------------------------
\49\ 48 FR 9266 (Mar. 4, 1983).
---------------------------------------------------------------------------
OHRP has interpreted the current exemption category 5 (Sec.
__.101(b)(5) in the current Common Rule) to apply only to those
research and demonstration projects designed to study a ``public
benefit or service program'' that a Common Rule department or agency
itself administers, and for which the public benefit or service program
exists independent of any research initiative. As an example, OHRP has
in the past said that a research study to evaluate a Centers for
Medicare & Medicaid Services (CMS)-administered demonstration project
comparing two different mechanisms for reimbursing providers under
Medicare or Medicaid would meet this exemption. However, this exemption
would not apply to some types of research, for example, the evaluation
of clinical trials (e.g., a National of Institutes of Health-funded
clinical trial comparing two treatment regimens for heart disease),
even if such studies would inform Medicare reimbursement policies.
(3) ANPRM Discussion
The ANPRM asked several questions about the interpretation and
applicability of current exemption category 5 (current Common Rule at
Sec. __.101(b)(5)), including the scope of the current interpretation
of the category 5 exemption. The ANPRM also asked if the current
category 5 guidance entitled, ``OPRR Guidance on 45 CFR 46.101(b)(5),''
\50\ should be revised, or if additional guidance on the interpretation
of exemption category 5 is needed.
---------------------------------------------------------------------------
\50\ See 48 FR 9266-9270 (Mar 4, 1983). (OPRR Guidance on 45 CFR
46.101(b)(5), Exemption for Research and Demonstration Projects on
Public Benefit and Service Programs, http://www.hhs.gov/ohrp/policy/exmpt-pb.html).
---------------------------------------------------------------------------
More specifically, the ANPRM asked whether this exemption should be
revised to assure that it is not misinterpreted or misapplied, whether
broadening it would result in inappropriately increasing risks to
subjects, how such risks might be mitigated, and whether OHRP guidance
should be revised.
(4) NPRM Proposal
The second proposed exemption category (NPRM at Sec. __.104(d)(2))
is for research and demonstration projects that are conducted or
supported by a Federal department or agency, or otherwise subject to
the approval of department or agency heads, and that are designed to
study, evaluate, or otherwise examine public benefit or service
programs, including procedures for obtaining benefits or services under
those programs, possible changes in or alternatives to those programs
or procedures, or possible changes in methods or levels of payment for
benefits or services under those programs.
It is proposed that each federal department or agency conducting or
supporting the research and demonstration projects would be required to
establish, on a publicly accessible federal Web site or in such other
manner as the department or agency head may prescribe, a list of the
research and demonstration projects that the Federal department or
agency conducts or supports under this provision. The research or
demonstration project would be required to be published on this list
prior to or upon commencement of the research. Agencies and departments
would be able to create or use their own Web sites for this purpose, or
use a Web site created by OHRP. Note that for studies exempted pursuant
to Sec. __.104(d)(2), the recordkeeping requirement at proposed Sec.
__.104(c) would be deemed to be satisfied by the published list
required under proposed Sec. __.104(d)(2)(i).
There were few responses to the questions posed on this exemption
in the 2011 ANPRM. However, those that did comment noted that this
category is often misunderstood by IRBs and, at best, would benefit
from clearer guidance. Commenters said that examples would help
investigators and IRBs understand when research activities included in
demonstration projects constitute human subjects research subject to
the Common Rule. Commenters noted that many activities in demonstration
projects do not contribute to generalizable knowledge as they produce
results that are relevant only to the program being assessed; as such,
many of these activities do not meet the Common Rule's regulatory
definition of ``research'' and thus fall outside of the rule. Other
commenters said that some activities in this category are mandated or
required by law or regulation and should not be considered to be under
the purview of the Common Rule. It was noted that the critical issue in
these studies should be protecting privacy and as long as measures are
in place to do so, additional protections are not required.
The revision of the language in this exemption clarifies the
original language to say that a federally conducted project examining
any aspect of a public benefit or service program would qualify for the
exemption. The clauses concerning procedures for obtaining benefits,
other changes in programs and procedures, and changes in methods or
levels of payment are merely examples of such projects, and are not
considered to be all-inclusive.
In addition, OHRP proposes to clarify its interpretation of public
benefit and service programs which are being evaluated as part of the
research to include public benefit or service programs that a Common
Rule department or agency does not itself administer through its own
employees or agents, but rather funds (i.e., supports) through a grant
or contract program. Therefore, the exemption would be clarified to
apply to research and demonstration projects supported through federal
grants or cooperative agreements, for example. These activities include
appropriate privacy, confidentiality and security safeguards for any
biospecimen and information used in this research. For example,
information collected in some demonstration projects are subject to the
protections of the HIPAA rules, and Federal agencies include conditions
in grants or cooperative agreements which require the recipient to
protect the confidentiality of all project-related information that
includes personally identifying information.
It is believed that these changes would make the exemptions easier
to apply. It is also designed to allow the Federal Government to carry
out important evaluations of its public benefit and service programs to
ensure that those programs are cost effective and deliver social goods.
The proposed changes to this exemption would require OHRP to revise its
existing guidance document on this exemption accordingly.
These changes would bring the language into conformance with other
provisions of the rule that refer to research ``conducted or
supported'' by Federal agencies. Both current practice and the edited
language cover such
[[Page 53959]]
research, whether it is conducted directly by federal staff or through
a contract, cooperative agreement, or grant. These methods of
administration are, of course, always subject to department or agency
head approval, directly or by delegation. In addition, some of these
research and demonstration projects are conducted through waivers,
interagency agreements, or other methods that also require agency head
approval. Accordingly, both the previous and the revised language allow
for the full panoply of methods by which research and demonstration
projects on public benefit or service programs can be carried out.
Although research such as that described above is exempt, an
additional requirement is proposed. In the interest of transparency,
each Federal department or agency conducting or supporting the research
and demonstration projects must establish, on a publicly accessible
federal Web site or in such other manner as the Secretary may
prescribe, a list of the research and demonstration projects which the
federal department or agency conducts or supports under this provision.
The research or demonstration project must be published on this list
prior to or upon commencement of the research. The agency determines
what will be included on this list and maintains its oversight.
Agencies that already publish research and demonstration projects on a
publicly accessible Web site could satisfy this proposed requirement if
the existing Web site were to include a statement indicating which of
the studies were determined to meet this exemption. The goal of this
proposed requirement is to promote transparency of federally conducted
or supported activities affecting the public that are not subject to
oversight under the Common Rule. It should not create any delay to the
research. HHS will develop a resource that all Common Rule agencies may
use to satisfy the requirement at proposed Sec. __.104(d)(2)(i).
Alternatively, an agency can make its own Web site.
Currently, there is no such comprehensive listing of studies that
have been determined to have met this exemption, so this requirement
would also enable Common Rule departments and agencies to better assess
the types of projects that use this exemption, and consider whether any
changes to its scope would be appropriate.
(5) Questions for Public Comment
36. Public comment is sought on whether this exemption category
should only apply to research activities in which notice is given to
prospective subjects or their legally authorized representatives as a
regulatory requirement. If so, comment is sought on what kind of
information should be included in the notice, e.g., the research
purpose, privacy safeguards, or contact information. Also comment on
how such a notice should be delivered; e.g., publication in a newspaper
or posting in a public place, or by individual email or postal
delivery. Would requiring notice as a condition of this exempt research
strike a good balance between autonomy and beneficence? In many cases,
it may be that individual notice or consent to all potentially affected
persons before the research or demonstration commences is ordinarily
impossible in the conduct of such studies. For example, if a research
or demonstration project will affect all inhabitants of a large
geographic area (e.g., a housing, a police patrol, a traffic control,
or emergency response experiment), or all clients or employees of a
particular program or organization or setting will be subject to a new
procedure being tested (e.g. a new approach to improving student
performance, a new anti-smoking or anti-obesity program, a new method
for evaluating employee performance), would it be possible to make
participation voluntary for all affected individuals, or even to
identify and inform all affected individuals in advance?
37. Public comment is sought on whether this exemption category is
appropriate based on the recognition that alternative processes are in
place in which ethical issues raised by research in public benefit or
service programs would be addressed by the officials who are familiar
with the programs and responsible for their successful operation under
state and federal laws, rather than meeting specific risk-based
criteria, or whether risk limitations should be included, and if so,
what those limitations should be. Though long-standing, this exemption
has never identified specific risk-based criteria, or risk limitations
to bound the type of projects that may be covered. When originally
promulgated, the exemption did stipulate that following the review of
such projects, if the Secretary determines that the research or
demonstration project presents a danger to the physical, mental, or
emotional well-being of a participant or subject, then written informed
consent would be required. Public comment is sought on whether to limit
the risk that can be imposed on subjects while using this exemption,
and if so, how to characterize those limits in a clear fashion. If more
than minimal risk interventions are included, public comment is sought
on whether, for transparency, this should be made clear in the
regulatory text.
With regard to the issue of risks encountered by participants in
such research or demonstration projects, comments are also sought
regarding the argument that any and every demonstration project
involving changes in public benefit or service programs (e.g., water or
sewage treatment programs or pollution control programs, programs
involving educational procedures, or programs involving emergency
procedures related to extreme weather events, etc.) exposes those
affected to possible risks of some kind. In this regard, those risks
are ordinarily and perhaps always no different in kind or magnitude
than those involved in simply making the change in procedures without
using research tools to evaluate them. For example, health care
providers could be required to perform certain sanitation reforms to
prevent patient infections whether or not such reforms were first
tested in practice through a research or demonstration project. It is
common for all Federal departments and agencies that regulate private
or public organizations to impose conditions of participation in public
programs providing for safety, program integrity, financial reporting,
etc. Public comment is sought regarding whether there should be
conditions (e.g., an individual notice or consent requirement) imposed
on such research or demonstration projects involving public benefit or
service programs which might lead to significant impediments or
limitations on testing and evaluation before or after being imposed
program-wide. Would the effect of imposing expensive or impracticable
conditions on public benefits or services evaluations be to reduce the
number of such evaluations and consequently to expose program
participants to increased risk through exposure to untested reforms?
38. Public comment is sought on whether the existing privacy
safeguards for such activities, including the Privacy Act, HIPAA rules,
and other federal or state privacy safeguards provide sufficient
independent controls, or whether other safeguards such as the privacy
safeguards of Sec. __.105 should be applied.
[[Page 53960]]
iii. Research involving benign interventions in conjunction with the
collection of data from an adult subject (NPRM at Sec. __.104(d)(3))
(1) NPRM Goal
The goal of this proposed new exemption for studies that involve
benign interventions is to eliminate IRB review of these low-risk
studies to reduce time and effort, allow IRBs to focus more attention
on research with higher risks or presenting other ethical challenges,
and to enable this research to go forward.
(2) Current Rule
Currently, research studies in the social and behavioral sciences
that do not qualify for exemption category 2 (current Common Rule at
Sec. __.101(b)(2)), but that involve certain types of well-understood
interactions with subjects (e.g., asking someone to watch a video and
then conducting word association tests), require either convened board
or expedited IRB review.
(3) ANPRM Discussion
The ANPRM considered whether to include on the list of exempt
studies certain types of social and behavioral research conducted with
competent adults that would involve specified types of benign
interventions commonly used in social and behavioral research, that are
known to involve virtually no risk to subjects, and for which prior
review does little to increase protections to subjects. These would be
methodologies that are familiar to people in everyday life and in which
verbal or similar responses would constitute the research data being
collected. The ANPRM asked whether this category should include
research in which there is deception.
(4) NPRM Proposal
The proposed exemption at Sec. __.104(d)(3) is new and includes
research involving benign interventions in conjunction with the
collection of data from an adult subject through verbal or written
responses (including data entry) or video recording if the subject
prospectively agrees to the intervention and data collection and at
least one of the following is met:
The information obtained is recorded in such a manner that
human subjects cannot be identified directly or through identifiers
linked to the subjects; or
Any disclosure of the human subjects' responses outside
the research would not reasonably place the subjects at risk of
criminal or civil liability or be damaging to the subjects' financial
standing, employability, educational advancement, or reputation.
For the purpose of this proposed provision, benign interventions
would be brief in duration, harmless, painless, not physically
invasive, not likely to have a significant adverse lasting impact on
the subjects, and it would be required that the investigator has no
reason to think the subjects will find the interventions offensive or
embarrassing. If these criteria were met, such benign interventions
might include research activities in which a subject is asked to read
materials, review pictures or videos, play online games, solve puzzles,
or perform cognitive tasks. If the research involves deceiving the
subjects regarding the nature or purposes of the research, this
exemption would not be applicable unless the subject authorizes the
deception. For the purpose of this proposed provision, authorized
deception would be prospective agreement by the subject to participate
in research where the subject is informed that he or she will be
unaware of or misled regarding the nature or purposes of the research.
Many commenters to the 2011 ANPRM supported adding another
exemption category of research for certain types of social and
behavioral activities, conducted with competent adults, that would
involve specified types of benign interventions beyond educational
tests, surveys, focus groups, interviews, and similar procedures that
are commonly used in social and behavioral research, that are known to
involve virtually no risk to subjects, and for which IRB review does
little to increase protections for subjects. However, many commenters
were opposed to the requirement that subjects be ``competent adults''
in order for the expanded exemption to apply, asking whether tests of
competency would be required for such research to proceed.
This new exemption category addresses research involving benign
interventions, in which information is collected through verbal or
written responses and recorded in a manner such that human subjects
cannot be identified, or where the disclosure of responses would not
place the subjects at risk of criminal or civil liability or be
damaging to the subjects' financial standing, employability,
educational advancement, or reputation. Here, a ``benign intervention''
is categorized as one that is temporary and painless, producing no
lasting negative impacts. Examples of benign interventions might
include research activities in which a subject is asked to read
materials, review pictures or videos, play online games, solve puzzles,
or perform cognitive tasks, so long as the interventions meet the
requirements for this category.
The NPRM proposes to allow this type of research to occur without
the requirements of informed consent or data security protections
because neither the intervention nor the identifiability of the
information is likely to result in harm to the subject, and the subject
must prospectively agree to the intervention and the data collection.
This exemption would include some research using authorized deception,
where there is a prospective agreement by the research subject to
participate in the activity after being informed that he or she will be
unaware or misled regarding the nature of the research (Sec.
__.104(d)(3)(iii)-(iv)). Subjects must be adults, but the provision
does not specify that they must be competent, and so tests of
competency are not necessary; however, the presumption is that in
keeping with the principle of respect for persons, these subjects will
not be taken advantage of. This new exemption category is being added
because respect for persons is accomplished through the prospective
subject's prospective agreement or authorization, the research
activities pose little risk to subjects, and the use of this exemption
for many social or behavioral studies will enable IRBs to devote more
time and attention to research studies involving greater risks or
ethical challenges.
(5) Questions for Public Comment
39. Public comment is sought on whether this exemption category
should only apply to research activities in which notice is given to
prospective subjects or their legally authorized representatives as a
regulatory requirement. If so, comment is sought on what kind of
information should be included in the notice, such as the research
purpose (if authorized deception is not utilized), privacy safeguards,
contact information, etc. Would requiring notice as a condition of this
exempt research strike a good balance between autonomy and beneficence?
40. Public comment is sought regarding what improvements could be
made to the language describing the type of interventions in this
exemption category so as to make clear what interventions would or
would not satisfy this exemption category.
41. Public comment is sought on whether it is reasonable, for
purposes of this exemption, to rely on the exemption determination
produced by the decision tool where investigators
[[Page 53961]]
themselves input the data into the tool, or whether there should be
further administrative review in such circumstances.
iv. Taste and Food Quality Evaluation and Consumer Acceptance Studies
(NPRM at Sec. __.104(d)(4); current Rule at Sec. __.101(b)(6))
The exemption proposed in Sec. __.104(d)(4) is found in the
current Common Rule at Sec. __.101(b)(6). This exemption is for taste
and food quality evaluation and consumer acceptance studies if
wholesome foods without additives are consumed, or if a food is
consumed that contains a food ingredient at or below the level and for
a use found to be safe, or agricultural chemical or environmental
contaminant at or below the level found to be safe, by FDA or approved
by the EPA or the Food Safety and Inspection Service of the U.S.
Department of Agriculture.
This exemption is retained unchanged from the current Common Rule.
The research activities included under this intervention are relatively
benign, no sensitive information is collected, and presumably subjects
are made aware of the nature of the activity before they participate,
and may exercise their autonomy in choosing whether or not to
participate. However, since the research activities involve physical
interventions with the subject, the rules relating to exemption
determinations and the record-keeping requirement for exempt activities
are appropriate.
(1) Question for Public Comment
42. Public comment is sought on whether this exemption category
should be narrowed to apply only to research activities in which notice
is given to prospective subjects or their legally authorized
representatives as a regulatory requirement. If so, comment is sought
on what kind of information should be included in the notice such as
the research purpose, privacy safeguards, contact information, etc.
Would requiring notice as a condition of this exempt research strike a
good balance between autonomy and beneficence? Should prospective
subjects be given the explicit opportunity to opt out of such research?
c. Exemptions Subject to the Documentation Requirements of Sec.
__.104(c) and the Privacy Safeguards Described in Sec. __.105
Two exemption categories are proposed which will be subject to the
documentation requirement and the new privacy safeguards. The first
exemption category is for certain research involving educational tests,
surveys, interviews, or observation of public behavior. The second
category is for secondary research use of identifiable private
information originally collected for non-research purposes where notice
was given.
One of the functions of IRB review when a study presents only
informational risks is to ensure the sufficiency of the investigator's
plan for protecting any identifiable private information that will be
collected, created, or used as part of the study. In keeping with one
of the goals of this NPRM and as discussed in section II.A.3 of this
preamble, to reduce burden associated with research that includes
sufficient protections to research subjects, this NPRM proposes to
eliminate the need for IRB review for studies involving the collection
of identifiable private information when collected through educational
tests (cognitive, diagnostic, aptitude, achievement), survey
procedures, interview procedures, or observation of public behavior
(including visual or auditory recording), or in studies involving only
the secondary analysis of identifiable private information originally
collected for non-research purposes when the proposed privacy
safeguards at Sec. __.105 are met. The newly proposed Sec. __.105
offers three avenues to meeting the data security and privacy
protection requirements, all three of which are posited to be at least
as protective as those usually that result from IRB review.
The investigator is required by law to comply with, or
voluntarily complies with, the HIPAA Rules;
The activity is conducted by federal departments and
agencies, and the activity is or will be maintained on information
technology that is subject to and in compliance with section 208(b) of
the E-Government Act of 2002, 44 U.S.C. 3501 note, if all of the
information collected, used, or generated as part of the activity will
be maintained in systems of records subject to the Privacy Act of 1974,
5 U.S.C. 552a, and the research will involve a collection of
information subject to the Paperwork Reduction Act of 1995, 44 U.S.C.
3501 et seq.; or
The investigator complies with the privacy safeguards
promulgated by the Secretary of HHS (which standards will be designed
so that they could be readily implemented by an individual
investigator, and would involve minimal cost and effort to implement).
It is believed that the protections afforded by the Paperwork
Reduction Act, section 208 of the E-Government Act, and the Privacy Act
in combination with each other are generally equivalent to the privacy
protections that result from IRB review. It is similarly believed that
the privacy protections afforded by HIPAA in the context of the studies
exempted under Sec. __.104(e) justify eliminating IRB review.
The proposed section 105 also includes limitations on the use,
release, and disclosure of the identifiable private information
collected or maintained for research subject to this Rule.
Although most if not all of these requirements are already in
effect for federal entities and HIPAA covered entities, they will
likely be new to some institutions and their investigators. The intent
is that Secretary would develop a list of ``reasonable and appropriate
safeguards'' that would be easily implemented by investigators. As
such, it is envisioned that the Secretary's privacy safeguards
described in proposed Sec. __.105 would be designed as a checklist
that could be easily monitored by investigators and IRB members alike.
In the case where IRB members have additional expertise, they may
choose to deviate from the Secretary's list. Acknowledging that it is
difficult for the public to fully comment on the implications of such a
checklist before it has been developed; the Rule includes a requirement
that the Secretary solicit public comment on the proposed minimum
safeguards.
i. Questions for Public Comment
43. Public comment is sought on the concept of requiring such
minimum safeguards and limitations on disclosure, as well as whether
the requirements of the proposed Sec. __.105 would constitute a
broadening of IRB responsibilities rather than a streamlining of the
implementation of responsibilities that many IRBs already adopted. If
an institution does view this as an inordinate broadening of
responsibilities, does the institution currently have in place
alternative mechanisms for ensuring data security and participant
privacy in a research context? Suggestions for alternative approaches
to meeting public expectation that federally sponsored research
safeguard their data and protect privacy are sought during this public
comment period.
44. Public comment is sought regarding whether the proposed Rule's
information security requirements for biological specimens and
identifiable private information are highly technical and require a
level of expertise not currently available to most IRBs. Do these
security requirements unrealistically expand IRB responsibilities
beyond current competencies?
[[Page 53962]]
ii. Research Involving Educational Tests, Surveys, Interviews, or
Observation of Public Behavior if the Information is Recorded with
Identifiers and even if the Information is Sensitive (NPRM at Sec.
__.104(e)(1))
(1) NPRM Goals
The goal of the proposed exemption at Sec. __.104(e)(1) is to
eliminate the need for IRB review of certain low-risk studies that
involve collecting information by means of educational tests, surveys,
interviews, or observation of public behavior. The intent is that this
change would reduce IRB and investigator time and effort in reviewing
and submitting protocols, and would allow IRBs to focus more attention
on research with higher risks or presenting other ethical challenges,
would respect autonomy, and would enable this research to go forward.
(2) Current Rule
The current Common Rule only allows these activities, involving the
recording of identifiable information about research subjects, to be
exempt if the disclosure of the identifiable information outside the
research could not reasonably place the subjects at risk of criminal or
civil liability or be damaging to the subjects' financial standing,
employability, or reputation.
(3) ANPRM Discussion
The ANPRM discussed criticisms of the current Common Rule that it
does not adequately calibrate the review process to the level of risk
of the research, particularly in social and behavioral research. It
also discussed whether answering questions should be sufficient
indication of willingness to participate in survey or interview
research. It distinguished between informational or psychological risks
and physical risks, and raised questions about how effectively IRB
review provides protections from informational or psychological risks.
Specifically, the ANPRM discussed expanding the current exemption
category 2 (current Rule at Sec. __.101(b)(2)) to include all studies
involving educational tests, surveys, interviews, and similar
procedures, so long as the subjects are competent adults, without any
further qualifications (but subject to the data security and
information protection standards).
(4) NPRM Proposal
The exemption proposed in Sec. __.104(e)(1) covers research, not
including interventions, involving the use of educational tests
(cognitive, diagnostic, aptitude, achievement), survey procedures,
interview procedures or observation of public behavior (including
visual or auditory recording), if the information obtained is recorded
in such a manner that human subjects can be identified directly or
through identifiers linked to the subjects. The research in this
category is exempt from most requirements of the NPRM, but
investigators must adhere to the privacy safeguards outlined in
proposed Sec. __.105. Note that the language used in this exemption is
very similar to that used in the current exemption 2, proposed
exclusion Sec. __.101(b)(2)(i), and the proposed exemption at Sec.
__.104(d)(3); unlike the language in those three places, however, the
proposed exemption at Sec. __.104(e)(1) would allow for research to be
exempt where sensitive identifiable private information is collected
the release of which could pose some measure of risk. However, the
exemption is subject to adherence to the proposed Sec. __.105 privacy
safeguards, which are designed to limit the chances that the release of
that information would lead to harm. This exemption category includes
research involving test development, and use of tests that have not
already been shown to be valid or reliable, inasmuch as such research
activity is desirable in order to determine the their validity and
reliability, and the exemption category provides safeguards to ensure
that results will not be used to evaluate student achievement. Note
that the activities that are currently exempted under exemption
category 2 (involving similar ways to collect information, but only
where either the identity of the subject is not recorded or disclosure
of the information would not have any adverse consequences to the
subject) would be moved under the NPRM to the proposed exclusion at
Sec. __.101(b)(2)(i), rather than being under an exemption. That
proposed exclusion is discussed in section II.A.2 of this preamble.
Note also that this proposed exemption would cover the research
activities under the exemption in the current Rule at Sec.
__.101(b)(3)(ii), such as the research activities funded subject to the
Department of Justice statute related to certificates of
confidentiality (42 U.S.C. 3789g) and the information collections
subject to the confidentiality provisions of the Education Sciences
Reform Act (20 U.S.C. 9573) of the Department of Education. Presumably
the safeguards provided by these statutes satisfy the privacy
safeguards of the proposed Sec. __.105.
Consistent with the spirit of the principle of respect for persons,
investigators should provide prospective subjects with sufficient
information to make an informed decision about participation. Public
comment is sought regarding whether some kind of notice must be given
as a regulatory requirement for this exemption, and if so, what kind of
information must be included in that notice.
The rationale for characterizing these activities as low-risk is
that prospective subjects can decline to participate or answer specific
questions in procedures they are already familiar with from the
experiences of daily life, and, importantly, that the information will
be protected through the new privacy safeguards of Sec. __.105. The
availability of this exemption is designed to reduce the volume of
information collection that IRBs process, thereby enabling them to
devote more time and attention to research studies which pose greater
risks or involve ethical challenges.
The underlying assumptions and rationale for this exemption mirror
the rationale for the exclusion proposed in Sec. __.101(b)(2)(i)(C).
Here again it is presumed that the subjects are sufficiently familiar
with survey and interview procedures and educational tests to be able
to knowingly and willingly provide the information, or decline to
participate. The rationale for this exemption category is that
prospective subjects can decline to participate or answer specific
questions in procedures they are already familiar with from the
experiences of daily life, and that the information collected will be
protected through the privacy safeguards of Sec. __.105.
However, there are situations in which these assumptions would not
always hold. For instance, administration of a questionnaire or
participation in a focus group on a sensitive topic may induce
significant stress in some individuals, or individuals approached about
taking a survey may feel compelled to participate. Whether and how this
exemption should be bounded so that the final rule archives a balance
among the principles of beneficence, autonomy, and justice is the
subject of a request for public comment on this proposed exemption. The
use of this exemption is designed to enable IRBs to devote more time
and attention to research studies which pose greater risks or involve
more challenging ethical concerns.
[[Page 53963]]
(5) Questions for Public Comment
45. Public comment is sought on whether the proposed exemption
regarding the use of educational tests, survey procedures, interview
procedures, or observation of public behavior (Sec. __.104(e)(1))
should be applied to research involving the use of educational tests
with children and whether it should also be applied to research
involving the use of survey or interview procedures with children. If
so, for research involving children, should the permissible survey or
interview topics be limited in some way?
46. Public comment is sought on whether this exemption category
should only apply to research activities in which notice is given to
prospective subjects or their legally authorized representatives as a
regulatory requirement. If so, comment is sought on what kind of
information should be included in the notice such as the research
purpose, privacy safeguards, contact information, etc. Would requiring
notice as a condition of this exempt research strike a good balance
between autonomy and beneficence? Should prospective subjects be given
the explicit opportunity to opt out of such research?
47. Public comment is sought on whether it is reasonable, for
purposes of this exemption, to rely on the exemption determinations
produced by the decision tool where investigators themselves input the
data into the tool, or whether there should be further administrative
review in such circumstances?
48. Public comment is sought on whether this exemption category
should be narrowed such that studies with the potential for
psychological risk are not included. Are there certain topic areas of
sensitive information that should not be covered by this exemption? If
so, please provide exemplary language to characterize such topic areas
in a manner that would provide clarity for implementing the Rule.
iii. Secondary Research Use of Identifiable Private Information (NPRM
at Sec. __.104(e)(2))
(1) NPRM Goal
The goal of the proposed new exemption category at Sec.
__.104(e)(2) is to facilitate secondary research using identifiable
private information that has been or will be collected or generated for
non-research purposes, when prior notice has been given and privacy
safeguards and prohibitions on re-use of the information are in place.
Technological developments and the creation of large databases have
significantly increased the potential benefits of secondary research
analyses. The proposed exemption category would eliminate the need for
IRB review of certain low-risk studies that only involve secondary use
of identifiable private information that was collected for non-research
purposes. The information would be protected under the privacy
safeguards of Sec. __.105, and respect for persons would be
demonstrated through a requirement for notice. The proposed exemption
is limited to the research use of the identifiable private information
for the purposes of the specific research for which the investigator or
recipient entity requested access to the information, not for any
further secondary research use. This proposed exemption is intended to
reduce IRB and investigator time and effort, and allow IRBs to focus
more attention on research with higher risks or presenting other
ethical challenges. The exemption would enable beneficial secondary
research to occur without being impeded by administrative or IRB
review, but with privacy safeguards to avoid harm and a notice
requirement to show respect for persons. Public comment is sought
regarding this proposal, including what limits in scope it should have,
what controls and protections should be attached above and beyond the
privacy safeguards of Sec. __.105, and how best to respect the
autonomy or other interests of the individuals who are the subjects of
the information.
(2) Current Rule
Under the current Common Rule, secondary research studies using
identifiable private information undergo IRB review and approval, often
using the expedited review procedure. If the activity satisfies the
relevant criteria, the IRB may waive the requirement for informed
consent, which IRBs typically do.
(3) ANPRM Discussion
The ANPRM proposed that with regard to an investigator's use of
pre-existing data (i.e., data that were previously collected for
purposes other than the currently proposed research study) originally
collected for non-research purposes, then, as is currently the rule,
written consent or waiver of consent would only be required if the
investigator obtains information that identifies the subjects. Under
the ANPRM, there would accordingly have been no change in the current
ability of investigators to conduct such research using de-identified
data or a limited data set, as such terms are used in the HIPAA Rules,
without obtaining consent.
Second, the ANPRM proposed that if the data were originally
collected for research purposes, then consent would be required
regardless of whether the investigator obtains identifiers. This would
have been a change with regard to the current interpretation of the
Common Rule in the case where the investigator does not obtain any
identifiers. That is, the allowable current practice of telling the
subjects, during the initial research consent, that the information
they are providing will be used for one purpose, and then after
stripping identifiers, allowing it to be used for a new purpose to
which the subjects never consented, would not have been allowed.
(4) NPRM Proposal
The NPRM proposal here is for a new exemption covering the
secondary research use of identifiable private information that has
been or will be acquired for non-research purposes, if the following
are met:
Prior notice has been given to the individuals to whom the
identifiable private information pertains that such information may be
used in research;
The privacy safeguards of Sec. __.105 are required; and
The identifiable private information is used only for
purposes of the specific research for which the investigator or
recipient entity requested access to the information.
Under the current system, IRBs frequently waive consent for
research involving the secondary use of identifiable private
information, particularly when the data sets are large or drawn from
multiple institutions. In such circumstances, IRBs often impose privacy
and data security protection requirements. However, since this proposed
exemption category requires that the privacy safeguards at Sec. __.105
are in place, requiring these studies to undergo IRB review will
provide little or no additional protections to subjects, while
continuing to generate potentially substantial burdens on investigators
and IRBs and diverting IRB resources away from research that may
involve more serious ethical challenges.
Under this proposed exemption there will be greater protections for
these research subjects than is currently the case. The new privacy
safeguards of Sec. __.105 would be applied to this research, and would
be the same safeguards that would be used for many other types of
research under the NPRM. In addition, the scope of the exemption is
limited to the specific research for
[[Page 53964]]
which the investigator or recipient entity requested access to the
information, so the otherwise permissible uses, releases and
disclosures under Sec. __.105(c) would not apply to research covered
by this exemption. Respect for persons would be given more weight
insofar as the subjects would now receive notice that research might
take place, which is currently not required.
Further, in many cases, other laws such as HIPAA also provide
protections in the research context for the information that would be
subject to this proposed exemption (e.g., clinical records), such that
additional Common Rule requirements for consent may not be necessary in
those contexts. Under HIPAA, these protections include, where
appropriate, requirements to obtain the individual's authorization for
future, secondary research uses of protected health information, or
waiver of that authorization by an IRB or HIPAA Privacy Board. This
proposal does not disturb those laws.
The NPRM proposal limits the use of this exemption to cases in
which individuals have been informed that the information may be used
in research with the goal of ensuring that research under this
exemption exhibits respect for persons. In particular, by ensuring that
subjects are notified that their information may be used for research,
this notice requirement may enhance subject autonomy.
Alternative scopes for this provision are also proposed for
consideration. A narrower scope could be envisioned that would limit
the exemption to data generated by the Federal Government for which a
privacy impact assessment has been conducted pursuant to section 208(b)
of the E-Government Act of 2002, 44 U.S.C. 3601 et seq., that fully
describes the ways that the information will be accessed, used,
maintained, disseminated, and protected, and there is a formal written
agreement between the investigator and the federal agency that requires
the investigator to apply the same practices and safeguards as those
addressed in the privacy impact assessment. Such a narrower
interpretation might be easier to implement, and the line between Sec.
__.104(e)(2) and (f)(2) would be clearer.
Alternatively, it could be broadened to allow additional research
uses of the information beyond the specific research for which the
investigator or recipient entity obtained the information.
The proposed exemption category could also be revised to change the
manner in which respect for persons would be demonstrated by requiring
that individuals have been given the opportunity to opt out of any
secondary research with their identifiable private information. This
would mean that subjects could exercise their autonomy to choose not to
allow their information to be used, although this would not meet the
even higher standard of fully informed active consent. Under this
alternative, which would give prospective subjects the opportunity to
opt out, it could be argued that the balance would be struck even more
in favor of respect for persons by limiting the exemption to research
where more than prior notice was required. This would restrict the
exemption to research where an even greater measure of respect for
persons had occurred, that is, that the individuals had been given the
right to decline to participate in research, rather than simply being
notified that such research was going to take place. Public comment is
sought regarding this alternative approach as well.
Finally, it also should be noted that section 511 of the Medicare
Access and CHIP Reauthorization Act of 2015 requires the Secretary to
issue a clarification or modification with respect to the application
of these regulations to certain activities involving clinical data
registries. This exemption category might allow certain research
activities of these clinical data registries not otherwise covered by
the proposed HIPAA-related exclusion at Sec. __.101(b)(2)(iv) (i.e.,
when the clinical data registries are not part of a HIPAA covered
entity or acting as a business associate), such as when a clinical data
registry may receive information from a health care entity for research
purposes.
(5) Questions for Public Comment
49. Public comment is sought on the types of research that should
fall under the proposed exemption. Should the proposed exemption be
available to all types of research using identifiable data collected
for non-research purposes or should the exemption be available only to
a more limited subset of research? For example, should the proposed
exemption apply only for research using records and information already
subject to comprehensive privacy and other protections in other Federal
laws (e.g., records held by the Federal Government subject to the
Federal Privacy Act, or records governed by HIPAA or FERPA)?
Depending upon the scope of the exemption, the relationship between
this exemption and the exemption proposed at Sec. __.104(f)(2) would
need to be clarified. Since a major justification for including this
exemption is to reduce burden on IRBs, should the proposed exemption
apply only to research for which IRBs typically waive informed consent,
that is, where the research could not practicably be carried out
without a waiver of informed consent, and the rights and welfare of
subjects will not be adversely affected by the waiver? Finally, is
there a sufficient need for this exemption at all given the other
proposed exclusions and exemptions?
50. Public comment is sought regarding whether the proposed
exemption should be limited to research in which individuals had been
informed of the potential future research use of their information, and
given the opportunity to opt out of having their identifiable private
information used for research. If the proposed exemption should be
limited in this way, what information should be included in the
opportunity to opt out? If the opportunity to opt out is made a
condition of the exemption category how should it be structured (e.g.,
how long and under what circumstances should it remain in effect) and
what, if any, impact should the opt out have on other provisions of the
rule, such as the ability of an IRB to waive informed consent for a
subsequent research study using the individual's information? Are there
other or alternative mechanisms that should be required to respect
individuals' autonomy and other interests?
51. Public comment is sought regarding what should constitute
notice for purposes of this exemption category. Given the many
different types of data that would be covered by this provision (e.g.,
data from private entities used for social or behavioral science
research, government records for which laws already establish standards
for notice, and data publicly available for harvesting from the
internet), would it be possible to develop a uniform ``notice''
requirement? What type of notice, in terms of its dissemination and
scope, should be considered to meet this requirement of the proposed
exemption? With regard to the dissemination of the notice, should the
notice requirement be permitted to be fulfilled through a general
public notice, not specifically directed to individuals who are
potential research subjects, such as the notice allowable under the
Privacy Act? Would a prominent notice posted in all clinics or other
relevant public places where information will be collected be
acceptable? Should each individual whose data could be used receive
their own notice, such as is required of direct treatment providers
covered by the
[[Page 53965]]
HIPAA Privacy Rule? With regard to the content of the notice required
by this proposed exemption, what kind of information should be included
in the notice, such as the types of research that might be conducted,
privacy safeguards, contact information, etc.?
52. Public comment is sought on whether, on the other hand, prior
notice is necessary. Is the notice requirement proposed for this
exemption a meaningful and important measure to respect individual
autonomy, particularly if the notice requirement could be fulfilled
through a general public posting? Current practices suggest that IRBs
will frequently waive informed consent for studies involving the
secondary use of identifiable private information collected for non-
research purposes. If the exemption were to exclude the notice
requirement, but continue to require application of the data security
and privacy safeguards of Sec. __.105 and restrict the use of
identifiable private information to only purposes of the specific
research for which the investigator obtained the information, would the
exemption better strike a reasonable balance between respect for
persons and beneficence, while eliminating the current requirement for
IRB review?
53. Public comment is sought as to whether this exemption would
provide appropriate protections for research conducted by clinical data
registries, while enabling these research activities to proceed without
delay, and what should be included in guidance regarding such
activities. Public comment is sought regarding the extent to which
other exclusions or exemption categories would apply to research
conducted by clinical data registries, such that the conditions of this
exemption category would not apply.
d. Exemptions Subject to the Documentation Requirements of Sec.
__.104(c), the Privacy Safeguards Described in Sec. __.105, Limited
IRB Review as Described in Sec. __.111(a)(9), and Broad Consent in
Accordance With Sec. __.116(c)
i. NPRM Goals
The goal of this proposed rule is to enable the conduct of research
in the rapidly growing area of research involving biospecimens,
especially genetic analyses, while recognizing the autonomy interests
of people to decide whether or not to participate in this area of
research. Some people have a particular interest in whether research
will be carried out with their biospecimens, and want to exercise some
control over their biospecimens. At the same time, biospecimen
repositories are being created to enable innumerable research studies
in the future, and the pace of technology development is such that the
specific research studies to be carried out with those biospecimens is
unknown at the time the biospecimens are collected.
ii. Current Rule
The current Rule requires IRB review and approval of research
involving identifiable private information, including individually
identifiable biospecimens. IRB waiver of informed consent is allowable
under the Common Rule, if the research study satisfies the criteria for
waiver of informed consent. The current Rule also allows for research
without consent when a biospecimen is used for research under
conditions where the investigator does not possess information that
would allow him or her to identify the person whose biospecimen is
being studied.
iii. ANPRM Discussion
The ANPRM considered requiring written general consent for
secondary research use of biospecimens originally collected in research
or non-research settings regardless of whether they include
identifiers. The ANPRM proposed an excused or exempt category for
research involving the secondary use of biospecimens originally
collected for either research or non-research purposes if there was
written broad consent for the research use of the biospecimens,
typically obtained at the time of the original collection. The ANPRM
also considered whether the broad consent should include check-off
boxes allowing subjects to consent or decline consent for types of
research raising unique concerns.
iv. NPRM Proposals
The NPRM includes two exemptions proposed in Sec. __.104(f) to
facilitate storage, maintenance, and secondary research use of
biospecimens and identifiable private information. Generally the
exemption at Sec. __.104(f)(1) will first be employed to allow the
storage or maintenance for secondary research use of biospecimens or
identifiable private information, by means of broad consent being
obtained. Following that, the secondary research that will be conducted
using such biospecimens or identifiable private information could often
be exempted under Sec. __.104(f)(2).
A majority of commenters opposed the suggestion that there be
consent requirements for the research use of non-identifiable
biospecimens collected for purposes other than the current research
study. Some commenters also favored requiring IRB review and approval
for specific studies involving the use of identifiable private
information and identifiable biospecimens, rather than permitting the
use of a broad consent for future use to satisfy the regulatory
requirement for consent. These commenters indicated that IRB review of
specific research studies, and the IRB's consideration of whether a
study-specific informed consent should be required or whether informed
consent could be waived, was more protective of human subjects than the
ANPRM recommendation permitting use of a broad consent for future use.
Commenters to the 2011 ANPRM were mostly concerned with the cost
and burden that would be imposed by the requirement to obtain consent
for future research use of all biospecimens, regardless of
identifiability. Commenters anticipated these costs to include
obtaining consent from participants and the administrative efforts
required to keep track of the consent status of biospecimens. Most
commenters did not provide detailed cost estimates with their comments;
data are specifically requested in response to this NPRM. In addition,
estimates of the type and number of studies that could not be pursued
using existing samples and data because of the absence of sufficient
consent are requested. Comment is also sought on the value to the
public and research participants of being asked their permission for
research use of their data and biospecimens.
While consideration was given to the opposition expressed by ANPRM
commenters of a consent requirement for secondary research use of non-
identified biospecimens, the NPRM proposes to require that consent be
obtained for the research use of non-identified biospecimens, but to
allow for that consent to be broad. Thus, while consent would be
required for the research use of non-identified biospecimens, one would
not have to obtain study-specific consent for the research use of those
biospecimens, drastically reducing the burden imposed by this new
requirement.
The NPRM proposal includes several protections for secondary
research use of biospecimens in addition to the broad consent. Research
activities falling under the exemption at Sec. __.104(f) are subject
to the requirements under proposed Sec. __.104(c). This would require
that exemption determinations be made by someone knowledgeable of the
regulations, or by the to-be-created exemption determination tool (when
utilized by an investigator or other
[[Page 53966]]
individual). Additionally, the documentation requirement would allow
institutions to better know the scope and volume of secondary research
studies conducted at an institution. Also note that Sec. __.104(f)(1)
requires that an IRB review the consent process through which broad
consent would be obtained in the non-research context, to further allay
ethical concerns about obtaining broad consent in clinical and other
non-research contexts.
(1) Exemption for the Storage or Maintenance of Biospecimens or
Identifiable Private Information for Secondary Research Use (NPRM at
Sec. __.104(f)(1))
The first exemption in this group, at proposed Sec. __.104(f)(1),
is for storage or maintenance for secondary research use of
biospecimens or identifiable private information that have been or will
be acquired for research studies other than for the proposed research
study, or for non-research purposes, if the following criteria are met:
Written consent for the storage, maintenance, and
secondary research use of the information or biospecimens is obtained
using the broad consent template that the Secretary of HHS will
develop. Oral consent, if obtained during the original data collection
and in accordance with the elements of broad consent outlined in Sec.
__.116(c) and (d)(3), would be satisfactory for the research use of
identifiable private information initially acquired in accordance with
activities excluded under Sec. __.101(b)(2)(i) or exempt in accordance
with Sec. __.104(d)(3) or (4), or Sec. __.104(e)(1); and
The reviewing IRB conducts a limited IRB review of the
process through which broad consent will be sought, and, in some cases,
of the adequacy of the privacy safeguards described in Sec. __.105.
This exemption category only allows for the storage or maintenance
for secondary research use of biospecimens or identifiable private
information. Note that this exemption does not exempt the creation of
any data or the actual new collection of any biospecimens from a person
through a research interaction or intervention. (For example, if the
proposed research activities involved creating a research repository of
DNA samples that would be obtained from people through cheek swabs, the
collection of the cheek swabs would mean that the creation of the
research repository would require IRB review, and would not be exempt.)
This exempt category is for secondary research use of biospecimens and
identifiable private information and applies to biospecimens and
identifiable private information that were initially collected for
purposes other than the proposed research activity. The term `other
than the proposed activity' here means that the information or
biospecimens were or will be collected for a different research study
or for a non-research purpose.
In the case of a research study involving the actual new collection
of biospecimens such as a clinical trial, the informed consent process
could include obtaining informed consent for the original study (which
study would not be exempt and would require IRB review and the usual
type of consent document as required under Sec. __.116(a) and (b)),
and for secondary research use of the biospecimens. The informed
consent form for the latter step (the secondary research use) could
make use of the Secretary's template, in which case the biospecimen
would be eligible for maintenance or storage under Sec. __.104(f)(1)
with limited IRB review or for a secondary research study under Sec.
__.104(f)(2). If the Secretary's template for broad consent is not
used, the storage or maintenance for secondary research use would not
meet this exemption and the consent form would need to be reviewed and
approved by an IRB, either along with the IRB review of the original
study, if the maintenance and storage for secondary research is known
and described, or later, if it is not. Note also that if the
Secretary's template is not used, the Sec. __.104(f)(2) exemption, as
discussed below, would not apply to exempt any actual secondary
research studies conducted using the stored biospecimens. IRB review
would be needed for each of those studies, unless the research met one
of the proposed exclusions at Sec. __.101(b)(1) or (b)(3), or the
exemption found in proposed Sec. __.104(d)(2).
This exemption requires written informed consent using the
Secretary's template for broad consent for secondary research, or oral
consent, in specified circumstances. This broad consent requirement
will enable subjects the choice to include their biospecimens and
information in this research. The consent form using the Secretary's
template would include the information required in Sec. __.116(c).
Oral broad consent would also need to include all of the elements of
consent at Sec. __.116(c), and would only be permissible for the
research use of identifiable private information, not biospecimens,
when the identifiable private information was initially acquired as
part of any of the following four excluded or exempt categories of
research: (1) The exclusion related to research, not involving
interventions, that involves the use of educational tests, survey
procedures, interview procedures, or observation of public behavior
(Sec. __.101(b)(2)(i)); (2) the exemption related to research
involving benign interventions (Sec. __.104(d)(3)); (3) the exemption
related to taste and food quality evaluation and consumer acceptance
studies (Sec. __.104(d)(4)); or (4) the exemption related to research
involving the use of educational tests, survey procedures, interview
procedures, or observation of public behavior (Sec. __.104(e)(1)).
It is proposed that oral broad consent only be permitted to satisfy
these exemptions regarding the secondary use of identifiable private
information (Sec. __.104(f)(1) and (f)(2)) if the identifiable private
information was initially acquired as part of any of the four above-
mentioned exclusion and exemption categories because these four
categories are the only ones that are expected to typically involve
some interaction with human subjects, and thus give investigators the
opportunity to obtain oral consent from subjects for the secondary use
of research data obtained as part of the initial research study.
This exemption also requires adhering to the privacy safeguards
described in the proposed section Sec. __.105.
The exemption also includes a requirement for limited IRB review
(Sec. __.111(a)(9)). The purpose of this limited IRB review is to
ensure that the process of obtaining consent will occur in an
appropriate way, because there may be some circumstances (for example,
when someone is admitted for emergency care), when the individual is
not able to make an informed considered decision. This IRB review will,
for many institutions, be essentially a ``one-time'' event (as opposed
to being needed for specific research studies); the IRB would review an
overall general institutional protocol for the manner in which people
can provide broad consent for the maintenance or storage of their
biospecimens for future secondary research. Such a general
institutional protocol would need to identify the circumstances in
which broad consent would be sought for secondary research use of
biospecimens so that the IRB could determine that these circumstances
are consistent with the requirements for voluntary informed consent as
described in the introductory language to proposed Sec. __.116.
In addition, if there will be a change in the way the biospecimens
and information will be maintained for the secondary research purposes,
rather
[[Page 53967]]
than simply changing the eligibility for secondary research status of
biospecimens or information already being maintained for other
purposes, then limited IRB review must also ensure that the biospecimen
and information protection standards are still met. For example, if it
is envisioned that the identifiable private information collected will
be stored both at the institution obtaining the information, and also
stored at a second institution, an IRB would also need to determine if
the Sec. __.105 privacy safeguards are adequate.
(2) Exemption for Secondary Research Use of Biospecimens or
Identifiable Private Information where Broad Consent has been Sought
and Obtained (NPRM at Sec. __.104(f)(2))
The second exemption in this exemption group, at Sec.
__.104(f)(2), is for research involving the use of biospecimens or
identifiable private information that have been stored or maintained
for secondary research use, if consent for the storage and maintenance
of the information and biospecimens was obtained as detailed using the
broad consent template that the Secretary of HHS will develop. Note
that oral broad consent would be allowed to the extent permitted under
proposed Sec. __.104(f)(1)(i)(A). If the investigator anticipates that
individual research results will be provided to a research subject, the
research may not be exempted under this provision and must be reviewed
by the IRB and informed consent for the research must be obtained to
the extent required by proposed Sec. __.116(a) and (b).
This exemption category at Sec. __.104(f)(2) is for the actual
secondary research studies that will be conducted using biospecimens or
identifiable private information that have been stored for unspecified
secondary research studies. This exemption does not include additional
analyses being conducted to support or augment the original research
study for which the information or biospecimens were originally
collected.
The proposed exemption category at Sec. __.104(f)(2) requires that
the privacy safeguards at Sec. __.105 are met, and that broad consent
to the earlier storage or maintenance of the biospecimens and
information had already been obtained consistent with the requirements
of Sec. __.104(f)(1). This means that for secondary research using
biospecimens informed consent must have been obtained using a consent
form using the Secretary's template. It is presumed that research
involving newborn blood spots would frequently take place using this
provision.
The rationale for these two exemptions is that they provide for
obtaining broad consent from subjects for the research use of
specimens, honoring the principle of respect for persons, they provide
protections for the information involved through the privacy safeguards
of Sec. __.105, and the limited IRB review proposed at Sec.
__.111(a)(9) ensures that the privacy safeguards and informed consent
process are indeed adequate.
The exemption at Sec. __.104(f)(2) would not apply to research in
which the investigator anticipates that research results will be
provided to a subject. If it is anticipated that individual research
results will be returned to subjects, then the research would not meet
this exemption and IRB review and approval would be required, and
informed consent would need to be obtained to the extent required by
Sec. __.116(a) and (b). If the investigator does not anticipate that
individual research results will be provided to a research subject as
part of the research plan, but later decides to return research results
to subjects, an IRB must review and approve the plan for returning
these results to the subjects. It is understood that the prospective
IRB review provision set forth here does not override existing law,
such as the HIPAA Privacy Rule or the Federal Privacy Act, which give
individuals the right to access certain information about themselves in
specified circumstances. In addition, it is recognized that clinical
care needs may demand prompt reporting of findings to patients who are
also human subjects, in which case it is expected that investigators
would anticipate that such research results will be provided to a
subject, and this exemption would not apply.
It is generally recognized that where, for example, a series of
genetic analyses are performed, in a significant percentage of
instances investigators will be learning information, not necessarily
related to the specific purpose of their studies, that would
nonetheless be significant to participants in terms of making decisions
about their health care. For example, it might be learned that a woman
has a gene mutation that significantly increases her risk of breast or
ovarian cancer. The proposed rule does not specifically impose any
obligations on investigators to provide such information to
participants, so long as the consent form is clear that no such
information will be given to the participants. This could have a
negative impact on the current efforts to increase the willingness of
people to allow their biospecimens to be used in research, if they are
less inclined to provide broad consent to such research when
investigators are not making any commitment to return important
information that is unexpectedly learned about a participant. This
could lead some investigators to decide to include in their protocols
provisions for returning such results to subjects. The consequence is
that such protocols will not be eligible for the proposed exemption at
Sec. __.104(f)(2), and thus would undergo full IRB review primarily
for the purpose of determining what information participants should be
provided regarding such ``unexpected'' (i.e., not related to the
purpose of the research) genetic findings. In contrast, if a study only
involved use of biospecimens, and no results were to be returned to
subjects, no IRB review would be required under the NPRM proposals
unless IRB review is required by law (e.g., FDA-regulated devices).
At the same time, it is likely that many IRBs do not have any
particular unique expertise in making these determinations about
returning results, which again could lead to inappropriate variability
in disclosure from study to study, and would seem to be in conflict
with the ethical goal of justice.
One option that has been considered would be to create a federal
panel of experts to make determinations about which unexpected findings
should be disclosed to human subjects in research, and what information
should be given to subjects about themselves. If this alternative
proposal were adopted, then it would not be necessary to have full IRB
review of these protocols. A consequence of this option would be that
these types of studies could be exempt even if they proposed to return
research results to subjects, so long as disclosures were made
consistent with the rules announced by the federal panel. However, it
is not clear that such a panel's guidance would be superior to that of
IRBs.
v. Questions for Public Comment
54. Public comment is sought on whether the NPRM's proposal of
exemption Sec. __.104(f)(2) is the best option, or whether there is a
better way to balance respect for persons with facilitating research.
55. Public comment is sought on whether and how the provision
regarding the return of research results in the proposed exemption
Sec. __.104(f)(2) should be revised.
56. Public comment is sought on whether there should be an
additional exemption that would permit the
[[Page 53968]]
collection of biospecimens through minimally invasive procedures (e.g.,
cheek swab, saliva).
e. Applicability of Exemptions to the Subparts (NPRM at Sec.
__.104(b); Current Rule at Footnote 1)
i. Current Rule
In the current Common Rule, the application of the exemptions
articulated in the current Common Rule in Sec. __.101(b) to the
subparts is specified through footnote 1 of the current Rule. It states
that the exemptions do not apply to research involving prisoners, and
are also limited in their application to research involving children.
The current exemption at Sec. __.101(b)(2) for research involving
educational tests, survey or interview procedures or observations of
public behavior does not apply to subpart D, except for research
involving educational tests or observations of public behavior when the
investigator does not participate in the activities being observed. The
current exemptions do apply to subpart B.
ii. NPRM Proposals
While the exemptions in the NPRM are based largely on exemptions in
the current Common Rule, not all of the exemptions proposed in the NPRM
will apply to subparts B-D. Language at Sec. __.104(b) explains how
the proposed exemptions may be applied to the subparts. The language at
Sec. __.104(b)(1) states that all of the exemptions at Sec. __.104
may be applied to research conducted under subpart B. Language at Sec.
__.104(b)(2) states that none of the Sec. __.104 exemptions may be
applied to research conducted under subpart C, except for research
aimed at a broader population that consists mostly of non-prisoners but
that incidentally includes some number of prisoners. Finally, Sec.
__.104(b)(3) states that the exemptions at Sec. __.104(d)(1), (2),
(4), Sec. __.104(e)(2) and (f)(1) and (2) may be applied to research
conducted under subpart D. The exemption at Sec. __.104(e)(1) cannot
be applied to research involving children under subpart D, because
protections including IRB review and parental permission are
appropriate for research involving educational tests, surveys or
interview procedures, or observation of public behavior when the
information collected may be individually identified and sensitive in
nature.
Although this NPRM does not propose changes to the HHS regulations
at 45 CFR part 46, subparts B, C and D, consideration is being given to
whether the proposed exemption categories articulated in Sec. __.104
should apply in research involving prisoners under subpart C, either if
the research consists mostly of non-prisoners and only incidentally
includes some number of prisoners, as proposed in the NPRM, or if the
research intends to involve prisoners as research subjects. Originally
developed in 1976 by the National Commission, subpart C has at times
come under scrutiny for its restrictive construction. The subpart was
written in the wake of harsh criticism regarding research abuses
involving prisoners that occurred or became public in the 1960s and
1970s. As a result, subpart C was written to permit research involving
incarcerated persons only if the study fits one of four categories at
45 CFR 46.306(a)(2) (an ``epidemiological waiver'' category was added
in 2002 \51\), and requires an institution to ``certify'' to the
Secretary, HHS, before research can proceed. An additional original
restriction conveyed through footnote 1 of the current Common Rule
specifies that research involving prisoners may not be considered
exempt under any of the current exemption categories.
---------------------------------------------------------------------------
\51\ 67 FR 62432 (Oct. 7, 2002).
---------------------------------------------------------------------------
Public comment is requested on whether the revised exemption
categories should be permitted to apply to research involving
prisoners. Considerations include the preponderance of low-risk, socio-
behavioral research focused on prisoner welfare, substance abuse
treatment, community reintegration, and services utilization; the
occurrence of prisoner-subjects in databases or registries; and the
broad interpretation of the subpart C ``prisoner'' definition that
includes, for example, subjects in court-mandated residential substance
abuse treatment.
ii. Questions for Public Comment
57. Public comment is sought on whether research involving
prisoners should be permitted to apply any or all of the exemption
categories found at proposed Sec. __.104, either if the research
consists mostly of non-prisoners and only incidentally includes some
number of prisoners, as proposed in the NPRM, or if the research
intends to involve prisoners as research subjects.
58. Would it be preferable for language at Sec. __.104(b)(2) to
resemble the 2002 epidemiologic waiver criteria and state that the
exemptions apply except for research where prisoners are a particular
focus of the research?
59. Is the proposed application of the exemptions to subparts B and
D appropriate?
f. What would change in the exemptions?
All exemption language would be found at Sec. __.104.
The eight proposed exemptions in Sec. __.104 would be
divided into three groupings: (1) Low-risk interventions where no other
requirement of the proposed rule (including informed consent and data
protection) are necessary other than the determination and recording
requirements (Sec. __.104(d)); (2) research activities where the
information protection measures at Sec. __.105 must be applied (Sec.
__.104(e)); (3) secondary research involving biospecimens and
identifiable private information that requires application of privacy
safeguards at proposed Sec. __.105, broad consent as discussed at
proposed Sec. __.116(c), and limited IRB review as discussed at
proposed Sec. __.111(a)(9).
Existing exemption categories 1, 5, and 6 (current Sec.
__.101(b)(1), (5), and (6)) would be retained at Sec. __.104(d)(1),
(2), and (4). Specifically the current exemption for research on public
benefit programs or demonstration projects (Sec. __.101(b)(5) in the
current Rule; Sec. __.104(d)(2) in the NPRM) would be clarified and
OHRP's guidance would be changed to include the applicability of the
exemption to cover research on public benefit and service programs that
an agency does not itself administer through its own employees or
agents. A requirement for publishing a list of studies under this
exemption would apply for Federal agencies or departments conducting or
supporting such studies.
A new exemption would be created for certain research
involving benign interventions.
A new exemption would be created for certain research
involving educational tests, survey or interview procedures, or
observation of public behavior where identifiable private information
was recorded so long as data protection standards are met.
A new exemption would be created for secondary research
use of identifiable private information originally collected for non-
research purposes.
A new exemption would be created for activities relating
to the storage and maintenance, for secondary research use, of
biospecimens and identifiable private information.
A new exemption would be created to exempt secondary
research studies
[[Page 53969]]
that would use the biospecimens and identifiable private information
stored or maintained under the above new exemption.
B. Proposed Changes To Obtaining, Waiving, and Documenting Informed
Consent (Sec. Sec. __.116 and __.117)
The NPRM proposals address: (1) The organization and presentation
of information included in the consent document and the process to
facilitate a prospective subject's decision about whether to
participate in research; (2) the elements of consent, basic and
additional; (3) broad consent to the storage or maintenance for
secondary research use of biospecimens and identifiable private
information, and the use of such stored biospecimens and information
for specific research studies; and (4) attendant changes in the waiver
or alteration criteria for consent.
The NPRM proposes several changes to the Common Rule with regard to
the elements of informed consent and when it must be obtained (see
further discussion below regarding proposed changes to the conditions
for waiver of consent). In addition, it makes several new proposals
that were not included in the ANPRM questions, but are offered in
response to public comments received as well as internal discussions
within HHS and with the other Common Rule agencies.
These include the development of a Secretary's template, which will
be issued in draft for public comment at a later date (the NPRM at
Sec. __.116(d)) for broad consent to the storage or maintenance for
secondary research use of biospecimens, and identifiable private
information and the use of such stored biospecimens and information for
specific research studies. Broad consent would be permissible for the
storage or maintenance for secondary research use of such information
and biospecimens that were originally collected for either research
studies other than the proposed research or non-research purposes. This
broad consent document would meet the consent requirements for the
storage or maintenance of biospecimens and identifiable private
information for secondary research, as well as the use of such stored
material for individual research studies.
Because biospecimens and information that have been collected for
clinical use or purposes other than for the proposed research are often
an important source of information and material for investigators, and
the re-use of existing information and materials can be an efficient
mechanism for conducting research without presenting additional
physical or psychological risks to the individual, it seems prudent to
consider changes to current regulations relating to those issues. Some
critics, including potential and former research subjects, object to
research performed on a person's biospecimens or information without
consent. Conversely, investigators and patient advocacy groups are
concerned that the need for informed consent for every use of a
biospecimen or data element will greatly inhibit research. They worry
that obtaining individual consent for each separate research study will
create unmanageable logistical demands, making valuable research
impossible.
As an additional means of increasing transparency and facilitating
the development of more informative informed consent forms, it is
proposed that a copy of the final version of the consent form for
clinical trials conducted or supported by a Common Rule department or
agency would need to be posted on a publicly available Federal Web
site. Within 60 days after the trial was closed to recruitment, the
awardee or the federal department or agency conducting the clinical
trial would be required to post the consent document, the name of the
clinical trial and information about whom to contact for additional
details about the trial.
In addition to the specific changes proposed to Sec. __.116,
comment is sought on whether Common Rule agencies should modify the
definition of ``legally authorized representative'' (LAR). The current
Rule defines LAR at Sec. __.102(c) as an individual or judicial or
other body authorized under applicable law to consent on behalf of a
prospective subject to the subject's participation in the procedure(s)
involved in the research. While the NPRM proposes to retain this
language, OHRP is aware that this definition has been problematic for
states in which there is no applicable law permitting an LAR to consent
in either a clinical or a research context. In the absence of such a
law, it is almost always the case that community or other standards
(such as institutional policies) define hierarchies or identify
individuals who may provide legally acceptable consent, for clinical
(non-research) purposes, on behalf of others who cannot consent for
themselves. However, the current regulations are interpreted to not
allow such standards to constitute applicable law for purposes of the
regulations, and thus such individuals are not considered legally
authorized representatives for purposes of the Common Rule. Concerns
that the Common Rule's current definition of LAR may be inappropriately
hindering the conduct of research with subjects who lack capacity to
consent have been raised by the Secretary's Advisory Committee on Human
Research Protections (SACHRP),\52\ the Presidential Commission for the
Study of Bioethical Issues,\53\ and others in the research community.
---------------------------------------------------------------------------
\52\ Secretary's Advisory Committee on Human Research
Protections. (2009, March 4). Recommendations from the Subcommittee
for the Inclusion of Individuals with Impaired Decision Making in
Research (SIIIDR). Retrieved from Office for Human Research
Protections: http://www.hhs.gov/ohrp/sachrp/20090715letterattach.html.
\53\ Presidential Commission for the Study of Bioethical Issues.
(2015). Gray Matters: Topics at Intersection of Neuroscience, Ethics
and Society. Retrieved from Projects: http://bioethics.gov/sites/default/files/GrayMatter_V2_508.pdf.
---------------------------------------------------------------------------
Comment is therefore sought on whether a revision that would expand
the current definition to also permit an LAR to be defined by an
accepted common practice standard that is used in a state for
determining who can legally consent to clinical care would be
consistent with the ethical principles underlying the Common Rule. Such
a revision would broaden the definition of LAR and permit investigators
to use accepted common practice, such as an established state or local
hierarchy, to allow another person to provide consent to research
participation. In the absence of such a revision, it would remain the
case that in certain states, there would appear to be no way (short of
taking the often difficult legal step of obtaining the appointment of a
legal guardian) to enroll subjects lacking decision-making capacity in
research studies. Given that the current interpretation of current
Sec. __.102(c) generally is based on the proposition that the person
who can legally consent on behalf of someone else for a particular
clinical procedure to take place should have the authority to consent
for research purposes, it could be viewed as inappropriate to maintain
the current Rule, which produces different results in terms of when
research can take place in those states that have specific laws
governing such clinical consent and those that accomplish the same
legal outcome through less formal regimes.
1. Required Elements of Informed Consent (NPRM at Sec. __.116(a), (b))
a. NPRM Goal
Many claim that consent forms have evolved to protect institutions
rather than to provide potential research subjects with some of the
most important pieces of information that a person would need in order
to make an informed decision about whether to
[[Page 53970]]
enroll in a research study.\54\ Instead of presenting the information
in a way that is most helpful to prospective subjects--such as
explaining why someone might want to choose not to enroll--the forms
often function as sales documents or as a means to protect against
institutional liability rather than as genuine aids to good decision-
making.\55\ There is also a growing body of literature that suggests
informed consent forms have grown too lengthy and complex, adversely
affecting their ability to convey the information needed for
prospective participants to make an informed decision about
participating in research.\56\
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\54\ Levine RJ. Informed consent: Some challenges to the
universal validity of the western model. J Law Med Ethics 1991;19(3-
4):207-213.
\55\ Menikoff J, Richards E. What the Doctor Didn't Say: The
Hidden Truth about Medical Research. New York, NY: Oxford University
Press; 2006:113-123.
\56\ Beardsley E et al. Longer Consent Forms for Clinical Trials
Compromise Patient Understanding: So Why Are They Lengthening?
Journal of Clinical Oncology. 2007 Mar 20;25(9):e13-4.
---------------------------------------------------------------------------
The goal of the proposed changes to the informed consent form and
process is to facilitate prospective subjects' decision about whether
or not to participate in a research study, thereby enhancing autonomy.
b. Current Rule
Currently, under the Common Rule, investigators generally must
ensure that the subjects' informed consent to participate in research
is obtained.\57\ The regulations currently require that the consent
forms include at least eight specific items of information. Various
aspects of the consent forms have been heavily criticized, as have the
amount of time IRBs devote to editing and revising them.
---------------------------------------------------------------------------
\57\ For general requirements for informed consent see Sec.
__.116 in the current Rule, and 21 CFR 50.20, .25 for FDA's
comparable requirements. There are provisions under the Common Rule,
that allow for the waiver of some or all of the elements of informed
consent (see Sec. __.116(c) and (d)). The Federal Food, Drug, and
Cosmetic Act limits the circumstances under which informed consent
can be waived. See, e.g., section 520(g) (21 U.S.C. 360j(g)) Thus,
FDA regulations contain only two exceptions from informed consent
under 21 CFR 50.23-24.
---------------------------------------------------------------------------
c. ANPRM Discussion
The ANPRM discussed revising the regulations to provide greater
specificity about how consent forms should be written and what
information they should contain. The goal would be consent documents
that are shorter, when appropriate, more readily understood, less
confusing, that contain all of the key information in sufficient
detail, and that can serve as an aid to help someone make an informed
decision about whether to participate in a study.
d. NPRM Proposals
Public comments were largely in favor of finding ways to improve
consent forms. However, commenters cited several systemic concerns that
could be obstacles to shortening and simplifying forms, such as
regulatory, legal, and institutional requirements, and the complexity
of some studies. Of those responding to questions about the causative
factors, blame for making forms long and complex was shared by sponsors
of clinical trials, IRBs, regulatory agencies, and institutional legal
counsel. The types of information cited as contributing to the
excessive lengths of forms included the requirement to describe all
reasonably foreseeable research risks and the complexity of study
procedures. There was no consensus on how to better explain
alternatives to research participation and few comments were submitted
on this topic.
Commenters offered a few suggestions for modifying or deleting the
required elements of consent, such as removing boilerplate language
that only protects institutions and research sponsors, as well as
removing some of the required elements for minimal risk research.
However, many felt that guidance, rather than regulatory change, would
better improve the development of consent forms. Although many
commenters noted the need for shorter and more comprehensible consent
forms, most felt that the required elements of consent articulated in
the Common Rule are sufficient. Commenters overwhelmingly supported the
goals articulated in the ANPRM, but cautioned against an overly
prescriptive or rigid approach to consent forms. However, several
commenters requested guidance on what might be included in a consent
form for future research use of identifiable information and
identifiable biospecimens to ensure that such forms satisfied the
consent requirements of the Common Rule.
A majority of commenters supported the development of regulations
or guidance designed to encourage assessment of the extent to which
human subjects comprehend consent forms, at least for certain types of
higher risk studies or certain types of subject populations. Others
argued that the regulations at Sec. __.116 already contain language
implying the need to ensure comprehension through the use of the terms
``legally effective informed consent'' and ``language understandable to
the subject.''
Finally, many commenters supported making changes to HIPAA
authorization requirements, as necessary, to conform to provisions of
the Common Rule. In addition, most commenters were supportive of
requiring investigators to disclose in consent forms certain
information about the financial relationships they have with study
sponsors.
To that end, the NPRM proposes adding new language to the
introductory text of Sec. __.116 to address the questions asked in the
ANPRM about strengthening the informed consent requirements. It
reorients the language to emphasize the need to first provide essential
information that a reasonable person would want to know in order to
make an informed decision about whether to participate, and to provide
an opportunity to discuss that information. It requires that the
information be presented in sufficient detail relating to the specific
research. Furthermore, in recognition of the complaints that current
consent forms are too commonly complicated documents that primarily are
used to protect sponsors from legal liability, the NPRM would require
(as described in the in the revised introductory language to Sec.
__.116) that the information in these forms be organized and presented
in a way that did not merely provide lists of isolated facts, but
rather facilitated the prospective subject's or representative's
understanding of the reasons why one might or might not want to
participate. For example, for some research studies, it could be
important for the discussion of the purpose of the research and the
reasonably foreseeable risks of the research to be discussed together
so that prospective subjects would better understand how participation
in the study might alter their clinical care and ultimately, their
health.
It is also proposed that in obtaining informed consent, the
investigator would be required to present first the information
required by this section, before providing other information, if any,
to the subject. This would mean that the consent document could only
include the elements of consent that were required by the rule, with
any other information included in an appendix. This is intended to lead
to substantially shorter consent forms, with prospective subjects
receiving the most important information in the body of these
relatively short forms, instead of that key information being buried in
a long and overly complex document.
Public comments did not provide consensus on desirable changes to
the elements of informed consent. Thus,
[[Page 53971]]
this language aims to emphasize the necessity of addressing the basic
elements of informed consent, as described in Sec. __.116(a), in a
user-friendly but sufficiently detailed manner that facilitates
comprehension of the risks and potential benefits of the research.
Because commenters agree that informed consent forms should be written
in appropriate language, this proposal reinforces the need to include
information using language understandable to the subject. This goal is
consistent with Federal Plain Language guidelines and the Federal Plain
Writing Act of 2010. The Secretary will publish guidance at a later
time to explain how consent forms can be written in order to comply
with the requirements of this policy. It is not envisioned that the
regulations would require a formal assessment to evaluate an
individual's competency, but that such a practice may be appropriate
for certain populations. That this ambiguity already exists in the
current regulations with regard to what constitutes ``legally effective
informed consent'' is acknowledged.
In addition, the NPRM proposes to clarify in the introductory
language at Sec. __.116 that if a HIPAA authorization is combined with
a consent form, the authorization elements required by 45 CFR 164.508
must be included in the consent document and not the appendices. In
other words, when consent is combined with authorization, the
authorization elements should be considered to constitute one of the
required elements of consent.
Since research with non-identified data does not involve ``human
subjects'' under proposed Sec. __.102(e), it is proposed that a new
element of informed consent be required to better ensure that subjects
are informed of the possibility that identifiers collected as part of a
research study could be removed from the data and then used for
secondary research studies without the protections provided by this
policy. The new basic element of consent at Sec. __.116(a)(9) would
apply to all research collecting identifiable private information.
Based on the investigator's plans, the informed consent form and
process would need to inform subjects either that: (1) Identifiers
might be removed from the data and that the non-identified data could
be used for future research studies or distributed to another
investigator for future research studies without additional informed
consent from the subject or the representative, if this might be a
possibility; or (2) the subject's data collected as part of the
research would not be used or distributed for future research studies,
even in a non-identified form. This proposed additional element of
informed consent is intended to create greater transparency and enable
prospective research subjects to make a more informed decision about
whether to participate in research. Prospective subjects can always
decline to participate in the initial research if they object to the
statement provided. These changes would not apply to ongoing human
subjects research in which human subjects were involved prior to the
effective date of this rule.
It is anticipated that very few investigators will elect to offer
the option to restrict the future research use of non-identified data,
in part because of the challenges of marking and tracking such
decisions. However, should they offer this option, then institutions
and investigators will have to develop a system for tracking
impermissible uses of non-identified information. Since most
investigators will likely elect to inform subjects that identifiers
might be removed from the data and distributed for future research
without additional informed consent, it would be reasonable for
investigators and institutions to generally assume that the secondary
research use of non-identified information would be permissible unless
marked otherwise.
It is possible that investigators could choose to include
additional statements about their plans to use non-identified data for
future research studies. For example, investigators could agree to give
subjects an option about whether subjects' non-identified research data
could be used for future research studies, or could agree to seek
additional informed consent from subjects before using or sharing non-
identified data for future research studies. However, it is anticipated
that such commitments by investigators would be uncommon, and so the
NPRM does not propose including such statements in the informed consent
form or process. If such commitments about the future use of non-
identified information were made by investigators in the informed
consent form or process, investigators would need to satisfy these
commitments, which would also require the development of a tracking
system.
The NPRM also proposes adding three additional elements of consent
at Sec. __.116(b)(7)-(9) that, when appropriate, would be required to
be included in the informed consent form and process. These three
additional elements of consent all pertain to issues that have become
more relevant in recent years as science has advanced and the nature of
research has changed. The proposed new element at Sec. __.116(b)(7)
would require that prospective subjects be informed that their
biospecimens may be used for commercial profit and whether the subject
will or will not share in this commercial profit. The proposed new
element at Sec. __.116(b)(8) would require that prospective subjects
be informed of whether clinically relevant research results, including
individual research results, will be disclosed to subjects, and if so,
under what conditions. The proposed new element at Sec. __.116(b)(9)
would provide subjects or their legally authorized representatives with
an option to consent, or refuse to consent, to investigators re-
contacting the subject to seek additional information or biospecimens
or to discuss participation in another research study. Since the
information that would be required to be disclosed under these three
proposed additional elements of consent is often relevant to an
individual's decision of whether to participate in a research study,
currently such information is sometimes included in informed consent
forms under the current Common Rule. The NPRM proposes to require
inclusion of these additional elements, when appropriate, to better
ensure that prospective subjects are more consistently provided with
this information when it is information that a reasonable person would
want to know in order to make an informed decision about whether to
participate in a research study. These three proposed additional
elements of consent are also relevant to seeking an individual's broad
consent to the storage, maintenance, and secondary research use of
biospecimens or identifiable private information, so it is proposed
that broad consent obtained under Sec. __.116(c) also include these
additional elements, when applicable. These clarifications and
additions would have to meet the documentation requirements at Sec.
__.117(b)(1)-(2).
e. What would change?
New language would strengthen the informed consent
requirements to make sure that the most appropriate information is
presented to prospective subjects in sufficient detail and in a format
that is tied to understandability.
New language would clarify that, when a HIPAA
authorization is combined with consent, the HIPAA authorization
elements must be part of the core elements of the consent.
When identifiable private information is collected for
research purposes, consent would be required to notify subjects if
their non-identified
[[Page 53972]]
information could be utilized for future research studies without
additional consent.
The Secretary will publish guidance in the future to
explain how consent forms can be written to comply with the regulatory
requirements.
Three additional elements of consent would be required,
when appropriate.
f. Question for Public Comment
60. What topics should be addressed in future guidance on improving
the understandability of informed consent?
2. Broad Consent to the Storage, Maintenance and Secondary Research Use
of Biospecimens and Identifiable Private Information (NPRM at Sec.
__.116(c), (d)).
a. NPRM Goal
One of the primary objectives of the NPRM is to make the strength
of protections commensurate with the level of risks of the research,
and by so doing, reduce unnecessary administrative burdens on research.
That objective has been viewed as being particularly relevant to
research involving only secondary use of biospecimens and identified
data, which is relatively low-risk if appropriate protections of
privacy and confidentiality are in place, including protections against
the misuse of biospecimens or data that could cause harm to research
subjects.
b. Current Rule
The increasing use of information and biospecimens in research,
often into the future and beyond the point at which an individual is
directly involved in the information or biospecimen collection,
requires rethinking the elements of consent in those circumstances to
ensure that potential research subjects understand how their
information or biospecimens might be used as well as the risks and
potential benefits of such use. Critics of the existing rules have
observed that the current requirements for informed consent for future
research with pre-existing information and biospecimens are confusing
and consume substantial amounts of investigators' and IRBs' time and
resources.
Under the current requirements of the Common Rule, if identifiers
are removed, biospecimens and data that have been collected for
purposes other than the proposed research can be used without any
requirement for informed consent. Similarly, under the HIPAA Privacy
Rule, if data are de-identified or HIPAA identifiers do not accompany
biospecimens, then the Privacy Rule does not apply. When identifiers
have not been removed, under the Common Rule investigators may be
allowed in certain situations to obtain a consent that is broader than
for a specific research study, such as for a research repository that
involves obtaining biospecimens from living individuals to create a
repository for future research studies. In these cases, an IRB may
determine that the original consent for the creation of the research
repository satisfies the requirements of the Common Rule for the
conduct of the future research, provided that the elements of consent
under Sec. __.116 continue to be satisfied for the future research.
Despite this existing flexibility in the Common Rule, it is believed
that the current elements of consent required under Sec. __.116 often
do not continue to be satisfied for the future research.
With respect to HIPAA, HHS's prior interpretation of the HIPAA
Privacy Rule was that authorizations for research needed to be study-
specific, and thus, that such authorizations could not authorize
certain future unspecified research. However, in January 2013, the
Office for Civil Rights modified its prior interpretation.\58\ Under
the new interpretation, an authorization now may be obtained from an
individual for uses and disclosures of protected health information for
future research purposes, so long as the authorization adequately
describes the future research such that it would be reasonable for the
individual to expect that his or her protected health information could
be used or disclosed for the future research purposes.
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\58\ 78 FR 5611-5613 (Jan 25, 2013).
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c. ANPRM Discussion
The ANPRM suggested generally requiring written consent for
research use of any biospecimens collected for clinical purposes after
the effective date of the new rules (such as research with excess
pathological specimens). Such consent could be obtained by use of a
brief standard consent form agreeing to generally permit future
research. This brief consent could be broad enough to cover all
biospecimens to be collected related to a particular set of encounters
with an institution (e.g., hospitalization) or even to any biospecimens
to be collected at any time by that institution. These studies using
biospecimens collected for clinical purposes would also fall under the
expanded and revised exempt categories, and thus would not require IRB
review or any routine administrative or IRB review but would be subject
to the data security and information protection standards. This
discussed modification would conform the rules for research use of
clinically collected biospecimens to the rules for biospecimens
collected for research purposes. The general rule would be that a
person needs to give consent, in writing, for research use of their
biospecimens, though that consent need not be study-specific, and could
cover open-ended future research. The ANPRM envisioned that consent
could be waived in certain limited circumstances and sought comment on
appropriate criteria for waiving consent.
The ANPRM suggested that this standardized broad consent form would
permit the subject to say no to all future research. In addition, the
ANPRM acknowledged that there are likely to be a handful of special
categories of research with biospecimens that, given the unique
concerns they might raise for a significant segment of the public,
could be dealt with by check-off boxes allowing subjects to separately
agree (or not) to that particular type of research. More specifically,
the ANPRM asked whether certain flexible consent requirements could be
imposed on some of these studies that would permit the use of a broad
consent for future use, with a requirement that a subject's specific
consent would be required before their biospecimens could be used for
special categories of research.
Further, the ANPRM suggested maintaining the current prohibition
that participation in a research study (such as a clinical trial) could
not be conditioned on agreeing to allow future open-ended research
using a biospecimen. With regard to the secondary research use of pre-
existing data, on those occasions when oral consent was acceptable
under the regulations for the initial data collection, the ANPRM
envisioned that subjects would have typically provided their oral
consent for future research at the time of the initial data collection;
a written consent form would not have to be signed in that
circumstance.
The ANPRM also noted that there would be rules that would allow for
waiver of consent under specified circumstances, though those
conditions would not necessarily be the same as those for other types
of research.
d. NPRM Proposal
Similar to what was discussed in the 2011 ANPRM, the NPRM proposes
to allow broad consent to cover the storage or maintenance for
secondary research use of biospecimens and identifiable private
information. Broad consent would be permissible for the storage or
maintenance for secondary research of such information and biospecimens
that
[[Page 53973]]
were originally collected for either research studies other than the
proposed research or non-research purposes. The broad consent document
would also meet the consent requirement for the use of such stored
biospecimens and information for individual research studies. As is
currently the case, consent would not be required for the secondary
research use of non-identified private information, such as the
research use of medical records that have had all identifiers removed.
The NPRM also proposes to facilitate research that uses information or
biospecimens collected for purposes other than the currently proposed
research by adding a new consent provision for such research at Sec.
__.116(c), which would permit individuals to provide broad consent for
the storage or maintenance for secondary research use of their
information and biospecimens that would not be study-specific, and
would be sufficient to satisfy the consent requirement for two proposed
exemptions at Sec. __.104(f)(1) and (f)(2).
Since it is proposed that the definition of human subject be
expanded to include all biospecimens, the NPRM proposes to facilitate
research using biospecimens by permitting broad consent to be obtained
for their storage or maintenance for secondary research. In addition, a
new exemption at Sec. __.104(f)(2) would permit the secondary research
use of biospecimens without a subject being given information about the
specific research study if broad consent under Sec. __.116(c) and (d)
was obtained and the privacy safeguards at Sec. __.105 were met.
Public comments on the 2011 ANPRM revealed variable opinions on the
issue of broad consent. Several commenters indicated that there is no
need for additional regulations, with one university stating that it
``strongly opposes more restrictive regulations about the use of these
biospecimens and sees no need to change the current regulations, even
or perhaps especially in the case of secondary data analysis.'' Other
commenters opposed broad consent, stating that investigators and
clinicians should obtain specific consent from individuals for each
research project. This opposition was made on the ethical grounds that
because individuals are not fully informed of specific research
purposes for broad consent, they can never be truly informed about the
use of their data. In contrast, other commenters expressed clear
support for general consent for secondary research use of biospecimens
and data collected during research to exempt the research from IRB
review, noting that ``we support the suggestion in the ANPRM to
encourage general consent for the secondary research use of
biospecimens and data and where this is not obtained IRB review is
required.'' Other commenters favored requiring IRB review over
permitting the use of a broad consent to approve secondary research use
of identifiable data or biospecimens. These commenters believed that
IRB consideration of consent requirements for individual research
studies was more protective of human subjects than the ANPRM
suggestions to permit broad consent for future use.
It is envisioned that the proposed broad consent provision would be
used by institutions and investigators to give individuals the choice
to either allow or disallow the use of their biospecimens and
identifiable private information for secondary research. In some cases,
institutions would be expected to seek broad consent under Sec.
__.116(c) and (d) as part of a research protocol to create a research
repository of biospecimens or information. However, in other cases it
is expected that institutions, particularly institutions that do not
typically conduct human subjects research, might not develop a research
protocol to create a research repository, but still choose to seek
broad consent from individuals for the research use of their
biospecimens or identifiable private information. In such cases, these
institutions might simply ``tag'' biospecimens and information as
either available or not available for secondary research.
Since broad consent is a different form of informed consent than
informed consent for a specific research study, in which individuals
must be given information about a particular research study to be
conducted with their biospecimens and information, the proposed
requirements for broad consent under Sec. __.116(c) and (d) would
include several of the basic and additional elements of informed
consent under Sec. __.116(a) and (b), but not all, and would include
several additional required elements. The proposed elements of broad
consent are intended to ensure that the individual would be provided
with sufficient information to make an informed decision about whether
to agree to provide broad consent for a wide variety of research that
may be unforeseen at the time in which consent is being sought.
The NPRM proposes to require that the broad consent describe the
biospecimens and identifiable private information that would be covered
by the consent, recognizing that the biospecimens and information to be
used in future research studies might be collected after the consent
was obtained. Broad consent for the research use of biospecimens or
identifiable private information that were originally collected for a
research study would generally be described in the consent document for
the study that would be generating the research biospecimens or
information. Therefore, it is proposed that broad consent to the
secondary research use of biospecimens and identifiable private
information collected as part of a research study could cover all such
research material.
However, in the non-research context, it is recognized that the
biospecimens and information that the subject would be asked to permit
to be stored or maintained and used for a wide range of secondary
research studies would not be as readily understood as in the research
context, since such non-research collections are usually less
predictable or defined. Therefore, the NPRM proposes that broad consent
for the research use of biospecimens or identifiable private
information obtained for non-research purposes would be limited to
covering either or both of the following: (1) Biospecimens or
identifiable private information that exist at the time at which broad
consent is sought; and (2) biospecimens or identifiable private
information that will be collected up to 10 years after broad consent
is obtained for adult subjects, and, for research involving children as
subjects, biospecimens or identifiable private information that will be
collected up to 10 years after broad consent is obtained or until the
child reaches the legal age of consent to the treatments or procedures
involved in the research, whichever comes first.
The rationale for these limitations is that individuals will not
know what biospecimens and information about them will be collected by
an institution in the future. The 10-year time limit may make it more
likely that an individual will have a better understanding of the
biospecimens and information that would be covered by the broad
consent, and may be a sufficiently long enough time period to
appropriately facilitate secondary research using biospecimens and
information. The NPRM proposes to include the standard for who is a
child based upon the definition of ``children'' as defined at 45 CFR
46.402(a). At the time the child became an adult, the broad consent or
permission would no longer be valid and either broad consent would need
to be sought from the child-turned adult, or the investigator would
need to seek a waiver of informed consent in order to use the
individual's
[[Page 53974]]
biospecimens or identifiable private information for research, unless
one of the exclusions or exemptions were applicable.
The Common Rule departments and agencies contemplated proposing
that the scope of broad consent to secondary research use of
individually identifiable clinical information or biospecimens that
were originally collected for non-research purposes would be limited to
(1) clinical information and biospecimens already existing at the
institution at the time broad consent was sought, and (2) clinical
information and biospecimens collected as part of an identified
clinical encounter. Although it was recognized that this limitation
related to an identified clinical encounter would give individuals more
meaningful information about the scope of future clinical information
and biospecimens that would be covered by their broad consent, it was
determined that limiting the scope of the broad consent in this manner
would be very difficult to implement and would require rigorous
tracking on an individual-subject basis. Therefore, this proposal was
not included in the NPRM, and was instead replaced with the above
proposal that uses a limitation based on a period of years.
In addition, the Common Rule departments and agencies contemplated
proposing that for nonclinical information collected for non-research
purposes (e.g., education and court records, financial records,
military records, employee records, or motor vehicle records), broad
consent would only be required to include a clear description of the
types of records or information that were or will be collected and the
period of time or event during which information collection may occur.
However, it was decided that all biospecimens and identifiable private
information originally collected for non-research purposes should be
bound by the same limitations, regardless of whether the materials were
originally collected for clinical or nonclinical purposes.
The proposed element of broad consent, at (Sec. __.116(c)(1)(iv)),
includes a requirement that subjects be informed that they may withdraw
consent, if feasible, for research use or distribution of the subject's
information or biospecimens at any time without penalty or loss of
benefits to which the subject is otherwise entitled. Information that
has been stripped of identifiers might not be traceable. Thus, it might
not be feasible to withdraw consent for future use or distribution in
this case. If, however, an investigator committed to permitting a
subject to discontinue the use of such information, it is expected that
the investigator would honor this commitment by not stripping
identifiers. The regulations would not require investigators to make
such a commitment.
Another of the proposed elements of broad consent, at (Sec.
__.116(c)(1)(viii)), relates to the public posting of non-identifiable
data about a subject. This proposed element of broad consent would
include an option, when relevant, for an adult subject or the subject's
legally authorized representative to consent or refuse to consent, to
the inclusion of the subject's data, with removal of the identifiers
listed in the HIPAA Privacy Rule at 45 CFR 164.514(b)(2)(i)(A) through
(Q), in a database that is publicly available and openly accessible to
anyone. This provision is being proposed in the context of increasing
interest in inviting study participants to allow their study data, in
some cases including genomic data, to be made publicly available in
order to maximize the potential for research that spurs increased
understanding of disease processes. Under this provision, the consent
document would be required to prominently note the option for the
participant to allow the investigator to publically post (e.g., on a
Web site) the participant's genomic or other potentially identifiable
sensitive information, and to include a description of the risks
associated with public access to the data.
To facilitate the use of broad consent, the NPRM proposes that the
Secretary of HHS will publish in the Federal Register templates for
broad consent that would contain all of the required elements of
consent in these situations. It is envisioned that there would be at
least two broad consent templates developed: One for information and
biospecimens originally collected in the research context, and another
for information and biospecimens originally collected in the non-
research context.
In addition, two exemptions are proposed related to facilitating
secondary research use of biospecimens and identifiable private
information when the Secretary's broad consent template is used. These
exemptions are described in section II.A.3 of this preamble.
The NPRM also proposes that the template for consent established by
the Secretary may serve as the written consent form in circumstances
when the proposed exemption categories at Sec. __.104(f) require
written consent. In circumstances where Sec. __.104(f)(1) allows for
oral consent, a subject's oral consent for secondary research use of
identifiable private information must be documented such that the
consent is associated with the subject's identifiable information. If
this requirement is met through the use of written documentation, the
subject would not be required to sign anything.
e. What would change?
No change would be made in the current regulatory
framework allowing research use of non-identified private information
without consent, except that, when relevant, individuals would be given
an option to consent or refuse to consent to the inclusion of their
data, with the removal of certain identifiers, in a publicly available
database.
Broad consent would be permissible for the storage or
maintenance for secondary research use of biospecimens and identifiable
private information, and for the use of such stored material for
individual research studies.
No change would be made to the definition of ``legally
authorized representative.''
f. Questions for Public Comment
61. Public comment is sought on whether broad consent to secondary
research use of information and biospecimens collected for non-research
purposes should be permissible without a boundary, or whether there
should be a time limitation or some other type of limitation on
information and biospecimens collected in the future that could be
included in the broad consent as proposed in the NPRM. If a time limit
should be required, is the NPRM proposal of up to 10 years a reasonable
limitation? Would a limitation related to an identified clinical
encounter better inform individuals of the clinical information and
biospecimens that would be covered by a broad consent document?
62. Public comment is sought on whether all of the elements of
consent proposed at Sec. __.116(c) should be required for the
secondary use of biospecimens or identifiable private information
originally collected as part of a research study that was conducted
without consent because either the original research study met an
exclusion or exempt category of research, or a waiver of consent was
approved by an IRB.
63. Public comment is sought on whether oral consent should be
permissible in limited circumstances as proposed under exemption Sec.
__.104(f)(1).
64. Would research subjects continue to be appropriately protected
if the
[[Page 53975]]
definition of ``legally authorized representative'' were broadened to
include individuals authorized by accepted common practice to consent
on behalf of another individual to participation in clinical
procedures? If the definition of ``legally authorized representative''
was broadened in this way, public comment is sought on the
interpretation of ``accepted'' and ``common'' as these terms would be
used in the revised definition.
3. Waiver of Informed Consent or Documentation of Informed Consent
(NPRM at Sec. Sec. __.116(e), (f) and __.117)
a. NPRM Goals
The goals of the proposals related to the waiver of informed
consent and the documentation of informed consent are to uphold
individuals' autonomy interests in determining whether their
biospecimens and identifiable private information may be used for
secondary research, to facilitate the recruitment of prospective
research subjects, and to create more flexible rules for documenting
informed consent for certain subject populations.
b. Current Rule
Currently the Common Rule permits an IRB to waive the requirements
for obtaining informed consent under two sets of circumstances
described at Sec. __.116(c) or (d)). The most common set of
circumstances requires that four specific criteria be satisfied (Sec.
__.116(d)).
Under the current Common Rule at Sec. __.117(c), IRBs may waive
the requirement for the investigator to obtain a signed consent form
for some or all subjects. The current criteria for such a waiver may
not be flexible enough for dealing with a variety of circumstances,
such as when federally sponsored research is conducted in an
international setting where for cultural or historical reasons signing
documents may be viewed as offensive and problematic.
c. ANPRM Discussion
The ANPRM asked whether changes to the regulations would clarify
the current four criteria for waiver of informed consent and facilitate
their consistent application. The ANPRM also asked for comments on the
information investigators should be required to provide to prospective
subjects in circumstances where the regulations would permit oral
consent. Additional questions focused on whether there are additional
circumstances under which it should be permissible to waive the usual
requirements for obtaining or documenting informed consent, and whether
there are types of research in which oral consent without documentation
should not be permitted.
d. NPRM Proposals
Many commentators have argued that these conditions for waiver of
consent are vague and applied haphazardly at different
institutions.59 60 In response to these concerns, SACHRP,
through its Subcommittee on Subpart A, developed several
recommendations regarding the interpretation of these waiver
criteria.\61\ In particular, commenters have questioned the meaning of
the criterion at Sec. __.116(d)(2) that the waiver or alteration will
not adversely affect the rights and welfare of the subjects. Questions
have also been raised about the meaning of the term ``practicably'' as
used in Sec. __.116(d)(3), which states that the research could not
practicably be carried out without the waiver or alteration.
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\59\ Green LA, Lowery JC, Kowalski CP, Wyszewianski L. Impact of
institutional review board practice variation on observational
health services research. Health Serv Res 2006;41:214-230.
\60\ Sanders AB, Hiller K, Duldner J. Researchers' understanding
of the federal guidelines for waiver of and exception from informed
consent. Acad Emerg Med 2005;12:1045-1049.
\61\ Secretary's Advisory Committee on Human Research
Protections (2008, January 31). SACHRP Letter to HHS Secretary.
Retrieved from Advisory Committee (SACHRP): http://www.hhs.gov/ohrp/sachrp/sachrpletter013108.html.
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Further, some have argued that the requirements for obtaining
waivers of informed consent or waivers of documentation of informed
consent are confusing and inflexible, which leads to inconsistent
application.\62\ These problems may not be inherent in the language of
the Common Rule, but there may be some changes to the regulations or
clarifications as to how to interpret and implement such regulations
that could improve informed consent forms and the informed consent
process.
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\62\ See supra note 59.
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The NPRM offers several proposals related to the waiver or
alteration of informed consent provisions (Sec. __.116(c) and (d) in
the current rule, Sec. __.116(e) and (f) in the NPRM). The NPRM
proposes at Sec. __.116(f)(1)(iv) to retain the language found in
Sec. __.116(d)(2) of the current Rule regarding the necessity to
evaluate the rights and welfare of subjects before issuing a waiver of
consent or altering consent procedures. Despite the vagueness of the
term, IRBs should consider whether there are considerations distinct
from the risk of harm and discomfort that the IRB should be able to
take into account in deciding whether to approve a waiver or alteration
of informed consent. Note that SACHRP's recommendations included a
comment that the IRB should determine ``. . . that the waiver or
alteration does not adversely impact the ethical nature or scientific
rigor of the research. . . ,'' which implies that there could be
ethical considerations other than the degree of risk that could
legitimately affect the IRB's decision.
This criterion can be interpreted to include rights conferred by
pertinent federal law or regulation, relevant state or local law, the
stipulations at Sec. __.101(e) and (f) (in both the NPRM and the
current Rule), or laws in other countries where research is to be
conducted. It could also include considerations of privacy or the right
to decide how someone is going to be treated, where the IRB determines
that subjects have such a right that the waiver would adversely impact,
or where the waiver would preclude them from obtaining a benefit they
would otherwise receive. We recognize that further guidance regarding
this criterion would be helpful.
HHS has also evaluated the utility of the term ``practicably''
contained in the elements of waiver or alteration of consent (Sec.
__.116(d)(3) in the current Rule). The NPRM proposes to keep this
terminology at Sec. __.116(f)(1)(ii) in the NPRM. SACHRP has noted
that the commonly accepted definitions of the term ``practicably'' are
(1) feasible; (2) capable of being effected, done or put into practice;
and (3) that may be practiced or performed; capable of being done or
accomplished with available means or resources. SACHRP emphasized this
criterion states that the research could not practicably be carried out
without the waiver or alteration. In other words, it would not be
practicable to perform the research (as it has been defined in the
protocol by its specific aims and objectives) if consent was required.
Thus it is impracticable to perform the research, and not just
impracticable to obtain consent. SACHRP also offered the following
concepts to help an IRB determine whether the research could not be
practicably carried out without the waiver of consent: (1) Scientific
validity would be compromised if consent was required; (2) ethical
concerns would be raised if consent were required; (3) there is a
scientifically and ethically justifiable rationale why the research
could not be conducted with a population from whom consent can be
obtained; (4) practicability should not be determined
[[Page 53976]]
solely by considerations of convenience, cost, or speed.\63\
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\63\ See Secretary's Advisory Committee on Human Research
Protections (2008, January 31). SACHRP Letter to HHS Secretary.
Retrieved from Advisory Committee (SACHRP): http://www.hhs.gov/ohrp/sachrp/sachrpletter013108.html.
---------------------------------------------------------------------------
SACHRP's recommendations are consistent with OHRP's interpretation
of this waiver criterion. Consideration was given to replacing the term
practicably with another term such as feasibly, but HHS is uncertain
whether such a change would improve the understanding of this
criterion. Thus the NPRM proposes to retain this phrase.
Few comments to the 2011 ANPRM were received on this topic although
many commenters expressed support for clarifying the key terms through
guidance or altering the criteria. In particular, most comments on this
topic noted the confusion that IRBs face when trying to understand the
meaning of the terms ``practicably'' and ``adversely affect the rights
and welfare of subjects.'' Some commenters expressed the opinion that
the waiver criterion concerning rights and welfare should be
interpreted to include reference to rights conferred by other federal
laws or regulations, state or local laws, or laws in other countries
where research is to be conducted. Some comments reflected concerns
about privacy or security. Several commenters also pointed to the need
to consider community norms throughout the consent process, including
its documentation.
The NPRM proposes to add a new waiver criterion at Sec.
__.116(f)(1)(iii), which would require that, for research involving
access to or use of identifiable biospecimens or identifiable
information, the research could not practicably be carried out without
accessing or using identifiers. This criterion was modeled on the
comparable criterion in the HIPAA Privacy Rule, which requires that the
research could not practicably be conducted without access to and use
of the protected health information. The principle embodied in this
additional criterion is that non-identified information should be used
whenever possible in order to respect subjects' interests in protecting
the confidentiality of their data and biospecimens.
Additional more stringent waiver conditions apply to research
involving biospecimens, specifically that (1) there are compelling
scientific reasons for the research use of the biospecimens; and (2)
the research could not be conducted with other biospecimens for which
informed consent was or could be obtained. Under this new, more
stringent waiver standard, the circumstances in which a waiver could be
granted by an IRB should be extremely rare.
The Common Rule departments and agencies considered whether to
require institutions or IRBs to report to OHRP when this waiver of
consent for research involving the use of biospecimens was approved by
an IRB. If such a reporting were required, it is envisioned that OHRP
could use the information to consider whether the waiver provision was
being implemented appropriately or whether regulatory changes might be
needed (e.g., because such waivers were too frequently being granted).
It is estimated that such a reporting requirement would constitute
almost no burden to institutions, since the very premise behind the
waiver provision is that such waivers should be extremely rare. It is
also recognized that such a reporting requirement might deter IRBs from
utilizing the waiver provision. The NPRM does not include a reporting
requirement to OHRP when this waiver of consent is approved by an IRB,
but public comments are requested on whether such a reporting
requirement should be included in the final rule.
The Common Rule departments and agencies also considered whether
the NPRM should propose that a waiver of consent not be permissible for
secondary research involving the use of biospecimens. The purpose of
such a requirement would be to encourage investigators to seek broad
consent for such research. This proposal was not included in the NPRM,
but public comments are requested on whether such a prohibition to
waive informed consent should be included in the final rule.
In addition, the NPRM proposes that the Common Rule prohibit IRBs
from waiving informed consent if individuals were asked and refused to
provide broad consent to the storage and maintenance for secondary
research use of biospecimens and identifiable private information. If a
subject refused to provide broad consent, it is proposed that this
refusal would need to be recorded by the investigator to better ensure
that the subject's wishes would be honored.
The proposal to not allow any waivers of consent by an IRB with
regard to the secondary research use of identifiable private
information if an individual was asked to consent to such use, and
refused to consent, was thoroughly considered during the drafting of
this document. On the one hand, a core initial motivation for this NPRM
has been the recognition that we should not be imposing unnecessary
burdens on low-risk research that is capable of producing important
knowledge. Re-using data that has been generated for other purposes,
when appropriate protections for privacy and confidentiality are in
place, seems to fit within that category.
Moreover, with society's growing abilities to rapidly generate
massive data sets, and manipulate such data using cutting-edge
algorithms, research using ``big data'' seems more important than ever.
At the same time, however, it is recognized that if an individual is
asked to provide consent and declines or refuses to do so, the
individual's choice should be honored, except perhaps under only very
rare circumstances that justify overriding an individual's autonomy
interest.
Most of the provisions in this NPRM regarding the research use of
identifiable private information have led to the conclusion that, when
there are appropriate privacy protections in place, the balance between
respect for persons and beneficence should come out in favor of
facilitating the research, including not requiring informed consent in
many instances. In recognition of this circumstance, while the NPRM
proposes new consent requirements related to biospecimens (justified
primarily by the special autonomy interest of a person in controlling
the research use of such biospecimens), it does not impose such consent
requirements with regard to research use of a person's identifiable
private information. Accordingly, in most respects, the current Rules--
which do allow such use without consent, provided that an IRB has
reviewed the study and found that it meets the criteria for the waiver
of consent--are retained with regard to the secondary research use of
such information. For research involving the secondary use of
identifiable private information, waivers of consent appear to
currently be quite frequently given by IRBs, and represent a
significant (and likely growing) portion of the research universe.
Accordingly, even after the implementation of this NPRM, an
individual will still generally not have the right to prevent secondary
research taking place using their identifiable private information, in
the event that an IRB approves a waiver of consent for such a study.
(Indeed, this is only one of the circumstances in which the NPRM allows
such research to take place without consent; the NPRM has actually
expanded such circumstances through some of the exclusions and
exemptions, based on the ethical analysis mentioned above.) The main
alteration of this rule by the NPRM
[[Page 53977]]
would be in the circumstance described above: Where the individual
happened to be asked to sign a broad consent regarding the use of that
information, and they refused to do so. If that happened, an IRB would
no longer be able to waive consent.
This is a complicated issue, and as discussed below, comments are
sought on various aspects of the proposal to allow for broad consent
for secondary use of identifiable private information, including
whether it is appropriate to include the limitation on an IRB's ability
to waive consent where a person has been asked to sign a broad consent
form, but refused.
The NPRM also clarifies that waivers of informed consent and the
waivers related to documenting informed consent might not be permitted
for research subject to FDA regulation. For example, research conducted
with a waiver of informed consent, or its documentation, may, if
submitted in support of a marketing application to FDA, become subject
to certain applicable informed consent requirements under 21 CFR part
50.
A provision has also been added at Sec. __.116(g) in the NPRM to
address concerns that the current regulations require an IRB to
determine that informed consent can be waived under the current Sec.
__.116(d) (Sec. __.116 (e) and (f) in the NPRM) before investigators
may record identifiable private information for the purpose of
identifying and contacting prospective subjects for a research study.
This requirement to waive informed consent is viewed as burdensome and
unnecessary to protect subjects, and is not consistent with FDA's
regulations, which do not require informed consent or a waiver of
informed consent for such activities. This proposal in the NPRM is
intended to address these concerns and to make the Common Rule
consistent with the FDA's regulations by eliminating the requirement
for the IRB to waive informed consent for these activities while
explicitly assuring that the information will be protected.
With regard to documentation requirements, the NPRM proposes to
alter the language at Sec. __.117(b)(1) to specify that the consent
document should include only the language required by Sec. __.116,
with appendices included to cover any additional information. The goal
here is to reduce the length and complexity of the document and to
ensure that the elements of information essential to decision-making
receive priority by appearing in the main document.
In addition, the NPRM would make it explicit in the regulatory
language at proposed Sec. __.117(c)(1)(iii) that if the subjects are
members of a distinct cultural group or community for whom signing
documents is not the norm, so long as the research presents no more
than minimal risk of harm to subjects and provided there is an
appropriate alternative mechanism for documenting that informed consent
was obtained, the requirement to obtain a signed consent form may be
waived. Documentation must include a description as to why signing
forms is not the norm for the distinct cultural group or community.
Finally, as discussed above, to facilitate tracking of broad
consent to storage or maintenance for secondary research use of
biospecimens or identifiable private information, and to provide
information to IRBs should IRB review be required, waiver of
documentation of consent for the research use of such biospecimens
would not be allowed based upon a new provision at Sec. __.117(c)(3).
The regulatory language proposed at Sec. __.117(c)(4) would also
clarify that waivers of documentation may not be permitted for research
subject to regulation by FDA.
e. What would change?
A new waiver criterion would be added at Sec.
__.116(f)(1)(iii) requiring that, for research involving access to or
use of biospecimens or identifiable information, the research could not
practicably be carried out without accessing or using identifiers.
Additional waiver criteria would apply to research
involving the use of biospecimens.
If a person was asked to provide broad consent to store or
maintain for secondary research use biospecimens or identifiable
private information and refused to do so, a waiver of consent would not
be allowed with respect to the research use of such person's
biospecimens or private identifiable information.
A new provision would be added at Sec. __.116(g) stating
that an IRB may approve a research proposal in which investigators
obtain identifiable private information without individuals' informed
consent for the purpose of screening, recruiting, or determining the
eligibility of prospective human subjects of research, through oral or
written communication or by accessing records, in order to obtain
informed consent, if the research proposal includes an assurance that
the investigator will implement standards for protecting the
information obtained in accordance with and to the extent required by
Sec. __.105.
The language at Sec. __.117(b)(1) would be altered to
specify that the consent document should include only the language
required by Sec. __.116, with appendices included to cover any
additional information. The goal here is to reduce the length and
complexity of the document and to ensure that the elements of
information essential to decision-making receive priority by appearing
in the consent document.
A new provision would be added at Sec. __.117(c)(1)(iii)
allowing a waiver of the requirement for a signed consent form if the
subjects are members of a distinct cultural group or community for whom
signing documents is not the norm. This would be allowed only if the
research presents no more than minimal risk of harm to subjects and
provided there is an appropriate alternative method for documenting
that informed consent was obtained.
f. Questions for Public Comment
65. Public comment is sought on how the waiver criterion regarding
``practicably'' at Sec. __.116(d)(3) could be explicitly defined or
otherwise clarified (e.g., what term should replace ``practicably''?).
66. Public comment is sought on the proposed differences between
the criteria for waiving informed consent for the research use of
biospecimens versus identifiable information.
67. Public comment is sought on whether the proposal to permit an
IRB to waive consent for research involving the use of biospecimens
should be included in the regulations.
68. Public comment is sought on the proposal to permit an IRB to
waive consent for the secondary use of biospecimens or information
originally collected for research purposes, even if the original
research study required subjects' informed consent.
69. Public comment is sought regarding how likely investigators are
to seek broad consent for the use of identifiable private information
(as contrasted with biospecimens), given that there are provisions
within the NPRM that would make it easier to do such research without
consent (such as the new exemption at Sec. __.104(e)(2)). In this
regard, note that the NPRM proposal to prohibit waiver of consent by an
IRB if a person has been asked for broad consent and refused to provide
it might create a disincentive on the part of investigators from
choosing to seek broad consent for research involving secondary use of
identifiable private information. Given the costs and time and effort
involved in implementing the system for obtaining broad consent for the
use of identifiable private
[[Page 53978]]
information and tracking when people provide consent or refuse to do
so, are the benefits to the system likely to outweigh the costs, and if
so, should the broad consent provisions be limited to obtaining broad
consent for research use of biospecimens?
70. Public comment is sought on the proposed prohibition on waiving
consent when an individual has been asked to provide broad consent
under Sec. __.116(c) and refused. In particular, how would this
prohibition on waiving consent affect the secondary research use of
identifiable private information? If an individual was asked to provide
such consent, should the absence of a signed secondary use consent be
considered a refusal? Does this prohibition on waiving consent for the
secondary use of identifiable private information create a disincentive
for institutions to seek broad secondary use consent and instead seek a
waiver of consent from an IRB? Under what circumstances, if any, would
it be justified to permit an IRB to waive consent even if an individual
declined or refused to consent?
4. Posting of Consent Forms
a. NPRM Goals
Public posting of consent forms is intended to increase
transparency, enhance confidence in the research enterprise, increase
accountability, and inform the development of future consent forms.
b. NPRM Proposal
Thus, the NPRM proposes a new provision at Sec. __.116(h)(1) that
would require that a copy of the final version of the consent form
(absent any signatures) for each clinical trial conducted or supported
by a Common Rule department or agency be posted on a publicly available
federal Web site that will be established as a repository for such
consent forms. The name of the protocol and contact information would
be required to be included with the submission of the consent form. The
primary purpose of this provision is to improve the quality of consent
forms in federally funded research by assuring that--contrary to
current practices, under which it is often very difficult to ever
obtain a copy of these documents--they eventually would become subject
to public scrutiny. It is anticipated that the Web site will be
searchable.
Under proposed Sec. __.116(h)(2), the consent form must be
published on the Web site within 60 days after the trial is closed for
recruitment. By final consent form, it is anticipated that
investigators generally will post the version of the consent form that
had been most recently approved by an IRB. Note that even though a
newer consent form could be developed after the timeframe specified
here, investigators would only be required to post one consent form.
Thus, even if a modification to a consent form occurs after it has been
posted, investigators would not be required to re-post an updated
document. Moreover, only one posting would be required for each multi-
site study. There is no expectation that a version would need to be
posted for each study site.
A Web site would be developed by HHS, which could be used by other
Federal departments or agencies, or the other Federal departments or
agencies could create their own Web sites for the posting of these
consent forms.
c. What would change?
A new provision at Sec. __.116(h) would require that, for
clinical trials conducted or supported by a Common Rule department or
agency, a copy of the final version of a consent form would have to be
posted on a publicly available federal Web site within 60 days after
the trial is closed for recruitment.
C. Proposed Changes To Protect Information and Biospecimens (NPRM at
Sec. __.105)
1. NPRM Goal
IRBs were not designed to evaluate risks to privacy and
confidentiality, and often have little expertise in these matters.
Setting uniform specific standards will help to assure appropriate
privacy and confidentiality protections to all subjects, without the
administrative burden of needing a specific committee review of the
privacy and confidentiality protections of each study.
Increasing research use of genetic information, information
obtained from biospecimens, and the ability to more easily merge
multiple sources of administrative and survey datasets (e.g., medical
records, claims data, vital records, and information about lifestyle
behaviors from surveys) have increased the stakes associated with data
breaches. For example, the unauthorized release or use of information
about subjects such as the disclosure of Social Security or Medicare
numbers may pose financial risks, and disclosure of illegal behavior,
substance abuse, or chronic illness might jeopardize subjects' current
or future employment, or cause emotional or social harm. The risks of a
large portion of social and behavioral research are also generally
informational risks.
The goal of the NPRM here is to create information privacy
protections that would apply to research, calibrated to the level of
identifiability and sensitivity of the information being collected.
2. Current Rule and Other Regulatory or Statutory Requirements
Currently, the Common Rule at Sec. __.111(a)(7) requires that IRBs
evaluate each study with regard to all levels of risk and are expected
to determine whether the privacy of subjects and the confidentiality of
their information are protected. Under the Common Rule, IRBs must
review each individual study's protection plan to determine whether it
is adequate with respect to the informational risks of that study.
In addition, the HIPAA Privacy Rule addresses some of these
informational risks by imposing restrictions on how individually
identifiable health information collected by health plans, health care
clearinghouses, and most health care providers (``covered entities'')
may be used and disclosed, including for research. In addition, the
HIPAA Security Rule (45 CFR parts 160 and 164, Subparts A and C)
requires that these entities implement certain administrative,
physical, and technical safeguards to protect this information when in
electronic form from unauthorized use or disclosure. However, the HIPAA
Rules apply only to covered entities (and in certain respects to their
business associates), and not all investigators are part of a covered
entity. Moreover, the Privacy Rule does not apply specifically to
biospecimens in and of themselves.
Separate from the HIPAA Rules, the Privacy Act of 1974, as amended
(5 U.S.C. 552a) requires Federal agencies to protect certain
information in their possession and control. However, it does not apply
to non-Federal investigators.
3. ANPRM Discussion
The ANPRM suggested establishment of mandatory data security and
information protection standards for all studies that involve the
collection, generation, storage, or use of identifiable or potentially
identifiable information that might exist electronically or in paper
form or contained in a biospecimen. It put forward the idea that these
standards might be modeled after certain standards of the HIPAA Rules
and asked a series of questions about how best to protect private
information.
[[Page 53979]]
4. NPRM Proposals
Some public comments reflected confusion about the focus of the
suggested standards and whether they would apply to information or
biospecimens that were not individually identifiable. Although most
commenters confirmed the need to protect the privacy and
confidentiality of information of human subjects in research, a
majority expressed serious concerns about the merits of requiring all
investigators to meet standards modeled on certain HIPAA standards,
such as those in the HIPAA Security Rule. Most commenters expressed the
opinion that certain HIPAA standards are not well suited to some
research of various kinds carried out by investigators not subject to
the HIPAA Rules. Some commenters claimed that the HIPAA privacy
safeguards do not adequately protect individuals' information. Many
commenters claimed that standards modeled after certain HIPAA standards
would be unnecessarily burdensome for studies in the behavioral and
social sciences where the data are often less sensitive than health
information.
Some comments maintained that HIPAA-like standards would not always
be suitable for the variety of research methods and procedures for the
collection and storage of information in research activities not
subject to the HIPAA Rules. Some commented that certain HIPAA standards
would not be suitable because of the location of the research activity,
or because the kind of institution supporting the research was
significantly different from a covered entity. Others thought the HIPAA
standards create confusion and complications for investigators and
institutions that would increase if standards modeled on certain HIPAA
standards were applied across the board. At the same time, regardless
of the specific standards to be employed under this approach, several
commenters noted that the additional administrative burden that might
be created by establishing a data security and information protection
system could be offset by the decreased time and attention IRBs would
have to invest in reviewing every study that required data or
biospecimen protections. They also noted that many institutions already
have required data and biospecimen protection systems in place.
Some commenters noted that expansion of some of the exemption
categories could only be ethically acceptable if those research
activities were subject to a requirement for data security and
information protection, because information collected for some research
studies would no longer be collected under a research plan approved by
an IRB. With regard to an absolute prohibition against re-identifying
de-identified data, many commenters expressed concern, and provided
reasons why re-identification might be valid or even desirable,
including the need to return clinically relevant research results to an
individual. For example, if the research uncovers information that
might have important clinical significance for an individual, re-
identification could be used so that the individual could get care. In
addition, they pointed out that the current Common Rule requires
investigators who re-identify non-identified private information as
part of a research study to comply with the current Common Rule
regulatory requirements.
The NPRM proposes to require that investigators and institutions
conducting research subject to the Common Rule implement reasonable
safeguards for protecting against risks to the security or integrity of
biospecimens or identifiable private information. Given the significant
concerns of public commenters about the idea discussed in the ANPRM of
adopting the standards solely modeled on certain standards of the HIPAA
Rules, the NPRM proposes several sets of standards, and allows a choice
about which to use. First, the NPRM proposes to have the Secretary of
HHS publish a list of specific measures that an institution or
investigator can use to meet the requirements. The list would be
evaluated and amended, as appropriate, after consultation with other
Common Rule departments and agencies. The proposed list will be
published in the Federal Register, and public comment on the proposed
list will be sought before the list is finalized.
The list of specific safeguards that would be identified by the
Secretary will be designed such that they could be readily implemented
by the individual investigator, could build on existing safeguards
already in place to protect research data, and would involve minimal
cost and effort to implement. These standards would include security
safeguards to assure that access to physical biospecimens or data is
limited only to those who need access for research purposes. These
standards would also assure that access to electronic information is
only authorized for appropriate use. Finally, these safeguards would
assure that information and biospecimens posing informational risks to
subjects would be protected according to appropriate standards.
Second, if an institution or investigator is currently required to
comply with the HIPAA rules, then the safeguards required by the Common
Rule would be satisfied. No additional requirements are proposed to
protect information that is subject to the HIPAA Rules. The NPRM also
proposes to clarify at Sec. __.105(d) that the provisions at Sec.
__.105 do not amend or repeal the requirements of 45 CFR parts 160 and
164 for the institutions or investigators to which these regulations
apply pursuant to 45 CFR 160.102. Institutions or investigators that
are not required to follow HIPAA could voluntarily implement the HIPAA
Rules and be considered to satisfy the Sec. __.105 privacy protections
requirements. For Federal departments and agencies that conduct
research activities that are or will be maintained on information
technology that is subject to and in compliance with section 208(b) of
the E-Government Act of 2002, 44 U.S.C. 3501 note, if all of the
information collected, used, or generated as part of the activity will
be maintained in systems of records subject to the Privacy Act of 1974,
5 U.S.C. 552a, and the research will involve a collection of
information subject to the Paperwork Reduction Act of 1995, 44 U.S.C.
3501 et seq., the requirements of Sec. __.105 will be deemed
satisfied.
For the purposes of informing the development of the Sec. __.105
privacy safeguards, comment is sought on what types of safeguards would
be appropriate.
There are additional statutes or acts that mandate the protection
of privacy and confidentiality of identifiable private information that
may be reasonable to include in Sec. __.105(b) as additional standards
which, if research is already subject to those standards or a
voluntarily election to comply with them is made, should perhaps be
viewed as meeting the new requirement. These include:
The Confidential Information Protection and Statistical
Efficiency Act, 44 U.S.C. 3501 note;
The Family Educational Rights and Privacy Act of 1974, 20
U.S.C. 1232g;
The Census Act, 13 U.S.C. 1 et seq.;
Agency for Healthcare Research & Quality (AHRQ) statutory
provision protecting the confidentiality of identifiable data obtained
for research purposes by AHRQ or its contractors and grantees, 42
U.S.C. 299c-3(c);
The CDC National Center for Health Statistics (NCHS)
statutory confidentiality provision at Section 308(d) of the Public
Health Service Act,
[[Page 53980]]
42 U.S.C. 242m(d) (using nearly identical language to the AHRQ
statutory provision referenced above);
The Substance Abuse and Mental Health Services
Administration authorizing statute regarding confidentiality of alcohol
and drug abuse patient records at 42 U.S.C. 290dd-2;
The Department of Justice statute related to
confidentiality of information used by the Office of Justice Programs
at 42 U.S.C. 3789g;
The Department of Education statute related to Education
Sciences Reform at 20 U.S.C. 9573.
Public comment is sought on whether any of the above referenced
statutes or acts would serve the goals of Sec. __.105. Note that the
statutes and acts referenced in Sec. __.105(b) are currently
referenced in the proposed exclusions at Sec. __.101(b)(2)(i)
(exclusion for surveys, educational tests, and public observation) and
Sec. __.101(b)(2)(iii) (exclusion for federal departments or agencies
to use pre-existing federally generated non-research data). To that
end, public comment is also sought as to whether the goals of the NPRM
are served by referencing any of the aforementioned statutes, acts, or
standards in the exclusions proposed in Sec. __.101(b)(2)(i) and
(iii).
In order to reduce burden on IRBs that may under the current
regulation be tasked with ensuring that safeguards are commensurate
with informational risk, IRB review of required safeguards generally
would not be required. Note that while the proposed language at Sec.
__.111(a)(7) requires that IRBs consider if the privacy safeguards at
Sec. __.105 are sufficient to protect the privacy of subjects and the
confidentiality of data, the presumption would be that these privacy
safeguards are sufficient in most circumstances.
The new section includes conditions for use and disclosure of
research information to other entities, consistent with those
protections to participants in research conducted by Federal employees
and their contractors. It requires that protections be in place when
biospecimens or identifiable private information are shared for
appropriate research or other purposes as specified in the rule. Unless
required by law, the NPRM would limit the re-disclosure of biospecimens
and identifiable private information that were obtained for research
purposes to the following four purposes: (1) For human subjects
research regulated under the Common Rule; (2) for public health
purposes; (3) for any lawful purpose with the consent of the subject;
or (4) for other research purposes if the institution or investigator
has obtained adequate assurances that: The recipient investigator will
implement and maintain the level of safeguards required by this
provision, and the research has been approved by an IRB under Sec.
__.111 (except for human subjects research that qualifies for exclusion
under proposed Sec. __.101(b) or exemption under proposed Sec. __.104
and the recipient will not further disclose the biospecimens or
identifiable private information except as permitted by this provision
(NPRM at Sec. __.105(c)).
These four purposes are additional uses or disclosures of
biospecimens or identifiable private information collected in research,
because the subjects themselves consented, or because the information
and biospecimens will continue to be safeguarded, or because the public
health will be served. For the purposes of this requirement, an
institution or investigator must obtain adequate assurances through the
use of a written agreement with the recipient of the biospecimens or
identifiable private information that the recipient will abide by these
conditions. In developing this provision, Common Rule departments and
agencies discussed whether it was appropriate to limit the re-
disclosure of biospecimens and identifiable private information
``unless [such a disclosure was] required by law'' or if some other
standard (such as ``unless [such a disclosure was] authorized by law'')
would be appropriate. Public comment is sought on whether limiting re-
disclosure to four specific circumstances unless such a disclosure was
``required by law'' is too restrictive, or whether more permissive
standards would better facilitate the NPRM goal of fostering the
secondary research use of information.
Also, research involving the collection and use of biospecimens or
identifiable private information that would qualify for an exemption
under section Sec. __.104(e) and (f) must conform to the privacy
safeguards proposed in Sec. __.105. A proposed change also appears at
Sec. __.115(c), requiring that IRB records that contain identifiable
private information also be safeguarded through compliance with the
safeguards proposed at Sec. __.105.
In addition to ensuring that biospecimens and identifiable private
information are protected, a benefit of this new provision is that IRBs
would not be required to review the individual plans for safeguarding
information and biospecimens for each research study, so long as
investigators will adhere to them. While there is a presumption that
the proposed Sec. __.105 privacy safeguards are sufficient, an IRB may
determine that a particular activity requires more than what is
discussed in Sec. __.105. Once IRBs are familiar with standard
institutional and investigator adopted protections, it is anticipated
that they will become more comfortable with the fact that they need not
review every protocol for privacy safeguards. In addition, there will
be an overall reduction in regulatory burden because IRBs will not have
to review security provisions on a case-by-case basis.
Finally, the proposed exemptions found at Sec. __.104(e) and (f),
which will permit a larger number of protocols to proceed without IRB
review if specific conditions are met, are conditioned on investigators
and institutions meeting these privacy and security requirements. Note
that there is currently no requirement for an IRB to determine whether
investigators are adhering to the Sec. __.105 privacy safeguards for
research exempted under Sec. __.104(e) or (f).
5. What would change?
The NPRM would create a set of standards for the
protection of information for research to create an effective and
efficient means of implementing appropriate protections for information
and biospecimens.
The NPRM also proposes to include limitations for the use
and disclosure of information and biospecimens.
IRBs would be required to safeguard their records in
compliance with the provisions at Sec. __.105 if the records contain
identifiable private information.
6. Questions for Public Comment
71. Public comment is sought regarding whether particular
information security measures should be required for certain types of
information or research activities and, if so, what measures and for
what types of information or research. Specifically, should the
safeguards be calibrated to the sensitivity of the information to be
collected?
72. Are the proposed limitations on re-disclosure more or less
restrictive than necessary? Are there additional purposes for which re-
disclosure of biospecimens or identifiable private information should
be permitted?
D. Harmonization of Agency Guidance (NPRM at Sec. __.101(j))
1. NPRM Goal
From the outset of the development of the Common Rule, the
importance of consistency across the Federal Government has been
recognized. Each
[[Page 53981]]
Common Rule department or agency may issue its own guidance regarding
the protection of human subjects. Consequently, there may be variations
in the guidance issued.
As the label of the Common Rule suggests, there seems to be a
compelling case for consistency across Federal departments and agencies
regarding guidance on the protections of human subjects. Nevertheless,
there are arguments in favor of some departments or agencies imposing
specific requirements, apart from the Common Rule, that are tailored to
certain types of research. The various agencies that oversee the
protection of human subjects range from regulatory agencies, to those
agencies and departments that conduct research, and to those that
support and sponsor research. In addition, in some cases, statutory
differences among the agencies have resulted in different regulatory
requirements and agency guidance. Not only do the agencies have
different relationships to the research, but they also oversee very
different types and phases of research and thus there may be reasonable
justifications for differences in guidance. Moreover, achieving
consensus across the entire Federal Government may be arduous,
preventing timely issuance of guidance.
2. Current Rule
Each Common Rule agency, and the FDA, is authorized to issue its
own guidance with regard to interpreting and implementing the
regulations protecting human subjects. That guidance may substantially
differ from agency to agency.
Currently, there are multiple efforts to address variation in
guidance across the Federal Government, but there is no regulatory
requirement for agencies to consult other departments prior to issuance
of a policy, to the extent appropriate. As a result, inter-departmental
communication is at times uneven, leading to potentially avoidable
inconsistencies. The Common Rule departments and agencies have
procedures for sharing proposed guidance before it is adopted, and
these procedures have generally been successful. Additionally, FDA and
OHRP have been working closely to ensure harmonization of guidance and
regulation to the extent possible, given the differing statutory
authorities and regulatory missions.
3. ANPRM Discussion
The ANPRM did not suggest any specific approaches to harmonization
but asked for public comment on a set of questions focused on: (1) The
extent to which differences in guidance on research protections from
different agencies strengthen or weaken protections for human subjects;
(2) the extent to which differences in guidance on research protections
from different agencies facilitate or inhibit the conduct of research
domestically and internationally; and (3) the desirability of all
Common Rule agencies issuing one set of guidance.
4. NPRM Proposal
Responses to questions in the 2011 ANPRM about the need for
harmonization across Common Rule agencies reflected widespread support
for such efforts. Several commenters acknowledged the difficulty of
getting all Common Rule agencies to agree on all issues, as each has a
different mission and research portfolio. However, they encouraged
seeking harmonized guidance whenever possible.
Thus, the NPRM proposes that the regulations contain language at
Sec. __.101(j) requiring consultation among the Common Rule agencies
for the purpose of harmonization of guidance, to the extent
appropriate, before federal guidance on the Common Rule is issued,
unless such consultation is not feasible.
The Department believes this proposal appropriately recognizes the
importance of harmonized guidance by creating an expectation that
guidance should only be issued after consultation among the Common Rule
agencies, while also permitting guidance to be issued without such
consultation when it is not feasible. The proposal also recognizes that
harmonization will not always be possible or desirable given the varied
missions of the agencies that oversee the protection of human subjects
and differences in statutory authorities. Although the NPRM proposal is
limited to requiring consultation for the purpose of harmonization, the
Common Rule agencies may wish to consult with one another before
issuing guidance for reasons other than the purpose of harmonization,
and the proposal would not preclude this. Some concerns have been
expressed that the proposed language in Sec. __.101(j) does not go far
enough to mandate harmonization in guidance between Common Rule
agencies. Others are concerned that this provision would, in effect,
mean that Common Rule agencies issue fewer guidance documents because
of lengthy internal government review and approval processes. Public
comment is sought about the effectiveness of the consultation language
proposed in Sec. __.101(j), and whether this language should require
more (or less) than consultation amongst Common Rule agencies before
guidance is issued.
For example, FDA intends to modify its regulations in light of this
NPRM, to the extent appropriate, considering its unique statutory
framework and regulatory mission. In developing guidance that
interprets its human subject protection regulations that mirror the
requirements found in the Common Rule, FDA may seek consultation with
the Common Rule agencies, to the extent feasible. Further, FDA and OHRP
will continue to work together in developing guidance on their
respective regulatory requirements that are found both in FDA
regulations and in the Common Rule, to the extent feasible.
5. What would change?
The regulations would contain language at Sec. __.101(j)
requiring consultation among the Common Rule agencies for the purpose
of harmonization of guidance, to the extent appropriate, before federal
guidance on the Common Rule is issued, unless such consultation is not
feasible.
6. Question for Public Comment
73. Will the proposed language at Sec. __.101(j) be effective in
achieving greater harmonization of agency guidance, and if not, how
should it be modified?
E. Cooperative Research (NPRM and Current Rule at Sec. __.114) and
Proposal To Cover Unaffiliated IRBs Not Operated by an Institution
Holding a Federalwide Assurance (NPRM at Sec. __.101(a))
1. NPRM Goal
The goal is to enhance and streamline the review process, reduce
inefficiencies, and hold unaffiliated IRBs directly accountable for
regulatory compliance, without compromising ethical principles and
protections.
2. Current Rule
Currently, an institution engaged in non-exempt human subjects
research conducted or supported by any Federal department or agency
that has adopted the Common Rule is required to hold an OHRP-approved
FWA or another assurance of compliance approved by the Federal
department or agency conducting or supporting the research. The FWA
mandates the application of the Common Rule only to certain federally
funded research projects. Most institutions voluntarily extend the
applicability of the Common Rule to all the research conducted at their
[[Page 53982]]
institutions, even research not conducted or supported by one of the
federal departments or agencies that have adopted the Common Rule.\64\
However, such extensions are not required. Many observers have called
for legislation that would extend the Common Rule protections to all
research with human subjects conducted in the United States, regardless
of funding source.
---------------------------------------------------------------------------
\64\ According to the OHRP's FWA Database, twenty-five percent
of institutions with an active FWA have formally extended the Common
Rule to all research conducted at those institutions, regardless of
funding source (by ``checking the box'' on their assurance).
Comments from the regulated community suggest that most
institutions, however, voluntarily follow the requirements of the
Common Rule in all research activities conducted at these
institutions.
---------------------------------------------------------------------------
In addition, IRBs not affiliated with an institution holding an FWA
are not directly subject to oversight for compliance through the
vehicle of the FWA. OHRP's current practice of enforcing compliance
with the Common Rule in situations where an institution relies on an
external IRB is through the institutions that are engaged in human
subjects research, even in circumstances when the regulatory violation
is directly related to the responsibilities of an external IRB. Thus,
certain aspects of the regulations are not directly applied to external
IRBs.
External IRB review of cooperative research may be problematic
given the current lack of direct regulatory accountability and the
large volume of cooperative reviews. The inefficiencies of multiple IRB
reviews for cooperative studies adds bureaucratic complexity to the
review process, and delays initiation of research projects without
evidence that multiple reviews provide additional protections to
subjects.
The Common Rule currently requires that each institution engaged in
a cooperative research study obtain IRB approval of the study, although
it does not require that a separate local IRB at each institution
conduct such review. In many cases, however, a local IRB for each
institution does independently review the research protocol, informed
consent forms and other materials, sometimes resulting in hundreds of
reviews for one study. When any one of these IRBs requires changes to
the research protocol that are adopted for the entire study,
investigators must re-submit the revised protocol to all of the
reviewing IRBs. This process can take many months and can significantly
delay the initiation of research projects and recruitment of subjects
into studies.
In 2006, the FDA issued guidance intended to assist sponsors,
institutions, IRBs, and clinical investigators by facilitating the use
of a centralized IRB review process in cooperative clinical trials of
investigational new drugs.\65\
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\65\ See FDA Guidance at: Guidance for Industry: Using a
Centralized IRB Review Process in Multicenter Clinical Trials.
(2006, March). Retrieved from U.S. Food and Drug Administration:
http://www.fda.gov/downloads/RegulatoryInformation/Guidances/UCM127013.pdf.
---------------------------------------------------------------------------
Currently, the choice to have cooperative research reviewed by a
central IRB, or by an IRB at another institution, is voluntary under
the Common Rule. In practice, most institutions have been reluctant to
replace review by their local IRBs with review by a central IRB.
3. Relevant Prior Proposals and Discussions
The choice to have cooperative research reviewed by a single
unaffiliated IRB (or by an external IRB operated by or affiliated with
another FWA-holding institution) currently is voluntary. In practice,
most institutions have been reluctant to replace review by their local
IRBs with review by a single IRB. Participants in two meetings on
alternative IRB models co-sponsored by OHRP in November 2005 and
November 2006 indicated that one of the key factors influencing
institutions' decisions about this issue is OHRP's current practice of
enforcing compliance with the Common Rule through the institutions that
were engaged in human subjects research,\66\ even in circumstances when
the regulatory violation is directly related to the responsibilities of
an external IRB.
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\66\ In general, an institution is considered engaged in a
particular non-exempt human subjects research project when its
employees or agents for the purposes of the research project obtain:
(1) Data about the subjects of the research through intervention or
interaction with them; (2) identifiable private information about
the subjects of the research; or (3) the informed consent of human
subjects for the research. Office for Human Research Protections.
(2008, October 16). Guidance on Engagement of Institutions in Human
Subjects Research. Retrieved from Policy & Guidance: http://www.hhs.gov/ohrp/policy/engage08.htmll.
---------------------------------------------------------------------------
In 2009, OHRP issued an ANPRM in the Federal Register requesting
information and comments from the public about whether the office
should pursue a notice of proposed rulemaking to enable OHRP to hold
IRBs and the institutions or organizations operating the IRBs directly
accountable for meeting certain regulatory requirements of the Common
Rule.\67\ OHRP contemplated this regulatory change to encourage
institutions to rely on IRBs that are operated by another institution
or organization, when appropriate. In this ANPRM, OHRP stated that it
believed that such a regulatory change in its enforcement authority
might address one of the main disincentives institutions have cited as
inhibiting them from exercising the regulatory flexibility that
currently permits institutions to implement a variety of cooperative
review arrangements and to rely on the review of an IRB operated by
another institution or organization. If institutions become more
willing to rely on cooperative review arrangements and on review of
IRBs operated by other institutions or organizations, this could reduce
administrative burdens associated with implementing the Common Rule
without diminishing human subject protections.
---------------------------------------------------------------------------
\67\ 74 FR 9568 (Mar. 5, 2009).
---------------------------------------------------------------------------
The ANPRM sought public comment on the feasibility, advantages, and
disadvantages of mandating that all domestic (United States) sites in a
study involving more than one institution rely on a single IRB for that
study. This would apply regardless of whether the study underwent
convened review or expedited review. Further, it would only affect
which IRB would be designated as the reviewing IRB for institutional
compliance with the IRB review requirements of the Common Rule. It
would not relieve any site of its other obligations under the
regulations to protect human subjects. Nor would it prohibit
institutions from choosing, for their own purposes, to conduct
additional internal ethics reviews, though such reviews would no longer
have any regulatory status in terms of compliance with the Common Rule.
Based on public comments received to the 2009 ANPRM \68\ on the
issue of IRB accountability and to address institutions' concerns about
OHRP's practice of enforcing compliance with the Common Rule through
the institutions that are engaged in human subjects research, the 2011
ANRPM also suggested that appropriate accompanying changes could be
made in enforcement procedures to hold external IRBs directly
accountable for compliance with certain regulatory requirements.\69\
This change was discussed only for United States sites in multi-
institutional studies. The ANPRM suggested that, in most cases,
independent local IRB reviews of international sites are appropriate
because it might be difficult for an IRB in the U.S. to adequately
evaluate local conditions in a foreign country that could play an
important role in the ethical evaluation of the study.
---------------------------------------------------------------------------
\68\ 74 FR 9578 (Mar. 5, 2009).
\69\ 74 FR 9578 (Mar. 5, 2009). Also available at http://www.hhs.gov/ohrp/newsroom/rfc/com030509.html.
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[[Page 53983]]
In late 2014, NIH issued a Request for Comments on the Draft NIH
Policy on the Use of a Single Institutional Review Board for Multisite
Research. The response to NIH's proposed policy was robust and largely
supportive, with many institutions citing both reduced duplication of
effort and faster initiation of research as important factors. A
minority, however, pointed to the importance of maintaining independent
local IRB review, and expressed doubt over the anticipated efficiencies
and cost savings that would be incurred through a centralized model.
SACHRP commented on this draft policy, and was generally supportive of
voluntary increased use of a single IRB for multi-site studies, as such
use may decrease differences among site implementation of protocols.
SACHRP concluded that a uniform mandate of single IRB review for all
domestic multi-site studies was premature, and recommended a more
incentivized approach at this time.\70\
---------------------------------------------------------------------------
\70\ Secretary's Advisory Committee on Human Research
Protections. (2015). Recommendations Regarding the Draft NIH Policy
on the Use of a Single Institutional Review Board for Multi-site
Research. Retrieved from Office for Human Research Protections:
http://www.hhs.gov/ohrp/sachrp/commsec/useofasingle_irb.html.
---------------------------------------------------------------------------
4. NPRM Proposals
These issues attracted a large number of comments to the 2011
ANPRM, and revealed nearly evenly divided perspectives. Investigators
and disease advocacy groups tended to favor the single IRB review
requirement. IRB and institutional representatives tended to be opposed
to the possible requirement, though many indicated single IRB review
should be encouraged. Support was especially strong for single IRB
review for cooperative clinical trials for which the evaluation of a
study's social value, scientific validity, and risks and benefits, and
the adequacy of the informed consent form and process generally do not
require the unique perspective of a local IRB. Moreover, depending on
the nature of the study, FDA may not permit differences in protocols
across sites, which further bolstered commenters' views that the
requirements be harmonized across the Common Rule and FDA requirements.
Commenters reported incidences of IRBs continuously second-guessing
each other, which delayed studies to the point that subject recruitment
opportunities were foregone or lost. This problem seemed especially
critical in studies of rare diseases and cancers, which nearly always
involve multiple research sites.
Support for the use of a single IRB, however, was not restricted to
clinical trials. Several commenters cited long delays and burdensome
requirements resulting from multiple reviews of studies in the
behavioral and social sciences. In addition to the view that these
administrative requirements do not enhance protections, supporters of a
single IRB review of cooperative studies cited the frequent need for
maintaining consistency across sites, which can be degraded by multiple
reviews.
Despite support for the ANPRM suggestion, several commenters
expressed concern about making such a provision mandatory, stating that
the current regulations at Sec. __.114 permit the use of joint review
arrangements for cooperative research. They noted that although this
option exists, institutions might be hesitant to use it because of
liability concerns and the unwillingness of institutions or IRBs to
rely on the judgment of other institutions or IRBs. However, several
commenters expressed concern about signaling the acceptability of a
single IRB for review while allowing institutions to continue to
conduct their own ethics review, fearing that such a policy would not
correct the current situation, which tends to favor multiple reviews.
Thus, they commented that mandating a single IRB might be the only way
to achieve the goals of streamlining review while ensuring protections.
Another issue raised was the need to set clearer expectations of
the responsibilities of local IRBs that are not designated as the
central IRB. A number of commenters supporting the requirement for a
central IRB also requested that OHRP issue guidance on how to select
the IRB, responsibilities of all parties, and compliance and
enforcement policies. Several commenters also requested that OHRP
develop a template for reliance agreements to replace inter-
institutional agreements currently in use.
Those who expressed concern about the use of a single IRB said some
studies, especially in the behavioral and social sciences, might
involve significant contextual issues reflecting community norms,
standards, and practices, or local culture and customs. Use of a
distant IRB might not consider and best protect subjects based on
community norms. Others noted that such concerns can be addressed by
investigators or IRBs submitting ``points to consider'' regarding
significant contextual or cultural considerations of relevance to their
site.
A primary issue posed by those opposed to mandating use of a single
IRB in cooperative studies focused on potential loss of accountability
and increased liability for the institutions where the research is
conducted but where the reviewing IRB is not located.
Taking into consideration this public debate and various sources of
public comments, the NPRM proposes a requirement at Sec. __.114(b)(1)
mandating that all institutions located in the United States engaged in
cooperative research rely on a single IRB as their reviewing IRB for
that study. Under proposed Sec. __.114(b)(2), this requirement would
not apply to: (1) Cooperative research for which more than single IRB
review is required by law (e.g., FDA-regulated devices); or (2)
research for which the Federal department or agency supporting or
conducting the research determines and documents that the use of a
single IRB is not appropriate for the particular study.
Based on comments to OHRP's 2011 ANPRM, the NPRM also proposes to
add a new provision at Sec. __.101(a) that would explicitly give
Common Rule departments and agencies the authority to enforce
compliance directly against unaffiliated IRBs that are not operated by
an assured institution. This change is proposed to address concerns
about OHRP's current practice of enforcing compliance with the Common
Rule through the institutions that are engaged in human subjects
research, even in circumstances when the regulatory violation is
directly related to the responsibilities of an external IRB. In large
part, this change was made to facilitate the use of a single IRB in
cooperative research, allowing OHRP to enforce compliance with the
Common Rule through non-compliant external IRBs rather than the
institutions that were engaged in human subjects research. This
proposal should encourage institutions to be more willing to rely on a
single IRB for cooperative research as required under the NPRM proposal
at Sec. __.114. It would reassure institutions using an external IRB
because compliance actions could be taken directly against the IRB
responsible for the flawed review, rather than the institutions that
relied on that review.
Some public commenters responding to the 2011 ANPRM cautioned that
extending compliance oversight to external IRBs might serve as a
disincentive for some IRBs to be the IRB of record for cooperative
research. A majority of commenters expressed an opposing view; that is,
holding external IRBs directly accountable for compliance with the
regulations would increase the comfort level of institutions in
accepting the regulatory review of an external IRB.
[[Page 53984]]
Related to this issue is a new provision proposed at Sec.
__.103(e) regarding policies for documenting an institution's reliance
on an external IRB. That provision states that for non-exempt research
involving human subjects covered by this policy that takes place at an
institution in which IRB oversight is conducted by an IRB that is not
affiliated with the institution, the institution and the IRB should
establish and follow written procedures identifying the compliance
responsibilities of each entity. These procedures should be set forth
in an agreement between the institution and the IRB specifying the
responsibilities of each entity in ensuring compliance with the
requirements of this policy.
This would only apply to U.S.-conducted portions of studies because
the flexibility to make use of external local IRB reviews of
international sites should be maintained; it might be difficult for an
IRB in the United States to adequately evaluate local conditions in a
foreign country that could play an important role in the ethical
evaluation of the study.
This policy would apply regardless of whether the study underwent
convened review or expedited review. This proposal only affects the
decision regarding how an IRB would be designated as the reviewing IRB
for institutional compliance with the IRB review requirements of the
Common Rule. The reviewing IRB is expected to be selected either by the
funding agency or, if there is no funding agency, by the lead
institution conducting the study. An agency may solicit input regarding
which IRB would be most appropriate to designate as the IRB of record.
Public comment is sought on how this will work in practice.
This policy would not relieve any site of its other obligations
under the regulations to protect human subjects. Nor would it prohibit
institutions from choosing, for their own purposes, to conduct
additional internal IRB reviews, though such reviews would no longer
have any regulatory status in terms of compliance with the Common Rule.
Although a local IRB may conduct its own additional internal review,
such a review would not be binding on the local site if not adopted by
the single IRB, and the terms of it would not be enforced by OHRP.
Relevant local contextual issues (e.g., investigator competence,
site suitability) pertinent to most studies can be addressed through
mechanisms other than local IRB review. For research where local
perspectives might be distinctly important (e.g., in relation to
certain kinds of vulnerable populations targeted for recruitment),
local IRB review could be limited to such consideration(s); but again,
IRB review is not the only mechanism for addressing such issues. The
evaluation of a study's social value, scientific validity, and risks
and benefits, and the adequacy of the informed consent form and process
generally do not require the unique perspective of a local IRB.
The proposal also modifies the current regulations by removing the
requirement that only with the approval of the department or agency
head may an institution participating in a cooperative project enter
into a joint review arrangement, rely upon the review of another IRB,
or make similar arrangements for avoiding duplication of effort. Such
approval is no longer required.
Some detractors of mandated single IRB review for cooperative
research point to concerns regarding implementation logistics, and the
time necessary to establish new policies, procedures, and agreements;
recognizing this concern, the proposed compliance date is three years
from the publication of the final rule.
5. What would change?
IRBs not affiliated with an assured institution that
review research covered by the Common Rule would be subject to direct
compliance oversight regarding IRB regulatory requirements.
All U.S. institutions engaged in a cooperative study would
rely upon a single IRB for that study, with some exceptions.
6. Questions for Public Comment
74. Is mandated single IRB review for all cooperative research a
realistic option at this time? Please provide information about the
likely costs and benefits to institutions. Will additional resources be
necessary to meet this requirement in the short term? Should savings be
anticipated in the long run?
75. What areas of guidance would be needed for institutions to
comply with this requirement? Is there something that OHRP could do to
address concerns about institutional liability, such as the development
of model written agreements?
76. Would it be useful for this requirement to include criteria
that Federal departments or agencies would need to apply in determining
whether to make exceptions to the use of a single IRB requirement? If
so, what should these criteria be?
77. Are the exceptions proposed appropriate and sufficient, or
should there be additional exceptions to this mandate for single IRB
review than those proposed in the NPRM? If additional exceptions should
be included, please provide a justification for each additional
exception recommended.
78. Is three years appropriate timing to establish compliance with
this provision?
F. Changes To Promote Effectiveness and Efficiency in IRB Operations
1. Continuing Review of Research (NPRM at Sec. __.109(f); Current Rule
at Sec. __.109(e))
a. NPRM Goal
The goal is to reduce or eliminate the need for continuing review
in specific circumstances, thereby reducing regulatory burden that does
not meaningfully enhance protection of subjects.
b. Current Rule
The current regulations at Sec. __.109(e) require that IRBs
conduct continuing review of research covered by this policy at
intervals appropriate to the degree of risk, but not less than once per
year. Except when an expedited review procedure is used, continuing
review of research must occur at convened meetings at which a majority
of the IRB members are present, including at least one member whose
primary concerns are in nonscientific areas. In order for research
undergoing continuing review to be approved, it must receive the
approval of a majority of those members present at the meeting (Sec.
__.108(b)).
An IRB may use an expedited review procedure to conduct continuing
review of research for some or all of the research appearing on the
list of research eligible for expedited review \71\ and found by the
reviewer(s) to involve no more than minimal risk. OHRP may restrict,
suspend, terminate, or choose not to authorize an IRB's use of the
expedited review procedure (Sec. __.110(d)).
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\71\ See Office for Human Research Protections (OHRP)--
Categories of Research That May Be Reviewed by the Institutional
Review Board (IRB) through an Expedited Review Procedure. November
9, 1998, http://www.hhs.gov/ohrp/policy/expedited98.html.
---------------------------------------------------------------------------
c. ANPRM Discussion
The ANPRM requested comments on eliminating continuing review for
all minimal risk studies that undergo expedited review, unless the
reviewer explicitly justifies why continuing review would enhance
protection of research subjects. For studies initially reviewed by a
convened IRB, continuing review would not be required, unless
[[Page 53985]]
specifically mandated by the IRB, after the study reaches the stage
where procedures are limited to either (1) analyzing data (even if it
is identifiable), or (2) accessing follow-up clinical data from
procedures that subjects would undergo as part of standard care for
their medical condition or disease.
d. NPRM Proposals
The NPRM proposes at Sec. __.109(f) eliminating continuing review
for many minimal risk studies (namely those that qualify for expedited
review), unless the reviewer documents why continuing review should
take place (as would be required by Sec. __.115(a)(8)). Moreover, for
studies initially reviewed by a convened IRB, continuing review would
not be required, unless specifically mandated by the IRB, after the
study reaches the stage where it involves one or both of the following:
(1) Analyzing data (even if it is identifiable private information), or
(2) accessing follow-up clinical data from procedures that subjects
would undergo as part of standard care for their medical condition or
disease.
In addition, continuing review would not be required for research
involving certain secondary research using information and biospecimens
that requires limited IRB review in order to qualify for exemption
under Sec. __.104(f)(1).
Further, the NPRM proposes at Sec. __.109(f)(2) that an IRB must
receive annual confirmation that such research is ongoing and that no
changes have been made that would require the IRB to conduct continuing
review (that is, the study still qualifies for expedited review because
it still meets the criteria listed above and still involves no greater
than minimal risk). This confirmation allows the IRB to
administratively account for research that is occurring without
continuing review. Investigators would continue to be required to
submit changes to the protocol to the IRB. This requirement aims to
address concerns some might have about institutional liability relating
to the status of ongoing research, the possibility for increased
noncompliance among investigators no longer required to ``check in,''
and possible breakdowns in lines of communications between
investigators and IRBs. Institutions will have significant flexibility
in how they implement this requirement. For example, some might rely on
an automated electronic communication with the investigator at one-year
intervals after the study was initiated that might merely require the
investigator to type ``yes'' indicating that the study is ongoing and
that no changes have been made. It is therefore anticipated that this
requirement can be met with minimal time and effort on the part of
investigators and IRBs. Investigators would still have the current
obligations to report various developments (such as unanticipated
problems or proposed changes to the study) to the IRB.
If an IRB chooses to conduct continuing review even when these
conditions are met, the rationale for doing so must be documented
according to a new provision at Sec. __.115(a)(8).
The NPRM, at Sec. __.115(a)(3), proposes a new requirement for
IRBs to maintain records of continuing reviews. Because the NPRM
proposes a new provision that eliminates the need for continuing review
under specific circumstances (Sec. __.109(f)(1)), the NPRM at Sec.
__.115(a)(8) also proposes that IRBs need to justify the need for
continuing review in cases where they will not follow the provision in
Sec. __.109(f)(1).
e. What would change?
Continuing review would be eliminated for all studies that
undergo expedited review, unless the reviewer explicitly justifies why
continuing review would enhance protection of research subjects. For
studies initially reviewed by a convened IRB, once certain specified
procedures are all that remain for the study, continuing review would
not be required, unless specifically mandated by the IRB. However,
investigators would be required to provide annual confirmation to the
IRB that such research is ongoing and that no changes have been made
that would require the IRB to conduct continuing review.
Continuing review would not be required for research
involving certain secondary research using information and biospecimens
that requires limited IRB review in order to qualify for exemption
under Sec. __.104(f)(1).
2. Expedited Review Procedures and the Definition of ``Minimal Risk''
(NPRM at Sec. Sec. __.110 and __.102(j))
a. NPRM Goal
IRBs report challenges in assessing the level of risk presented by
some studies in order to make the critical minimal risk determination.
This is, in part, due to the difficulties in applying the current
definition of minimal risk within the Common Rule, particularly because
the terms ``ordinarily encountered in daily life'' and ``routine
physical or psychological examinations'' are not clarified. The goal is
to help eliminate this ambiguity as it pertains to expedited review,
and improve the efficiency and consistency of minimal risk
determinations for some activities.
b. Current Rule
The concept of ``minimal risk'' is central to numerous aspects of
the Common Rule, the determination of which affects the type of review
required, considerations for IRBs in the review process, and the
frequency of review. In sum, the review process has been calibrated,
for the most part, to the risk of the research.
The current definition of minimal risk at Sec. __.102(i)
encompasses research activities where ``the probability and magnitude
of harm or discomfort anticipated in the research are not greater in
and of themselves than those ordinarily encountered in daily life or
during the performance of routine physical or psychological
examinations or tests.''
Under the Common Rule at Sec. __.110, a research study can receive
expedited review if the research activities to be conducted appear on
the list of activities published by the Secretary of HHS that are
eligible for such review,\72\ and is found by the reviewer(s) to
involve no more than minimal risk. Under an expedited review procedure,
the review may be carried out by the IRB chairperson or by one or more
experienced reviewers designated by the chairperson from among the
members of the IRB. Research that is eligible for expedited review
requires continuing review at least annually.
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\72\ See Office for Human Research Protections (OHRP)--
Categories of Research That May Be Reviewed by the Institutional
Review Board (IRB) through an Expedited Review Procedure. November
9, 1998, http://www.hhs.gov/ohrp/policy/expedited98.html.
---------------------------------------------------------------------------
c. ANPRM Discussion
The ANPRM suggested updating the current list of research
activities eligible for expedited review; this list was last updated in
1998. It also considered mandating that a federal panel periodically
(such as every year or every two years) review and update the list,
based on a systematic, empirical assessment of the levels of risk. This
would provide greater clarity about what would be considered to
constitute minimal risk, and create a process that allows for routinely
reassessing and updating the list of research activities that would
qualify as minimal risk. The ANPRM asked for public comments on
categories of research that should be considered for addition to the
current list.
[[Page 53986]]
The ANPRM asked for public comment on whether the current
regulatory definition of minimal risk is appropriate. The ANPRM further
suggested that the ``default'' assumption would be that a study
otherwise eligible for expedited review will be considered minimal risk
unless a reviewer documents the rationale for classifying the study as
involving more than minimal risk.
Finally, the ANPRM discussed the idea that continuing review would
not be required of studies that are eligible for expedited review
unless the reviewer, at the time of initial review, determines that
continuing review is required, and documents why. In follow-up to this
discussion, the ANPRM asked for comments on whether IRBs should be
required to report instances when they overrode the default presumption
that research appearing on the posted list did not warrant review by a
convened IRB.
d. NPRM Proposal
Based on public comments on the ANPRM, the NPRM proposes changes to
the current regulatory language at Sec. __.110(b)(1) regarding
expedited review, and will allow expedited review to occur for studies
on the Secretary's list unless the reviewer(s) determine(s) that the
study involves more than minimal risk. This is in contrast to the
current regulations, which require that an IRB use the expedited review
procedure only if the reviewer determines that the research involves no
more than minimal risk; in addition, OHRP has indicated that the
activities on the current list should not be deemed to be of minimal
risk simply because they are included on the list. Therefore, this
proposed change represents a change to the default position, and now
says that research included on the list only involves minimal risk,
unless the IRB makes a determination that the research is actually
greater than minimal risk. Thus, it is anticipated that more studies
that involve no more than minimal risk would undergo expedited review,
rather than full review, which would relieve burden on IRBs.
This proposal is in line with public comment to the 2011 ANPRM.
Commenters overwhelmingly welcomed the clarification that categories of
research found on the published list should be presumed to be minimal
risk. However, commenters were largely opposed to requiring IRBs to
report instances when they conducted a review by the convened
membership (versus an expedited review) for studies appearing on the
list. They were opposed because of the additional administrative burden
and also because they felt such a requirement would undermine the
purview of local review and open IRBs up to second-guessing by OHRP.
Public comments to the 2011 ANPRM expressed both a desire to retain
the current definition (slightly less than half) and a desire for
changing it (slightly more than half). There were few common themes in
the suggested changes to the language other than seeking clarification
on what baselines an IRB should consider in determining the meaning of
``daily life'' and ``routine physical or psychological examinations.''
Several commenters acknowledged the difficulty of arriving at a concise
definition for all circumstances. Those opposed to changing the
definition said that IRBs generally understand how to interpret the
language and that difficult or challenging application of the
definition will persist regardless of the definition for those areas of
research where risks are difficult to assess. Commenters recognized
that the risks encountered in daily life can vary greatly depending on
many factors, for example, where people live, what kind of work they
are involved in, what their social and economic environment is, and
their baseline health status. Thus, IRBs need to consider all of these
issues in making a determination about the level of risk.
Thus, the NPRM does not propose to modify the definition of minimal
risk (NPRM at Sec. __.102(j)), but rather proposes adding to the
definition a requirement that the Secretary of HHS create and publish a
list of activities that qualify as ``minimal risk.'' This Secretary's
list will be re-evaluated periodically, but at least every 8 years,
based on recommendations from federal departments and agencies and the
public. Note that this will not be an exhaustive list of all activities
that should be considered minimal risk under the Common Rule, but will
allow IRBs to rely on the determination of minimal risk for activities
appearing on the list. IRBs will still need to make minimal risk
determinations about activities that do not appear on this list.
In addition, the NPRM proposes to eliminate the parenthetical
phrase ``of one year or less'' at Sec. __.110(b)(2) since annual
continuing review of research eligible for expedited review and
research that progresses to the point of only involving specified
limited activities will no longer be required for all ongoing human
subjects research. The NPRM also proposes that the regulations be
revised at Sec. __.110(a) to require evaluation of the list of
expedited review categories every 8 years, followed by publication in
the Federal Register and solicitation of public comment. A revised list
will be prepared for public comment outside the scope of the NPRM.
For several reasons, the NPRM proposes no changes in the
requirement that expedited review be conducted by an IRB member. First,
public comments on the 2011 ANPRM were divided on the value of allowing
a non-IRB member to conduct such reviews. Those with concerns
questioned whether permitting someone other than an IRB member to
conduct expedited review would have unintended consequences, such as
either increasing or decreasing the number of studies deemed acceptable
for expedited review, or by increasing liabilities for the institution.
Second, IRB staff members would likely constitute the pool of non-IRB
members qualified to conduct expedited review, and the current
regulations permit IRB staff members to be IRB members. HHS does not
believe a regulatory change is warranted to facilitate expedited
review.
Finally, the NPRM contains a requirement at Sec. __.115(a)(9) that
IRBs document the rationale for an expedited reviewer's determination
that research appearing on the expedited review list is more than
minimal risk (i.e., an override of the presumption that studies on the
Secretary's list are minimal risk). Such documentation could provide a
basis for the Secretary's future determinations about the
appropriateness of the list, and allow for greater internal consistency
at institutions. In response to public comment on the 2011 ANPRM, the
NPRM does not propose to require that institutions report such
determinations directly to OHRP. Commenters were largely opposed to
requiring IRBs to report instances when they conducted a review by the
convened membership (versus an expedited review) for studies appearing
on the list. They were opposed because of the additional administrative
burden and also because they felt such a requirement would undermine
the purview of local review and open IRBs up to second-guessing by
OHRP.
e. What would change?
Expedited review can occur for studies on the Secretary's
list unless the reviewer(s) determine(s) that the study involves more
than minimal risk.
Evaluation of the list of expedited review categories
would occur every 8 years, followed by publication in the Federal
Register and solicitation of public comment.
IRBs will be required to document their rationale when
they override the presumption that studies on the
[[Page 53987]]
Secretary's expedited review list involve greater than minimal risk.
The Secretary of HHS will create and publish and maintain
a list of activities that should be considered minimal risk.
f. Questions for Public Comment
79. How often should the Secretary's list of minimal risk
activities be updated? Should advice be solicited from outside parties
when updating the list?
80. Is this Secretarial list of minimal research activities a
useful tool for the research community, or does it represent a loss of
IRB flexibility in risk determination?
G. Proposed Changes to IRB Operational Requirements
1. Proposed Criteria for IRB Approval of Research (NPRM at Sec.
__.111)
a. NPRM Goals
These revisions modernize the rule by (1) creating new forms of IRB
review for activities relating to storing or maintaining data and
biospecimens for later secondary use, and for the review of studies
involving certain types of such secondary use; (2) revising two of the
existing criteria for approval of research, where there are special
considerations related to the involvement of vulnerable populations and
for privacy and confidentiality of data provisions; and (3) adding a
provision regarding plans to review the return of individual results to
participants.
b. Current Rule
There are several determinations that an IRB must generally make
before it can approve a study, which are spelled out in current Common
Rule at Sec. __.111. These relate, among other things, to minimizing
risks to subjects, determining that there is an appropriate
relationship between risks and benefits, and assuring the equitable
selection of subjects. The regulations generally require all of these
determinations to be made with regard to any study that must undergo
IRB review.
c. ANPRM Discussion
The ANPRM asked whether all of the Sec. __.111 criteria should
still be required for approval of studies that qualify for expedited
review, and if not, which ones should not be required. Currently,
before an IRB may approve a research study, including research that is
being reviewed under an expedited procedure, the IRB must find that the
criteria at Sec. __.111 have been met.
d. NPRM Proposals
Based on comment to the 2011 ANPRM, the NPRM does not propose to
modify the Sec. __.111 criteria that apply to research reviewed under
the expedited procedure versus research reviewed under full board
review. The NPRM does however propose a number of changes regarding the
criteria for IRB approval of research, including (1) creating a new
form of IRB review for activities relating to storing or maintaining
data and biospecimens for later secondary use; (2) revising two of the
existing criteria for approval of research, where there are special
considerations related to the involvement of vulnerable populations and
for privacy and confidentiality of data provisions; and (3) adding a
provision regarding plans to review the return of individual results to
participants.
The first set of changes relates to updating the IRB review
criteria for research activities relating to storing or maintaining
information and biospecimens, and to the secondary use of such
information and biospecimens. Paragraph (a)(9)(i) of proposed Sec.
__.111 would apply to storage or maintenance for secondary research use
of biospecimens or identifiable private information. This provision
would eliminate the need for an IRB to make the usual determinations
with regard to such an activity. Instead, the IRB would be required to
determine that the procedures for obtaining broad consent to the
storage or maintenance of the biospecimens or information were
appropriate, and met the standards included in the introductory
paragraph of Sec. __.116. In addition, if these storage and
maintenance activities involved a change for research purposes from the
way the biospecimens or information had been stored or maintained, then
the IRB would have to determine that the biospecimen and privacy
safeguards at Sec. __.105 are satisfied for the creation of any
related storage database or repository. Note that in many instances
there will be no such change. For example, an individual could sign a
consent form allowing broad unspecified future research use of
information contained in their medical records, and that information
would remain where it is, but be tagged in some manner to indicate that
the individual has provided such consent.
This in effect means that the default for such secondary research
studies using either biospecimens or identifiable information will be
that the initial broad consent would be sufficient, and that there will
be no need to obtain a new consent from individuals for each specific
research study that is conducted with the biospecimens and information.
The second proposal, relating to vulnerable subjects, is intended
to address an inconsistency in the current regulations among three
provisions in the current Common Rule that address requirements related
to the consideration of vulnerable populations: Sec. Sec. __.107(a),
__.111(a)(3), and __.111(b). Under the current Rule, only Sec.
__.111(b) of these three provisions provides that vulnerability to
coercion or undue influence is the type of vulnerability that should be
considered. It is proposed that the criterion at Sec. __.111(a)(3) be
revised to align with the language of Sec. __.111(b) to reflect that
the vulnerability of the populations in these research studies should
be considered to be a function of the possibility of coercion or undue
influence, and that this vulnerability alone should be the IRB focus of
concern with respect to this criterion. The proposed change is intended
to provide greater consistency and clarity in IRB consideration of
vulnerability of subject populations in research activities and
appropriate protections. A comparable change is also proposed at Sec.
__.107(a), pertaining to IRB membership. In addition, of these same
three provisions in the current Rule, only Sec. __.107(a) identifies
``handicapped'' individuals (which the NPRM proposes be changed to
``physically disabled'' individuals as discussed below in section
II.G.2.c. of the preamble) as a vulnerable category of subjects.
Therefore, to enhance consistency and clarity among these three
provisions, it is proposed that the term ``physically disabled'' be
inserted at Sec. __.111(a)(3) and (b). This would mean that physically
disabled persons would be among the individuals that the IRB may
consider in determining that the selection of subjects is equitable
(Sec. __.111(a)(3)), and that the IRB may consider to be vulnerable to
coercion or undue influence (Sec. __.111(b)). Public comment is being
sought on these proposed changes to the provisions related to
vulnerable populations. Since it is proposed that the only
vulnerability that needs to be considered is vulnerability to coercion
or undue influence, and not other types of vulnerability, it is
appropriate to review the subject populations to determine whether all
of these subject populations identified in these three provisions
should be considered vulnerable to coercion or undue influence. In
particular, public comment is sought
[[Page 53988]]
about whether pregnant women and those with physical disabilities
should be characterized as vulnerable to coercion or undue influence.
Whether or not these subpopulations are considered vulnerable to
coercion or undue influence would not affect the applicability of
subpart B.
The third proposed change would be an addition of paragraph (a)(8)
to Sec. __.111 clarifying that if an investigator submits as part of
the protocol a plan for returning individual research results, the IRB
will evaluate the appropriateness of the plan. IRBs need not determine
whether there should be a plan for returning individual research
results. Although many IRBs probably already review plans for return of
results, many studies do not include this feature. Challenges can arise
regarding return of individual research results when it is not clear if
the findings have clinical validity or utility, or when the knowledge
imparted may cause psychological distress or social harm. These issues
have been the subject of frequent discussion, particularly regarding
the Clinical Laboratory Improvement Amendments of 1988, 42 U.S.C.
263a.\73\ \74\ \75\
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\73\ Presidential Commission for the Study of Bioethical Issues.
(2013, December). Anticipate and communicate: Ethical management of
incidental and secondary findings in the clinical, research, and
direct-to-consumer contexts. Retrieved from Presidential Commission
for the Study of Bioethical Issues: http://bioethics.gov/sites/default/files/FINALAnticipateCommunicate_PCSBI_0.pdf.
\74\ Wolf SM et al. Managing incidental findings in human
subjects research: Analysis and recommendations. J Law Med Ethics
2008 Summer; 36(2):219-248, 211.
\75\ Ofri D. 2013. Medicine's problem of `incidental findings.'
Atlantic Monthly.
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An additional change is related to the proposed changes at Sec.
__.105, and would clarify that it is not an IRB responsibility to
review the security plans for biospecimens and identifiable private
information for every protocol (i.e., on a case-by-case basis). It is
assumed that once institutions and investigators have established
policies and procedures for compliance with the new privacy safeguards
at Sec. __.105 (and it is expected that many already have already such
procedures in place), that IRBs will be confident in omitting that
aspect of their review of research, as it does not pose unusual privacy
or security risks to subjects. It is proposed that this requirement
will be modified to recognize that the requirements at Sec. __.105
will apply to all non-excluded research (unless the criteria for
exemptions are met). The default position should be that if the privacy
safeguards at Sec. __.105 are being met, there is no need for
additional IRB review of a research study's privacy and security
protections. However, there might be extraordinary cases in which an
IRB determines that privacy safeguards above and beyond those called
for in Sec. __.105 are necessary. Therefore, it is proposed that IRBs
will be responsible for ensuring there are adequate provisions to
protect the privacy of subjects and to maintain the security of data
only if the IRB determines that the protections required in Sec.
__.105 are insufficient.
e. What would change?
A new version of more limited IRB approval criteria would
be created for activities relating to the storage or maintenance of
biospecimens and identifiable private information for the purposes of
later doing secondary research with them.
IRBs considering the Sec. __.111(a)(3) approval criterion
regarding equitable selection of subjects would need to focus on issues
related to coercion or undue influence in research with vulnerable
populations and not other considerations related to vulnerability.
Physically disabled persons would be among the individuals
that the IRB may consider in determining that the selection of subjects
is equitable (Sec. __.111(a)(3)), and that the IRB may consider to be
vulnerable to coercion or undue influence (Sec. __.111(b)).
IRBs would need to consider the requirements for
investigators to protect information, and biospecimens as a criterion
for approval of research only if they find the protections under Sec.
__.105 are not sufficiently protective.
If a plan for returning research results is included as
part of a protocol, IRBs would be required to determine whether the
plan is appropriate. IRBs would not be required to determine whether
such a plan is needed.
f. Questions for Public Comment
81. What should IRBs consider when reviewing the plans for
returning research results, for example, what ethical, scientific, or
clinical concerns?
82. Is the Sec. __.111(a)(3) and (b) focus on issues related to
coercion or undue influence in research with vulnerable populations,
and not other considerations related to vulnerability, appropriate?
Note that this focus also appears in proposed Sec. __.107(a).
83. Should pregnant women and those with physical disabilities be
included in the category of subpopulations that may be vulnerable to
coercion or undue influence?
2. Proposed Revisions to IRB Operations, Functions, and Membership
Requirements
a. NPRM Goal
The goal is to improve IRB operations and make relevant sections
consistent with other areas of the NPRM.
b. Current Rule
The current Rule outlines IRB functions and operations at
Sec. Sec. __.108 and __.103, and membership requirements at Sec.
__.107.
c. NPRM Proposals
The NPRM contains several proposals for changes in IRB operations,
functions, and membership requirements. First, the requirements for
recordkeeping by IRBs no longer appear in Sec. __.103 of the rule.
They are now described in Sec. __.108(a)(2), (3), and (4).
Also as previously discussed, IRBs would be required to safeguard
their records in compliance with the privacy protections described in
proposed Sec. __.105 if the records contain individually identifiable
information.
Finally, there are four changes to the IRB membership requirements
at Sec. __.107(a). The first change is the elimination of the
requirement that IRBs not consist entirely of individuals of one gender
or profession. This provision is unnecessary, because the requirement
that IRB membership reflect members of varying backgrounds and
diversity, including gender, will accomplish the same effect. The
deletion of this provision in the NPRM is not intended to alter the
composition of IRBs from what had been established in the current Rule.
For the reasons discussed above in section II.G.1.d, three
additional changes are proposed to Sec. __.107(a). It is proposed that
Sec. __.107(a) be modified so that consideration of vulnerability of a
subject population would be limited to vulnerability to coercion or
undue influence. This proposed change is consistent with the proposal
at Sec. __.111(a)(3). The proposed change is intended to result in
greater consistency and clarity in IRB consideration of vulnerability
of subject populations in research activities and appropriate
protections.
The third change in Sec. __.107(a) is the insertion of
``economically or educationally disadvantaged persons'' as an example
of a vulnerable population, requiring an IRB to give consideration to
membership expertise in this area. This language is already included in
the current Rule at Sec. __.111(a)(3) and Sec. __.111(b). Adding this
category of individuals to
[[Page 53989]]
those who may be considered vulnerable to coercion or undue influence
at Sec. __.107(a) is intended to create greater consistency among
these three provisions.
In order to modernize the regulatory language, the fourth change in
proposed Sec. __.107(a) is the replacement of the term ``handicapped''
persons with ``physically disabled persons'' as an example of a
vulnerable population, requiring an IRB to give consideration to
membership expertise in this area.
d. What would change?
The provision regarding IRBs avoiding membership that
consists entirely of individuals of one gender or profession would be
eliminated because the requirement that IRB membership reflect members
of varying backgrounds and diversity, including gender, would
accomplish the same goal.
The provision regarding the IRB's expertise in the review
of research involving a vulnerable category of subjects would be
limited to the subjects' vulnerability to coercion or undue influence
The phrase economically or educationally disadvantaged
persons is included as an example of a vulnerable category of subjects,
requiring an IRB to give consideration to membership expertise in this
area.
The term ``handicapped'' persons is replaced with
``physically disabled persons'' as an example of a vulnerable category
of subjects, requiring an IRB to give consideration to membership
expertise in this area.
e. Question for Public Comment
84. Should populations be considered vulnerable for reasons other
than vulnerability to coercion or undue influence? Are the proposed
categories appropriate?
H. Other Proposed Changes
1. Proposal To Extend the Common Rule to All Clinical Trials (With
Exceptions) (NPRM at Sec. __.101(a)(1))
a. NPRM Goals
The goal of this proposal is to ensure that studies that generally
pose the most risk to potential subjects (such as surgical clinical
trials), are encapsulated by the Common Rule. The proposal attempts to
balance the goals of ensuring that studies where the Common Rule
provides meaningful protections to subjects are covered under the rule,
while studies where the administrative burdens of the Common Rule
outweigh any potential benefits to subjects are not covered.
b. Current Rule
The Common Rule applies to all research involving human subjects
that is conducted or supported by a Federal department or agency that
has adopted the policy (Sec. __.101(a)).
c. ANPRM Discussion
The ANPRM discussed the possibility of the Common Rule applying to
all studies, regardless of funding source, that are conducted by a U.S.
institution that receives some federal funding for human subjects
research from a Common Rule agency.
The ANPRM also asked the public to consider a regulatory option to
partially fulfill the goal of extending Common Rule protections to all
human subjects research in the United States. The discussed policy
would require domestic institutions that receive some federal funding
from a Common Rule agency for non-exempt research with human subjects
to extend the Common Rule protections to all human subjects research
studies conducted at their institution.
d. NPRM Proposal
In response to ANPRM feedback, the Common Rule NPRM proposes an
extension that would ensure that clinical trials are covered by the
Common Rule if conducted at an institution in the United States that
receives federal support for non-exempt and non-excluded human subjects
research, regardless of the funding source of the specific clinical
trial.
Note that the purpose of the clinical trials extension is to ensure
that clinical trials that would otherwise not be covered by some body
of federal research ethics regulations are covered. To that end, if a
clinical trial is already subject to FDA oversight but not Common Rule
oversight, since that clinical trial is subject to human subjects
protection regulations, this change would not affect it. Also note that
this proposed extension is based on whether an institution receives
funding specifically for non-exempt and non-excluded research. This is
because the Common Rule departments and agencies have a more
substantial relationship with institutions that receive support from a
Common Rule department or agency to conduct non-exempt and non-excluded
human subjects research than those institutions that receive such
support for only exempt and excluded human subjects research.
Although supporting the principle that all human subjects research
regardless of funding source should be conducted ethically, public
commenters generally expressed concern and caution about the ANPRM
consideration for a variety of reasons. Behavioral and social science
investigators thought that this approach would unnecessarily bring
less-than-minimal-risk research funded by non-federal sources (e.g.,
surveys or observational studies supported by the nonprofit sector)
under burdensome regulatory requirements while not enhancing
protections. Some commenters argued that the increased regulatory
burden that would ensue was not warranted and would shift scarce
oversight resources to review of research studies that are generally
non-problematic and frequently supported by non-federal funds, such as
some student or institutional research.
Others argued that such a change was an overreach of federal
oversight and constituted an unfunded mandate. Commenters from large
academic research institutions felt that this change inappropriately
focused heavily on academic institutions, which generally extend
protections to all human subjects research at their institution, even
if they have not ``checked the box'' \76\ on their FWA indicating that
they do so. They argued that such a change would not reach those
institutions already operating outside the federal research system and
would limit flexibility in making risk-based determinations about the
levels of review required.
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\76\ The FWA covers all non-exempt human subjects research at
the submitting institution that is conducted or supported by HHS, or
funded by any other federal department or agency that has adopted
the Common Rule and relies upon the FWA. It is not project specific.
Domestic institutions may voluntarily extend their FWA (and thus a
Common Rule department or agency's regulatory authority) to cover
all human subjects research at the submitting institution regardless
of the source of support for the particular research activity. See
Office for Human Research Protections. (2011, June 17). What
research does the Federalwide Assurance (FWA) cover? Retrieved from
Frequently Asked Questions: http://www.hhs.gov/ohrp/policy/faq/assurance-process/what-research-does-fwa-cover.html.
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Industry also expressed concern about having to comply with two
sets of regulations, that is, FDA regulations as well as the Common
Rule. The ANPRM did not clarify that the changes under consideration
would not require compliance with the Common Rule of non-federally
funded research subject to regulation by FDA. However, there might
continue to be research that would be subject to both sets of
regulations involving federal funding of research concerning an FDA-
regulated product.
[[Page 53990]]
Those commenters who supported a formal extension of the
regulations cited the need to have one set of standards for all
research, regardless of funding source; however, many noted that absent
legislation covering all human subjects research conducted in the
United States, it would be difficult to cover all research through a
regulatory approach alone--gaps would still remain.
Thus, the NPRM proposes changes in the regulatory language at Sec.
__.101(a)(2) to state that the policy extends to all clinical trials as
defined by this policy, irrespective of funding source, that meet all
of three conditions: (1) The clinical trials are conducted at an
institution that receives support from a federal department or agency
for human subjects research that is not excluded from this policy under
Sec. __.101(b)(2), and the research does not qualify for exemption in
accordance with Sec. __.104; (2) The clinical trials are not subject
to FDA regulation; and (3) The clinical trials are conducted at an
institution located within the United States.
For purposes of this policy, the NPRM proposes at Sec. __.102(b)
that a clinical trial be a research study in which one or more human
subjects are prospectively assigned to one or more interventions (which
may include placebo or other control) to evaluate the effects of the
interventions on biomedical or behavioral health-related outcomes. By
the term ``behavioral outcomes,'' the NPRM contemplates the reality
that clinical trials may occur outside of the biomedical context. The
studies addressed in the proposed definition of clinical trial at Sec.
__.102(b) are more likely to involve greater-than-minimal risk, and,
therefore, require the highest level of oversight. Limiting the
extension of the regulations to only the highest risk research is
consistent with the goal of a more risk-based approach to review. For
example, surgical clinical trials that do not receive support from a
Common Rule department or agency often are outside of the scope of
FDA's human subjects protection regulations. Thus, many of these
unfunded activities are currently not subject to the protections
afforded by the human subjects protection system. This NPRM proposal
would cause many of these trials to come under the purview of the
Common Rule.
e. What would change?
Clinical trials as defined by proposed Sec. __.102(b),
irrespective of funding source, would be subject to oversight, given
specified conditions.
f. Questions for Public Comment
85. Public comment is sought on whether there might be unintended
consequences from the clinical trials expansion proposed in the NPRM in
Sec. __.101(a)(2)(i)). Unintended consequences may include an increase
in burden or costs, or an inappropriate redistribution of costs.
86. Public comment is sought as to whether the criterion that the
policy extends to all clinical trials conducted at an institution that
receives federal support (see the NPRM at Sec. __.101(a)(2)(i)) should
be further clarified in some way. For example, should it specify a
timeframe for support (e.g., within the past number of years), or a
minimum monetary threshold value?
87. Public comment is sought on whether the definition of clinical
trial (NPRM at Sec. __.102(b)) should include additional explanation
of what is encompassed by the term behavioral health-related outcomes.
2. Changes to the Assurance Process (NPRM at Sec. Sec. __.103 and
__.108; Current Rule at Sec. __.103)
a. NPRM Goal
There has been concern expressed by some, such as SACHRP, that the
current assurance process may be unduly burdensome for institutions and
does not provide meaningful protections for human subjects. The changes
proposed to the assurance process are intended to reduce unnecessary
administrative burdens.
b. Current Rule
Requirements at Sec. __.103 delineate procedural requirements for
institutions and IRBs to follow to comply with the Common Rule.
c. NPRM Proposals
A number of substantive and procedural modifications are proposed
to Sec. __.103 of the Common Rule. The NPRM proposes to move the IRB
recordkeeping requirements from Sec. __.103(b)(4) and (5) of the
Common Rule. They are now described in the NPRM in Sec. __.108(a)(3)
and (4), which pertains to IRB functions and operations
Additionally, the NPRM proposes to eliminate the current Common
Rule requirement at Sec. __.103(b)(1) that an institution provide a
statement of ethical principles with which an institution will abide as
part of the assurance process. This change was made because this
provision is generally not enforced. Further, for international
institutions that may receive U.S. government funding for research
activities, it creates the impression that these international
institutions must modify their internal procedures to comport with the
set of principles designated on the FWA for activities conducted at
those institutions that receive no U.S. government funding. OHRP
specifically has received many questions about the extent to which
international institutions must adhere to the ethical principles
designated as part of the assurance process in research activities
conducted by the institution that receive no Common Rule department or
agency funding. In order to provide clarity to these international
institutions that such measures are not required, the NPRM proposes to
delete the requirement at Sec. __.103(b)(1).
The NPRM also proposes to eliminate the requirement in Sec.
__.103(b)(2) that an institution designate one or more IRBs on its FWA
established in accordance with the Common Rule. The requirement in the
current Common Rule at Sec. __.103(b)(2) that IRBs have sufficient
meeting space and staff to support IRB reviews and recordkeeping
requirements is found in the NPRM at Sec. __.108(a)(1). Note that
federal departments or agencies retain the ability to ask for
information about which IRBs review research conducted at an
institution as part of the assurance process, even if that requirement
is not explicitly mandated in the regulations.
Additionally, the NPRM proposes to eliminate the current
requirement in Sec. __.103(b)(3) that an up-to-date list of the IRB
members and their qualifications be included in an institution's
assurance. Instead, proposed Sec. Sec. __.108(a)(2) and __.115(a)(5)
require that an IRB or the institution prepare and maintain a current
list of IRB members. This modification also eliminates the current
requirement in Sec. __.103(b)(3) that changes in IRB membership be
reported to the department or agency head or to OHRP when the existence
of an assurance approved by HHS for federalwide use is accepted. SACHRP
recommended on March 28, 2008, that OHRP pursue harmonizing the Common
Rule with FDA's human subjects protection regulations by eliminating
the requirement to submit IRB membership lists. SACHRP members felt
that submitting IRB membership lists and reporting all changes in IRB
membership to OHRP added little to the protection of human subjects and
that eliminating these requirements therefore would reduce unnecessary
[[Page 53991]]
administrative burdens on institutions and OHRP.\77\
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\77\ Secretary's Advisory Committee on Human Research
Protections. (2008, September 18). SACHRP Letter to HHS Secretary.
Retrieved from Office for Human Research Protections: http://www.hhs.gov/ohrp/sachrp/sachrpletter091808.html.
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Note that in implementing the NPRM an additional, non-regulatory
change is planned to the assurance mechanism. The current option of
``checking the box'' on an FWA to extend HHS's (or other Common Rule
supporting agencies') regulatory authority to studies conducted by an
institution that do not receive federal support would be eliminated.
Importantly, for research other than clinical trials, institutions
could, if they so desired, continue for purposes of their own internal
rules to voluntarily extend the regulations to all research conducted
by the institution, but this voluntary extension would no longer be
part of the assurance process and the research would not be subject to
OHRP oversight. This change would be expected to have the beneficial
effect of encouraging some institutions to explore a variety of new
flexible approaches to overseeing low-risk research that is not funded
by a Common Rule agency, thus furthering the goal of this NPRM to
decrease inappropriate administrative burdens on such research.
In addition, the NPRM proposes to remove the provision found in the
current Common Rule at Sec. __.103(d) that a department or agency
head's evaluation of an assurance will take into consideration the
adequacy of the proposed IRB(s) designated under the assurance in light
of the anticipated scope of the institution's activities and the types
of subject populations likely to be involved, the appropriateness of
the proposed initial and continuing review procedures in light of the
probable risks, and the size and complexity of the institution.
To further strengthen the new provision at Sec. __.101(a) giving
Common Rule departments and agencies explicit authority to enforce
compliance directly against IRBs that are not affiliated with an
assured institution, language is proposed at Sec. __.103(e) requiring
each IRB, institution, or organization that has oversight
responsibility for non-exempt research involving human subjects covered
by this policy and conducted by another institution to have and follow
procedures for documenting the institution's reliance on the
unaffiliated IRB and the respective responsibilities of each entity for
meeting the regulatory requirements of this policy. This is already a
requirement under the terms of a FWA. Such agreements would have to be
included as part of the IRB records, per a proposed requirement at
Sec. __.115(a)(10). This change is proposed to address concerns about
OHRP's current practice of enforcing compliance with the Common Rule
through the institutions that were engaged in human subjects research,
even in circumstances when the regulatory violation is directly related
to the responsibilities of an external IRB.
Finally, the NPRM would eliminate the requirement in the current
Common Rule at Sec. __.103(f) that grant applications undergo IRB
review and approval for the purposes of certification. The grant
application is often outdated by the time the research study is
submitted for IRB review and contains detailed information about the
costs of a study, personnel, and administrative issues that go beyond
the mission of the IRB to protect human subjects. Therefore, experience
suggests that review and approval of the grant application is not a
productive use of IRB time.
Note that each assured institution continues to have responsibility
for ensuring that the IRBs upon which it relies are registered with
OHRP and are appropriately constituted to review and approve the human
subjects research, as required under Sec. Sec. __.107 and __.108.
In developing the NPRM proposals related to the assurance process,
consideration was given to the 2014 SACHRP recommendation that the
assurance of compliance required under Sec. __.103 be provided through
the grant-making or contract process, as one of multiple
``Representations and Certifications'' already made by institutions
when they apply for federal grants, contracts or cooperative
agreements.\78\ SACHRP suggested that such a proposal may reduce
administrative burden on IRB offices responsible for the FWA process
without significantly diminishing the protection that these offices
provide human subjects.
---------------------------------------------------------------------------
\78\ See Secretary's Advisory Committee on Human Research
Protections (SACHRP). (2014, March 13). Final Recommendations on
Assurances and Engagement. Retrieved from SACHRP's Meetings: http://www.hhs.gov/ohrp/sachrp/mtgings/mtg03-14/assurancesandengagementrecommendations.html.
---------------------------------------------------------------------------
Ultimately, SACHRP's recommendation was not adopted as an NPRM
proposal because of concerns regarding the impact that removal of the
FWA process would have on the ability for Common Rule departments and
agencies to determine their compliance authority in certain
circumstances. As part of SACHRP's recommended change to the assurance
process, it was envisioned that only the primary awardee of a grant or
contract would be required to obtain an assurance, and that this
assurance would be provided through the grant-making or contract
process. Subawardees or subcontractors may also be engaged in human
subjects research, which extends the funding Common Rule department's
or agency's authority to such institutions. However, Common Rule
departments or agencies may not be able to ascertain that such
institutions are required to follow the Common Rule for such human
subjects research at their institution in the absence of an assurance
filed with a Common Rule department or agency (including OHRP). In
addition, some institutions have over a thousand grants or contracts
with Common Rule departments and agencies and therefore would have over
a thousand assurances. Certain institutional changes (for example,
changes in the signatory official or human protections administrator)
will require assurances to be updated. Ensuring that assurances are
appropriately updated and keeping track of these updates are likely to
pose challenges to Common Rule departments or agencies.
d. What would change?
The regulatory requirement that an institution identify a
set of ethical principles on which an institution will rely in all
research conducted at that institution, regardless of funding source
for the activity, would be deleted.
The regulatory requirement that a written assurance
include a list of IRB members for each IRB designated under the
assurance would be replaced by the requirement that a written assurance
include a statement that, for each designated IRB, the institution, or
when appropriate the IRB, prepares and maintains a current detailed
list of the IRB members with information sufficient to describe each
member's chief anticipated contributions to IRB deliberation and any
employment or other relationship between each member and the
institution.
The regulatory requirement specifying that changes in IRB
membership be reported to the department or agency head, or to OHRP
when the existence of an HHS-approved assurance is accepted, would be
deleted.
The requirement would be deleted that a department or
agency head's evaluation of an assurance take into consideration the
adequacy of the proposed IRB in light of the anticipated scope of the
institution's activities and
[[Page 53992]]
the types of subject populations likely to be involved, the
appropriateness of the proposed initial and continuing review
procedures in light of the probable risks, and the size and complexity
of the institution.
For non-exempt human subjects research that takes place at
an institution in which IRB oversight is conducted by an IRB not
affiliated with that institution, the institution and non-affiliated
IRB must establish and follow written procedures that identify
compliance responsibilities of each entity that are set forth in a
written agreement between the institution and the IRB.
e. Question for Public Comment
88. Would protection to human subjects in research be enhanced if
OHRP conducted routine periodic inspections to ensure that the
membership of IRBs designated under FWAs satisfy the requirements of
Sec. __.107?
3. Department or Agency Discretion about Applicability of the Policy
(NPRM at Sec. __.101(c), (d), (i)) and Discretion Regarding Additional
Requirements Imposed by the Conducting or Supporting Department or
Agency (NPRM and current Rule at Sec. __.124)
a. NPRM Goals
The goals of the NPRM revisions in these sections are to: (1)
Formally codify the general practice that the ethical standards
articulated in the Belmont Report is the ethical standard that Common
Rule departments or agencies will use in determining whether an
activity is covered under this policy; and (2) ensure that when
relevant, either the department or agency conducting or supporting an
activity may require additional protections for human subjects.
b. Current Rule
The current Common Rule allows in Sec. __.101(c), (d), (i) for
Federal department or agency heads to determine which specific
activities or classes of activities are covered by the rule.
c. NPRM Proposals
As described in section II.A.2 above, the NPRM proposes to exclude
specific categories of low-risk research and non-research activities
from the scope of the Common Rule in order to reduce regulatory burden.
Of course, there will be cases that call for the exercise of careful
judgment in determining whether activities are in an exclusion
category, or whether they are within the scope of the Common Rule. The
NPRM proposes to retain the Common Rule's current requirement that
Federal department or agency heads retain final judgment about the
coverage of particular research activities under the Common Rule (Sec.
__.101(c)) and proposes an additional clause that Federal department or
agency heads must exercise their authority consistent with the
principles of the Belmont Report, in order to require these Federal
department and agency heads to make these judgments in consideration of
the ethical protection of human research subjects.
The NPRM also proposes at Sec. __.101(d) that the agency may
require additional protections for specific types of research supported
or conducted by the agency or department; however advance public notice
will be required when those additional requirements apply to entities
outside of the Federal agency itself. This requirement is intended to
promote harmonization between Federal agencies or departments, to the
extent possible, and to ensure transparency between funding entities
and the regulated community.
Finally, at Sec. __.101(i) the NPRM proposes to amend the criteria
for a department or agency waiving the applicability of some or all of
the provisions of the policy, by stating that the waiver must be
supported by an argument that the alternative procedures to be followed
are consistent with the principles of the Belmont Report. Here again,
the addition of this provision is to make explicit the ethical basis
underpinning how waiver decisions have and must be considered.
New definitions of ``Department or agency head'' and ``Federal
department or agency'' are provided at Sec. __.102(c) and (d) in the
NPRM to help clarify these requirements. The NPRM proposes in Sec.
__.102(d) adding a definition of ``Federal department or agency'' in
order to avoid confusion as to whether this phrase encompasses Federal
departments or agencies that do not follow the Common Rule, and to
clarify that this phrase refers to the department or agency itself, not
its bureaus, offices or divisions. This is consistent with HHS's
historical interpretation of the current Rule. To distinguish this from
the definition of Department or agency head found in the current
regulations at Sec. __.102(a) (and found in the NPRM at Sec.
__.102(c)), the example of the Secretary of HHS has been inserted to
provide clarity. In addition, the definition of ``institution'' has
been changed at Sec. __.102(f) in the NPRM to clarify that departments
can be considered institutions for the purposes of this policy.
4. Research Covered by This Policy Conducted in Foreign Countries (NPRM
at Sec. __.101(h))
The current Common Rule at Sec. __.101(h) articulates that when
research covered by this policy takes place in foreign countries,
procedures normally followed in the foreign countries to protect human
subjects may differ from those set forth in this policy. The current
provision provides the Declaration of Helsinki, as amended in 1989, as
an example of internationally recognized ethical standards that a
foreign country might use as its ethical base. In this situation, the
current Common Rule provides that if a department or agency head
determines that the procedures prescribed by the institution afford
protections that are at least equivalent to those provided in this
policy, the department or agency head may approve the substitution of
the foreign procedures in lieu of the procedural requirements provided
in this policy.
The NPRM proposes to remove the specific example provided in this
provision. A concern with providing a specific example of
internationally recognized ethical document is that such a document is
subject to change independent of HHS or other Common Rule agencies, and
therefore could be modified to contain provisions that are inconsistent
with U.S. laws and regulations.
I. Effective and Compliance Dates of New Rule (NPRM at Sec. __.101(k))
1. Effective Dates
It is anticipated that the effective date of the final rule will be
one year after publication in the Federal Register. The compliance date
of the new rules would also be one year from the publication of the
Final Rule, with two exceptions discussed below. However, a provision
that is anticipated to provide additional regulatory flexibility to
institutions or investigators could voluntarily be implemented 90 days
from the publication of the Final Rule. This 90-day delay would give
the Common Rule departments and agencies time to develop the documents
and tools needed to assist institutions in implementing some of these
provisions (e.g., the Secretary's broad consent template, and privacy
safeguards under Sec. __.105). The provisions that would provide
additional regulatory flexibility include:
the proposed exclusions in Sec. __.101(b);
[[Page 53993]]
the proposed exemptions in Sec. __.104(d), (e) and (f);
the proposal to no longer require IRB review of grant
applications (Sec. __.103(f) in the current Common Rule);
the proposal to eliminate the regulatory requirement in
Sec. __.103 specifying that changes in IRB membership be reported to
the department or agency head, or to OHRP when an HHS-approved
assurance is approved;
the proposed provision in Sec. __.109(f) to eliminate the
continuing review requirement for studies that undergo expedited review
and for studies that have completed study interventions and are merely
analyzing data or involve only observational follow up in conjunction
with standard clinical care;
the proposed provision in Sec. __.116(g) stating that an
IRB may approve a research proposal in which investigators obtain
identifiable private information without individuals' informed consent
for the purpose of screening, recruiting, or determining the
eligibility of prospective human subjects of research, through oral or
written communication or by accessing records, in order to obtain
informed consent, if the research proposal includes an assurance that
the investigator will implement standards for protecting the
information obtained in accordance with and to the extent required by
the Sec. __.105 privacy safeguards; and
the new provision in Sec. __.117(c)(1)(iii) allowing a
waiver of the requirement for a signed consent form if the subjects are
members of a distinct cultural group or community for whom signing
documents is not the norm, the research presents no more than minimal
risk of harm to subjects, and there is an appropriate alternative
method for documenting that informed consent was obtained.
In two cases, institutions would have longer than one year to
comply: (1) The proposal for the Common Rule to cover all biospecimens
(Sec. __.102(e) in the NPRM); and (2) the proposal in Sec.
__.114(b)(1) regarding identifying a single IRB that would be
responsible for the review of certain multi-institutional clinical
trials. The compliance date for these requirements would be three years
after the publication of the final rule to allow institutions the
necessary time to develop institutional policies and procedures
necessary to implement these provisions. Comment is sought about
whether a different approach to phasing in these provisions would allow
the regulated community to better implement the changes proposed in
this NPRM. Additional possibilities discussed amongst the Common Rule
agencies included providing smaller institutions more time to implement
these two changes, and somehow incentivizing early compliance with
these provisions.
Further, the extension of the regulations to clinical trials that
are not directly funded by a Common Rule department or agency, but that
are conducted at an institution that receives funding from a Common
Rule department or agency for other human subjects research, would not
apply to an institution until the institution received federal funding
for non-exempt research in an award made after the effective date of
the final rule.
2. Transition Provisions
The ANPRM suggested that any change related to the extent to which
biospecimens are covered under the Common Rule would only apply to
biospecimens collected after the effective date of the revised Common
Rule. Commenters noted concerns about imposing consent requirements on
the use of biospecimens already collected--that is, not grandfathering
in such resources--especially if these biospecimens are non-identified.
Requiring that consent be obtained for the use of these materials could
result in their being rendered useless for research, which would
represent a cost of its own in terms of lost opportunity. This concern
was based on the practical limitations involved in obtaining consent
for biospecimens that were de-identified in the past, given that it may
not be possible to re-contact the original source.
a. Research Initiated Prior to the Effective Date of This Subpart (NPRM
at Sec. __.101(k)(1))
The NPRM addresses the transition provisions for human subjects
research (as defined in the NPRM) initiated before the effective date
of the policy. Ongoing human subjects research initiated prior to the
effective date of the final rule may choose to comply with the
provisions that provide additional regulatory flexibility discussed
above, but would not need to comply with additional requirements
related to:
Coverage of clinical trials (Sec. __.101(a)(2));
Written procedures for documenting an institution's
reliance on an unaffiliated IRB (Sec. __.103(e));
New exempt research categories and determination
requirements (Sec. __.104(c)-(f));
Information and biospecimen protection requirements (Sec.
__.105);
New IRB roster and written procedural requirements (Sec.
__.108(a)(2));
Continuing review requirements (Sec. __.109(f)(2));
Additional IRB approval criteria for information
safeguards and return of results plans (Sec. __.111(a)(7) and (8));
Requirements for cooperative research (Sec. __.114);
IRB recordkeeping requirements for documenting an
institution's reliance on an unaffiliated IRB and exemption
determinations (Sec. __.115(a)(10) and (11)); and
Requirements for obtaining and documenting informed
consent (Sec. Sec. __.116 and __.117) that become effective on the
date of the final rule.
b. Use of Prior Collections of Biospecimens (NPRM at Sec.
__.101(k)(2))
Research involving the use of prior collections of biospecimens is
permitted if the biospecimens were collected for either research or
non-research purposes before the effective date of this subpart, and
research use of the biospecimens occurs only after removal of any
individually identifiable information associated with the biospecimens.
If prior collections of biospecimens are not individually
identifiable, research using such non-identified biospecimens would
continue to be not covered by the regulations even after the effective
date of this policy.
Similarly, if prior collections of biospecimens are being stored or
maintained in an individually identifiable form, but identifiers are
removed from the biospecimens before being obtained by an investigator,
the investigator's use of such nonidentifiable biospecimens would
continue to be not covered by the regulations even after the effective
date of this policy.
III. Regulatory Impact Analyses
A. Introduction
HHS has examined the impacts of this proposed rule under Executive
Order 12866 on Regulatory Planning and Review (September 30, 1993);
Executive Order 13563 on Improving Regulation and Regulatory Review
(January 18, 2011); the Regulatory Flexibility Act of 1980, Public Law
96-354 (September 19, 1980); the Unfunded Mandates Reform Act of 1995,
Public Law 104-4, (March 22, 1995); and Executive Order 13132 on
Federalism (August 4, 1999).
Executive Order 12866 directs agencies to assess all costs and
benefits of available regulatory alternatives and, if regulation is
necessary, to select
[[Page 53994]]
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety effects; distributive
impacts; and equity). Executive Order 13563 is supplemental to and
reaffirms the principles, structures, and definitions governing
regulatory review as established in Executive Order 12866. HHS expects
that this proposed rule would have an annual effect on the economy of
$100 million or more in any one year and therefore is a significant
regulatory action as defined by Executive Order 12866.
The Regulatory Flexibility Act (RFA) requires agencies that issue a
regulation to analyze options for regulatory relief of small businesses
if a rule has a significant impact on a substantial number of small
entities.\79\ The RFA generally defines a ``small entity'' as (1) a
proprietary firm meeting the size standards of the Small Business
Administration (SBA); (2) a nonprofit organization that is not dominant
in its field; or (3) a small government jurisdiction with a population
of less than 50,000 (states and individuals are not included in the
definition of ``small entity'').\80\ HHS considers a rule to have a
significant economic impact on a substantial number of small entities
if at least 5 percent of small entities experience an impact of more
than 3 percent of revenue. HHS anticipates that the proposed rule would
not have a significant economic impact on a substantial number of small
entities. Supporting analysis is provided in section III.G below.
---------------------------------------------------------------------------
\79\ 5 U.S.C. 603
\80\ 5 U.S.C. 601
---------------------------------------------------------------------------
Section 202(a) of the Unfunded Mandates Reform Act of 1995 \81\
requires that agencies prepare a written statement, which includes an
assessment of anticipated costs and benefits, before proposing ``any
rule that includes any Federal mandate that may result in the
expenditure by State, local, and tribal governments, in the aggregate,
or by the private sector, of $100,000,000 or more (adjusted annually
for inflation) in any one year.'' The current threshold after
adjustment for inflation is $141 million, using the most current (2013)
implicit price deflator for the gross domestic product. HHS expects
this proposed rule to result in expenditures that would exceed this
amount.
---------------------------------------------------------------------------
\81\ 2 U.S.C. 1532
---------------------------------------------------------------------------
Executive Order 13132 establishes certain requirements that an
agency must meet when it promulgates a rule that imposes substantial
direct requirement costs on state and local governments or has
federalism implications. HHS has determined that the proposed rule, if
finalized, would not contain policies that would have substantial
direct effects on the States, on the relationship between the National
Government and the States, or on the distribution of power and
responsibilities among the various levels of government. The proposed
changes in the rule represent the Federal Government regulating its own
program. Accordingly, HHS concludes that the proposed rule does not
contain policies that have federalism implications as defined in
Executive Order 13132 and, consequently, a federalism summary impact
statement is not required.
B. Summary of the Proposed Rule
This NPRM is being issued to propose revisions to modernize,
strengthen, and make more effective the current regulations for
protecting human subjects. This proposed rule enhances clarity and
transparency of the consent process by imposing stricter new
requirements regarding the information that must be given to
prospective subjects including the elements of consent in a variety of
circumstances. It will also allow consent to the secondary research use
of biospecimens and identifiable private information, given specific
conditions are met. Enhanced protections to subjects are also achieved
through greater transparency by posting of informed consent forms used
in clinical trials. Several proposed changes (such as explicitly
excluding certain activities from the rule, expanding the categories of
research exempt from some of the requirements of the proposed rule, and
eliminating continuing review by an IRB in some situations) would
relieve the burden of unnecessary or unwarranted stringent review of
some low-risk studies that do not pose threats to the welfare of
subjects. Other proposed changes expand the reach of the regulations by
covering all clinical trials, regardless of funding source, and by
changing the definition of human subject to include research in which
an investigator uses, studies, or analyzes a biospecimen. Single IRB
review for multi-institutional studies would also be generally
required, except where local IRB review is required by law, to reduce
duplicative IRB reviews. Still other revisions clarify or revise
requirements for and responsibilities of IRB review and documentation.
New exempt categories are proposed, requiring that investigators and
institutions comply with minimum standards for protecting privacy. A
new process is also proposed through which investigators may input
information about a prospective study into a tool in order for that
tool to generate exemption determinations.
1. Accounting Table
Table 1 summarizes the quantified and non-quantified benefits and
costs of all proposed changes to the Common Rule. Over the 2016-2025
period, present value benefits of $2,629 million and annualized
benefits of $308 million are estimated using a 3 percent discount rate;
present value benefits of $2,047 million and annualized benefits of
$291 million are estimated using a 7 percent discount rate. Present
value costs of $13,342 million and annualized costs of $1,564 million
are estimated using a 3 percent discount rate; present value costs of
$9,605 million and annualized costs of $1,367 million are estimated
using a 7 percent discount rate. Non-quantified benefits include
improved human subjects protections in clinical trials and biospecimen
research not currently subject to oversight; enhanced oversight of
research reviewed by unaffiliated IRBs; increased uniformity in
regulatory requirements among Common Rule agencies; standardization of
human subjects protections when variation among review IRBs is not
warranted; revised informed consent forms and processes; improved
protection of biospecimens and identifiable private information; and
increased transparency of Common Rule agency-supported clinical trials
to inform the development of new consent forms. Non-quantified costs
include the time needed for consultation among Common Rule agencies
before federal guidance is issued; and the time needed by investigators
to obtain, document, and track the permissible uses of biospecimens and
identifiable private information for secondary research use.
[[Page 53995]]
Table 1--Accounting Table of Benefits and Costs of All Proposed Changes
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits..................... 2,629 2,047 308 291
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Improved human subjects protections in clinical trials and biospecimen research not currently subject to
oversight; enhanced oversight in research reviewed by unaffiliated IRBs; increased uniformity in regulatory
requirements among Common Rule agencies; ethical benefit of respecting an individual's wishes in how his or
her biospecimens are used in future research; standardization of human subjects protections when variation
among review IRBs is not warranted; improved informed consent forms and processes; improved protection of
biospecimens and identifiable private information; better ensuring availability of biospecimens for future
research activities; and increased transparency of Common Rule-supported clinical trials to inform the
development of new consent forms...........................................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs 13,342 9,605 1,564 1,367
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
Time for consultation among Common Rule agencies before federal guidance is issued; time for investigators
to obtain consent for secondary use of biospecimens or identifiable private information....................
----------------------------------------------------------------------------------------------------------------
Table 2 summarizes the quantified present value benefits and costs
of each proposed change to the Common Rule using a 3 percent discount
rate.
Table 2--Accounting Table of Quantified Benefits and Costs of Each
Proposed Change
------------------------------------------------------------------------
Present value of 10 years at a 3
percent discount rate (millions of
Proposed change 2013 dollars)
-------------------------------------
Benefits Costs
------------------------------------------------------------------------
Costs to Learn New Requirements ................. 208
and Develop Training Materials;
OHRP Costs to Develop Training
and Guidance Materials, and To
Implement the Rule...............
Extending Oversight to IRBs ................. 84.6
Unaffiliated With an Institution
Holding an FWA...................
Extending Common Rule Compliance ................. 18.3
Oversight to Clinical Trials
Regardless of Funding Source.....
Excluding Activities from the 74.0 .................
Requirements of the Common Rule
because They are not Research....
Excluding Low-Risk Research from 740 .................
the Requirements of the Common
Rule.............................
Clarifying and Harmonizing ................. .................
Regulatory Requirements and
Agency Guidance..................
Expanding the Definition of Human ................. 101
Subject to Include Research
involving Non-Identified
Biospecimens and Creating an
Exemption for Secondary Research
Using Biospecimens or
Identifiable Private Information.
Modifying the Assurance 5.81 .................
Requirements.....................
Requirement for Written Procedures ................. 11.3
and Agreements for Reliance on
External IRBs....................
Eliminating the Requirement that 310 .................
the Grant Application Undergo IRB
Review and Approval..............
Tracking and Documenting Exemption ................. .................
Determinations...................
Amending the Research and 37.0 0.36
Demonstration Project Exemption..
Expansion of Research Activities 70.0 .................
Exempt from IRB Review...........
Exemption for the Storage and ................. 1.58
Maintenance of Biospecimens and
Identifiable Private Information
for Future, Unspecified Secondary
Research Activities after Consent
has been Sought and Obtained.....
Protection of Information and ................. 457
Biospecimens.....................
Elimination of Continuing Review 145 38.8
of Research Under Specific
Conditions.......................
Amending the Expedited Review 16.8 2.71
Procedures.......................
Revised Criteria for IRB Approval 126 0.07
of Research......................
Cooperative Research.............. 1,103 155
Changes in the Basic Elements of ................. 4.55
Consent, Including Documentation.
Obtaining Consent to Secondary Use ................. 12,245
of Biospecimens and Identifiable
Private Information..............
Elimination of Requirement to 1.21 .................
Waive Consent in Certain Subject
Recruitment Activities...........
Requirement for Posting of Consent ................. 14.6
Forms for Clinical Trials
supported by Common Rule
Department or Agencies...........
Alteration in Waiver for ................. .................
Documentation of Informed Consent
in Certain Circumstances.........
------------------------------------------------------------------------
C. Need for the Proposed Rule
Federal regulations governing the protection of human subjects in
research have been in place for more than three decades, and 20 years
have passed since the Common Rule was adopted by 15 Federal departments
and agencies \82\ in
[[Page 53996]]
an effort to promote uniformity, understanding, and compliance with
human subject protections. Today 18 departments and agencies have
adopted the rule.\83\ As such, compliance with the Common Rule is a
condition for receiving federal funding from one of these agencies.
Note that an additional agency (Department of Labor) is joining this
proposed rulemaking in order to promulgate the Common Rule in DOL
regulations and to apply the regulations to human subjects research
that DOL may conduct or support, pending the scope of the final rule.
Although professional organizations have codes of conduct and
guidelines for members conducting research, only the Federal government
has the authority to regulate the activities of institutions using
public funds for human subjects research. Since the Common Rule was
developed, the volume of research has increased, evolved, and
diversified. Although the regulations have been amended over the years,
the enterprise has changed to the point that the current regulations
might be outdated in some important ways.
---------------------------------------------------------------------------
\82\ The current 15 Common Rule signatory agencies are:
Department of Agriculture; Department of Energy; National
Aeronautics and Space Administration; Department of Commerce;
Consumer Product Safety Commission; Agency for International
Development; Department of Housing and Urban Development; Department
of Justice; Department of Defense; Department of Education;
Department of Veterans Affairs; Environmental Protection Agency;
Department of Health and Human Services; National Science
Foundation; and Department of Transportation.
\83\ In addition to the signatory Common Rule departments and
agencies, three departments and agencies have not issued the Common
Rule but currently apply 45 CFR Part 46: The Central Intelligence
Agency, the Social Security Administration, and the Department of
Homeland Security.
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Under the current system, the regulated community notes that
limited IRB resources are often diverted away from focusing on higher-
risk studies because of the considerable time spent reviewing low-risk
and minimal-risk research. Theoretically, this can result in inadequate
attention devoted to research that could seriously harm subjects and
unnecessary delay of very low-risk research. From the perspective of
human subjects participating in research, the length and complexity of
consent forms has been increasing even for relatively low-risk studies,
hindering subject understanding of the research activities in which
they participate. Current and prospective research subjects have
increasingly indicated that they would like to be asked about the
future research use of their biospecimens. This desire is not
necessarily based on concern of inappropriate disclosure or use of
personally identifiable private information generated from the
biospecimen, but rather is rooted in the sense that subjects should,
whenever possible, be asked about such future research use. Finally,
the current system contains some oversight gaps that should be
addressed to ensure that the system is covering the riskiest studies
and that should compliance-related issues occur, the IRBs responsible
for these issues may be held responsible. Provisions are needed to
ensure the Rule's consistency with the principles of Belmont Report and
to protect privacy in the context of increasing cybercrime and the
introduction of modern research methods that may jeopardize subject
privacy while not unnecessarily slowing research.
Thus, this NPRM proposes a number of measures to address the issues
described above. Provisions that strengthen the requirements for
informed consent and promote transparency in the informed consent
process include: (1) Requiring that the informed consent form be
designed and presented in such a way that facilitates a prospective
subject's understanding of why one would want to participate in a
research study or not; (2) requiring that the informed consent form
present the required information before providing any other information
to a prospective subject; (3) revising and adding to the required
elements of consent; (4) requiring for certain clinical trials the
posting of a copy of at least one version of a consent form on a
publicly available federal Web site; and (5) changing the conditions
and requirements for waiver or alteration of consent to remove
ambiguity, including a new provision that under specific conditions an
IRB may approve a research proposal in which investigators obtain
identifiable private information without individuals' informed consent
for the purpose of screening, recruiting, or determining eligibility of
prospective human subjects of research.
Provisions that strengthen humans subjects protections include: (1)
A provision that would hold IRBs not affiliated with engaged
institutions directly responsible for compliance; (2) extending the
scope of the policy to research most likely to involve greater-than-
minimal risk, that is, clinical trials; and (3) creating standard
privacy safeguards for biospecimens and information.
Provisions that strengthen the extent to which the ethics system
promotes the principle of respect for persons: (1) Requiring informed
consent for most research activities involving biospecimens, regardless
of identifiability; (2) allowing for waiver of informed consent in
research activities involving biospecimens only in rare circumstances;
and (3) adding a provision that would prohibit waiver of consent if
someone has been asked to provide their broad consent for future
research use of their biospecimens or identified private information,
and that person refuses to give such consent.
New provisions that would allow IRBs greater flexibility to focus
resources on higher-risk research include: (1) Distinguishing
categories of activities that would be excluded from the rule; and (2)
expanding and clarifying categories of exempt research. Provisions that
streamline or reduce burden for IRBs or institutions include: (1)
Requiring consultation among the Common Rule agencies for the purpose
of harmonizing guidance; (2) eliminating an administrative requirement
for reporting IRB rosters; (3) removing the requirement that IRBs must
review and approve grant applications; (4) eliminating under certain
specific circumstances, continuing review for minimal risk studies that
undergo expedited review; (5) clarifying when expedited review can
occur; and (6) mandating use of a single IRB for multi-institutional
studies.
D. Analysis of Benefits and Costs
In this section, the analysis of the quantified and non-quantified
benefits and costs of the proposed changes to the Common Rule are
presented. First, the common assumptions of the analysis are discussed.
Then, this section presents the estimated quantified and non-quantified
benefits and costs of the specific changes. Because of the lack of
available data about IRB effectiveness and how IRBs function
operationally,\84\ many of the estimations in this analysis are based
on anecdotal evidence. On all assumptions and estimates presented
below, public comment is requested on the accuracy of these assumptions
and on whether better data sources are available to support the
analysis.
---------------------------------------------------------------------------
\84\ See, e.g.,, L Abbott and C. Grady, A Systematic Review of
the Empirical Literature Evaluating IRBs: What We Know and What We
Still Need to Learn. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235475/.
---------------------------------------------------------------------------
1. Analytic Assumptions
The analysis relies on common data elements and assumptions,
detailed below, concerning the domestic entities, individuals, and IRB
reviews affected by the proposed changes to the Common Rule. Many of
the estimates are derived from a 1998 NIH-sponsored evaluation of the
implementation of Section 491 of the Public Health Service Act, which
involved nationally representative surveys of IRBs, institutions, and
investigators. Based on a review of the literature, this study contains
the best available data on the time spent on protocol reviews as well
as the
[[Page 53997]]
characteristics of the reviews themselves. As previously stated, public
comment is requested on these and other estimates used throughout the
analysis.
According to the OHRP database of registered institutions and IRBs,
there are approximately 8,035 institutions with a FWA, of which 2,871
have an IRB. Some institutions have multiple IRBs and some IRBs are not
affiliated with an institution with an FWA, for a total of 3,499 IRBs.
The OHRP database of registered institutions and IRBs shows that
there are 675,390 annual reviews of non-exempt protocols involving
human subjects. It is estimated that there are 324,187 initial protocol
reviews (48 percent) and 351,203 continuing protocol reviews (52
percent) based on estimates reported in Bell et al.\85\ In each
category, it is estimated that 69 percent of these reviews are convened
and 31 percent are expedited based on estimates reported in Bell et al.
It is estimated that there are 472,773 reviews of single-site protocols
(70 percent) and 202,617 reviews of multi-site protocols (30 percent)
based on estimates reported in Bell et al. This analysis also assumes
that there are on average 5 IRB reviews per multiple-site protocol.
This implies that there are 472,773 single-site protocols and 40,523
multi-site protocols, for a total of 513,296 protocols. The above
implies that there are approximately 246,382 new protocols each year.
---------------------------------------------------------------------------
\85\ Bell J, Whiton J, and Connelly S, Final Report: Evaluation
of NIH Implementation of Section 491 of the Public Health Service
Act, Mandating a Program of Protection for Research Subjects, 1998.
---------------------------------------------------------------------------
Based on queries of ClinicalTrials.gov, it is estimated that HHS
supports 909 new clinical trials annually, of which 575 are regulated
by FDA. In addition, it is estimated that there are 1,399 clinical
trials currently not subject to oversight by either the Common Rule or
FDA regulations. Finally, based on queries of ClinicalTrials.gov,
Common Rule agencies support approximately 5,270 studies total.
Many individuals in various occupations would be affected by the
proposed changes to the Common Rule. It is estimated that an average of
one institution official at each institution with an FWA would be
affected by these changes, for a total of 2,871 institution officials.
The OHRP database of registered institutions and IRBs shows that there
are 10,197 full-time equivalents (FTEs) staff persons at IRBs working
as administrators or administrative staff, and that 89.8 percent of
IRBs have an administrator. It is assumed that these individuals work
full-time, implying a total of 3,193 IRB administrators and 7,004 IRB
administrative staff. The OHRP database of IRB rosters contains 3,359
individuals who serve as IRB chairs and an additional 32,518 voting
members. The number of IRB chairs is less than the number of IRBs
because some individuals chair multiple IRBs. It is assumed that there
are 439,968 investigators who conduct human subjects research in the
United States.\86\
---------------------------------------------------------------------------
\86\ To derive this estimate, the number of new protocols,
estimated above, is divided by the average number of new protocols
submissions reported per investigator. This is estimated to be 2.8
based on Bell et al. This number is then multiplied by the average
number of investigators working on each protocol (which is assumed
to be 5). This allows for an accounting of investigators working on
multiple protocols as well as protocols with multiple investigators.
---------------------------------------------------------------------------
The hourly wages of individuals affected by the proposed changes to
the Common Rule is estimated using information on annual salaries
provided by the U.S. Bureau of Labor Statistics and the U.S. Office of
Personal Management. The salary of postsecondary education
administrators is used as a proxy for the salary of institution
officials; the salary of lawyers is used as a proxy for the salary of
institution legal staff and IRB administrators; the salary of office
and administrative support workers is used as a proxy for the salary of
IRB administrative staff; the salary of postsecondary health teachers
is used as a proxy for the salary of IRB chairs and IRB voting members;
the salary of postsecondary teachers is used as a proxy for the salary
of investigators; the salary of database and systems administrators and
network architects is used as a proxy for the salary of database
administrators; and the salary of all occupations, as a proxy for the
salary of prospective human subjects. The federal employees affected by
the proposed changes to the Common Rule are assumed to be Step 5 within
their GS-level and earn locality pay for the District of Columbia,
Baltimore, and Northern Virginia. Annual salaries are divided by 2,087
hours to derive hourly wages. To project wages over 2016-2025, wages
are adjusted for growth over time using the average annual per capita
growth in real wage income over 1929-2012 reported by the U.S. Bureau
of Economic Analysis, which is 2.1 percent. The total dollar value of
labor, which includes wages, benefits, and overhead, is assumed to be
equal to 200 percent of the wage rate.
The RIA calculates person-hours by occupation per initial protocol
review and per continuing protocol review based on each occupation's
share of total person-hours reported in Bell et al. In particular, Bell
et al. reports that institution officials account for 4 percent, IRB
administrators account for 28 percent, IRB administrative staff account
for 30 percent, IRB chairs account for 7 percent, and IRB voting
members account for 31 percent of total person-hours. The RIA assumes
that the average number of person-hours spent per review equals the
weighted average of the person-hours spent per convened review and the
person-hours spent per expedited review. It is further assumed that
convened review requires twice as many person-hours as expedited
review.
Table 3 shows the number of entities affected by the proposed
changes to the Common Rule and other common assumptions of the analysis
(described above).
Table 3--Number of Affected Entities and Other Common Assumptions
------------------------------------------------------------------------
Description Estimate
------------------------------------------------------------------------
U.S. Institutions and IRBs
------------------------------------------------------------------------
Institutions with a Federalwide Assurance............... 8,035
Institutions with an IRB................................ 2,871
Institutions without an IRB............................. 5,164
IRBs.................................................... 3,499
------------------------------------------------------------------------
Occupations
------------------------------------------------------------------------
Institution officials................................... 2,871
[[Page 53998]]
IRB administrators...................................... 3,193
IRB administrative staff................................ 7,004
IRB chairs.............................................. 3,359
IRB voting members...................................... 32,518
Investigators........................................... 439,968
------------------------------------------------------------------------
Hourly Wages
------------------------------------------------------------------------
Institution officials (2013)............................ $48.20
Institution legal staff (2013).......................... $63.24
IRB administrators (2013)............................... $63.24
IRB administrative staff (2013)......................... $16.72
IRB chairs (2013)....................................... $46.36
IRB voting members (2013)............................... $46.36
Investigators (2013).................................... $35.75
Database administrators (2013).......................... $38.69
Prospective Human Subjects (2013)....................... $22.25
Federal employees in the District of Columbia,
Baltimore, and Northern Virginia (2013):
GS-9 Step 5........................................ $28.04
GS-13 Step 5....................................... $48.35
GS-14 Step 5....................................... $57.13
GS-15 Step 5....................................... $67.21
Average annual per capita growth in real wage income.... 2.1%
------------------------------------------------------------------------
IRB Reviews of Human Subjects Research Protocols at U.S. Institutions
------------------------------------------------------------------------
Annual reviews of non-exempt protocols.................. 675,390
Initial protocol reviews (48%)...................... 324,187
Convened reviews (69%)......................... 223,689
Expedited reviews (31%)........................ 100,498
Continuing protocol reviews (52%)................... 351,203
Convened reviews (69%)......................... 242,330
Expedited reviews (31%)........................ 108,873
Annual reviews of single-site protocols (70%)........... 472,773
Annual reviews of multi-site protocols (30%)............ 202,617
------------------------------------------------------------------------
Human Subjects Research Protocols at U.S. Institutions
------------------------------------------------------------------------
Active protocols........................................ 513,296
Single-site protocols............................... 472,773
Multi-site protocols................................ 40,523
New protocols (48%)..................................... 246,382
Average number of IRB reviews per active multi-site 5
protocol...............................................
------------------------------------------------------------------------
Clinical Trials
------------------------------------------------------------------------
New clinical trials supported by HHS annually........... 909
Regulated by FDA.................................... 575
Active clinical trials currently not regulated by the 1,399
Common Rule or FDA regulations.........................
Clinical Trials supported by Common Rule Agencies....... 5,270
------------------------------------------------------------------------
Person-Hours per Protocol Reviewed by Occupation and Type of Review
------------------------------------------------------------------------
Institution officials:
Initial protocol reviews
Convened reviews................................ 0.52
Expedited reviews............................... 0.26
Continuing protocol reviews:
Convened reviews................................ 0.10
Expedited reviews............................... 0.05
IRB administrators:
Initial protocol reviews:
Convened reviews................................ 3.64
Expedited reviews............................... 1.82
Continuing protocol reviews:
Convened reviews................................ 0.68
Expedited reviews............................... 0.34
IRB administrative staff:
Initial protocol reviews:...........................
Convened reviews................................ 3.91
Expedited reviews............................... 1.95
Continuing protocol reviews:
Convened reviews................................ 0.73
[[Page 53999]]
Expedited reviews............................... 0.36
IRB chairs:
Initial protocol reviews:
Convened reviews................................ 0.91
Expedited reviews............................... 0.46
Continuing protocol reviews:
Convened reviews................................ 0.17
Expedited reviews............................... 0.08
IRB voting members:
Initial protocol reviews:
Convened reviews................................ 2.70
Expedited reviews............................... 1.35
Exempt reviews.................................. 0.50
Continuing protocol reviews:
Convened reviews................................ 0.75
Expedited reviews............................... 0.38
Investigators:
Initial protocol reviews:
Convened reviews................................ 13.65
Expedited reviews............................... 7.15
Exempt reviews.................................. 0.50
Continuing protocol reviews:
Convened reviews................................ 6.83
Expedited reviews............................... 3.58
------------------------------------------------------------------------
2. Analysis of Proposed Changes
Presented below is an analysis of the quantified and non-quantified
benefits and costs of the proposed changes to the Common Rule. For each
proposed change, we describe and explain the need for the change,
provide a qualitative summary of the anticipated benefits and costs,
describe the methods we use to quantify benefits and costs, and then
present estimates.
a. Costs for the Regulated Community to Learn New Requirements and
Develop Training Materials; Costs for OHRP to Develop Materials and
Guidance
Domestic institutions, IRBs, and investigators would need to spend
time learning the proposed changes to the Common Rule once training
materials become available to them. In addition, IRBs and OHRP would
need to update training materials for investigators. Finally, OHRP
would need to develop guidance, templates, lists, and a number of
electronic resources (as stated in the NPRM).
The RIA estimates that institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators would each spend 5 hours to learn the proposed changes to
the Common Rule. It is also estimated that institution officials would
spend two hours to learn new procedures, IRB administrators would spend
20 hours, and administrative staff would spend 80 hours. Based on the
estimates presented in Table 3, the dollar value of their time is
calculated by multiplying hours by their estimated 2016 wages and
adjusting for overhead and benefits. For example, to calculate the
dollar value of time spent by institution officials to learn the
proposed changes to the Common Rule in 2016, we multiply the number of
institution officials (2,871) by the number of hours spent per
institutional official (5), by the projected hourly wage of institution
officials ($48.20), and by the adjustment factor for benefits and
overhead (2).
In order to develop the resources required by the NPRM, it is
anticipated that OHRP would need:
Three staff people at the GS-14 level to: (1) Promote
harmonization efforts to issue guidance across Common Rule agencies and
departments; (2) develop a number of ``Secretary's Lists'' (akin to
guidance documents) referenced in the rule that would be periodically
reviewed and revised; (3) develop template agreements/contracts for use
by the regulated community; (4) manage the administrative transition to
the new processes proposed in the NPRM; and, (5) develop the language
and technical requirements for a web-based tool that would allow
investigators (and others) to determine if a project fits into a
category of research exempt from certain regulatory requirements.
One staff person at the GS-13 level to manage process
changes proposed in the NPRM, and assist with implementation for the
web-based tools and portals proposed.
One staff person at the GS-9 level to provide technical
support for the web-based portals proposed in the NPRM.
In addition, the first year after a final rule is published
staffing resources beyond what is described above would be necessary:
Three staff people at the GS-14 level to draft new
guidance and revise old guidance.
One staff person at the GS-14 level to conduct educational
seminars.
OHRP also anticipates the following in non-personnel costs:
Technical development of a web-based tool that
investigators (and others) may use to determine if a project fits into
a category of research that is exempt from certain regulatory
requirements ($350,000)
Technical development of two web-based portals for
investigators to post final consent forms for HHS-funded clinical
trials, and for investigators that conduct certain types of
demonstration projects to post information about said projects
($200,000)
Developing five educational seminars (including travel) to
educate the public about the requirements of the new rule ($200,000)
Upgrading equipment for education activities ($50,000)
Present value costs of $208 million and annualized costs of $24.3
million are estimated using a 3 percent discount rate; present value
costs of $199 million and annualized costs of $28.3 million are
estimated using a 7 percent discount rate. Table 4 summarizes the
quantified
[[Page 54000]]
and non-quantified benefits and costs to learn new requirements and
develop training materials.
Table 4--Summary of Estimated Benefits and Costs To Learn New Requirements and Develop Training Materials
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
None (although benefits discussed in
association with other provisions
would be impossible without this
activity)..........................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Time and money to learn new 208 199 24.3 28.3
requirements, update training
materials, and develop tools.......
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
b. Extending Oversight to IRBs Unaffiliated With an Institution Holding
a Federalwide Assurance (NPRM at Sec. __.101(a))
The NPRM proposes a change to place unaffiliated IRBs within the
realm of entities to which the policy applies. This new provision gives
Common Rule departments and agencies explicit authority to enforce
compliance directly against IRBs that are not affiliated with an
assured institution. This change addresses concerns about OHRP's
current practice of enforcing compliance with the Common Rule through
the institutions that were engaged in human subjects research, even in
circumstances when the regulatory violation is directly related to the
responsibilities of an external IRB. This change should encourage
institutions to more willingly rely on qualified unaffiliated IRBs for
cooperative research, as is required under the proposed changes at
Sec. __.114 (see section III.D.2.s of this RIA below).
The OHRP database of assured institutions and registered IRBs shows
that there are approximately 449 IRBs not affiliated with an
institution holding an FWA that would now be subject to oversight.
These IRBs would develop an estimated average of 10 written agreements
with other institutions each year as a result of this proposal. It is
further estimated that each agreement would require an average of 10
hours of institution legal staff time and 5 hours of IRB administrator
time to complete.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value costs of $84.6 million and annualized costs of $9.93
million are estimated using a 3 percent discount rate; present value
costs of $69.2 million and annualized costs of $9.86 million are
estimated using a 7 percent discount rate. Table 5 summarizes the
quantified and non-quantified benefits and costs of extending oversight
to IRBs unaffiliated with an institution holding an FWA.
Table 5--Summary of Estimated Benefits and Costs of Extending Oversight to IRBs Unaffiliated With an Institution
Holding an Federalwide Assurance (NPRM at Sec. __.101(a))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Encouragement to institutions to rely on unaffiliated IRBs when appropriate.
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Developing IRB authorization 84.6 69.2 9.93 9.86
agreements.........................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
[[Page 54001]]
c. Extending Common Rule Compliance Oversight to Clinical Trials
Regardless of Funding Source (NPRM at Sec. __.101(a)(2))
The proposed rule would extend the regulations to cover clinical
trials conducted at an institution in the United States that receives
federal support from a Common Rule department or agency for non-exempt,
non-excluded human subjects research, regardless of the funding source
of the specific clinical trial. Extension of the rules would not apply
to clinical trials already regulated by FDA.
A small percentage of clinical trials currently are not subject to
oversight by either the Common Rule or FDA regulations. This change in
policy gives OHRP the authority to conduct oversight compliance of
clinical trials not otherwise subject to human subjects protection
regulations. The benefits to be gained in terms of equitable and just
distribution of protections to all subjects of clinical trials warrant
closing this gap in the current system. Moreover, while it is expected
that this extension would apply to only a small percentage of clinical
trials, they are the type of studies that often pose the greatest risks
to subjects. Since this extension is expected to bring research that
poses the most risk to research subjects under the rules, it is
presumed that the current option in the FWA that allows institutions to
voluntarily extend the funding Common Rule department or agency's
compliance oversight authority to all research conducted at an
institution regardless of funding source (i.e., ``checking the box'')
would be unnecessary.
Although more research would be covered by the policy, the
extension is contingent on an entity receiving federal support for non-
exempt human subjects research; thus, the entity already should have an
established IRB in place and would not incur costs establishing one or
contracting with an unaffiliated IRB.
The RIA estimates that there are 1,399 clinical trials currently
not subject to oversight by either the Common Rule or FDA regulations.
It is estimated that in 2016 all 1,399 of these clinical trials would
undergo convened initial review. In subsequent years, an estimated 672
protocols would undergo convened initial review, 502 would undergo
convened continuing review, and 225 would undergo expedited continuing
review based on the distribution of reviews presented in Table 3.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value costs of $18.3 million and annualized costs of $2.15
million are estimated using a 3 percent discount rate; present value
costs of $15.1 million and annualized costs of $2.15 million are
estimated using a 7 percent discount rate. Table 6 summarizes the
quantified and non-quantified benefits and costs of oversight for
clinical trials currently not subject to oversight.
Table 6--Summary of Estimated Benefits and Costs of Extending Common Rule Compliance Oversight for Clinical
Trials Regardless of Funding Source (NPRM at Sec. __.101(a)(2))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Improving institutional willingness to use unaffiliated IRBS, thereby facilitating the implementation of the
proposed changes to Sec. __.114 (Cooperative Research).
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Increase in number of reviews....... 18.3 15.1 2.15 2.15
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
d. Activities Excluded From the Requirements of the Common Rule Because
They Are Not Research (NPRM at Sec. __.101(b)(1))
Six categories of activities would be excluded from the regulatory
requirements of the Common Rule because they are not considered
research as defined in Sec. __.102(l) in the NPRM: (1) Certain data
collection and analysis activities conducted for an institution's own
internal operation and program improvement purposes; (2) certain
activities that focus directly on the specific individuals about whom
the information is collected (i.e., oral history, journalism,
biography, and historical scholarship); (3) certain collection and
analysis activities conducted by a criminal justice agency solely for
criminal justice investigative purposes; (4) certain quality assurance
or improvement activities; (5) certain public health surveillance
activities; and (6) certain activities conducted by a defense, national
security, or homeland security authority. The proposal in the NPRM to
explicitly list certain activities that are not considered ``research''
for the purposes of this policy is not intended to suggest that these
are the only six categories that may be considered not to meet the
definition of ``research.''
Federal agencies (and some institutions in the regulated community)
engaged in activities considered in these exclusions already interpret
such activities as excluded from the regulations. Thus, in general, the
exclusions found in proposed Sec. __.101(b)(1) represent a proposed
codification of current practice. However, comments to the ANPRM
suggested that at many institutions, activities that would now be
explicitly excluded from the policy are being routinely reviewed by
IRBs. While many
[[Page 54002]]
institutions are specifically creating policies to state that oral
history or journalism activities do not require IRB review,\87\
institutions vary and some continue to require IRB review for other
activities (such as quality improvement activities \88\) that may not
meet the Common Rule's definition of research. Thus, explicitly
excluding these six categories because they are to be considered not
research would provide clarity to the regulatory community about what
constitutes research per this policy, and also likely result in a
modest decrease in the number of IRB reviews that occur each year in
institutions.
---------------------------------------------------------------------------
\87\ See e.g., Schrag, ZM ``Smithsonian Frees Oral History,
Journalism, and Folklore,'' Institutional Review Blog, 30 July 2010,
http://www.institutionalreviewblog.com/2010/07/smithsonian-frees-oral-history.html. See also ``More Universities Deregulate Oral
History'', 7 April 2010, http://www.institutionalreviewblog.com/2010/04/more-universities-deregulate-oral.html.
\88\ See e.g., Baily, MA ``Quality Improvement Methods in Health
Care,'' in From Birth to Death and Bench to Clinic: The Hastings
Center Bioethics Briefing Book for Journalists, Policymakers, and
Campaigns, ed. Mary Crowley (Garrison, NY: The Hastings Center,
2008), 147-152 http://www.thehastingscenter.org/Publications/BriefingBook/Detail.aspx?id=2204.
---------------------------------------------------------------------------
Institutions, investigators, and IRBs involved in supporting,
conducting, or reviewing these activities would no longer incur the
costs of IRB review and approval and continuing review. Activities that
were not intended to be subject to the regulations would clearly be
excluded, allowing such activities to proceed without delays caused by
the need for IRB submission, review, and approval.
It is estimated that 6,754 annual reviews of protocols (1.0
percent) would no longer be conducted as a result of the exclusions
proposed in Sec. __.101(b)(1). Of these reviews, 2,237 would have
undergone convened initial review, 1,005 would have undergone expedited
initial review, 2,423 would have undergone convened continuing review,
and 1,089 would have undergone expedited continuing review based on the
distribution of reviews presented in Table 3.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value benefits of $74.0 million and annualized benefits of
$8.67 million are estimated using a 3 percent discount rate, and
present value benefits of $60.5 million and annualized benefits of
$8.61 million are estimated using a 7 percent discount rate. Table 7
summarizes the quantified and non-quantified benefits and costs of
excluding these activities from the requirements of the Common Rule.
Table 7--Summary of Estimated Benefits and Costs of Excluding Activities From the Requirements of the Common
Rule Because They Are Not Research (NPRM at Sec. __.101(b)(1))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Reduction in number of reviews...... 74.0 60.5 8.67 8.31
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Increased clarity in what must be reviewed; ability for IRBs to focus efforts on reviews of higher-risk,
more complex, research activities.
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
e. Low-Risk Research Activities Excluded From the Requirements of the
Common Rule Because They Are Already Subject to Independent Controls
(NPRM at Sec. __.101(b)(2))
The NPRM proposes that four additional categories of research
activities be explicitly excluded from the regulatory requirements of
the Common Rule because they are low-risk and already subject to
independent controls in the absence of the protections of the Common
Rule. These are: (1) Certain research activities that involve the use
of certain educational tests, survey procedures, interview procedures,
or observation of public behavior (a revised version of current
exemption category 2); (2) certain research activities involving the
collection or study of information (a revised version of current
exemption category 4); (3) certain research activities conducted by a
government agency using government-generated, non-research data; and
(4) certain data collection and analysis activities using identifiable
health information subject to the HIPAA Privacy Rule.
The current Common Rule articulates two exemptions (current Rule at
Sec. __.101(b)(2) and (4)) that appear in a similar format in the
proposed NPRM exclusions. Current Common Rule exemption category 2 is
found in the NPRM in Sec. __.101(b)(2)(i); current exemption category
4 is found in NPRM Sec. __.101(b)(2)(ii). In addition to being
considered excluded from the rule (rather than exempt from certain
requirements of the rule), current exemption category 2 (NPRM Sec.
__.101(b)(2)(i)) has been clarified to state that interventions in
conjunction with collection of data through the use of educational
tests, survey procedures, interview procedures or observation of public
behavior uninfluenced by the investigator (including visual or auditory
recording) may not be used in research activities that qualify for this
exclusion. For the research activities at issue in the NPRM at Sec.
__.101(b)(2)(i), it is presumed that the activities poses little to no
risk to subjects, and that the subjects knowingly and willingly
[[Page 54003]]
provide the information, or decline to participate. Thus, IRB review of
the research and consent related documents are not believed to be
necessary for such activities.
Four changes are proposed to current exemption category 4 (NPRM at
Sec. __.101(b)(2)(ii)). First, the provision would now be considered
excluded from the rule, not just exempt from certain requirements of
the rule. Second, the provision no longer includes pathological
specimens or diagnostic specimens. Third, NPRM Sec. __.101(b)(2)(ii)
removes the word ``existing'' from the provisions. This is intended to
clarify the scope of the exclusion to allow for information that will
be collected in the future. Finally, a condition is added requiring
that the exclusion may only be used when the investigator has no plans
to contact subjects, re-identify subject, or otherwise conduct an
analysis that could lead to creating identifiable private information.
Neither the exclusion at NPRM Sec. __.101(b)(2)(iii) (certain
research activities conducted by a government agency using government-
generated, non-research data) nor the exclusion at NPRM Sec.
__.101(b)(2)(iv) (certain data collection and analysis activities using
identifiable health information subject to the HIPAA Privacy Rule)
appear in the current Rule. These research activities are excluded
because human subjects are independently protected through other
mechanisms or laws. It is anticipated that the exclusion of activities
regulated by HIPAA as health care operation activities, public health
activities, or research (NPRM at Sec. __.101(b)(2)(iv)) would
represent a significant reduction in the volume of activities an IRB
reviews. For example, the proposed exclusion at Sec. __.101(b)(2)(iv)
would mean that at institutions subject to the HIPAA regulations,
projects where one is simply analyzing protected health information
from medical charts would not be required to undergo IRB review.
Institutions, investigators, and IRBs involved in supporting,
conducting, or reviewing these activities would no longer incur the
costs of IRB review, approval, and continuing review. Activities that
were not intended to be subject to the regulations would clearly be
excluded, allowing such activities to proceed without delays caused by
the need for IRB submission, review, and approval.
The RIA estimates that 67,539 annual reviews of protocols (10.0
percent) would no longer be conducted as a result of the proposed
exclusions in Sec. __.101(b)(2). It is anticipated that the exclusion
of certain activities covered by the HIPAA Privacy Rule would drive the
estimated reduction in annual IRB reviews of protocols. Of these
reviews, 22,369 would have undergone convened initial review, 10,050
would have undergone expedited initial review, 24,233 would have
undergone convened continuing review, and 10,887 would have undergone
expedited continuing review based on the distribution of reviews
presented in Table 3.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value benefits of $740 million and annualized benefits of
$86.7 million are estimated using a 3 percent discount rate, and
present value benefits of $605 million and annualized benefits of $86.1
million are estimated using a 7 percent discount rate. Table 8
summarizes the quantified and non-quantified benefits and costs of
excluding these activities from the requirements of the Common Rule.
Table 8--Summary of Estimated Benefits and Costs of Excluding Low-Risk Research From the Requirements of the
Common Rule (NPRM at Sec. __.101(b)(2))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Reduction in number of reviews...... 740 605 86.7 86.1
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Clarity in what research activities must be reviewed; ability for IRBs to focus efforts on reviews of higher-
risk, more complex, research activities.
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
f. Clarifying and Harmonizing Regulatory Requirements and Agency
Guidance (NPRM at Sec. __.101(j)
The proposed rule would require consultation among the Common Rule
agencies for the purpose of harmonization of guidance, to the extent
appropriate, before federal guidance on the Common Rule is issued,
unless such consultation is not feasible. The proposal also recognizes
that harmonization would not always be possible or desirable given the
varied missions of the agencies that oversee the protection of human
subjects and differences in statutory authorities. Note that this is a
codification of harmonization efforts currently occurring across Common
Rule agencies.
This proposal appropriately recognizes the importance of harmonized
guidance for the regulated community by creating, as much as possible,
consistent interpretations of the regulations.
There is no compliance requirement for the regulated community
associated with this provision. It is anticipated that harmonization
would create greater
[[Page 54004]]
uniformity in the regulatory requirements for investigators,
institutions, and IRBs, which could reduce confusion and time spent
complying with multiple sets of regulations. Costs for achieving
harmonization would be borne by the Common Rule agencies.
As this change likely would not impact staffing requirements at
Common Rule agencies, no costs are quantified here. It is possible
however, that the harmonization requirement could result in it taking
longer for Common Rule agency guidance to be approved and issued to the
public. Similarly, as it is unclear the extent to which this change
would reduce the time IRBs spend on reviewing protocols, benefits are
also not quantified. Table 9 summarizes the non-quantified benefits and
costs of clarifying and harmonizing regulatory requirements and agency
guidance.
Table 9--Summary of Estimated Benefits and Costs of Clarifying and Harmonizing Regulatory Requirements and
Agency Guidance (NPRM at Sec. __.101(j))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Increased uniformity in regulatory requirements among Common Rule agencies; increased clarity to the
regulated community about how regulations should be interpreted.
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
Time for consultation among Common Rule agencies before federal guidance is issued.
----------------------------------------------------------------------------------------------------------------
g. Expanding the Definition of Human Subject To Include Research
Involving Non-Identified Biospecimens and Creating an Exemption for
Secondary Research Using Biospecimens or Identifiable Private
Information (NPRM at Sec. Sec. __.102(e), __.101(b)(3)(i), and
__.104(f)(2))
The NPRM proposes to expand the definition of human subjects to
include research in which an investigator obtains, uses, studies or
analyzes a biospecimen. This would apply regardless of the
identifiability of the biospecimen. Generally, investigators would not
be allowed to remove identifiers from biospecimens without obtaining
informed consent or a waiver of consent. Written consent would
generally be required for such activities. Thus, this change will
significantly expand the amount of research that is subject to the
Common Rule. This requirement would not apply to biospecimens and
information already collected at the time the final rule is published.
Proposed Sec. __.101(b)(3)(i) would exclude research activities
involving non-identified biospecimens where no new information about an
individual is generated. While activities such as developing new
testing assays could be excluded under this provision, it is
anticipated that under the NPRM proposals, most research with
biospecimens would now fall under the Rule.
At its core, this proposal is intended to promote the ethical
principle of respect for persons. In addition to promoting respect for
persons in the research enterprise, the proposed regulatory structure
for research with biospecimens (whereby consent is sought for almost
all research activities involving biospecimens) will encourage
investigators to retain identifiers, which can enhance research by
preserving the ability to link to important additional information
about the subject. Additionally, members of the regulated community
have reported situations where, even though not currently required by
regulation, investigators were told by an IRB that they needed to
obtain study-specific consent for research activities involving non-
identified biospecimens. Under the current NPRM proposals, such a
situation would not occur because consent--be it broad or study
specific--would always be obtained for research involving biospecimens.
While this proposal will promote the ethical principle of respect
for persons, it also will significantly increase the volume of studies
for which investigators must seek and document informed consent (unless
more stringent waiver criteria are met). The RIA estimates that there
are 250,000 studies using biospecimens each year that are not currently
subject to oversight by either the Common Rule or FDA regulations
because they have been stripped of identifiers. Extrapolations from
1999 data \89\ suggest that biospecimens are collected from as many as
30 million individuals and are stored each year for both clinical and
research purposes. Approximately 9 million individuals' biospecimens
(30 percent) are collected for research purposes. As a conservative
estimate, approximately 6.3 million individuals' biospecimens (30
percent) could potentially be used in future research studies. Thus, it
is possible that investigators would seek consent to secondary use of
biospecimens or a waiver of consent for an additional 15 million
individuals annually for secondary use of biospecimens.
---------------------------------------------------------------------------
\89\ Eiseman, E., Haga, S. (1999). Handbook of Human Tissue
Sources: A National Resource of Human Tissue Samples. Washington,
DC: RAND Corporation.
---------------------------------------------------------------------------
In the absence of comprehensive data, to calculate the number of
protocols that will now be covered, two approaches are proposed; public
comment is requested on these estimates and approaches. Under method
one, it is estimated that approximately 50 biospecimens will be used on
average per research protocol involving biospecimens. This gives a
potential 300,000 new research protocols using
[[Page 54005]]
non-identified biospecimens. This estimate of 300,000 new research
protocols is rounded down to 250,000 new studies because based on ANPRM
comments and industry data, it seems reasonable to assume that, as a
conservative estimate, the number of new biospecimen studies
encapsulated by the proposed rule would equal the total number of new
protocols conducted each year (i.e., the number of new biospecimen
studies is likely close to the estimate of 246,382 new annual studies).
Under method two, biospecimen repository representatives report
that roughly 90 percent of their collections are used in non-identified
form in research activities that do not fall under the current Common
Rule. Thus, only 10 percent of biospecimen studies are currently
covered by the Common Rule, representing a 9:1 ratio of studies
involving non-identified biospecimens to studies involving identifiable
biospecimens. Of the 246,382 new protocols each year that are non-
exempt (Table 3), we assume conservatively that 10-15 percent are using
identifiable biospecimens. This equates to between 24,638 and 36,957
new studies each year using identifiable biospecimens. As previously
discussed, it is estimated that the number of biospecimen studies that
occur on non-identified biospecimens each year is approximately 9 times
the number of studies using identifiable biospecimens, or between
221,741 and 332,613 studies each year. Thus, under method two, an
estimate of 250,000 new studies on non-identified biospecimens each
year is also reasonable.
In order to facilitate research with biospecimens, the NPRM
proposes to create separate elements of broad consent (NPRM at Sec.
__.116(c), discussed in III.D.2.u below) such that investigators and
institutions may seek, and individuals may grant, consent for future
unspecified research activities. The NPRM also proposes an exemption
that relies on obtaining broad consent for future, unspecified research
studies (NPRM at Sec. __.104(f)(2)). In order to be eligible for the
exemption proposed in Sec. __.104(f)(2), broad consent must have been
sought and obtained using the Secretary's template for broad consent
(described in proposed Sec. __.116(d)(3)), and the investigator must
not anticipate returning individual research results to subjects. To
facilitate secondary research using biospecimens and identifiable
private information, the NPRM also proposes an exemption for the
storage and maintenance of biospecimens and identifiable private
information for future, unspecified, secondary research activities
(NPRM at Sec. __.104(f)(1)), which is described in more detail in
Section III.D.2.n below).
The exemption proposed at Sec. __.104(f)(2) is specifically for
secondary research studies involving biospecimens and identifiable
private information that have been or will be acquired for purposes
other than the currently proposed research study. If a secondary
research study does not meet the requirements of this exemption
category, the investigator would need to seek IRB review of the study,
and would need to obtain either study-specific consent or a waiver of
informed consent under the Common Rule. Note that for biospecimens an
IRB would apply the more stringent waiver criteria at proposed Sec.
__.116(e)(2) or (f)(2). For identifiable private information, an IRB
would apply the waiver criteria at proposed Sec. __.116(e)(1) or
(f)(1), which are almost identical to the waiver criteria in the
current Common Rule.
The proposed exemption at Sec. __.104(f)(2), also ensures that in
secondary research conducted with biospecimens or identifiable private
information, appropriate privacy safeguards are in place (through
requiring adherence to the privacy safeguards described in Sec.
__.105). Thus, although this provision is an expansion in the nature of
research that is exempt, it is accompanied by certain requirements and
safeguards.
It is anticipated that a majority of studies that utilize this
exemption will be biospecimen studies. The extent to which individuals
conducting secondary research studies involving identifiable private
information will utilize this exemption is unknown given that there are
additional pathways under this proposed rule to facilitate secondary
research activities involving identifiable private information is
unknown. To that end, the benefits and costs associated with this
provision only take into consideration secondary research involving
biospecimens. It is further anticipated that these revisions will
result in higher value research with biospecimens being conducted with
subjects' consent and without the need for full IRB review, or the need
to go back to subjects to obtain consent for every secondary research
study, as long as certain conditions are met.
Because the estimated 250,000 biospecimen studies each year that
will be newly covered under the rule as a result of the proposed
modification to the definition of human subject will likely be low or
minimal risk, the RIA assumes that all of these will be eligible for
the Sec. __.104(f)(2) exemption (so long as consent--broad or study
specific--was sought and obtained). Benefits and costs associated with
obtaining and tracking broad consent are discussed below in section
III.D.2.u of this RIA. Because the compliance date for the expansion to
the definition of human subject will be three years after the date of
publication of a final rule, the benefits and costs described below
assume a start date of 2019.
As required under Sec. __.104(c), an exemption determination must
be made and documented for each of the 250,000 newly covered
biospecimen studies. It is anticipated that in 50 percent of these
studies (125,000 studies), investigators will spend 30 minutes entering
information into the HHS-created decision tool in order for that tool
to generate an exemption determination. In the remaining 125,000
studies, it is anticipated that investigators will spend 30 minutes
preparing and submitting information about the study to an individual
able to make exemption determinations (per Sec. __.104(c)). An
individual at the IRB voting member level will spend an estimated 30
minutes per study to make an exemption determination.
In the absence of the proposed exempt category of research at Sec.
__.104(f)(2) but taking into consideration the expansion to the
definition of human subject, it is estimated that each year, all
250,000 of these studies will undergo convened initial review. In
subsequent years, it is estimated estimate that 120,000 protocols would
undergo convened initial review, 89,700 would undergo convened
continuing review, and 40,300 would undergo expedited continuing review
based on the distribution of reviews presented in Table 3.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value costs of $101 million and annualized costs of $11.9
million are estimated using a 3 percent discount rate; present value
costs of $77.8 million and annualized costs of $11.1 million are
estimated using a 7 percent discount rate. Table 10 summarizes the
quantified and non-quantified benefits and costs of amending the
definition of human subject.
[[Page 54006]]
Table 10--Summary of Expanding the Definition of Human Subject To Include Research Involving Non-Identified
Biospecimens and Creating an Exemption for Secondary Research Using Biospecimens or Identifiable Private
Information (NPRM at Sec. Sec. __.102(e), __.101(b)(3)(i), and __.104(f)(2))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Reduction in number of IRB reviews ................ ................ ................ ................
that would have otherwise occurred
as a result of the expansion of the
definition of human subject........
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Ethical benefit of respecting an individual's wishes in how his or her biospecimens are used in future;
ensuring protection of human subjects in research activities involving non-identifiable biospecimens.
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Determining that these studies are 101 77.8 11.9 11.1
exempt in accordance with Sec.
__.104(c)..........................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
Potential reduction in number of biospecimens available for research........................................
----------------------------------------------------------------------------------------------------------------
h. Modifying the Assurance Requirements (current Rule at Sec.
__.103(b)(1), (b)(3), (d))
The NPRM proposes to modify the requirements of the assurance
process in the following ways. First, the NPRM proposes to delete the
requirement in the current Common Rule at Sec. __.103(b)(1) of
identifying a statement of principles governing all research at an
institution. As discussed in section II.H.2 of this preamble, the
requirement for institutions to designate a set of ethical principles
to which that institution will abide in all research activities is
generally not enforced. Further, for international institutions that
may receive U.S. government funding for research activities, it creates
the impression that these international institutions must modify their
internal procedures to comport with the set of principles designated on
the FWA for activities conducted at those institutions that receive no
U.S. government funding. In order to provide clarity to these
international institutions that such measures are not required for
activities that receive no Common Rule department or agency support,
this provisions has been deleted.
The requirement that a written assurance include a list of IRB
members for each IRB designated under the assurance would be replaced
by the requirement that the assurance include a statement that for each
designated IRB the institution, or when appropriate the IRB, prepares
and maintains a current detailed list of the IRB members with
information sufficient to describe each member's chief anticipated
contributions to IRB deliberation; and any employment or other
relationship between each member and the institution. The regulatory
requirement at Sec. __.103(b)(3) that changes in IRB membership be
reported to the department or agency head, or to OHRP when the
existence of an HHS-approved assurance is accepted, would be deleted,
eliminating the requirement. Instead, an institution would be required
under proposed Sec. __.108(a)(2) to maintain a current IRB roster, but
such a roster would not need to be submitted to OHRP or other agency
managing the assurance of compliance process.
The proposed changes to the IRB roster requirement are expected to
reduce administrative burden and have the following additional
beneficial effects, without having any significant impact on the
protection of human subjects:
Reduction in the administrative burdens on institutions
related to the submission of IRB membership lists to OHRP and, in some
cases, to the departments and agencies that process their own
assurances;
Reduction in the administrative burdens on OHRP with
respect to reviewing and processing new and updated IRB membership
lists as part of the IRB registration process, as well as reductions,
in some cases, in the administrative burdens on other departments and
agencies that receive and review IRB membership lists and changes in
IRB membership as part of their own assurance processes;
In some cases, reduction in the volume of records that
need to be created and retained by the departments and agencies
regarding the review and processing of IRB membership lists; and
Simplification of the process for the electronic
submission and acceptance of IRB registrations via the OHRP Web site.
In addition, HHS anticipates modifying the FWA so that institutions
would no longer have the option to ``check the box'' on an assurance
and voluntarily extend the funding Common Rule department or agency's
regulatory authority to all research conducted at an institution
regardless of funding source. For research other than clinical trials,
institutions could continue to voluntarily apply the regulations to all
research conducted by the institution, but this voluntary extension
would no longer be part of the FWA. Members of the regulated community
report that whether or not they ``check the box'' on an assurance form,
they tend to voluntarily apply the regulations to all research
activities taking place at an institution regardless of funding. Thus,
the removal of this option on an assurance form likely would not impact
community practice. To that end, no costs have been associated with
this provision.
Finally, the current requirement at Sec. __.103(d) that a
department or agency head's evaluation of an assurance take into
consideration the adequacy of the proposed IRB in light of the
anticipated scope of the institution's activities and the types of
subject populations likely to be involved, the appropriateness of the
proposed initial
[[Page 54007]]
and continuing review procedures in light of the probable risks, and
the size and complexity of the institution, would be deleted.
The deletion of this provision would eliminate an administrative
process that is no longer meaningful given the purpose and design of
the FWA and OHRP's processes for reviewing IRB registrations and
reviewing and approving FWAs. This change also harmonizes the Common
Rule with FDA's human subjects protection regulations by eliminating
the requirement to submit IRB membership lists.
The RIA estimates that administrative staff at each IRB would spend
5 fewer hours complying with the assurance requirements. Based on the
estimates presented in Table 3, the dollar value of their time is
calculated by multiplying hours by their estimated 2016-2025 wages and
adjusting for overhead and benefits.
Present value benefits of $5.81 million and annualized benefits of
$0.68 million are estimated using a 3 percent discount rate; present
value benefits of $4.10 million and annualized benefits of $0.58
million are estimated using a 7 percent discount rate. Table 11
summarizes the quantified and non-quantified benefits and costs of the
proposed change to the IRB roster requirement.
Table 11--Summary of Estimated Benefits and Costs of Proposed Change To Modifying the Assurance Requirements
(Current Rule at Sec. __.103(b)(1), (b)(3), (d))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Reduction in time for IRB 5.81 4.10 0.68 0.58
administrative staff and OHRP staff
to submit, review, and process IRB
membership lists...................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Reduction in volume of records created by an institution....................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
i. Requirement for Written Procedures and Agreements for Reliance on
External IRBs (NPRM at Sec. Sec. __.103(e) and __.115(a)(10))
Language is proposed at Sec. __.103(e) requiring each IRB,
institution, or organization that has oversight responsibility for non-
exempt research involving human subjects covered by this policy and
conducted by another institution to have a written agreement
identifying the respective responsibilities of the IRB organization and
the engaged institution for meeting the regulatory requirements of this
policy. This is already a requirement under the terms of an FWA but
this requirement increases the level of detail that has to be included
in such agreements, specifically the roles and responsibilities of each
party. In addition, a requirement is added at Sec. __.115(a)(10) that
institutions or IRBs retain the agreement between the institution and
IRB specifying the responsibilities that each entity would undertake to
ensure compliance with the requirements of proposed Sec. __.103(e).
The new requirements for agreements between institutions and
external IRBs would not apply to research initiated before the
effective date of the rule. However, the new requirements would affect
existing agreements between institutions and external IRBs in cases
where the existing agreements are not study-specific, but rather
pertain to all research conducted by the institution or to a category
or categories of human subjects research.
Initially, costs would be involved in drafting, revising, and
conducting managerial review of agreements to ensure they satisfy these
new requirements. Anticipated benefits include enhanced protection of
human subjects in research reviewed by nonaffiliated IRBs, and greater
reliance on external IRBs as the IRB of record for cooperative
research, as stipulated in proposed Sec. __.114.
Table 3 shows that there are 5,164 FWA-holding institutions without
an IRB and 2,871 FWA-holding institutions with an IRB. We assume that
the 5,164 FWA-holding institutions without an IRB have an average of 1
IRB authorization agreement that would need to be modified as a result
of the new requirements for agreements between institutions and
external IRBs in 2016. In addition, we assume that the 2,871 FWA-
holding institutions with an IRB have an average of 0.20 IRB
authorization agreements that would need to be modified in 2016. We
estimate that each agreement would require an average of 10 hours of
institution legal staff time and 5 hours of IRB administrator time to
complete. The dollar value of their time is calculated by multiplying
hours by their estimated 2016 wages and adjusting for overhead and
benefits.
Present value costs of $11.3 million and annualized costs of $1.32
million are estimated using a 3 percent discount rate; present value
costs of $10.8 million and annualized costs of $1.54 million are
estimated using a 7 percent discount rate. Table 12 summarizes the
quantified and non-quantified benefits and costs of the requirement for
written procedures and agreements for reliance on external IRBs
(Sec. Sec. __.103(e) and __.115(a)(10) in the NPRM).
[[Page 54008]]
Table 12--Summary of Requirement for Written Procedures and Agreements for Reliance on External IRBs (NPRM at
Sec. Sec. __.103(e) and __.115(a)(10))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Enhanced human subjects protections in research reviewed by nonaffiliated IRBs and encouragement to
institutions to rely on external IRBs when appropriate.....................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Time to modify written agreements 11.3 10.8 1.32 1.54
between IRBs and institutions......
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
j. Eliminating the Requirement That the Grant Application Undergo IRB
Review and Approval (Current Rule at Sec. __.103(f))
The proposed rule would eliminate the requirement in the current
Rule at Sec. __.103(f) that grant applications undergo IRB review and
approval for the purposes of certification. As described in section
II.h.2 of this preamble, the grant application is often outdated by the
time the research study is submitted for IRB review and contains
detailed information about the costs of a study, personnel, and
administrative issues that go beyond the mission of the IRB to protect
human subjects. Therefore, experience suggests that review and approval
of the grant application is not a productive use of IRB time.
Eliminating the requirement that the grant application undergo IRB
review and approval would reduce administrative costs to investigators
and IRB voting members. The proposed change likely would not reduce
protections for human subjects or impose other costs.
The RIA estimates that there are 324,187 initial reviews of
protocols annually, of which 223,689 involve convened review and
100,498 involve expedited review based on the distribution of reviews
presented in Table 3. For the purpose of this analysis, it is assumed
that each protocol reviewed by an IRB is associated with one grant
application or other funding proposal. The RIA estimates that
investigators spend an average of 15 minutes compiling their grant
applications when they submit a protocol for initial review. Further,
it is estimated that IRBs typically use two primary reviewers for
convened review and one primary reviewer for expedited review, and that
primary reviewers spend an average of 30 minutes reviewing the grant
application. Based on the estimates in Table 3, the dollar value of
their time is calculated by multiplying hours by their estimated 2016-
2025 wages and adjusting for overhead and benefits.
Present value benefits of $310 million and annualized benefits of
$36.3 million are estimated using a 3 percent discount rate, and
present value benefits of $219 million and annualized benefits of $31.1
million are estimated using a 7 percent discount rate. Table 13
summarizes the quantified and non-quantified benefits and costs of
eliminating the requirement that the grant application undergo IRB
review and approval.
Table 13--Summary of Estimated Benefits and Costs of Eliminating the Requirement That the Grant Application
Undergo IRB Review and Approval (Current Rule at Sec. __.103(f))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Decreased time associated with 310 219 36.3 31.1
review.............................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
[[Page 54009]]
k. Tracking and Documenting Exemption Determinations (NPRM at
Sec. Sec. __.104(c) and __.115(a)(11))
New in the NPRM is a proposal at Sec. __.104(c) that Federal
departments and agencies would develop an exemption determination tool
for use by investigators and institutions. Under the proposed rule,
unless otherwise required by law, exemption determinations may be made
by (1) an individual who is knowledgeable about the exemption
categories and who has access to sufficient information to make an
informed and reasonable determination, or (2) the investigator who
accurately inputs information into the federally created web-based
decision tool (NPRM at Sec. __.104(c)). Also new in the NPRM is a
requirement at proposed Sec. __.115(a)(11) that an IRB maintain
records of exemption determinations. Additionally, proposed Sec.
__.104(c) specifies that the use of the exemption determination tool
would satisfy the documentation requirement in proposed Sec.
__.115(a)(11).
While the documentation requirement for exemption determinations is
new, comments from members of the regulated community suggest that most
institutions have systems in place already to make and document
exemption determinations. Thus, the requirement of proposed Sec.
__.115(a)(11) would likely have a negligible impact on institutions.
Additionally, it is anticipated that use of the exemption determination
tool described in proposed Sec. __.104(c) would likely represent a
reduction in burden for institutions and investigators. First,
institutions are not responsible for creating the decision tool; the
Federal Government is. The costs associated with the development and
maintenance of this tool are discussed above in section III.D.2.a of
this RIA. Second, except for protocols for which IRB review is required
by law and those for which the exemption tool is unable to issue
determinations (and therefore still have to be submitted to an IRB for
review), IRB offices would no longer need to devote significant
resources to processing and reviewing studies for exemption because the
use of the tool by the investigator would suffice. Third, the
investigator would no longer need to engage in the time-intensive task
of developing and submitting a formal application to an IRB for an
exemption determination, which is standard practice at many
institutions. Instead, the investigator would be able to answer
questions in the to-be-created tool, and then be able to commence work
if determination generated by the tool indicates that the proposed
research activity meets one of the exemption categories.
The quantifiable benefits and costs associated with the use of the
Sec. _.104(c) decision tool are documented in each RIA discussion of
exemption categories (sections II.D.2.f, l, m, n of this RIA). Note
that while Sec. _104(c) requires that an exemption determination be
made before an exempt study may begin, the use of the proposed
exemption determination tool is not mandated. Rather, the tool to be
created by HHS is an option proposed in order to reduce burden on the
investigators and institutions. Additionally, note that at present it
is unknown how many studies are exempted under the current Rule each
year. Thus, this RIA is only able to provide quantifiable benefits and
costs for studies that are estimated to be newly exempted.
Table 14 summarizes the non-quantified benefits and costs of the
tracking requirements for exemption determinations and the criteria for
those eligible to make exemption decisions in NPRM Sec. _.104(c).
Table 14--Summary of Estimated Benefits and Costs of Tracking and Documenting Exemption Determinations (NPRM at
Sec. Sec. __.104(c) and __.115(a)(11))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Reduced administrative burden for IRBs in reviewing exemption determinations, reduced time for investigators
to receive an exemption determination......................................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
l. Exemption for Research and Demonstration Projects (NPRM at Sec.
_.104(d)(2))
The current exemption related to research and demonstration
projects (current Rule at Sec. _.101(b)(5)) would be revised to
clarify that certain Common Rule agency or department supported
activities currently fall within that scope. OHRP also proposes to
broaden its interpretation of public benefit and service programs which
are being evaluated as part of the research to include public benefit
or service programs that an agency does not itself administer through
its own employees or agents, but rather funds (i.e., supports) through
a grant or contract program. It has been OHRP's interpretation that the
current exemption category 5 only applies to those research and
demonstration projects designed to study a ``public benefit or service
program'' that a Common Rule agency or department itself administers,
and for which the public benefit or service program exists independent
of any research initiative.
The proposed regulatory revision and change in OHRP's
interpretation of the exemption is designed to clarify and broaden the
scope of the exemption so that more research studies would be exempt.
It is believed that these changes would make the exemption easier to
apply appropriately and is expected to
[[Page 54010]]
reduce the number of studies that would be required to undergo IRB
review. It is also designed to allow the Federal Government to carry
out important evaluations of its public benefit and service programs to
ensure that those programs are cost effective and deliver social goods
without requiring IRB review and approval. The proposed changes to this
exemption would require OHRP to revise its existing guidance document
on this exemption accordingly. Costs associated with this revision are
accounted for in section III.D.2.a above.
In addition, a requirement has been added that each Federal
department or agency conducting or supporting the research and
demonstration projects must establish on a publicly accessible federal
Web site or in such other manner as the Secretary of HHS may prescribe,
a list of the research and demonstration projects which the Federal
department or agency conducts or supports under this provision. The
research or demonstration project must be published on this list prior
to or upon commencement of the research. This exemption is needed for
government entities to carry out activities related to their important
public health mission and functions; in acknowledgement of the fact
that more-than-minimal-risk studies could be conducted under this
exemption, the posting requirement promotes increased transparency in
these activities.
Note that a study's exemption documentation requirement at Sec.
_.104(c) is satisfied by a Federal department or agency posting minimal
information about the research or demonstration project on a federal,
publicly accessible Web site. Thus, in general, an institutional
official would not have to post any information to this Web site.
It is estimated that approximately 1,000 exempt research and
demonstration studies are currently conducted each year.\90\ It is
further estimated that due to the change in OHRP's interpretation of
the research and demonstration project exemption, an additional 3,377
annual reviews of protocols (0.5 percent) would no longer be conducted.
Of these 3,377 reviews, 1,118 would have undergone convened initial
review, 502 would have undergone expedited initial review, 1,212 would
have undergone convened continuing review, and 544 would have undergone
expedited continuing review based on the distribution of reviews
presented in Table 3. Comment is requested on the accuracy of the
estimates of the number of research and demonstration projects
conducted each year.
---------------------------------------------------------------------------
\90\ Estimates based on queries of clinicaltrials.gov and a
search of the CMS Web site. See e.g., http://www.medicaid.gov/medicaid-chip-program-information/by-topics/waivers/waivers_faceted.html, and https://www.cms.gov/Research-Statistics-Data-and-Systems/Statistics-Trends-and-Reports/ActiveProjectReports/APR_2011_Edition.html.
---------------------------------------------------------------------------
The 4,377 estimated annual studies conducted under this exemption
would need to be posted to a federal Web site as required by Sec.
_.104(d)(2)(i). It is anticipated that it would take individuals at the
IRB administrative staff level 15 minutes per study to post the study
to the Web site. Note that costs related to developing the Web site to
which information about demonstration projects would be posted are
calculated in section III.D.2.a of this RIA.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value benefits of $37.0 million and annualized benefits of
$4.34 million are estimated using a 3 percent discount rate, and
present value benefits of $30.3 million and annualized benefits of
$4.31 million are estimated using a 7 percent discount rate. Present
value costs of $0.36 million and annualized costs of $0.04 million are
estimated using a 3 percent discount rate; present value costs of $0.30
million and annualized costs of $0.04 million are estimated using a 7
percent discount rate. Table 15 summarizes the quantified and non-
quantified benefits and costs of amending an exempt category.
Table 15--Summary of Estimated Benefits and Costs of Amending the Research and Demonstration Project Exemption
(NPRM at Sec. __.104(d)(2))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Reduction in the number of studies 37.0 30.3 4.34 4.31
requiring IRB review...............
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Reduction in time to determine whether the exemption applies to research and demonstration studies;
increased transparency to the public in the types of research activities conducted under this exemption....
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Communication of the exempt research 0.36 0.30 0.04 0.04
and demonstration studies..........
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
Possible delays in commencement of exempt research and demonstration studies until posting has occurred;
revising federal guidance documents........................................................................
----------------------------------------------------------------------------------------------------------------
[[Page 54011]]
m. Expansion of Research Activities Exempt From IRB Review (NPRM at
Sec. __.104(d)(3), (e)(1), (e)(2))
Three proposed exemptions in the NPRM would expand the types of
activities that could occur without any IRB review (expedited or full-
board). A new exemption at proposed Sec. __.104(d)(3) covers research
involving benign interventions in conjunction with the collection of
data from an adult subject through verbal or written responses
(including data entry) or video recording if the subject prospectively
agrees to the intervention and data collection and at least one of two
criteria is met.
A second exemption at proposed Sec. __.104(e)(1) covers research
involving the use of educational tests (cognitive, diagnostic,
aptitude, achievement), survey procedures, interview procedures or
observation of public behavior (including visual or auditory
recording), if the information obtained is recorded in such a manner
that human subjects can be identified directly or through identifiers
linked to the subjects. A third exemption at proposed Sec.
__.104(e)(2) would permit the secondary research use of identifiable
private information originally collected for non-research purposes, so
long as notice was provided to the prospective human subjects about the
research activities and the identifiable private information is used
only for purposes of the specific research for which the investigator
or recipient entity obtained the information.
Because the new exemptions at Sec. __.104(e)(1) and (2) permits
investigators to record potentially sensitive information about
research subjects in an identifiable form, such activities must comply
with the privacy safeguards found at Sec. __.105 in the proposed Rule.
Some of this research may be eligible for expedited review under the
current rule, and would now be exempt from even that level of IRB
review under the proposed rule. This would result in costs savings
associated with IRB submission, review, and approval. In addition, most
institutions already have information protection systems and policies
in place and are likely to already meet the privacy safeguards of
proposed Sec. __.105.
It is estimated that 6,754 annual reviews of protocols (0.5
percent) would no longer be conducted as a result of these proposed
changes. Of these reviews, 2,236 would have undergone convened initial
review, 1,004 would have undergone expedited initial review, 2,424
would have undergone convened continuing review, and 1,088 would have
undergone expedited continuing review based on the distribution of
reviews presented in Table 3.
As required under Sec. __.104(c), an exemption determination must
be made and documented for each of these 6,754 newly exempted studies.
It is anticipated that in 50 percent of these studies (3,377 studies),
investigators will spend 30 minutes entering information into the HHS-
created decision tool in order for that tool to generate an exemption
determination. In the remaining 3,377 studies, it is anticipated that
investigators will spend 30 minutes preparing and submitting
information about the study to an individual able to make exemption
determinations (per Sec. __.104(c)). An individual at the IRB voting
member level will spend an estimated 30 minutes per study to make an
exemption determination.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
The estimated costs associated with new privacy and security
standards are presented section III.D.2.o of this RIA. Present value
benefits of $70.0 million and annualized benefits of $8.20 million are
estimated using a 3 percent discount rate, and present value benefits
of $57.2 million and annualized benefits of $8.16 million are estimated
using a 7 percent discount rate. Table 16 summarizes the quantified and
non-quantified benefits and costs of modifying the exemption categories
for research involving adults.
Table 16--Summary of Estimated Benefits and Costs of Creating New Exemption Categories (NPRM at Sec.
__.104(d)(3), (e)(1), (e)(2)))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Reduction in number of reviews...... 70.0 57.2 8.20 8.16
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
[[Page 54012]]
n. Exemption for the Storage and Maintenance of Biospecimens and
IdentPrivate Information for Future, Unspecified Secondary Research
Activities After Consent Has Been Sought and Obtained (NPRM at
Sec. Sec. __.104(f)(1) and __.111(a)(9))
The NPRM proposes a specific exemption for storage and maintenance
of biospecimens (regardless of identifiability) and identifiable
private information for future, unspecified secondary research
activities after consent has been sought and obtained. The idea behind
this exemption is that an institution can store and maintain
biospecimens and identifiable private information for future research
studies without being required to have a specific repository creation
protocol developed, reviewed, and approved by an IRB. To be eligible
for the exemption, the institution or an investigator must seek broad
consent for the future use of biospecimens and information using the
Secretary's broad consent template. Biospecimens and identifiable
private information from both the research or non-research contexts may
be designated under this exemption for future unspecified research
studies. As part of the condition for this proposed exemption, an IRB
would be required to do a one-time, limited review of the consent
process using the expedited review procedure (as would be required in
proposed Sec. _ _.111(a)(9)). The privacy safeguards outlined in
proposed Sec. _ _.105 would apply to these activities. Note that if
moving the biospecimens or information collected for use in future
unspecified research studies is envisioned, as part of the limited IRB
review described in Sec. _ _.111(a)(9), an IRB would also need to
review the adequacy of the privacy safeguards described in Sec. _
_.105.
Non-quantified benefits of this provision include clearer
instructions to the regulated community about the extent to which
creating system for storing and maintaining biospecimens and
identifiable private information for future, unspecified secondary
research activities is governed by this rule. Additionally, by reducing
the IRB burden associated with approving this type of activity, this
provision also incentivizes the creation of institution-wide,
comprehensive systems for the storage and maintenance of biospecimens
and identifiable private information for future, unspecified secondary
research activities, which would foster more research while remaining
respectful of subject autonomy. Because of the benefits to
investigators of being eligible for a new exemption if secondary
research activities are conducted using biospecimens or identifiable
private information maintained or stored according to Sec. _
_.104(f)(1), institutions would be further incentivized to implement
and develop such a system. Also note that while FDA is unable to
harmonize with the Common Rule on many of the exemptions due to
specific requirements in FDA's authorizing statutes, including the
Sec. _ _.104(f)(2) exemption, research that is also subject to the FDA
regulations would be eligible for this exemption.
Because of the proposal for the rule to cover all biospecimens
regardless of identifiability, it is anticipated that a majority of
institutions would elect to develop a system for storing and
maintaining biospecimens and identifiable private information for
future, unspecified secondary research activities as allowed under the
proposed exemption at Sec. _ _.104(f)(1). This RIA estimates that
6,428 FWA holding institutions (80 percent) would develop such a
mechanism for storing and maintaining biospecimens and identifiable
private information for future, unspecified secondary research
activities. The RIA anticipates that 1,607 FWA institutions (20
percent) would not develop this type of mechanism, either due to the
lower volume of research overall conducted at that institution or
because the institution conducts mostly social and behavioral research.
At each of the 6,428 institutions where a storage and maintenance
schema exemptible under NPRM Sec. _ _.104(f)(1) is developed, it is
assumed that an individual at the IRB administrator level would spend
two hours at each institution reviewing the consent process through
which a subject's broad consent to future research uses of his or her
biospecimens or information is sought.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value costs of $1.58 million and annualized benefits of
$0.19 million are estimated using a 3 percent discount rate, and
present value benefits of $1.48 million and annualized benefits of
$0.21 million are estimated using a 7 percent discount rate. Table 17
summarizes the quantified and non-quantified benefits and costs of
modifying the exemption categories for research involving adults.
Table 17--Exemption for the Storage and Maintenance of Biospecimens and Identifiable Private Information for
Future, Unspecified Secondary Research Activities After Consent Has Been Sought and Obtained (NPRM at Sec. Sec.
__.104(f)(1) and __.111(a)(9))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Fostering research with biospecimens and identifiable private information...................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
[[Page 54013]]
Obtaining limited IRB review of 1.58 1.48 0.19 0.21
consent process....................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
o. Privacy Safeguards for Biospecimens and Identifiable Private
Information (NPRM at Sec. Sec. __.105 and __.115(c))
Increasing research use of genetic information, information
obtained from biospecimens, medical records, and administrative claims
data has altered the nature of the risks to those whose information is
being used in research. The risks related to these types of research
are not physical but rather are informational through, for example, the
unauthorized release or use of information about subjects. Currently,
IRBs evaluate each study with regard to all levels of risk and are
expected to determine whether the privacy of subjects and the
confidentiality of their information is protected. Under the current
Common Rule, IRBs must review each individual study's protection plan
to determine whether it is adequate with respect to the informational
risks of that study.
The proposed rule would impose a new requirement that institutions
and investigators implement appropriate security safeguards for
biospecimens and identifiable private information. The purpose of these
safeguards is to assure that access to biospecimens and individually
identifiable private information is only authorized in appropriate
circumstances and that informational risks are managed by applying
appropriate safeguards to information and biospecimens. To ensure that
the requisite limitations on use and disclosure are met, an institution
or investigator can obtain adequate assurances through the use of a
written agreement with the recipient of the information or
biospecimens. In addition, a new provision is proposed at Sec.
__.115(c) that requires that the institution or IRB retaining IRB
records shall safeguard, if relevant, individually identifiable private
information contained in those records in compliance with the privacy
safeguards proposed at Sec. __.105.
Under the proposal, the HHS Secretary would develop a set of
minimum standards for the protection of information for research
outside of the current scope of the HIPAA standards to create an
effective and efficient means of implementing appropriate protections
for biospecimens and information. This list would be developed in
consultation with other Common Rule agencies and would be published in
the Federal Register.
Consequently, the IRBs would not be required to review the
individual plans for safeguarding information and biospecimens for each
research study, so long as investigators would adhere to one or the
other set of standards. It is anticipated that once IRBs are familiar
with standard institutional- and investigator-imposed protections they
would become more comfortable with the fact that they need not review
every protocol for security standards. In addition, IRBs would not have
to review security provisions on a case-by-case basis, which would
result in cost savings in terms of time.
It is expected that most research institutions would already have
most of these protections in place, especially those institutions that
are subject in whole or part to the HIPAA rules. Other fiduciary,
legal, and proprietary responsibilities related to obtaining and
storing biospecimens are likely to encompass the protections proposed
for securing biospecimens. Also note that the envisioned security
measures that will appear on the Secretary's List would be less
stringent than what many institutions have already implemented. It
should also be noted that the NPRM proposal would result in uniform
baseline standards for security. Costs associated with developing the
Secretary's List in accordance with proposed Sec. __.105 are accounted
for in section III.D.2.a of this RIA.
It is estimated that 803 of the 8,035 institutions with FWAs (10
percent) would need to update their privacy and security standards to
comply with the new requirements. At these institutions, institutional
officials and institutional legal staff would each spend an estimated
80 hours in 2016 and 20 hours in subsequent years to update and monitor
their privacy and security standards. In addition, the RIA estimates
that 43,997 of 439,968 investigators (10 percent) would be required to
adopt the updated privacy and security standards. These investigators
would each spend an 40 hours in 2016 and 10 hours in subsequent years
to comply. Based on the estimates presented in Table 3, the dollar
value of their time is calculated by multiplying hours by their
estimated 2016-2025 wages and adjusting for overhead and benefits.
Public comments are requested on these estimates.
Present value costs of $457 million and annualized costs of $53.6
million are estimated using a 3 percent discount rate; present value
costs of $347 million and annualized costs of $49.4 million are
estimated using a 7 percent discount rate. Table 18 summarizes the
quantified and non-quantified benefits and costs to protect information
and biospecimens.
[[Page 54014]]
Table 18--Summary of Estimated Benefits and Costs of Protection of Information and Biospecimens (NPRM at Sec.
Sec. __.105 and __.115(c))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Improved protection of individually identifiable private information and biospecimens.......................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs 457 347 53.6 49.4
----------------------------------------------------------------------------------------------------------------
Time for institutions to update and adopt new privacy and security standards................................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
p. Elimination of Continuing Review of Research under Specific
Conditions (NPRM at Sec. Sec. __.109(e), (f) and __.115(a)(3), (8))
The NPRM proposes eliminating continuing review for many minimal
risk studies, unless the reviewer explicitly justifies why continuing
review would enhance protection of research subjects. For studies
initially reviewed by a convened IRB, continuing review would not be
required, unless specifically mandated by the IRB, after the study
reaches the stage where it involves one or both of the following: (1)
Analyzing data (even if it is identifiable private), or (2) accessing
follow-up clinical data from procedures that subjects would undergo as
part of standard care for their medical condition or disease. If an IRB
chooses to conduct continuing review even when these conditions are
met, the rationale for doing so must be documented according to a new
provision at Sec. __.115(a)(3).
It is also proposed that continuing review of research eligible for
expedited review in accordance with Sec. __.110 not be required,
although an IRB may determine that continuing review of research
eligible for expedited review is necessary. When an IRB requires
continuing review of such studies, this too must be documented in
compliance with a proposed requirement at Sec. __.115(a)(8).
Requiring continuing review for studies that are minimal risk (and
eligible for expedited review at the onset) or that no longer pose
greater than minimal risk presents a regulatory burden that does not
meaningfully enhance protection of subjects. Further, the requirement
takes time from the IRB's review of higher risk studies.
This would result in less time spent by institutions, IRBs, and
investigators in terms of time spent preparing for and conducting
continuing review. This is a one-time compliance burden in Year 1 for
institutions to update their systems to no longer send continuing
review reminders to certain investigators. There would be increased
recordkeeping requirements, however, for institutions to comply with
Sec. __115(a)(3) and (a)(8). Because we estimate that 90 percent of
protocols that previously had to undergo continuing view would no
longer need to, there is an overall net benefit. However, 10 percent of
studies would require a new recordkeeping component. The benefits in
terms of cost savings would begin in year one and extend indefinitely.
However, costs would be associated with the requirement that IRBs
document cases in which they elect to conduct continuing review when it
is not a regulatory requirement.
The RIA estimates that there are 108,873 expedited continuing
reviews of protocols annually based on the distribution of reviews
presented in Table 3. Of these reviews, the RIA further estimates that
81,546 reviews (75 percent) would not be eliminated by other proposed
changes to the Common Rule (such as the modifications proposed at
Sec. Sec. __.101(b); __.104(d)(1)-(3), (e)(1), and (f)). It is
estimated that 40,773 of these 81,546 reviews (50 percent) would be
discontinued and the remaining 40,773 reviews (50 percent) would
continue and require documentation of the rationale for doing so. The
RIA also estimates that IRB voting members would spend 1 hour per
review providing documentation. In addition, administrative staff at
each IRB would spend an estimated 10 hours in 2016 updating their
communication systems to no longer send continuing review reminders to
certain investigators.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value benefits of $145 million and annualized benefits of
$17.0 million are estimated using a 3 percent discount rate, and
present value benefits of $119 million and annualized benefits of $16.9
million are estimated using a 7 percent discount rate. Present value
costs of $38.8 million and annualized costs of $4.55 million are
estimated using a 3 percent discount rate; present value costs of $31.9
million and annualized costs of $4.54 million are estimated using a 7
percent discount rate. Table 19 summarizes the quantified and non-
quantified benefits and costs of the elimination of continuing review
of research under specific conditions.
[[Page 54015]]
Table 19--Summary of Estimated Benefits and Costs of the Elimination of Continuing Review of Research Under
Specific Conditions (NPRM at Sec. Sec. __.109(e), (f) and __.115(a)(3), (8))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits 145 119 17.0 16.9
Reduction in number of continuing
reviews............................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Time to document rationale for 38.8 31.9 4.55 4.54
conducting continuing review and
update IRB communication systems...
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
q. Expedited Review Procedures (NPRM at Sec. Sec. __.110 and
__.115(a)(9))
The proposed rule would make minor changes regarding expedited
review, to change the default position such that expedited review can
occur for studies on the HHS Secretary's list unless the reviewer(s)
determine(s) that the study involves more than minimal risk. The NPRM
also proposes that, in consultation with other Common Rule departments
or agencies, the expedited review categories be reviewed every eight
years and amended as appropriate, followed by publication in the
Federal Register and solicitation of public comment. Finally, there
would be a new requirement at proposed Sec. __.115(a)(9) concerning
IRB records that IRBs document the rationale for an expedited
reviewer's determination that research appearing on the expedited
review list is more than minimal risk (i.e., an override of the
presumption that studies on the Secretary's list are minimal risk).
Additionally, in order to assist institutions in determining whether an
activity is minimal-risk, the NPRM proposes in Sec. __.102(j) that the
Secretary of HHS will maintain guidance that includes a list of
activities considered to be minimal risk. The costs associated with
developing and maintaining this guidance document are accounted for
above in III.D.2.a of this RIA.
The proposed changes to the expedited review procedures are
expected to reduce the IRB workload by increasing the number of studies
that undergo expedited review rather than convened review. The
documentation requirement does not produce additional requirements
because IRBs must keep records of determinations regardless. This just
stipulates that the reason for an override must be described. However,
costs would be associated with the requirement that IRBs document cases
in which they elect to conduct convened IRB review when it is not a
regulatory requirement.
It is estimated that there are 223,689 convened initial reviews and
242,330 convened continuing reviews of protocols annually based on the
distribution of reviews presented in Table 3. Of these 223,689 convened
initial reviews, it is estimated that 2,237 reviews (1 percent) are
eligible for expedited review because they are in a category of
research that appears on the HHS Secretary's list. Of these 2,237
reviews, it is estimated that 1,118 reviews (50 percent) would undergo
expedited review and the remaining 1,118 reviews (50 percent) would
undergo convened review and require documentation of the rationale for
doing so.
Of the 242,330 convened continuing reviews, it is estimated that
2,423 reviews (1 percent) are eligible for expedited review because
they are in a category of research that would appear on the Secretary's
list. Of these 2,423 reviews, the RIA estimates that 1,212 reviews (50
percent) would undergo convened review and would require documentation
of the rationale for doing so. Due to the proposed elimination of
continuing review of research under specific conditions (Sec.
__.109(e) and (f); Sec. __.115(a)(3) and (a)(8)), the remaining 1,212
reviews (50 percent) would not require review. Of these 1,212 reviews,
the RIA estimates that 606 reviews (50 percent) would not occur and the
remaining 606 reviews (50 percent) would undergo expedited continuing
review and require documentation of the rationale for doing so. The RIA
estimates that IRB voting members would spend 1 hour per review
providing documentation when required. The cost associated with
reviewing and amending the list is accounted for in section III.D.2.a
of this RIA.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
Present value benefits of $16.8 million and annualized benefits of
$1.97 million are estimated using a 3 percent discount rate, and
present value benefits of $13.7 million and annualized benefits of
$1.95 million are estimated using a 7 percent discount rate. Present
value costs of $2.71 million and annualized costs of $0.32 million are
estimated using a 3 percent discount rate; present value costs of $2.21
million and annualized costs of $0.32 million are estimated using a 7
percent discount rate. Table 20 summarizes the quantified and non-
quantified benefits and costs of the elimination of expedited review
procedures.
[[Page 54016]]
Table 20--Summary of Estimated Benefits and Costs of Amending the Expedited Review Procedures (NPRM at Sec.
Sec. __.110 and __.115(a)(9))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits 16.8 13.7 1.97 1.95
Reduction in number of reviews......
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Time to document rationale for 2.71 2.21 0.32 0.32
conducting expedited review........
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
r. Revised Criteria for IRB Approval of Research (NPRM at Sec. __.111)
Two changes are proposed in the criteria for IRB approval of
research. One pertains to the new requirements proposed at Sec. __.105
to protect biospecimens and individually identifiable private
information used in research. The regulations at Sec. __.111(a)(7)
currently require that in order to approve research covered by this
policy, the IRB shall determine that when appropriate, there are
adequate provisions to protect the privacy of subjects and to maintain
the confidentiality of data. This requirement would be modified to
recognize that the requirements at Sec. __.105 would apply to all non-
exempt research (unless the criteria for exemptions are met). The
default position should be that if the provisions at Sec. __.105 are
being met, there is no need for additional IRB review of a research
study's privacy and confidentiality protections. However, there might
be extraordinary cases in which an IRB determines that privacy
safeguards above and beyond those called for in Sec. __.105 are
necessary. Therefore, it is proposed that IRBs would be responsible for
ensuring there are adequate provisions to protect the privacy of
subjects and to maintain the confidentiality of data only if the IRB
determines that the protections required in Sec. __.105 are
insufficient.
The second proposed change relates to the new exemption at Sec.
__.104(f)(2) that includes a criterion at (f)(2)(ii) that the
exemptions do not apply if the investigator intends to return
individual research results to subjects. Thus, a new provision would be
added at Sec. __.111(a)(8) clarifying that IRBs need to review any
plan in a research protocol for returning individual research results
to subjects and to determine whether it is appropriate. Although many
IRBs probably already review plans for return of results, and many
studies do not include this feature, it would not be required that IRBs
review all projects to determine if there should be a plan.
The RIA estimates that there are 324,187 initial reviews of
protocols annually, of which 223,689 involve convened review and
100,498 involve expedited review based on the distribution of reviews
presented in Table 3. The RIA estimates that IRBs typically use two
primary reviewers for convened review and one primary reviewer for
expedited review, and that primary reviewers spend an average of 15
minutes reviewing the security plans for biospecimens or identifiable
private information. Of the 324,187 initial reviews, we estimate that
108,062 reviews (33 percent) would include a plan for returning results
to subjects and that primary reviewers would spend an average of 15
minutes reviewing these plans. Based on the estimates in Table 3, the
dollar value of their time is calculated by multiplying hours by their
estimated 2016-2025 wages and adjusting for overhead and benefits.
Present value benefits of $126 million and annualized benefits of
$14.8 million are estimated using a 3 percent discount rate, and
present value benefits of $89.1 million and annualized benefits of
$12.7 million are estimated using a 7 percent discount rate. Present
value costs of $66.6 thousand and annualized costs of $7.8 thousand
using a 3 percent discount rate; present value costs of $62.3 thousand
and annualized costs of $8.9 thousand using a 7 percent discount rate.
Table 21 summarizes the quantified and non-quantified benefits and
costs of the revised criteria for IRB approval of research.
Table 21--Summary of Estimated Benefits and Costs of Revised Criteria for IRB Approval of Research (NPRM at Sec.
__.111)
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Decreased time associated with each 126 89.1 14.8 12.7
review.............................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Increased opportunities for research subjects to learn the results of studies in which they participated....
----------------------------------------------------------------------------------------------------------------
[[Page 54017]]
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Time to review plans for returning 0.07 0.06 0.008 0.009
results to subjects................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
s. Cooperative Research (NPRM at Sec. Sec. __.114, __.103(e), and
__.101(a))
The proposed rule would mandate that all domestic sites in a
cooperative study rely upon a single IRB for that study, regardless of
the source of funding, unless otherwise required by law (e.g., FDA-
regulated device studies). Common Rule funding departments or agencies
would also have the authority to determine that use of a single
reviewing IRB is not appropriate for a particular study (so long as
that decision is documented). This policy would apply regardless of
whether the study underwent convened IRB review or expedited review.
This proposal only affects the decision about which IRB would be
designated as the reviewing IRB for compliance purposes. Related to
this is a new provision at Sec. __.103(e) requiring procedures that
the institution and IRB would follow for documenting the institution's
reliance on the IRB for oversight and the responsibilities of each
entity. Also related to this, a new provision at Sec. __.101(a) would
give Common Rule departments and agencies the explicit authority to
enforce compliance directly against IRBs that are not affiliated with
an assured institution. In addition, the proposed rule would be
modified to remove the current requirement at Sec. __.103(d) that only
with the approval of the department or agency head, an institution
participating in a cooperative project may enter into a joint review
arrangement, rely upon the review of another IRB, or make similar
arrangements for avoiding duplication of effort.
Currently, the choice to have cooperative research reviewed by a
single IRB is voluntary under the Common Rule. In practice, most
institutions have been reluctant to replace review by their local IRBs
with review by a single IRB in part because of OHRP's current practice
of enforcing compliance with the Common Rule through the institutions
that were engaged in human subjects research, even in circumstances
when the regulatory violation is directly related to the
responsibilities of an external IRB. Review by multiple IRBs for
cooperative research can add bureaucratic complexity to the review
process and delay initiation of research projects without evidence that
multiple reviews provide additional protections to subjects. Thus, the
proposed changes at Sec. __.101(a) are included in this NPRM to
address this concern in anticipation of greater reliance on external
IRBs in cooperative research, and to promote less bureaucratic
complexity in the review process in multi-site studies.
Ultimately, these revisions are expected to lower costs associated
with multiple reviews for investigators, institutions, and IRBs. There
may be some cost shifting as certain IRBs take on the role of reviewing
IRB; however, these will be offset by savings at other IRBs no longer
required to conduct additional reviews of the same research study.
Initially, IRBs and institutions will have to draft and revise their
policies regarding their reliance on single IRBs. It is expected that
over time standardization in agreements will be achieved, and that
reliance on single IRBs will be accepted because of their assured
inclusion in oversight, which will result in reduced costs associated
with multiple reviews and time savings for investigators who no longer
must wait for multiple reviews to occur, with subsequent revisions and
amendments. Likely, the hours spent here will replace hours spent
reviewing and processing a submission that otherwise would be approved
by the institution's IRB.
The OHRP database of registered institutions and IRBs shows that
there are 8,035 institutions with an FWA. The RIA estimates that these
institutions would develop an average of 10 written joint review
agreements with other institutions in 2019 prior to the first year of
compliance. The RIA further estimates that each agreement would require
an average of 10 hours of institution legal staff time and 5 hours of
IRB administrator time to complete. The dollar value of their time is
calculated by multiplying hours by their estimated 2016 and 2019 wages
and adjusting for overhead and benefits.
It is estimated that there are 202,617 annual reviews of multi-site
protocols, and an average of 5 reviews per multi-site protocol,
implying that there are 40,523 multi-site protocols reviewed each year.
Of these protocols, an estimated 36,471 protocols (90 percent) do not
involve medical devices; as a result, 4 of every 5 reviews would be
eliminated. Accordingly, the RIA estimates that 145,884 annual reviews
of protocols would no longer be conducted as a result of these proposed
changes. Of these reviews, 48,317 would have undergone convened initial
review, 21,708 would have undergone expedited initial review, 52,343
would have undergone convened continuing review, and 23,517 would have
undergone expedited continuing review based on the distribution of
reviews presented in Table 3.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews and based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2019-2025 wages and adjusting for
overhead and benefits.
Present value benefits of $1,103 million and annualized benefits of
$129 million are estimated using a 3 percent discount rate, and present
value benefits of $849 million and annualized benefits of $121 million
are estimated using a 7 percent discount rate. Present value costs of
$155 million and annualized costs of $18.1 million are estimated using
a 3 percent discount rate; present value costs of $138 million and
[[Page 54018]]
annualized costs of $19.7 million are estimated using a 7 percent
discount rate. Table 22 summarizes the quantified and non-quantified
benefits and costs of cooperative research.
Table 22--Summary of Estimated Benefits and Costs of Cooperative Research (NPRM at Sec. Sec. __.114,
__.103(e), and __.101(a))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Reduction in number of reviews...... 1,103 849 129 121
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Standardization of human subjects protections when variation among review IRBs is not warranted.............
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Time requirement to develop model 155 138 18.1 19.7
reliance agreement and written
joint review agreements............
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
t. Changes in the Elements of Consent, Including Documentation
(NPRM at Sec. Sec. __.116(a)(9), (b)(7)-(9), and __.117(b) in the
NPRM)
A new element of consent at Sec. __.116(a)(9) applies to
identifiable private information collected as part of a research
activity. When identifiable private information is collected for
research purposes, subjects must be provided with a statement
describing the extent to which a subject's information will be made
non-identified and used in future activities. An investigator must
include in a consent form one of two statements:
A statement that all identifiable information might be
removed from the data and the data that is not identifiable could be
used for future research studies or distributed to another investigator
for future research studies without additional informed consent from
the subject, if this might be a possibility; or
A statement that the subject's data collected as part of
the research, from which identifiable information is removed, will not
be used or distributed for future research studies.
The addition of the requirement to notify subjects of how their
non-identified information might be used is viewed as a measure of
respect for subjects, by informing them of possible uses of their
information. Potential subjects can always decline to participate in
the initial research if they are not willing to consent to the
statement provided. This measure addresses concerns about people not
being fully informed that their non-identified information could be
used for research without their consent. These changes are expected to
improve informed consent forms and processes, and ideally result in
more informed decisions by prospective research subjects about whether
to participate in research. The intent is to create greater
transparency and improve the informed consent process. This addition
would have to meet the documentation requirements at Sec. __.117(b).
While this new provision would require investigators to inform
prospective subjects of how their non-identified information originally
collected for research purposes might be used in future research
studies, it is not expected that this change to have a measurable
effect on the administrative costs to the research system. Under the
current regulations, a majority of investigators do not restrict the
future research use of non-identifiable information. Therefore, it is
expected that in implementing this new notification requirement, the
vast majority of investigators would elect option (1). In addition,
under the current regulations, investigators may voluntarily restrict
the future research use of non-identifiable information, such as in
certain research involving vulnerable populations or a rare disease. We
do not expect the new notification requirement to result in an increase
in the number of investigators who would include option (2) in their
consent forms and processes. When investigators choose to restrict the
future research use of non-identifiable information under the current
Rules, statements about such restricted future use are generally
already included in the consent forms and processes. Therefore, for
such research, the notification requirement is not expected to result
in any change in practice.
Since this notification requirement is not expected to change
investigators' secondary use of non-identifiable information originally
collected for research purposes, it is anticipated that investigators
and institutions already have systems in place to track any
restrictions investigators currently choose to implement. As likely is
currently the case, it is anticipated that very few investigators would
elect to offer the second option listed above because of the challenges
of marking and tracking such decisions. Furthermore, since most
investigators will likely elect the first option listed above, it would
be reasonable for investigators and institutions to assume that the
secondary research use of information would be permissible unless
marked otherwise. Therefore, it would not be necessary to routinely
track information obtained using the first option.
Three additional elements of consent are proposed in Sec.
__.116(b)(7)-(9). These three require that a subject be informed of the
following, when relevant:
That the subject's biospecimens may be used for commercial
profit and whether the subject will or will not share in this
commercial profit;
Whether clinically relevant research results, including
individual research results, will be disclosed to subjects, and if so,
under what conditions; and
[[Page 54019]]
An option for the subject or the representative to
consent, or refuse to consent, to investigators re-contacting the
subject to seek additional information or biospecimens or to discuss
participation in another research study.
These additional elements of consent are proposed to promote the
goal of respect for persons and greater transparency in the research
enterprise. Additionally, including the information referenced in these
provisions in a consent form will help ensure that prospective subjects
are given all information necessary for understanding why one might
want to participate (or not) in a research study.
The RIA estimates that there are 246,382 new protocols annually
using identifiable information. For each protocol, it is estimated that
investigators would spend an average of 15 minutes in 2016 updating
consent forms to comply with the new requirements found in the NPRM at
Sec. __.116(a)(9) or (b)(7)-(9). Based on the estimates presented in
Table 3, the dollar value of investigators' time is calculated by
multiplying hours by their estimated 2016 wages and adjusting for
overhead and benefits.
The RIA assumes that no additional investigators would elect to
offer the second option at Sec. __.116(a)(9), and that the
investigators who currently offer equivalent options already track the
permissible and impermissible uses of information in line with the
requirements discussed above. As a result, the RIA estimates that there
are no additional costs associated with tracking. Public comment is
requested on these assumptions.
Present value costs of $4.55 million and annualized costs of $0.53
million are estimated using a 3 percent discount rate; present value
costs of $4.25 million and annualized costs of $0.60 million are
estimated using a 7 percent discount rate. Table 23 summarizes the
quantified and non-quantified benefits and costs of changes in the
basic elements of consent, including documentation.
Table 23--Summary of Estimated Benefits and Costs of Changes in the Elements of Consent, Including Documentation
(NPRM at Sec. Sec. __.116(a)(9), (b)(7)-(9) and __.117(b))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Improved informed consent forms and processes...............................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Time to update consent forms........ 4.55 4.25 0.53 0.60
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
u. Obtaining Consent to Secondary Use of Biospecimens and Identifiable
Private Information (NPRM at Sec. Sec. __.116(c)(1), (d)(1), (d)(4)
and __.117(c)(3))
The NPRM proposes to allow the use of broad consent to secondary
research use of biospecimens or identifiable private information for
unspecified research purposes. Such broad consent would have specified
elements and limitations, and could be collected in both the research
and non-research setting.
Given the creation of the exemption for the maintenance and storage
of biospecimens and identifiable private information for future,
unspecified secondary research activities found in the NPRM at Sec.
__.104(f)(1), it is envisioned that institutions creating these
research repositories would need to develop tracking systems to monitor
which biospecimens or what information may be used in secondary
research by investigators. The Secretary of HHS would publish in the
Federal Register one or more templates for broad consent (NPRM at Sec.
__.116(d)(1)) that would contain all of the required elements of
consent for broad, secondary use consent (NPRM at Sec. __.116(c)). If
investigators or institutions use the consent template without any
changes and seek to use the exemption at Sec. __.104(f)(2), IRB review
is not required for these secondary studies, unless IRB review is
required by law (e.g., FDA-regulated device studies).
Seeking and obtaining consent to secondary research use of
biospecimens and identifiable information is an additional flexibility
proposed in the NPRM. However, it is not required. If broad consent has
not been sought for the future research use of biospecimens or
identifiable private information, then an investigator would need to
have his or her project reviewed by an IRB and seek either study-
specific consent or a waiver of informed consent under the Common Rule.
As discussed in section II.B of this preamble, the NPRM proposes
stricter waiver criteria (NPRM at Sec. __.116(e)(2) and (f)(2)) for
biospecimens than for identifiable private information; these strict
waiver criteria would apply regardless of whether the biospecimens are
readily identifiable to the investigator. These waiver criteria would
in effect make secondary research using a biospecimen largely
impossible in the absence of obtaining subjects' broad consent for
future use of their biospecimens. Because investigators would be
required to use the Secretary's template for obtaining broad consent in
order to be eligible for the new exemptions proposed in Sec.
__.104(f), it is expected that minimal time would be spent updating
consent forms or drafting wholly new consent forms. OHRP would develop
one or more Secretary's templates for obtaining broad consent to
secondary use of biospecimens or identifiable private information for
subsequent use by investigators and institutions. OHRP staff time
associated with developing this resource is
[[Page 54020]]
accounted for in section III.D.2.a of this RIA.
As discussed earlier in this RIA (section III.D.2.n) it is
anticipated that 6,428 FWA holding institutions (80 percent) would
store and maintain clinical and non-clinical biospecimens and
identifiable private information for unspecified future research
studies in the manner prescribed under the new proposed exemption at
Sec. __.104(f)(1).
As also discussed previously, extrapolations from 1999 data \91\
suggest that biospecimens are collected from as many as 30 million
individuals and are stored each year for both clinical and research
purposes. Approximately 9 million individuals' biospecimens (30
percent) are collected for research purposes, and thus consent would be
sought in the research context for the secondary use of these
biospecimens. For these 9 million individuals per year, an investigator
would spend an estimated five minutes per person conducting the consent
process specific to seeking broad consent, and the subjects would spend
an estimated five minutes engaging in the process of having their broad
consent for future research uses of their biospecimens or information
sought. This estimate of the investigator's time also includes the time
for the investigator to log the information into the appropriate
database. The RIA further estimates that investigators would spend 10
minutes of time per protocol updating their study-specific consent form
to include the language from the Secretary's consent template.
---------------------------------------------------------------------------
\91\ Eiseman, E., Haga, S. (1999). Handbook of Human Tissue
Sources: A National Resource of Human Tissue Samples. Washington,
DC: RAND Corporation.
---------------------------------------------------------------------------
In the clinical setting, approximately 21 million individuals'
biospecimens (70 percent of the estimated 30 million individuals'
biospecimens collected each year) are collected for clinical purposes.
In the first year that the rule is implemented, as many as 21 million
broad, secondary use consent forms could be collected from individuals.
The RIA anticipates 10 minutes of a subject's time to engage in the
consent process. The RIA further anticipates 10 minutes of an
institutional employee's time at the IRB Administrative Staff level to
seek consent and put the information in the appropriate tracking
system.
The NPRM proposes in Sec. __.116(c)(1)(ii)(B) that once an
individual gives broad consent to use his or her biospecimens in
future, unspecified research studies, that consent may cover any
biospecimen collected over the course of a 10 year period. Note that an
institution may retain and use the biospecimens collected indefinitely.
This provision is merely stating that every 10 years an institution
must ask people whether or not they may use newly collected
biospecimens in research. Given that an institution must seek broad
consent from an individual only once over the course of a 10 year
period, it is assumed that after the first year the rule is
implemented, the number of individuals from whom an institution seeks
broad consent will decrease.
To account for this, the RIA assumes that after the first year that
the rule is implemented, a fraction of the clinical subjects from whom
secondary use consent is sought in year one would be sought in
subsequent years. It is anticipated that in year two, secondary use
consent would be sought in the clinical context from 10.5 million
subjects (50 percent of the number of individuals involved in the year
one estimates). It is anticipated that in year three and after,
secondary use consent would be sought in the clinical context from
approximately 6.3 million subjects each year (30 percent of the number
of individuals involved in the year one estimates). As in year one, the
RIA assumes that a prospective subject would spend 10 minutes of time
undergoing the consent process and that an institutional employee at
the IRB Administrative Staff level would spend 10 minutes of time
conducting the consent process with an individual and updating the
appropriate tracking system.
Note that assumptions are not made about the extent to which
institutions will use the tracked broad consent for the use of
identifiable private information. While all institutions that conduct
research with biospecimens will essentially need to create a research
repository to continue that type of work under the NPRM proposals, such
is not the case with identifiable private information. Identifiable
private information is covered under the NPRM as it is under the
current Rule. To that end, a research repository containing
identifiable private information is not necessary to the research
enterprise. Thus, the RIA notes that institutions likely will elect to
store identifiable private information in these repositories, but it is
unknown the extent to which institutions will elect to do this and the
volume of identifiable private information that might be stored.
Therefore, estimates are not provided specifically about the potential
costs of obtaining broad consent and tracking the consent for future
use of identifiable private information.
The costs of the tracking system associated with an institution-
wide secondary use research repository are the design, implementation,
and operation of the informatics system that would be required to
document and keep up with thousands of consent documents per year. In
addition, the institution would have to come up with some system to
``mark'' or otherwise note which biospecimens and pieces of
identifiable private information had been consented for use, and which
ones had not, to make sure an individual's wishes regarding future use
of his or her biospecimens and identifiable private information are
carried out. It is estimated that these requirements would impose
additional costs to develop or modify existing tracking systems at 80
percent of 8,035 institutions with FWAs. It is estimated that these
requirements would require 1.0 database administrator FTEs on average
at these institutions. Based on the estimates presented in Table 3, we
calculate the dollar value of their time by multiplying hours by their
estimated 2016-2025 wages and adjusting for overhead and benefits.
Public comment is requested on these estimates.
Present value costs of $12,245 million and annualized costs of
$1,435 million are estimated using a 3 percent discount rate; present
value costs of $8,697 million and annualized costs of $1,238 million
are estimated using a 7 percent discount rate. Table 24 summarizes the
quantified and non-quantified benefits and costs of obtaining consent
to secondary use of biospecimens and identifiable private information.
[[Page 54021]]
Table 24--Summary of Estimated Benefits and Costs of Obtaining Consent to Secondary Use of Biospecimens and
Identifiable Private Information (NPRM at Sec. Sec. __.116(c)(1), (d)(1), (d)(4) and __.117(c)(3))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Improved informed consent forms and processes, and reduction in time that would have been spent seeking and
obtaining consent for secondary research use; retaining identifiers in research; better ensuring of the
availability of biospecimens for future research activities................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Time to update consent forms, 12,245 8,697 1,435 1,238
document, and submit permissible
and impermissible secondary uses of
data; develop and maintain tracking
system.............................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
v. Elimination of Requirement To Waive Consent in Certain Subject
Recruitment Activities (NPRM at Sec. __.116(g))
The proposed rule would allow an IRB to approve a research proposal
in which investigators obtain identifiable private information without
individuals' informed consent for the purpose of screening, recruiting,
or determining the eligibility of prospective human subjects of
research, through oral or written communication or by accessing
records, if the research proposal includes appropriate provisions to
protect the privacy of those individuals and to maintain the
confidentiality of the identifiable private information.
This addresses concerns that the current regulations require an IRB
to determine that informed consent can be waived under the current
Sec. __.116(d) before investigators may record identifiable private
information for the purpose of screening, recruiting, or determining
the eligibility of prospective subjects for a research study, provided
that the research proposal includes an assurance that the investigator
would meet the requirements for protecting the information as described
in proposed Sec. __.105. The current requirement is viewed as
burdensome and unnecessary to protect subjects, and is inconsistent
with FDA's regulations, which do not require a waiver of consent for
such recruitment activities.
This should result in some time and cost savings for both
investigators and IRBs, but it would likely be small. The savings would
come from IRBs no longer needing to consider whether informed consent
can be waived for such preparatory-to-research activities. Savings
would accrue for investigators who can proceed with such activities in
less time.
The RIA estimates that 1,621 annual initial reviews of protocols
(0.5 percent) involve a waiver of consent for recruitment activities
that would not be required as a result of these proposed changes. Of
these reviews, 1,118 would have undergone convened initial review and
502 would have undergone expedited initial review based on the
distribution of reviews presented in Table 3. It is estimated that
investigators spend an average of 15 minutes requesting a waiver of
consent for recruitment activities when they submit a protocol for
initial review. It is further estimated that IRBs typically use two
primary reviewers for convened review and one primary reviewer for
expedited review, and that primary reviewers spend an average of 15
minutes determining whether informed consent can be waived. Based on
the estimates in Table 3, the dollar value of their time is calculated
by multiplying hours by their estimated 2016-2025 wages and adjusting
for overhead and benefits.
Present value benefits of $1.21 million and annualized benefits of
$0.14 million are estimated using a 3 percent discount rate, and
present value benefits of $0.85 million and annualized benefits of
$0.12 million are estimated using a 7 percent discount rate. Table 25
summarizes the quantified and non-quantified benefits and costs of
eliminating the requirement to waive consent in certain subject
recruitment activities.
Table 25--Summary of Estimated Benefits and Costs of Elimination of Requirement To Waive Consent in Certain
Subject Recruitment Activities (NPRM at Sec. __.116(g))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
Decreased time associated with 1.21 0.85 0.14 0.12
review.............................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
[[Page 54022]]
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
w. Requirement for Posting of Consent Forms for Common Rule Agency-
Supported Clinical Trials (NPRM at Sec. __.116(h))
A new provision would require that investigators or institutions
post a copy of the final version of the consent form for each clinical
trial conducted or supported by HHS on a publicly available federal Web
site that would be established as an archive for such consent forms.
The name of the clinical trial and information about whom to contact
for additional information must be published with the consent form. The
consent form must be published on the federal Web site within 60 days
after the trial is closed to recruitment.
It is recognized that certain information contained in an informed
consent form is protected from disclosure under the Freedom of
Information Act, the Trade Secrets Act, and/or FDA implementing
regulations, and, therefore all informed consent forms for FDA-
regulated trials covered by this requirement would be subject to
redaction before being posted.
It is believed that public posting of consent forms would increase
transparency, enhance confidence in the research enterprise, increase
accountability, and inform the development of future consent forms,
possibly resulting in future savings in time for investigators
developing consent forms.
It is expected that the Federal Web site would enable consent
documents to be easily uploaded. Additional costs to the government
would involve managing and maintaining the archive.
According to queries of clinicaltrials.gov, there are an estimated
5,270 clinical trials conducted or supported by Common Rule agencies,
of which an estimated 575 are regulated by provisions in the Federal
Food, Drug, and Cosmetic (FD&C) Act and Trade Secrets Act based on the
information presented in Table 3. For the purpose of this analysis, it
is assumed that each clinical trial is associated with one consent form
that must be submitted to the HHS system by an investigator. The RIA
estimates that investigators would spend an average of 15 minutes
submitting each consent form. In addition, for the 575 clinical trials
regulated by provisions in the FD&C Act and Trade Secrets Act, it is
estimated that investigators would spend an average of 30 minutes
redacting information before submission.
In addition, submitted consent forms must be reviewed and made
accessible to persons with disabilities in compliance with Section 508
Amendment to the Rehabilitation Act of 1973. We estimate that each
consent form contains an average of 10 pages and that 508-compliance
costs an average of $30 per page. Based on the estimates presented in
Table 3, the dollar value of their time is calculated by multiplying
hours by their estimated 2016-2025 wages and adjusting for overhead and
benefits.
Present value costs of $14.6 million and annualized costs of $1.71
million are estimated using a 3 percent discount rate; present value
costs of $10.4 million and annualized costs of $1.49 million are
estimated using a 7 percent discount rate. Table 26 summarizes the
quantified and non-quantified benefits and the requirement for posting
of consent forms for HHS-supported clinical trials.
Table 26--Summary of Estimated Benefits and Costs of Requirement for Posting of Consent Forms for Common Rule
Agency-Supported Clinical Trials (NPRM at Sec. __.116(h))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Increase transparency of HHS-supported clinical trials and inform the development of new consent forms......
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Development and management of 14.6 10.4 1.71 1.49
website, and preparation and
submission of consent forms for
posting............................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
[[Page 54023]]
x. Alteration in Waiver for Documentation of Informed Consent in
Certain Circumstances (NPRM at Sec. __.117(c)(1)(iii))
A new provision would be added allowing a waiver of the requirement
to obtain a signed informed consent form if the subjects are members of
a distinct cultural group or community for whom signing documents is
not the norm. This would be allowed only if the research presents no
more than minimal risk of harm to subjects and provided there is an
appropriate alternative method for documenting that informed consent
was obtained.
Under the current Rule IRBs may waive the requirement for the
investigator to obtain a signed consent form for some or all subjects.
The current criteria for such a waiver may not be flexible enough for
dealing with a variety of circumstances, such as when federally
sponsored research that is conducted in an international setting where,
for example, cultural or historical reasons suggest that signing
documents may be viewed as offensive and problematic.
This should not involve costs as its intent is to improve the
informed consent process by providing more flexibility regarding the
documentation of consent, an ethical gain, while reducing
administrative requirements for investigators and research subjects in
specific circumstances.
Benefits and costs of this new provision are not quantified. Table
27 summarizes the non-quantified benefits and costs of alteration in
waiver for documentation of informed consent in certain circumstances.
Table 27--Summary of Estimated Benefits and Costs of Alteration in Waiver for Documentation of Informed Consent
in Certain Circumstances (NPRM at Sec. __.117(c)(1)(iii))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Improved informed consent process for distinct cultural groups and communities..............................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
E. Sensitivity Analysis
The total estimated costs of the proposed changes to the Common
Rule are sensitive to assumptions regarding consent to secondary use of
biospecimens and information. The RIA estimates that 60 percent of
institutions with an assurance would implement a tracking system. Those
institutions would require 1.0 FTEs on average to develop and maintain
a tracking system. The sensitivity of estimated costs to these baseline
assumptions is analyzed by calculating costs under alternative
assumptions. That these institutions could instead require 0.75 FTEs or
1.25 FTEs on average to develop and maintain a tracking system is
considered. That 50 percent or 70 percent of assurance holding
institutions could implement such a tracking system (rather than 60
percent) is also considered. Table 28 reports present value costs using
a 3 percent discount rate for these alternative and baseline
assumptions.
Table 28--Estimated Present Value Costs Using a 3 Percent Discount Rate (Millions of 2013 Dollars) of Costs of
Obtaining Consent to Secondary Use of Biospecimens and Identifiable Private Information Using Baseline and
Alternative Assumptions
----------------------------------------------------------------------------------------------------------------
Percentage of institutions that implement a
tracking system
FTEs required at each institution -----------------------------------------------
70 percent 80 percent 90 percent
----------------------------------------------------------------------------------------------------------------
0.75 FTEs....................................................... 8,700 9,666 10,633
1.00 FTEs....................................................... 10,956 12,245 13,534
1.25 FTEs....................................................... 13,212 14,823 16,435
----------------------------------------------------------------------------------------------------------------
F. Alternative Approaches to the Definition of Human Subject (NPRM at
Sec. __.102(e)) and Related Provisions
Two alternative approaches for the treatment of biospecimens under
the proposed rule were considered. These alternative proposals centered
on concerns about potential identifiability of biospecimens and data
derived from biospecimens.
Alternative Proposal A: Expand the Definition of ``Human Subject'' to
Include Whole Genome Sequencing (WGS)
Under Alternative Proposal A, the regulations at proposed Sec.
__.102(e) would be amended to expand the
[[Page 54024]]
definition of human subjects to include more specifically whole genome
sequencing data, or any part of the data generated as a consequence of
whole genome sequencing, regardless of the individual identifiability
of specimens used to generate such data. Investigators would not be
allowed to remove identifiers from specimens or data to conduct whole
genome sequencing without obtaining informed consent or a waiver of
consent, because obtaining whole genome sequencing data about an
individual would in and of itself cause the individual to meet the
definition of a human subject. Written consent would generally be
required for such activities.
This requirement would not apply to specimens and information
already collected at the time the final rule is published.
Recent developments have made it possible to use whole genome
sequencing information to re-identify non-identified data. Thus, even
if such information is not ``individually identifiable'' (per the
current Rule's standard of identifiability) it is appropriate to expand
the definition of human subjects research in this way to afford
individuals who are the subjects of such research the same protections
as those given to the subjects of research using identifiable
information or specimens. Therefore, it is anticipated that this change
would increase protections for subjects of whole genome sequencing
research. It would also increase the volume of studies for which
investigators must seek and document informed consent, unless more
stringent waiver criteria were met, and institutions will have to track
the consent status of specimens and data. In addition, IRBs would have
to review these studies unless the research meets the new proposed
exemption in proposed Sec. __.104(f)(2).
It is estimated that there are 300 studies using whole genome
sequencing data that are not subject to oversight by either the Common
Rule or FDA regulations. This RIA estimates that under this
alternative, 90 percent of these studies (270) would be eligible for
the exemption proposed in Sec. __.104(f)(2). For the remaining 30
studies, it is anticipated that these would not be eligible for the
exemption, and would require full IRB review. As required under Sec.
__.104(c), an exemption determination would be made and documented for
each of the 270 exemptible whole genome sequencing studies. It is
anticipated that in 50 percent of these studies (135 studies),
investigators will spend 30 minutes entering information into the HHS-
created decision tool in order for that tool to generate an exemption
determination. In the remaining 135 studies, it is anticipated that
investigators will spend 30 minutes preparing and submitting
information about the study to an individual able to make exemption
determinations (per Sec. __.104(c)). An individual at the IRB voting
member level will spend an estimated 30 minutes per study to make an
exemption determination.
In the absence of the proposed exempt category at Sec.
__.104(f)(2), we estimate that in 2016 all 300 of these studies would
undergo convened initial review. In subsequent years, an estimated 144
protocols would undergo convened initial review, 108 would undergo
convened continuing review, and 48 would undergo expedited continuing
review, based on the distribution of reviews presented in Table 3.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
For Alternative Proposal A, present value costs of $0.57 million
and annualized costs of $0.07 million are estimated using a 3 percent
discount rate; and present value costs of $0.47 million and annualized
costs of $0.07 million are estimated using a 7 percent discount rate.
Table 29 summarizes the quantified and non-quantified benefits and
costs of amending the definition of human subject.
Table 29--Summary of Estimated Benefits and Costs of the Alternative Proposal A for Modifying the Definition of
Human Subject (NPRM at Sec. __.102(e))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Ensuring human subjects are protected in whole genome sequencing research not currently subject to
oversight..................................................................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Increase in number of reviews....... 0.57 0.47 0.07 0.07
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
Time to obtain consent for activities involving whole genome sequencing.....................................
----------------------------------------------------------------------------------------------------------------
Alternative Proposal B: Classifying Certain Biospecimens Used in
Certain Technologies as Meeting the Criteria for ``human subject''
Under Alternative Proposal B, the regulations at proposed Sec.
__.102(e) would be expanded to include biospecimens used in a
technology capable of producing biologically unique information about a
subject as well as the biologically unique information derived from a
biospecimen. Only those technologies specifically listed on a newly
created Secretary's List would be considered to have met this
definition. For example, if whole genome sequencing was a technology
included on the Secretary's List, then activities where a biospecimen
(regardless of the investigator's ability to readily identify the
person from whom the biospecimen was collected) was used in whole
[[Page 54025]]
genome sequencing research would be subject to the rules. Additionally,
activities involving the information generated from a biospecimen used
in a technology that appeared on this Secretary's List (regardless of
the investigator's ability to readily identify a subject) would also
fall under these regulations. Information derived from a technology
appearing on the Secretary's List described above would be referred to
as ``bio-unique'' information.
This expansion would modestly increase the studies encompassed
under the rule. This estimate is based on what is known about whole
genomic research technologies that results in genome sequencing data
(including DNA and RNA sequence data) that is unique to a single
individual. It is estimated that there are 898 genomic research studies
not currently subject to oversight that result in genome sequencing
data unique to a single individual.
One of the primary objectives of the NPRM has been to make the
strength of protections commensurate with the level of risks of the
research, and by doing so reduce unnecessary administrative burdens on
research. That objective has been viewed as being particularly relevant
to research involving only secondary use of biospecimens and data,
which is relatively low-risk if appropriate protections of privacy and
confidentiality are in place. Alternative Proposal B targets activities
involving biospecimens where concerns about information risks indicate
that additional regulatory oversight for these studies is appropriate.
When the proposed exemption category at Sec. __.104(f)(2) is
considered, this RIA estimates that under Alternative Proposal B, 808
studies (90 percent) would be eligible for exemption. For the remaining
89 studies, it is anticipated that these would not satisfy the Sec.
__.104(f)(2) requirements and would require full IRB review.
As required under Sec. __.104(c), an exemption determination would
be made and documented for each of the 808 exemptible genomic research
studies described above. It is anticipated that in 50 percent of these
studies (404 studies), investigators will spend 30 minutes entering
information into the HHS-created decision tool in order for that tool
to generate an exemption determination. In the remaining 404 studies,
it is anticipated that investigators will spend 30 minutes preparing
and submitting information about the study to an individual able to
make exemption determinations (per Sec. __.104(c)). An individual at
the IRB voting member level will spend an estimated 30 minutes per
study to make an exemption determination.
In the absence of the proposed exempt category of research at Sec.
__.104(f)(1), the RIA estimates that as a result of the proposed
expansion to the definition of human subject, all 898 of these studies
would undergo convened initial review. In subsequent years, an
estimated 431 protocols will undergo convened initial review, 322 will
undergo convened continuing review, and 145 will undergo expedited
continuing review based on the distribution of reviews presented in
Table 3.
The estimated costs to institution officials, IRB administrators,
IRB administrative staff, IRB chairs, IRB voting members, and
investigators of conducting these reviews are based on the estimates
presented in Table 3. The dollar value of their time is calculated by
multiplying hours by their estimated 2016-2025 wages and adjusting for
overhead and benefits.
For Alternative B, present value costs of $1.69 million and
annualized costs of $0.20 million are estimated using a 3 percent
discount rate; present value costs of $1.39 million and annualized
costs of $0.20 million are estimated using a 7 percent discount rate.
Table 30 summarizes the quantified and non-quantified benefits and
costs of amending the definition of human subject.
Table 30--Summary of Estimated Benefits and Costs of the Alternative Proposal B for Modifying the Definition of
Human Subject (NPRM at Sec. __.102(e))
----------------------------------------------------------------------------------------------------------------
Present value of 10 years by Annualized value over 10 years by
discount rate (millions of 2013 discount rate (millions of 2013
Benefits dollars) dollars)
-----------------------------------------------------------------------
3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Benefits
None................................ ................ ................ ................ ................
----------------------------------------------------------------------------------------------------------------
Non-quantified Benefits
Ensuring that informational risks are minimized in research activities involving technologies capable of
producing bio-unique information...........................................................................
----------------------------------------------------------------------------------------------------------------
Costs 3 Percent 7 Percent 3 Percent 7 Percent
----------------------------------------------------------------------------------------------------------------
Quantified Costs
Increase in number of reviews....... 1.69 1.39 0.20 0.20
----------------------------------------------------------------------------------------------------------------
Non-quantified Costs
Time to obtain consent for activities involving the generation or use of bio-unique information.............
----------------------------------------------------------------------------------------------------------------
G. Regulatory Flexibility Analysis
As discussed above, the RFA requires agencies that issue a
regulation to analyze options for regulatory relief of small entities
if a rule has a significant impact on a substantial number of small
entities. HHS considers a rule to have a significant economic impact on
a substantial number of small entities if at least 5 percent of small
entities experience an impact of more than 3 percent of revenue.
We calculate the costs of the proposed changes to the Common Rule
to institutions with an FWA over 2016-2025 and then subtract the cost
savings to these institutions over the same period. The estimated
average annualized net cost to institutions with an FWA is $153,671
using a 3 percent discount rate. The U.S. Small Business Administration
establishes size standards that define a small entity. According to
these standards, colleges, universities, and professional schools with
revenues below $27.5 million and hospitals with revenues below $38.5
million are considered small entities. It is not anticipated that a
majority of
[[Page 54026]]
institutions with an FWA are in one of these categories.
IV. Environmental Impact
We have determined under 21 CFR 25.30(k) that this action is of a
type that does not individually or cumulatively have a significant
effect on the human environment. Therefore, neither an environmental
assessment nor an environmental impact statement is required.
V. Paperwork Reduction Act
This proposed rule contains collections of information that are
subject to review and approval by the Office of Management and Budget
(OMB) under the Paperwork Reduction Act (PRA), as amended (44 U.S.C.
3501-3520). A description of these provisions is given in this document
with an estimate of the annual reporting and recordkeeping burden.
We invite comments on these topics: (1) The accuracy of the
estimate of burden of the proposed collection of information; (2) ways
to enhance the quality, utility, and clarity of the information to be
collected; and, (3) ways to minimize the burden of the collection of
information on respondents, including through the use of automated
collection techniques, when appropriate, and other forms of information
and technology.
Title: Federal Policy for the Protection of Human Subjects.
Description: In this document is a discussion of the regulatory
provisions we believe are subject to the PRA and the probable
information collection burden associated with these provisions. In
general, the following actions trigger the PRA: (i) Reporting; (ii)
Disclosure; (iii) Recordkeeping.
Description of Respondents: The reporting and recordkeeping
requirements in this document are imposed on Institutions,
Institutional Review Boards, and Investigators involved in human
subjects research conducted or supported or otherwise subject to
regulation by any Federal department or agency that takes
administrative action that makes the policy applicable to such
research.
Sec. __.101. To what does this policy apply (OMB Control No. 0990-
0260)
Section __.101 is being amended to place unaffiliated Institutional
Review Boards (IRBs) within the realm of entities to which the policy
applies as described in Sec. __.101(a) . This new provision gives
Common Rule departments and agencies explicit authority to enforce
compliance directly against IRBs that are not affiliated with an
assured institution. This change should encourage institutions to more
willingly rely on qualified unaffiliated IRBs for cooperative research,
as is required under the proposed changes at Sec. __.114. Burden
estimates are included below in Sec. __.114 summary.
Section __.101 is also being amended to extend the regulations to
cover clinical trials conducted at an institution in the United States
that receives federal support from a Common Rule department or agency
for non-exempt human subjects research, regardless of the funding
source of the trial as described in Sec. __101(a)(2). Extension of the
regulations would not apply to clinical trials already regulated by
FDA. We estimate that there are 1,399 clinical trials currently not
subject to oversight by either the Common Rule or FDA regulations. We
estimate that in 2016 all 1,399 of these clinical trials will undergo
convened initial review. In subsequent years, we estimate that 672
protocols will undergo convened initial review, 502 will undergo
convened continuing review, and 225 will undergo expedited continuing
review. We estimate the burden to institution officials, IRB
administrators, IRB administrative staff, IRB chairs, IRB voting
members, and investigators of conducting these reviews (24 hours per
protocol) based on the estimates presented in Table 3 of section III of
the preamble.
Sec. __.103. Assuring Compliance With This Policy--Research Conducted
or Supported by Any Federal Department or Agency (OMB Control No. 0990-
0260)
Section __.103 is being amended, at Sec. __.103(e), to require
that for non-exempt research involving human subjects covered by this
policy that takes place at an institution in which IRB oversight is
conducted by an unaffiliated IRB that is not operated by the
institution, the institution and the organization operating the IRB
shall establish and follow procedures for documenting the institution's
reliance on the IRB for oversight of the research and the
responsibilities that each entity will undertake to ensure compliance
with the requirements of this policy (e.g., in a written agreement
between the institution and the IRB, or by implementation of an
institution-wide policy directive providing the allocation of
responsibilities between the institution and an IRB that is not
affiliated with the institution). Burden estimates are included below
in Sec. __.114.
Sec. __.104 Exempt Research (OMB Control No. 0990-0260)
Section __.104 is being proposed, as described in Sec. __.104(c),
to require federal departments and agencies to develop a decision tool
to assist in exemption determinations. Under the proposed rule, unless
otherwise required by law, exemption determinations may be made by an
individual who is knowledgeable about the exemption categories and who
has access to sufficient information to make an informed and reasonable
determination, or by the investigator or another individual at the
institution who enters accurate information about the proposed research
into the decision tool, which would provide a determination as to
whether the study is exempt. If the tool is used, further assessment or
evaluation of the exemption determination is not required. Burden
estimates are included below in Sec. __.115(a)(11).
Section __.104 is being proposed, as described in Sec.
__.104(d)(2), to require each federal department or agency conducting
or supporting the research or demonstration projects exempted under
Sec. __.104(d), to establish on a publicly accessible federal Web site
or in such other manner as the department or agency head may prescribe,
a list of the research and demonstration projects that the federal
department or agency conducts or supports under this provision. The
research or demonstration project must be published on this list prior
to or upon commencement of the research. We estimate that 4,377 exempt
research and demonstration studies will be posted to the Web site
annually, and that the information will be submitted to the Web site by
individuals at the IRB administrative staff level, an estimate of 1.82
person-hours per protocol (7966.14 burden hours).
Sec. __.105 Protection of Biospecimens and Identifiable Private
Information, (OMB Control No. 0990-0260)
Section __.105 is being proposed, as detailed in Sec. __.105(a),
to require institutions and investigators conducting research subject
to the Common Rule, or that is exempt under Sec. Sec. __.104(e) or (f)
to implement and maintain reasonable and appropriate safeguards to
protect biospecimens, or identifiable private information they collect,
store or use for research. The Secretary of HHS will establish and
publish a list of specific measures that the institution or
investigator may implement that will be deemed to satisfy the
requirement for reasonable
[[Page 54027]]
and appropriate safeguards. The list will be evaluated as needed, but
at least every 8 years, and amended, as appropriate, after consultation
with other federal departments and agencies. Institutions and
investigators may choose either to apply the safeguards identified by
the Secretary as necessary to protect the security or integrity of and
limit disclosure of biospecimens and electronic and non-electronic
identifiable private information or to apply safeguards that meet the
standards in 45 CFR 164.308, 164.310, 164.312, and 45 CFR 164.530(c).
For federal departments and agencies that conduct research activities
that is or will be maintained on information technology that is subject
to and in compliance with section 208(b) of the E-Government Act of
2002, 44 U.S.C. 3601 et seq., if all of the information collected,
used, or generated as part of the activity will be maintained in
systems of records subject to the Privacy Act of 1974, 5 U.S.C. 552a,
and the research will involve a collection of information subject to
the Paperwork Reduction Act of 1995, 44 U.S.C. 3501 et seq., these
research activities automatically will be considered in compliance with
the Secretary's reasonable and appropriate safeguards standards, unless
or until any additional safeguards are identified by the Secretary of
HHS.
We estimate that 803 of the 8,035 institutions with FWAs (10
percent) will be required to update their privacy and security
standards to comply with the new requirements. At these institutions,
we estimate that institutional officials and institutional legal staff
will each spend 80 hours in 2016 and 20 hours in subsequent years to
update and monitor their privacy and security standards. In addition,
we estimate that 43,997 of 439,968 investigators (10 percent) will be
required to adopt the updated privacy and security standards. We
estimate that these investigators will each spend 40 hours in 2016 and
10 hours in subsequent years to do so.
Sec. __.111 Criteria for IRB Approval of Research, (OMB Control No.
0990-0260)
Section __.111 is being amended at Sec. __.111(a)(8) to add a new
requirement that if the investigator proposes a research plan for
returning relevant results to subjects, then the IRB must determine
that the plan is appropriate. We estimate that there are 324,187
initial reviews of protocols annually. Of the 324,187 initial reviews,
we estimate that 108,062 reviews (33 percent) will include a plan for
returning results to subjects and that primary reviewers will spend an
average of 15 minutes reviewing these plans.
Sec. __.114 Cooperative Research (OMB Control No. 0990-0260)
Section __.114 is being amended, as described in Sec. __.114(b)(1)
to require any institution located in the United States (U.S.) that is
engaged in cooperative research to rely upon approval by a single IRB
for that portion of the research conducted in the U.S. As described in
Sec. __.114(b)(2), cooperative research for which more than single IRB
review is required by law (e.g., FDA-regulated device studies); or
research for which the federal department or agency supporting or
conducting the research determines and documents that the use of a
single IRB is not appropriate for the particular study need not comply
with this requirement. The OHRP database of registered institutions and
IRBs shows that there are 8,035 institutions with an FWA. We estimate
that these institutions will develop an average of 10 written joint
review agreements with other institutions in 2018 prior to the first
year of compliance. We estimate that each agreement will require an
average of 10 hours of institution legal staff time and 5 hours of IRB
administrator time to complete.
Sec. __.115 IRB Records (OMB Control No. 0990-0260)
Section __.115 is being amended, in Sec. __.115(a)(8), to require
the rationale for requiring continuing review for research that
otherwise would not require continuing review as described in Sec.
__.109(f)(1).
We estimate that there are 108,873 expedited continuing reviews of
protocols annually based on the distribution of reviews presented in
Table 3 of the Regulatory Impact Analyses section of the preamble. Of
these reviews, we estimate that 81,546 reviews (75 percent) will not be
eliminated by other proposed changes to the Common Rule at Sec. Sec.
__.101(b), __.104(d)(1)-(3), __.104(e)(1). We estimate that 40,773 of
these 81,546 reviews (50 percent) will be discontinued and the
remaining 40,773 reviews (50 percent) will continue and require
documentation of the rationale for doing so. We estimate that IRB
voting members will spend 1 hour per review providing documentation. In
addition, we estimate that administrative staff at each IRB (total of
3,499 IRBs) will spend 10 hours in 2016 updating their communication
systems to no longer send continuing review reminders to certain
investigators.
Section __.115 is being amended at Sec. __.115(a)(9) to require
that the rationale for an expedited reviewer's determination that
research appearing on the expedited list described in Sec.
__.111(b)(1)(i) is more than minimal risk (i.e., an override of the
presumption that studies on the Secretary's list are minimal risk).
We estimate that there are 223,689 convened initial reviews and
242,330 convened continuing reviews of protocols annually based on the
distribution of reviews presented in Table 3 of the Regulatory Impact
Analyses section of the preamble. Of these 223,689 convened initial
reviews, we estimate that 2,237 reviews (1 percent) are eligible for
expedited review because they are in a category of research that
appears on the Secretary's list. Of these 2,237 reviews, we estimate
that 1,118 reviews (50 percent) will undergo expedited review and the
remaining 1,118 reviews (50 percent) will undergo convened review and
require documentation of the rationale for doing so.
Of the 242,330 convened continuing reviews, we estimate that 2,423
reviews (1 percent) are eligible for expedited review because they are
in a category of research that appears on the HHS Secretary's list. Of
these 2,423 reviews, we estimate that 1,212 reviews (50 percent) will
undergo convened review and will require documentation of the rationale
for doing so. Due to the proposed elimination of continuing review of
research under specific conditions (Sec. Sec. __.109(f); __.115(a)(3),
(8)), the remaining 1,212 reviews (50 percent) will not require review.
Of these 1,212 reviews, we estimate that 606 reviews (50 percent) will
not occur and the remaining 606 reviews (50 percent) will undergo
expedited continuing review and require documentation of the rationale
for doing so. We estimate that IRB voting members will spend 1 hour per
review providing documentation when required.
Section__.115 is being amended, at Sec. __.115(a)(10) to require
the written agreement between an institution and an external IRB
specifying the responsibilities that each entity will undertake to
ensure compliance with the requirements described in Sec. __.103(e).
Table 3 of section III of the preamble shows that there are 5,164
FWA-holding institutions without an IRB and 2,871 FWA-holding
institutions with an IRB. We assume that the 5,164 FWA-holding
institutions without an IRB have an average of 1 IRB authorization
agreement that would need to be
[[Page 54028]]
modified as a result of the new requirements for agreements between
institutions and external IRBs in 2016. In addition, we assume that the
2,871 FWA-holding institutions with an IRB have an average of 0.20 IRB
authorization agreements that would need to be modified in 2016. We
estimate that each agreement will require an average of 10 hours of
institution legal staff time and 5 hours of IRB administrator time to
complete.
Section __.115, is being amended, in Sec. __.115(a)(11), to
require records relating to exemption determinations as described in
Sec. __.104(c). As part of this new requirement, OHRP will create an
interactive exemption determination tool. We estimate that 6,754 annual
reviews of protocols would no longer be conducted as a result of
proposed changes under Sec. __.104. As required under Sec. __.104(c),
an exemption determination must be made and documented for each of
these 6,754 newly exempted studies. It is anticipated that in 50
percent of these studies (3,377 studies), investigators will spend 30
minutes entering information into the HHS-created decision tool in
order for that tool to generate an exemption determination. In the
remaining 3,377 studies, it is anticipated that investigators will
spend 30 minutes preparing and submitting information about the study
to an individual able to make exemption determinations (per Sec.
__.104(c)). An individual at the IRB voting member level will spend an
estimated 30 minutes per study to make an exemption determination.
Sec. Sec. __.116 and __.117 General Requirements for Informed Consent
(OMB Control No. 0990-0260)
Section __.116 is being amended, as described in Sec.
__.116(a)(9), to add a new basic element of consent that would apply to
any research collection of identifiable private information. One of the
following statements about such research collection much be provided to
subjects: (i) A statement that identifiers might be removed from the
data and the data that is not identifiable could be used for future
research studies or distributed to another investigator for future
research studies without additional informed consent from the subject
or the representative, if this might be a possibility; or, (ii) a
statement that the subject's data collected as part of the research,
from which identifiers are removed, will not be used or distributed for
future research studies. We estimate that there are 246,382 new
protocols annually using individually identifiable information. For
each protocol, we estimate that investigators will spend an average of
15 minutes in 2016 updating consent forms to comply with the new
requirements.
Section __.116 is being amended, as described in Sec. __.116(c) to
allow broad consent to cover the storage, maintenance, and secondary
research use of biospecimens and identifiable private information.
Broad consent would be permissible for the storage or maintenance for
secondary research of such information and biospecimens that were
originally collected for either research studies other than the
proposed research or non-research purposes. The broad consent document
would also meet the consent requirement for the use of such stored
biospecimens and information for individual research studies.
We anticipate 6,428 FWA holding institutions (80 percent) will
develop an institution-wide research repository of biospecimens and
identifiable private information available for future research in the
manner prescribed under the new proposed exemption at Sec.
__.104(f)(1). We estimate that 80 percent of institutions with an FWA
(6,428 institutions) will implement a tracking system. Those
institutions will require 1.0 FTEs on average to develop and maintain a
tracking system.
It is anticipated that many investigators will choose to seek such
consent in order to save time and burden by avoiding the need to (1)
seek and obtain consent to every specific future research use, (2) seek
full IRB review for research that meets one of the exempt research
categories, or (3) seek IRB review for a waiver of consent.
Section__.116 is being amended, as described in Sec. __.116(h), to
require that a copy of the final version of the consent form for each
clinical trial conducted or supported by a Federal department or agency
component conducting the trial on a publicly available federal Web site
that will be established as a repository for such consent forms. The
informed consent form must be posted in such form and manner as the
department or agency head may prescribe, which will include at a
minimum posting, in addition to the informed consent form, the name of
the clinical trial and information about whom to contact for additional
details about the clinical trial. The consent form must be published on
the federal Web site within 60 days after the trial is closed to
recruitment.
We estimate that Common Rule departments and agencies supports
5,270 new clinical trials annually, of which 575 are regulated by
provisions in the FD&C Act and Trade Secrets Act based on the
information presented in Table 3 of the Regulatory Impact Analyses
section of the preamble. For the purpose of this analysis, we assume
that each clinical trial is associated with one consent form that must
be submitted by an investigator. We estimate that investigators will
spend an average of 15 minutes submitting each consent form. In
addition, for the 575 clinical trials regulated by provisions in the
FD&C Act and Trade Secrets Act, we estimate that investigators will
spend an average of 30 minutes redacting information before submission.
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The total estimated burden imposed by these information collection
requirements is 12,155,926 burden hours.
It should be noted that the burden estimates for the Common Rule
include those approved information requirements in: (1) OMB No. 0990-
0260, Protection of Human Subjects: Compliance with Federal Policy/IRB
Recordkeeping/Informed Consent/Consent Documentation, approved through
May 31, 2018; (2) OMB No. 0990-0263, Assurance Identification/IRB
Certification/Declarations of Exemption Form (Common Rule), approved
through March 31, 2018; (3) OMB No. 0990-0278, Federalwide Assurance
(FWA) for the Protection of Human Subjects, approved through August 31,
2017; and, (4) OMB No. 0990-0279, HHS, Registration of an Institutional
Review Board ((IRB), approved through August 31, 2015. As such, they
will be amended and submitted to OMB as revisions to currently approved
collections once the rule is finalized and the collections are due for
renewal.
To ensure that comments on these new information collection
requirements are received, OMB recommends that written comments be
faxed to the Office of Information and Regulatory Affairs, OMB, Attn:
[OS Desk Officer, FAX: 202-395-6974, or emailed to
oira_submission@omb.gov. All comments should be identified with the
title ``Federal Policy for the Protection of Human Subjects.''
In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3507(d)), the information collection provisions of this proposed rule
will be submitted to OMB for review. These requirements will not be
effective until OMB approves them.
VI. Summary of Comments Received on the 2011 Common Rule ANPRM
A. Initial Step Toward Modernization of the Common Rule: The Advance
Notice of Proposed Rulemaking (ANPRM)
In considering changes in the Common Rule, the ANPRM requested
comment on possible changes to seven aspects of the current regulatory
framework.
1. Ensuring Risk-Based Protections
2. Streamlining IRB Review of Cooperative Studies
3. Improving Informed Consent
4. Strengthening Data Protections To Minimize Information Risks
5. Data Collection To Enhance System Oversight
6. Extension of Federal Regulations
7. Clarifying and Harmonizing Regulatory Requirements and Agency
Guidance
Public comments on the ANPRM initially were requested by September
26, 2011; however, in response to public requests for an extension, the
comment period was extended until October 26, 2011. A total of 1,051
comments were received, with many commenters responding to all 74
questions posed. Investigators comprised the largest group of
commenters. Comments were also received from: Trade and professional
associations; medical and social/behavioral research organizations;
disease and patient advocacy groups; IRB members and staff; individual,
private companies and the organizations representing them; and patients
and research subjects. A large number of comments were lengthy and
detailed, reflecting thoughtful consideration of the issues discussed.
Many responses reflected the input of large research and health care
organizations, including public university systems, research
universities, academic medical centers, and medical schools, as well as
networked health care providers. The greatest number of comments
focused on the section addressing risk-based protections.
In addition to reviewing the public responses to the ANPRM, in
preparing the NPRM, the deliberations of the Presidential Commission
for the Study of Bioethical Issues (the Commission) were taken into
account. Consideration was also given to public comments received on
the request for information issued by the Commission on March 2,
[[Page 54034]]
2011, that sought public comment on the current federal and
international standards for protecting the health and well-being of
participants in scientific studies supported by the federal
government.\92\
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\92\ 76 FR 11482 (Mar. 2, 2011).
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These suggested revisions to the Common Rule may affect other
regulatory protections, such as the other subparts of the HHS human
subjects protection regulations in 45 CFR part 46 (Subparts B, C, and
D, which deal with particular populations of vulnerable subjects, and
Subpart E which addresses registration of IRBs), FDA regulations, and
the HIPAA Privacy Rule (45 CFR parts 160 and 164, Subparts A and E). It
is contemplated that other regulatory provisions implicated by the
changes to the Common Rule may need to be harmonized, to the extent
appropriate, with any final regulations modifying the Common Rule,
through rule modification or guidance. Additionally, guidance and other
information would also be revised and/or written to the extent
necessary and appropriate.\93\
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\93\ Research not subject to the Common Rule may still be
subject to FDA regulation or the HIPAA Privacy Rule.
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B. ANPRM Issues and Public Comments Related To Improving Protections
1. Expanding the Scope of the Common Rule
The ANPRM asked for public comments regarding two potential changes
to the regulations at Sec. __.101. The first would subject
unaffiliated IRBs (IRBs that are not operated by an FWA-holding
institution) that review research covered by the Common Rule to the
requirements of the Common Rule. The second would extend the scope of
research covered by the regulations.
Holding Unaffiliated IRBs Directly Accountable for Compliance With
Certain Regulatory Requirements: To address institutions' concerns
about OHRP's practice of enforcing compliance with the Common Rule
through the institutions that are engaged in human subjects research,
the ANPRM asked for comments on making appropriate changes to the
Common Rule enforcement procedures so external IRBs are held directly
accountable for compliance with certain regulatory requirements.\94\
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\94\ See, e.g., the proposal on IRB accountability released by
OHRP in 2009, at http://www.hhs.gov/ohrp/newsroom/rfc/com030509.html.
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Based on public comments received to a 2009 ANPRM \95\ on the issue
of IRB accountability, the July 2011 Common Rule ANPRM considered
adding a new provision that would give Common Rule departments and
agencies the authority to enforce compliance directly against IRBs that
are not affiliated with an institution that has an assurance registered
with HHS. This provision would not extend the scope of research that is
covered by the regulations; rather, it would expand the scope of those
entities subject to compliance oversight.
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\95\ 74 FR 9578 (Mar. 5, 2009).
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Some public commenters responding to the 2011 ANPRM cautioned that
extending compliance oversight to unaffiliated IRBs might serve as a
disincentive for some IRBs to be the IRB of record for cooperative
research. A majority of commenters expressed an opposing view; that is,
holding external IRBs directly accountable for compliance with the
regulations would increase the comfort level of institutions in
accepting the regulatory review of an external IRB.
Extension of Common Rule to Domestic Sites Funded by Common Rule
Agencies: The ANPRM asked the public to consider a regulatory option to
partially fulfill the goal of extending Common Rule protections to all
human subjects research in the United States. The discussed policy
would require domestic institutions that receive some federal funding
from a Common Rule agency for nonexempt research with human subjects to
extend the Common Rule protections to all human subjects research
studies conducted at their institution.
Although supporting the principle that all human subjects research
regardless of funding source should be conducted ethically, public
commenters generally expressed concern and caution about the ANPRM
consideration for a variety of reasons. Behavioral and social science
researchers thought that this approach would unnecessarily bring less-
than-minimal-risk research funded by non-federal sources (e.g., surveys
or observational studies supported by the nonprofit sector) under
burdensome regulatory requirements while not enhancing protections.
Some commenters argued that the increased regulatory burden that would
ensue was not warranted and would shift scarce oversight resources to
review of research studies that are generally non-problematic and
frequently supported by non-federal funds, such as some student or
institutional research.
Others argued that such a change was an overreach of federal
oversight and constituted an unfunded mandate. Commenters from large
academic research institutions felt that this change inappropriately
focused heavily on academic institutions, which generally extend
protections to all human subjects research at their institution, even
if they have not ``checked the box'' \96\ on their FWA indicating that
they do so. They argued that such a change would not reach those
institutions already operating outside the federal research system and
would limit flexibility in making risk-based determinations about the
levels of review required.
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\96\ The FWA covers all nonexempt human subjects research at the
submitting institution that is HHS-conducted or -supported, or
funded by any other federal department or agency that has adopted
the Common Rule and relies upon the FWA. It is not project specific.
Domestic institutions may voluntarily extend their FWA (and thus a
Common Rule department or agency's regulatory authority) to cover
all human subjects research at the submitting institution regardless
of the source of support for the particular research activity. See
Office for Human Research Subject Protections. (2011, June 17). What
research does the Federalwide Assurance (FWA) cover? Retrieved from
Frequently Asked Questions: http://www.hhs.gov/ohrp/policy/faq/assurance-process/what-research-does-fwa-cover.html.
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Industry also expressed concern about having to comply with two
sets of regulations, that is, FDA regulations at 21 CFR parts 50 and 56
as well as the Common Rule. The ANPRM did not clarify that the changes
under consideration would not require compliance with the Common Rule
of non-federally funded research subject to regulation by FDA. However,
there might continue to be research that would be subject to both sets
of regulations involving federal funding of research concerning an FDA-
regulated product.
Those commenters who supported a formal extension of the
regulations cited the need to have one set of standards for all
research, regardless of funding source; however, many noted that absent
legislation covering all human subjects research conducted in the
United States, it would be difficult to cover all research through a
regulatory approach alone--gaps would still remain.
2. Safeguards for Information
Definition of Private Information and Applying the HIPAA Standards
of ``Identifiability'' to Research Governed by the Common Rule: The
ANPRM suggested that the definition of ``identifiability'' in the
Common Rule be modified to better harmonize it with other regulatory
definitions of ``identifiability'' within HHS. The ANPRM considered
adopting for purposes of the Common Rule the HIPAA Privacy Rule's
standards of what constitutes individually identifiable information, a
limited data set, and de-
[[Page 54035]]
identified information, in order to address inconsistencies regarding
these definitions and concepts between the HIPAA Privacy Rule and the
Common Rule. In addition, the ANPRM indicated that a prohibition on the
re-identification of de-identified information (as defined in the HIPAA
Privacy Rule) was being considered.
Private information is not considered to be identifiable under the
Common Rule if the identity of the subject is not or may not be
``readily ascertained'' by the investigator from the information or
associated with the information. In contrast, under the HIPAA Privacy
Rule, health information is de-identified and thus exempt from the Rule
only if it neither identifies nor provides a reasonable basis to
believe that the information can be used to identify an individual. The
HIPAA Privacy Rule provides two ways to de-identify information: (1) A
formal determination by a qualified expert that the risk is very small
that an individual could be identified; or (2) the removal of all 18
specified identifiers of the individual and of the individual's
relatives, household members, and employers, as long as the covered
entity has no actual knowledge that the remaining information could be
used to identify the individual (45 CFR 164.514(b)).
The HIPAA Privacy Rule addresses some informational risks by
imposing restrictions on how individually identifiable health
information collected by health plans, health care clearinghouses, and
most health care providers (``covered entities'') may be used and
disclosed, including for research. In addition, the HIPAA Security Rule
(45 CFR parts 160 and Subparts A and C of part 164) requires that these
entities implement certain administrative, physical, and technical
safeguards to protect this information, when in electronic form, from
unauthorized use or disclosure. However, the HIPAA Rules apply only to
covered entities (and in certain respects to their business
associates), and not all investigators are part of a covered entity.
Moreover, the HIPAA Rules do not apply specifically to biospecimens in
and of themselves.
A majority of the public commenters strongly opposed the ideas
discussed in the ANPRM regarding the definition of ``identifiability''.
Many indicated that the HIPAA Privacy Rule's more stringent standard of
identifiability would expand what is considered identifiable for
purposes of the Common Rule and thus greatly impede generally low-risk
research without adding meaningful protections for human subjects. In
particular, they asserted that the HIPAA standards were created to
protect against disclosure of health information contained in medical
records. As such, commenters argued, they are not appropriate for many
types of research that would be covered by the Common Rule (e.g.,
behavioral and social science research). Others said this would be an
extreme change in response to an as yet unidentified or clear problem.
Commenters said that the information most at risk for inappropriate
disclosure is the type of private health information that is already
protected under the HIPAA Rules. Commenters feared that such a change
in policy, while ``harmonizing'' the Common Rule certain HIPAA
standards, would create inordinate burdens in terms of new
documentation requirements and result in a requirement to apply the
HIPAA standards to all types of research, regardless of the level of
risk.
Several commenters expressed concern about a prohibition against
re-identifying de-identified private information (as defined by HIPAA),
noting that sometimes it will be appropriate for investigators to re-
identify such information, for example, to return research results that
have clinical relevance to the subjects. Also, some commenters noted
that some research is specifically designed to test strategies for re-
identifying de-identified (as defined by HIPAA) information, so an
absolute prohibition against re-identification would halt such
research.
Protecting Information: The ANPRM suggested establishment of
mandatory data security and information protection standards for all
studies that involve the collection, generation, storage, or use of
identifiable or potentially identifiable information that might exist
electronically or in paper form or contained in a biospecimen. It put
forward the idea that these standards might be modeled after certain
standards of HIPAA Rules and asked a series of questions about how best
to protect private information.
Some public comments reflected confusion about the focus of the
suggested standards and whether they would apply to information or
biospecimens that were not individually identifiable. Although most
commenters confirmed the need to protect the privacy and
confidentiality of information of human subjects in research, a
majority expressed serious concerns about the merits of requiring all
investigators to meet standards modeled on certain HIPAA standards,
such as those in the HIPAA Security Rule. Most commenters expressed the
opinion that certain HIPAA standards are not well suited to some
research of various kinds carried out by investigators not subject to
the HIPAA Rules. Some commenters claimed that the HIPAA privacy
standards do not adequately protect individuals' information. Many
commenters claimed that standards modeled after certain HIPAA standards
would be unnecessarily burdensome for studies in the behavioral and
social sciences where the data are often less sensitive than health
information.
Some comments maintained that HIPAA like standards would not always
be suitable for the variety of research methods and procedures for the
collection and storage of information in research activities not
subject to the HIPAA Rules. Some commented that certain HIPAA standards
would not be suitable because of the location of the research activity,
or because the kind of institution supporting the research was
significantly different from a covered entity. Others thought the HIPAA
standards create confusion and complications for investigators and
institutions that would increase if standards modeled on certain HIPAA
standards were applied across the board. At the same time, regardless
of the specific standards to be employed under this approach, several
commenters noted that the additional administrative burden that might
be created by establishing a data security and information protection
system could be offset by the decreased time and attention IRBs would
have to invest in reviewing every study that required data or
biospecimen protections. They also noted that many institutions already
have required data and biospecimen protection systems in place.
Some commenters noted that expansion of some of the exemption
categories could only be ethically acceptable if those research
activities were subject to a requirement for data security and
information protection, because information collected for some research
studies would no longer be collected under a research plan approved by
an IRB. With regard to an absolute prohibition against re-identifying
de-identified data, many commenters expressed concern, and provided
reasons why re-identification might be valid or even desirable,
including the need to return clinically relevant research results to an
individual. For example, if the research uncovers information that
might have important clinical significance for an individual, re-
identification could be used so that the individual could get care. In
addition, they pointed out that
[[Page 54036]]
the current Common Rule requires investigators that re-identify
nonidentified private information as part of a research study to comply
with the current Common Rule regulatory requirements.
3. Improving Informed Consent, Including Requiring Informed Consent for
Research Use of Biospecimens and the Use of Broad Consent for Secondary
Research Use of Biospecimens and Information
The public was asked to comment on: The length and complexity of
informed consent forms; additional information, if any, that should be
required by the regulations to assure that consent forms appropriately
inform subjects about alternatives to participation, as well as whether
or not there should be modifications or deletions to the required
elements; whether subject comprehension should be assessed, and if so,
under what circumstances; whether changes to the Common Rule would
necessitate conforming changes to the authorization requirements of the
HIPAA privacy requirements; and whether additional requirements in the
consent process are warranted, such as financial disclosures by
investigators. The ANPRM also requested comment on the need for
regulation of consent for the following: Research use of biospecimens
collected for clinical purposes, consent for research use of pre-
existing data, and consent to secondary research use of data and
biospecimens.
Consent for Research Use of Biospecimens and Information Generally:
The ANPRM also requested comment on the value of generally requiring
written consent for research use of any biospecimens collected for
clinical purposes after the effective date of the new rules (such as
research with excess pathology biospecimens). Such consent could be
obtained by use of a brief standard consent form agreeing to generally
permit future research. This brief consent could be broad enough to
cover all biospecimens to be collected related to a particular set of
encounters with an institution (e.g., hospitalization) or even to any
biospecimens to be collected at any time by that institution. The
general rule as discussed in the ANPRM would be that a person needs to
give consent, in writing, for research use of their biospecimens,
though that consent need not be study-specific, and could cover open-
ended future research.
The ideas presented in the ANPRM would be a substantial change from
the current Rules in several ways. First, the current Rules allow
research without consent when a biospecimen is used for research under
conditions where the researcher does not possess information that would
allow them to identify the person whose biospecimen is being studied.
Thus, biospecimens collected as part of a non-research protocol (e.g.,
clinical care) could be made nonidentified and used in research as long
as the researcher cannot identify the source of the biospecimen. The
ANPRM consideration would no longer allow that to occur, generally
requiring researchers to obtain consent for research use of clinical
biospecimens, even if nonidentified. A waiver of consent under limited
circumstances was contemplated in the ANPRM, but no specific waiver
criteria were discussed.
A majority of the commenters opposed the ANPRM's suggested
requirement to have consent for research use of all biospecimens,
regardless of identifiability, on both administrative and ethical
grounds. Administrative reasons for opposition to the suggested consent
requirements included the prohibitive costs to collect, log, and track
consent status of data and biospecimens, and the considerable
administrative efforts that would be required to keep track of the
consent status. Commenters opposed to the suggested consent
requirements on ethical grounds cited increased privacy risks to
subjects arising from the need to maintain links between the consent
documents and the biospecimens or data in order to ensure that any
restrictions on the research use of such resources were honored. They
also expressed their belief that convincing evidence of harm caused by
research use of nonidentified clinical biospecimens without consent is
lacking, especially when considering the public health benefit of such
use, and noting that they were not convinced that the principle of
autonomy outweighs or trumps the principle of beneficence. Some patient
advocacy organizations also expressed concerns about the consequences
of requiring consent for the use of nonidentified biospecimens. Yet,
most of the comments from individual members of the public strongly
supported consent requirements for use of their biospecimens,
regardless of identifiability, or data.
Many commenters expressed the opinion that the existing regulatory
framework is adequate and that current practices should be maintained,
stressing that the research use of nonidentified data or biospecimens
does not involve risk to the research participant. One commenter noted
that ``In our extensive professional experience working with
biospecimens on a daily basis, the current system has worked well and
has greatly enriched the opportunity for discoveries that were unknown
at the time of collection and when research does not require subject
identification or involve patient risk.'' In contrast, some commenters
supported the idea of requiring consent for research use of all
biospecimens, with one commenter noting simply that ``research use of
data initially collected for non-research purposes should always
require informed consent.'' Commenters particularly noted concerns
about imposing consent requirements on the use of biospecimens already
collected--that is, not grandfathering in such resources--especially if
these biospecimens are nonidentified. Requiring that consent be
obtained for the use of these materials could result in their being
rendered useless for research, which would represent a cost of its own
in terms of lost opportunity. This concern was based on the practical
limitations involved in obtaining consent for biospecimens that were
de-identified in the past, given that it may not be possible to re-
contact the original source.
The objections raised by the commenters about the possible adverse
consequences of requiring consent for the use of nonidentified
biospecimens--including, in particular, the proposition that such a
change might significantly compromise an important and relatively low-
risk area of research--resulted in suggestions in the comments that
this should be systematically assessed before suggesting any new rules.
In fact, several commenters suggested that data be collected on the
cost and feasibility of instituting such a requirement before revising
the Common Rule.
Consent Rules for Research Use of Pre-existing Data: The ANPRM
asked for comments on revising the consent rules for research use of
data previously collected for purposes other than the suggested
research study. First, if the data were originally collected for non-
research purposes, then, as is currently the rule, written consent
would only be required if the researcher obtains information that
identifies the subjects. There would accordingly be no change in the
current ability of researchers to conduct such research using de-
identified data or a limited data set, as such terms are used in the
HIPAA Rules, without obtaining consent.
Second, if the data were originally collected for research
purposes, then consent would be required regardless of whether the
investigator obtains identifiers. Note that this would be a
[[Page 54037]]
change with regard to the current interpretation of the Common Rule in
the case where the researcher does not obtain any identifiers. That is,
the allowable current practice of telling the subjects, during the
initial research consent, that the information they are providing will
be used for one purpose, and then after stripping identifiers, allowing
it to be used for a new purpose to which the subjects never consented,
would not be allowed.
Consent to Secondary Research Use of Data and Biospecimens Through
Broad Consent: The ANPRM suggested that consent for the use of
biospecimens or data could be obtained using a standard, short form, in
which the subject could be asked to provide broad consent, that is,
consent for a variety of potential future uses of their biospecimens or
data. The requirement for consent could be waived in certain
circumstances. These changes would apply only to biospecimens and data
collected after the effective date of a new final rule.
Public comments revealed variable opinions on this issue. Several
commenters indicated that there is no need for additional regulations,
with one university stating that it ``strongly opposes more restrictive
regulations about the use of these biospecimens and sees no need to
change the current regulations, even or perhaps especially in the case
of secondary data analysis.'' Other commenters opposed broad consent,
stating that researchers and clinicians should obtain specific consent
from individuals for each research project. This opposition was made on
the ethical grounds that because individuals are not fully informed of
specific research purposes for broad consent, they can never be truly
informed about the use of their data. In contrast, other commenters
expressed clear support for general consent for secondary research use
of biospecimens and data collected during research to exempt the
research from IRB review, noting that ``we support the suggestion in
the ANPRM to encourage general consent for the secondary research use
of biospecimens and data and where this is not obtained IRB review is
required.'' Other commenters favored requiring IRB review over
permitting the use of a broad consent to approve secondary research use
of identifiable data or biospecimens. These commenters believed that
IRB consideration of consent requirements for individual research
studies was more protective of human subjects than the ANPRM
suggestions to permit broad consent for future use.
With regard to the burden of obtaining consent for the research use
of de-identified biospecimens, this requirement could be less
burdensome than anticipated due to the ANPRM's suggested allowance of
broad consent. While the ANPRM suggested requiring consent for the use
of biospecimens, it suggested allowing a one-time, broad consent for
future uses to be obtained with a template form which, if used without
changes, would not require IRB review, and could be obtained at the
same time as the initial research or clinical consent. Some commenters,
particularly patients and patient advocacy groups, expressed concern
about the burden of re-consenting patients for broad consent after
biospecimens were collected.
Several commenters suggested that data be collected on the cost and
feasibility of instituting such a requirement before revising the
Common Rule.
In most instances, the consent requirements described above would
have been met at the time that the biospecimens or data were initially
collected, when, under the ANPRM the subject would have signed a
standard, brief general consent form allowing for secondary research.
This brief consent could be broad enough to cover all data and
biospecimens to be collected related to a particular set of encounters
with an institution (e.g., hospitalization) or to any data or
biospecimens to be collected at any time by the institution, even as
part of a research protocol.
The ANPRM suggested that this standardized broad consent form would
permit the subject to say no to all future research. In addition, the
ANPRM acknowledged that there are likely to be a handful of special
categories of research with biospecimens that, given the unique
concerns they might raise for a significant segment of the public,
could be dealt with by check-off boxes allowing subjects to separately
say agree or disagree to that particular type of research.
Further, the ANPRM suggested that the current prohibition that
participation in a research study (such as a clinical trial) could not
be conditioned on agreeing to allow future open-ended research using a
biospecimen would be maintained. With regard to the secondary research
use of pre-existing data, on those occasions when oral consent was
acceptable under the regulations for the initial data collection, the
ANPRM envisioned that subjects would have typically provided their oral
consent for future research at the time of the initial data collection;
a written consent form would not have to be signed in that
circumstance.
The ANPRM suggested that these changes would only be applied
prospectively, not retrospectively. In other words, they would only
apply to biospecimens and data that are collected after the effective
date of the new rules. It also noted that there would be rules that
would allow for waiver of consent under specified circumstances, though
those conditions would not necessarily be the same as those for other
types of research.
Improving Consent Forms and Modifying the Required Elements of
Consent: Public comments were largely in favor of finding ways to
improve consent forms. However, commenters cited several systemic
concerns that could be obstacles to shortening and simplifying forms,
such as regulatory, legal, and institutional requirements, and the
complexity of some studies. Of those responding to questions about the
causative factors, blame for making forms long and complex was shared
by sponsors of clinical trials, IRBs, regulatory agencies, and
institutional legal counsel. The types of information cited as
contributing to the excessive lengths of forms included the requirement
to describe all reasonably foreseeable research risks and the
complexity of study procedures. There was no consensus on how to better
explain alternatives to research participation and few comments were
submitted on this topic.
Commenters offered a few suggestions for modifying or deleting the
required elements of consent, such as removing boilerplate language
that only protects institutions and research sponsors, as well as
removing some of the required elements for minimal risk research.
However, many felt that guidance, rather than regulatory change, would
better improve the development of consent forms. Although many
commenters noted the need for shorter and more comprehensible consent
forms, most felt that the required elements of consent articulated in
the Common Rule are sufficient. Commenters overwhelmingly supported the
goals articulated in the ANPRM, but cautioned against an overly
prescriptive or rigid approach to consent forms. However, several
commenters requested guidance on what might be included in a consent
form for future research use of identifiable information and
identifiable biospecimens to ensure that such forms satisfied the
consent requirements of the Common Rule.
A majority of commenters supported the development of regulations
or guidance designed to encourage
[[Page 54038]]
assessment of the extent to which human subjects comprehend consent
forms, at least for certain types of higher risk studies or certain
types of subject populations. Others argued that the regulations at
Sec. __.116 already contain language implying the need to ensure
comprehension through the use of the terms ``legally effective informed
consent'' and ``language understandable to the subject.''
Finally, many commenters supported making changes to HIPAA
authorization requirements, as necessary to conform to provisions of
the Common Rule. In addition, most commenters were supportive of
requiring investigators to disclose in consent forms certain
information about the financial relationships they have with study
sponsors.
Criteria for Waiver of Consent: The ANPRM asked whether changes to
the regulations would clarify the current four criteria for waiver of
informed consent and facilitate their consistent application. Few
comments were received on this topic although many commenters expressed
support for clarifying the key terms through guidance or altering the
criteria. In particular, most comments on this topic noted the
confusion that IRBs face when trying to understand the meaning of the
terms ``practicable'' and ``adversely affect the rights and welfare of
subjects.'' Some commenters expressed the opinion that the waiver
criterion concerning rights and welfare should be interpreted to
include reference to rights conferred by other federal laws or
regulations, state or local laws, or laws in other countries where
research is to be conducted. Some comments reflected concerns about
privacy or security.
The ANPRM also asked for comments on the information investigators
should be required to provide to prospective subjects in circumstances
where the regulations would permit oral consent. Additional questions
focused on whether there are additional circumstances under which it
should be permissible to waive the usual requirements for obtaining or
documenting informed consent, and whether there are types of research
in which oral consent without documentation should not be permitted.
There were few responses to these questions and no common themes or
consensus among those submitted. However, several commenters pointed to
the need to consider community norms throughout the consent process,
including its documentation.
4. Improving the Collection and Analysis of Adverse Event Reports
The ANPRM asked the public to consider a number of changes to
improve the current system for the real-time prompt collection of data
regarding adverse events. The changes that the ANPRM stated were under
consideration were intended to simplify and consolidate the reporting
of information that is already required to be reported by an
investigator, and not to expand the information that has to be
reported. In addition to these changes, the ANPRM indicated that the
Federal Government was also considering creating a central web-based
repository to house a great deal of the information collected through
the portal.
Although a number of commenters applauded the goal of easing and
harmonizing reporting requirements, most expressed concerns about
collecting data on unanticipated problems and adverse events in a
central database. Those who supported the concept of centralized
reporting asked for more detail on what such a system would entail.
More specifically, several commenters noted that IRBs sometimes
struggle with what should be reported and with distinguishing between
the Common Rule term ``unanticipated problems'' and the FDA term
``adverse events.'' Commenters noted that under the Common Rule at
Sec. __.103(b)(5), each institution determines through its own
policies the procedures for reporting unanticipated problems to
department or agency heads. As a result, there is no standardized
definition of ``unanticipated problems,'' so each institution may be
reporting different events. Commenters also sought better guidance on
those terms and encouraged agencies to clarify meanings and reporting
requirements.
Commenters stated that a standardized, streamlined set of data
elements, a single web-based reporting tool that facilitates delivery
to agencies and oversight bodies, and harmonized Federal agency
guidance would simplify the process. However, many expressed skepticism
that harmonization across Federal agencies could occur.
With regard to a centralized database, many commenters expressed
concerns regarding the value in terms of cost and time with compiling
such data, gleaned from diverse studies and sources, in order to
conduct an integrated analysis. They commented that it is unclear how
the data would be useful beyond a specific study and unclear who would
have access to the data and how it would be managed and interpreted to
better inform the regulatory process. Commenters asked, if the data
reporting is real-time, who is expected to develop such a system and
review incoming data to coordinate the appropriate response? Many
commenters questioned the validity of data collected in such a generic
manner and the ability to draw generalizable conclusions based on data
collected from varied sources and contexts. Several commenters said
that before implementing such a central repository, a thorough cost-
benefit analysis should be conducted regarding strengths and
limitations of similar data repositories. Until the utility of such a
centralized system could be demonstrated, especially when compared to
the current decentralized system, many felt the burden of creating such
a system would not be counterbalanced by the benefit of added
protections. Along these lines, commenters also questioned the utility
of counting how many human subjects are enrolled in trials, stating
that this would not be a meaningful way to develop risk estimates.
Many commenters cited the adequacy of current reporting systems,
despite the need for improvement. Centralized reporting of adverse
events would represent a dramatic change from how events are collected
and reported now. For example, sponsors of clinical trials are
responsible for continuously monitoring their trials, adverse events
must be reported to sponsors, and new reporting would not substitute
for reports to sponsors. In addition, under FDA regulations, when
applicable, safety information from non-U.S. clinical trials may need
to be reported. Moreover, sponsors and funding agencies probably would
not rely on extracting information from a federal database as the
source of information to meet all of their safety oversight obligations
and would likely still require investigators to complete adverse event
case report forms as well as rely on the use of Data Safety Monitoring
Boards. Commenters also raised concerns that the use of an electronic
centralized reporting system could be a substantial burden on
investigators, may potentially decrease investigators' willingness to
participate in trials, and may encourage the conduct of studies outside
the regulations. If reporting systems were now required to also gather
and store unanticipated problems in addition to adverse events,
commenters said the system would become unwieldy, run the risk of
creating long lag times in analysis, and draw low risk events into a
system that should be focused on the
[[Page 54039]]
highest risk studies. Several commenters recommended that more efforts
be made to improve current reporting systems, particularly
ClinicalTrials.gov.
Based on the public comments, the NPRM does not pursue a
centralized reporting system and thus this issue is not addressed
further. OHRP will continue to engage in discussions with FDA and
Common Rule departments and agencies regarding clarifying reporting
terms and requirements.
5. Identifiability of Biospecimens
The ANPRM suggested that, regardless of what information is
removed, it is possible to extract DNA from a biospecimen itself and
potentially link it to otherwise available data to identify
individuals. In addition, irrespective of whether biospecimens are
considered individually identifiable, the ANPRM sought comment on
whether the regulations should be changed to respect individuals'
interest in being able to decide whether their biospecimens would be
available for research, even if the biospecimen was not associated with
any identifiable information. Consequently, it asked for public comment
on the value of categorizing all research involving the primary
collection of biospecimens as well as storage and secondary analysis of
existing biospecimens as research involving identifiable information.
The ANPRM asked whether some types of genomic data should be
considered identifiable and, if so, which types (e.g., genome-wide
single nucleotide polymorphism [SNP] analyses or whole genome
sequences). It also asked whether human biospecimens should be
considered inherently identifiable. A majority of commenters opposed
changing the Common Rule to consider all biospecimens identifiable as
defined by the existing regulations at Sec. __.102(f)(2) (and thereby
categorizing their use as research involving a human subject), and
expressed concern that doing so would significantly slow advances in
research and human health. Several commenters noted that, although it
is theoretically plausible to identify a person based on his or her
biospecimen, the likelihood remains remote enough to argue against the
presumption that the sources of all biospecimens are identifiable and
cited a study showing that the risk of re-identification from a system
intrusion of databases was only 0.22%.\97\ Other commenters cited the
administrative burden that would be exacted should such an
interpretation be implemented, without sufficient evidence that such an
interpretation would be reasonable or enhance protections.
---------------------------------------------------------------------------
\97\ Kwok P et al. Harder Than You Think: A Case Study of Re-
Identification Risk of HIPAA-Compliant Records. NORC at The
University of Chicago and Office of the National Coordinator for
Health Information Technology. 2011. http://www.amstat.org/meetings/jsm/2011/onlineprogram/AbstractDetails.cfm?abstractid=302255.
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Commenters were mostly concerned with the cost and burden that
would be imposed by the requirement to obtain consent. Commenters
anticipated these costs to include obtaining consent from participants
and the administrative efforts required to keep track of the consent
status of biospecimens. Most commenters did not provide detailed cost
estimates with their comments; data are specifically requested in
response to this NPRM. In addition, estimates of the type and number of
studies that could not be pursued using existing samples and data
because of the absence of sufficient consent are requested. Comment is
also sought on the value to the public and research participants of
being asked their permission for research use of their data and
specimens.
Several commenters also stated that if the Common Rule were
modified such that all biospecimens were covered under the rule
regardless of their identifiability, there still might be some
activities involving biospecimens or types of biospecimens that should
be considered exempt or ``excused.'' Suggestions included:
Identifying markers for cancer prognosis or prediction of
response to cancer therapy, or identifying cancer molecular targets
(molecular research)
Basic science research (including analysis of biological
processes)
Research of rare conditions and diseases
Pediatric research
Research with samples that lack potentially identifying
information, such as serum or plasma not containing DNA
Biospecimens lacking nucleic acids (such as certain red
blood cells, expiratory gases)
Blood culture bacteria
Bacterial and viral specimens (this was listed in a
comment as a public health issue)
Protein analysis
Statistical method development (to the extent that this
development is related to biospecimens)
New molecular methods to detect infectious agents
Use of specimens to develop and validate new assays for
infectious agents
Archival paraffin blocks
One commenter also suggested that the Rule could propose a
definition for biospecimen such that the term does not include sample
types that lack DNA.
In addition, some commenters noted that the recommendation to
require consent might privilege the Belmont Report's principle of
autonomy over the principle of justice, because requiring consent could
result in lower participation rates in research by minority groups and
marginalized members of society. The literature on consent rates in
studies involving biospecimens suggests that while minority consent
rates in some cases may be lower than non-minorities, when asked to
consent, minority consent rates are still higher than
projected.98 99 100 Furthermore, better communication and
community engagement with members of specific minority groups is needed
to understand and address concerns related to research, and these
measures could substantially improve participation rates. An increase
in trust and partnership is likely to increase participation rates;
using their samples and data without permission will hinder true
partnership.
---------------------------------------------------------------------------
\98\ Pentz RD et al. Research on Stored Biological Samples:
Views of African American and White American Cancer Patients.
American Journal of Medical Genetics, Part A. 2006 Apr 1;
140(7):733-9.
\99\ Chen DT et al. Research With Stored Biological Samples;
What Do Research Participants Want? Archives of Internal Medicine.
2005 Mar 28; 165(6):652-5.
\100\ Scott et al. Biospecimen Repositories: Are Blood Donors
Willing to Participate? Transfusion. 2010 September; 50(9): 1943-
1950.
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C. ANPRM Issues and Public Comments Related To Reducing Regulatory
Burden
1. Activities Excluded From the Policy
The ANPRM asked questions about the definition of research and
whether various activities should be excluded from the Common Rule,
either by changing the definition of research or by adding exemptions,
or both. The ANPRM sought comment on whether and, if so, how, the
Common Rule should be changed to clarify whether quality improvement
activities, program evaluation studies, or public health activities are
covered. It also asked whether there are specific types of studies for
which the existing rules are inappropriate. If so, comments were sought
on whether this problem should be addressed through modifications to
the exemption categories, or by changing the definition of ``research''
used in the Common Rule to exclude
[[Page 54040]]
some of these studies, or a combination of both.
If the definition of research were to be changed, public comment
was sought on how excluded activities should be defined (e.g.,
``quality improvement'' or ``program evaluation''). With regard to
quality improvement activities, the public was asked to comment on
whether it might be useful to adopt the distinction made by the HIPAA
Privacy Rule, which distinguishes between ``health care operations''
and ``research'' activities, defining ``health care operations'' to
include, among other activities, ``conducting quality assessment and
improvement activities, including outcomes evaluation and development
of clinical guidelines, provided that the obtaining of generalizable
knowledge is not the primary purpose of any studies resulting from such
activities.''
A majority of public comments supported excluding the following
from the regulatory requirements: quality improvement activities,
public health activities, and program evaluation. Many of these
commenters argued that the public benefits resulting from these
activities justified their practice, particularly given the generally
low risk involved. Some argued that for some legally mandated
activities designed to accomplish a public good, it would be
inappropriate for IRBs or individuals to be able to impede or thwart
the execution of those mandated activities. A majority of comments also
favored distinguishing between research and health care operations, as
such terms are defined in the HIPAA Privacy Rule, and excluding the
latter from the policy.
Some commenters noted that people involved in these various
activities are protected in other ways, and alluded to the sorts of
measures that provide a measure of protection. Others suggested that
any exclusions should be limited to data collection and analysis
activities, or to activities below a certain threshold of risk (i.e.,
minimal risk). A minority of comments objected to these exclusions,
arguing that these activities represent encroachments on their
individual rights and privacy, and that oversight in accordance with
the Common Rule requirements would be more protective.
The overwhelming majority of public comments responding to the
question about excluding specific fields of study from the regulatory
requirements of the Common Rule supported explicitly excluding certain
activities from the definition of research versus modifying the
exemption categories. The overwhelming majority of these comments
focused on oral history. Some of the comments were virtually identical
and appear to have been coordinated. Many of the comments reflected the
view that the Common Rule was not designed or intended to include oral
history activities, and that the ethical codes pertaining to oral
history procedures are not consistent with the application of ethical
principles reflected in the Common Rule.
A smaller number of similar comments were submitted with respect to
various humanities disciplines and journalism. A significant minority
of commenters opposed the exclusion of any fields of study, arguing
that the activity itself rather than the academic discipline or
training of the investigator should be the basis for the assessment of
whether the activity should be excluded. Some of the commenters
recommended that the definition of research be focused more explicitly
by being limited to ``biomedical and behavioral research,'' in
accordance with the statutory provision underlying the Common Rule. A
significant number of commenters recommended that guidance should be
issued to clarify how the definition of research should be applied,
with cases and explanations.
2. Research Exempt From IRB Oversight
Exemption Determination: The ANPRM discussed a mechanism to (1)
register exempt research, and (2) audit a small but appropriate portion
of such research, which would still be subject to other regulatory
protections such as the suggested data security and information
protection standards and certain consent requirements. The term
``excused'' rather than ``exempt'' was recommended to describe these
categories of research, because they are not entirely exempt from
oversight.
The ANPRM discussed a tracking mechanism to enable institutions to
assure that such research meets the criteria for inclusion in the
suggested ``excused'' categories. The original recommendations would
require investigators to register their study with an institutional
office by completing a brief form, thus eliminating the current
practice of not allowing investigators to begin conducting such studies
until a reviewer had determined it met the criteria for excused
research. This would make the institution aware of key information
about the research (such as the purpose of the research and the name of
the study's principal investigator), without also requiring that the
activity undergo a review that, if not done in a timely manner, could
slow the research without adding any significant protection to
subjects. In addition the institution could choose to review some of
the submissions at the time they are filed and, if deemed appropriate,
require that the study be sent for expedited review or, in rare cases,
convened IRB review. It would be made clear that the regulations would
not require, and in fact, would discourage, having each of these
registration forms undergo a comprehensive administrative or IRB review
prior to commencing the study or even afterward.
The auditing requirement was intended to encourage institutions to
use the regulatory flexibility suggested for the ``excused'' categories
of research. The auditing requirement would have provided institutions
with information needed to assess their compliance with the new
``excused'' categories without unnecessarily subjecting all such
research to either prospective review, or even routine review sometime
after the study is begun. Note that currently, OHRP recommends that
there be some type of review by someone other than the investigator to
confirm that a study qualifies as exempt, and many institutions do
impose such a requirement even though such a requirement is extra-
regulatory.\101\
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\101\ Office for Human Research Protections. (2011, January 20).
Exempt Research Determination FAQs. Retrieved from Frequently Asked
Questions About Human Research: http://www.hhs.gov/ohrp/policy/faq/index.html.
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The ANPRM also asked whether this research should be called
``excused'' or some other term, whether it was acceptable for
investigators to independently determine whether their research was
excused, whether review of all registrations should be required, and
whether there should be a time limitation or waiting period before
excused research could begin. The ANPRM also asked whether it was
appropriate to require institutions holding an FWA to conduct
retrospective audits of a percentage of the excused studies to make
sure they qualify for inclusion in an excused category, and if so, how
such audits should be conducted.
Commenters overwhelmingly expressed concerns about adopting the
term ``excused'' to describe this area of research and suggested the
term ``registered'' should such a system be adopted. Commenters
recommended the term ``registered'' because such studies would not be
exempt or excused from other requirements, such as compliance with data
and security provisions as well as, in certain circumstances, informed
consent requirements. In general, commenters were not necessarily
opposed to the concept of registration but sought further information
on what this process would entail.
[[Page 54041]]
Public commenters also expressed concerns about allowing an
investigator to independently make the determination that his or her
research is exempt. Other commenters suggested that this practice would
be acceptable for some investigators, whose research is well known to
IRB members, and is clearly within an exempt category. The ANPRM noted
concerns that some exempt research was unnecessarily delayed by
requirements of some institutions to review the research to make an
exemption decision.
Several institutions reported that they already as a matter of
policy require investigators to submit exempt studies to the IRB, not
necessarily for full board review, but to ensure that the exempt
determination is valid. These decisions typically are made by the IRB
administrator and never involve full review unless there is concern
about the exemption status. Thus, they felt the registration
requirement was unnecessary and would add new administrative burdens
for research already considered low risk.
Other commenters, such as investigators conducting research
currently considered exempt, were strongly opposed to a registration
requirement because it would add a new burden to conducting less than
minimal risk and exempt research. In addition, commenters raised
concerns about the administrative burden and need for a retrospective
audit system of registered research.
Exemption Categories: The ANPRM considered revising the regulations
regarding studies currently considered exempt by expanding the current
exemption category 2 (research involving educational tests, surveys,
focus groups, interviews, and similar procedures, found in the current
Rule at Sec. __.101(b)(2)) to include all studies involving
educational tests, surveys, interviews, and similar procedures so long
as the subjects are competent adults, without any further
qualifications. It also considered adding a new category for certain
types of behavioral and social science research that goes beyond using
only survey methodology, but nonetheless involves only specified
minimal risk procedures, so long as the subjects are competent adults
(but subject to the data security and information protection
standards). The term ``competent'' as used in the ANPRM referred to
adults who would be able to provide ``legally effective informed
consent,'' as currently required by Sec. __.116.\102\
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\102\ Informed consent is legally effective if, in part, it is
both obtained from the subject or the subject's legally authorized
representative and documented in a manner that is consistent with
the HHS protection of human subjects regulations and with applicable
laws of the jurisdiction in which the research is conducted. See
Office for Human Research Protections. (2011, January 20). What is
the meaning of ``legally effective informed consent?''. Retrieved
from Frequently Asked Questions: http://www.hhs.gov/ohrp/policy/faq/informed-consent/what-is-legally-effective-informed-consent.html.
---------------------------------------------------------------------------
The ANPRM also considered whether to include on the list of exempt
studies certain types of social and behavioral research conducted with
competent adults that would involve specified types of benign
interventions commonly used in social and behavioral research, that are
known to involve virtually no risk to subjects, and for which prior
review does little to increase protections to subjects. These would be
methodologies that are familiar to people in everyday life and in which
verbal or similar responses would constitute the research data being
collected. For example, an investigator might ask subjects to watch a
video, read a paragraph, or solve puzzles, and then ask them some
questions to elicit word associations or time performance of
activities. The specific methodologies might be spelled out in
regulations, or they might be promulgated via a periodic mechanism to
announce and update lists similar to the list that is published for
activities that may be reviewed by an IRB using the expedited review
procedures.\103\
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\103\ 63 FR 60364 (Nov 9, 1998). Also available at, http://www.hhs.gov/ohrp/policy/expedited98.html.
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A majority of commenters supported the ANPRM discussion on
expanding current exemption category 2 (current Rule at Sec.
__.101(b)(2)) by eliminating the limitations related to the recording
of identifiable information and the harm that could result if a
subject's responses were disclosed. However, many commenters were
opposed to the requirement that subjects be ``competent adults'' in
order for the expanded exemption to apply, asking whether tests of
competency would be required for such research to proceed.
Many commenters also supported adding another exemption category of
research for certain types of social and behavioral activities,
conducted with competent adults, that would involve specified types of
benign interventions beyond educational tests, surveys, focus groups,
interviews, and similar procedures that are commonly used in social and
behavioral research, that are known to involve virtually no risk to
subjects, and for which IRB review does little to increase protections
for subjects.
The ANPRM asked questions about whether the current limitations
specified in exempt category 4 (research involving the use of existing
information or biospecimens, Sec. __.101(b)(4) in the current Rule)
should be eliminated. Specifically, the ANPRM suggested that the
category would be revised to eliminate the word ``existing.'' With this
elimination, the exemption would be broadened to cover the use of
information or biospecimens that were or will be collected for purposes
other than the suggested research, rather than requiring that all of
the information or biospecimens already exist at the time the study is
suggested for exemption.
The ANPRM also discussed whether research involving only the use of
data or biospecimens collected for other purposes, even if the
investigator intends to retain identifiers, should come within a new
exemption category; studies that include a plan to provide individual
research results to subjects would not qualify for this proposed
exemption. In addition, the ANPRM asked whether certain flexible
consent requirements could be imposed on some of these studies that
would permit the use of a broad consent for future use, with a
requirement that a subject's specific consent would be required before
their biospecimens could be used for special categories of research.
Many of the comments supported the discussion in the ANPRM of
eliminating the requirement that the information or biospecimens be
``existing'' at the time the study was suggested for exemption.
However, a majority strongly disagreed that biospecimens should be
considered or treated as though they were inherently identifiable. A
majority also opposed the suggestion that there be consent requirements
for the research use of nonidentifiable biospecimens collected for
purposes other than the current research study.
Some commenters also favored requiring IRB review and approval for
the use of identifiable private information and identifiable
biospecimens, rather than permitting the use of a broad consent for
future use to satisfy the regulatory requirement for consent. These
commenters indicated that IRB review of specific research studies, and
the IRB's consideration of whether a study specific informed consent
should be required or whether informed consent could be waived, was
more protective of human subjects than the ANPRM recommendation of
permitting use of a broad consent for future use.
The ANPRM asked several questions about the interpretation and
applicability of current exemption category 5 (current Rule at
[[Page 54042]]
Sec. __.101(b)(5)), including the scope of the current interpretation
of the category 5 exemption. The ANPRM also asked if the current
category 5 guidance entitled, ``OPRR Guidance on 45 CFR 46.101(b)(5)''
\104\ should be revised, or if additional guidance on the
interpretation of exemption category 5 is needed.
---------------------------------------------------------------------------
\104\ See 48 FR 9266-9270 (Mar 4, 1983). (OPRR Guidance on 45
CFR 46.101(b)(5), Exemption for Research and Demonstration Projects
on Public Benefit and Service Programs, http://www.hhs.gov/ohrp/policy/exmpt-pb.html).
---------------------------------------------------------------------------
There were few responses to these questions. However, those that
did comment noted that this category is often misunderstood by IRBs
and, at best, would benefit from clearer guidance. Commenters said that
examples would help investigators and IRBs understand when research
activities included in demonstration projects constitute human subjects
research subject to the Common Rule. Commenters noted that many
activities in demonstration projects do not contribute to generalizable
knowledge as they produce results that are relevant only to the program
being assessed; as such, many of these activities do not meet the
Common Rule's regulatory definition of ``research'' and thus fall
outside of the rule. Other commenters said that some activities in this
category are mandated or required by law or regulation and should not
be considered to be under the purview of the Common Rule. It was noted
that the critical issue in these studies should be protecting privacy
and as long as measures are in place to do so, additional protections
are not required.
3. Expedited Review
The ANPRM discussed and sought comment on three possible changes to
the review of research through expedited review: (1) Revising the
definition of minimal risk, which is one of the criteria for
determining whether a study is eligible for expedited review; (2)
changing the default position so that research on the expedited review
list could generally be presumed to involve minimal risk; (3) revising
the criteria for approval of research studies under expedited review;
and (4) allowing appropriately trained individuals who are not IRB
members to conduct expedited reviews.
Definition of Minimal Risk: The ANPRM asked for public comment on
whether the current regulatory definition of minimal risk \105\ was
appropriate. The definition of minimal risk has relevance to
determining whether a protocol is eligible for expedited review. Public
comments expressed both a desire to retain the current definition
(slightly less than half) and a desire for changing it (slightly more
than half). There were few common themes in the suggested changes to
the language other than seeking clarification on what baselines an IRB
should consider in determining the meaning of ``daily life'' and
``routine physical or psychological examinations.'' Several commenters
acknowledged the difficulty of arriving at a concise definition for all
circumstances. Those opposed to changing the definition said that IRBs
generally understand how to interpret the language and that difficult
or challenging application of the definition will persist regardless of
the definition for those areas of research where risks are difficult to
assess. Commenters recognized that the risks encountered in daily life
can vary greatly depending on many factors, for example, where people
live, what kind of work they are involved in, what their social and
economic environment is, and their baseline health status. Thus, IRBs
need to consider all of these issues in making a determination about
the level of risk.
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\105\ The current rule states that minimal risk means that the
probability and magnitude of harm or discomfort anticipated in the
research are not greater in and of themselves than those ordinarily
encountered in daily life or during the performance of routine
physical or psychological examinations or tests. (45 CFR 46.102(i)).
---------------------------------------------------------------------------
Eligibility for Expedited Review: The ANPRM suggested updating the
current list of research activities eligible for expedited review; this
list was last updated in 1998. It also considered mandating that a
federal panel periodically (such as every year or every two years)
review and update the list, based on a systematic, empirical assessment
of the levels of risk. This would provide greater clarity about what
would be considered to constitute minimal risk, and create a process
that allows for routinely reassessing and updating the list of research
activities that would qualify as minimal risk. The ANPRM asked for
public comments on categories of research that should be considered for
addition to the current list.
Several commenters provided suggestions for additions to the list
of research activities eligible for expedited review. Others encouraged
OHRP to consider developing principles for expedited review, rather
than creating a revised list of research activities. Commenters
suggested a more timely and consistent review of the list because of
the rapidly changing state of science and technology.
The ANPRM also discussed the potential adoption of a default
presumption in the rule that a study that includes only activities on
the expedited review list is a minimal risk study and should receive
expedited review. A reviewer would have the option of determining that
the study should be reviewed by a convened IRB when that conclusion is
supported by the specific circumstances of the study. The ANPRM also
asked for comments on whether IRBs should be required to report
instances when they overrode the default presumption that research
appearing on the posted list did not warrant review by a convened IRB.
Commenters overwhelmingly welcomed the clarification that
categories of research found on the published list should be presumed
to be minimal risk. However, commenters were largely opposed to
requiring IRBs to report instances when they conducted a review by the
convened membership (versus an expedited review) for studies appearing
on the list. They were opposed because of the additional administrative
burden and also because they felt such a requirement would undermine
the purview of local review and open IRBs up to second-guessing by
OHRP.
Criteria for Approval under Expedited Review: The ANPRM asked
whether all of the Sec. __.111 criteria should still be required for
approval of studies that qualify for expedited review, and if not,
which ones should not be required. Currently, before an IRB may approve
a research study, including research that is being reviewed under an
expedited procedure, the IRB must find that the criteria at Sec.
__.111 have been met.
With regard to revising the criteria used for expedited review,
comments were mixed. Nearly half of those commenting expressed concerns
about establishing two sets of ethical standards for IRB review--one
for convened review and one for expedited review. They asserted ethical
and administrative concerns about operating under two sets of
conditions and principles--that is, expedited review should not be
viewed as less stringent than review conducted by a convened IRB.
Those commenters in favor of retaining the current criteria wrote
that a double standard could result in arbitrary IRB decision making.
In addition, many wrote that the current criteria are well understood
by IRB members and the tendency to review a protocol through a convened
IRB when expedited review would be permissible is more a function of
institutional
[[Page 54043]]
concerns about liability than the regulatory requirements. They cited
the regulatory language at Sec. __.111, which frequently contains the
phrase ``wgeb appropriate,'' so that the reviewer(s) can exercise
discretion in whether all of the criteria need to be applied.
Those in favor of revising the elements most often cited the
irrelevance of some of the criteria for minimal risk research, such as
the need to ensure that risks to subjects are reasonable in relation to
anticipated benefits (Sec. __.111)(a)(2)). They stated that in the
case of minimal risk research, the need to balance risks with benefits
is not pertinent. Some commenters asked OHRP to develop guidance for
the expedited reviewer in interpreting the most relevant criteria
during expedited review.
Several commenters noted that if the revised regulations remove the
requirement for continuing review of studies initially reviewed through
expedited review it would alleviate administrative burden; thus more
extreme measures such as revising the review criteria would be less
compelling.
Who May Conduct Expedited Reviews: The ANPRM asked for public
comment on the advantages and disadvantages of requiring that expedited
review be conducted by an IRB member versus an appropriately trained
individual, such as the manager of the IRB office, who need not be a
member of the IRB.
With regard to allowing a non-IRB member to conduct expedited
review, comments were divided nearly evenly between those who opposed
such a change and those who supported it. Those who opposed it cited
the need for continuity and consistency across IRBs, as well as
expressing concerns about accountability and liability. Those in favor
of such a revision cited the expertise of IRB staff members and their
ability to review many expedited studies at the same level as a member
of the IRB.
4. Streamlining IRB Review
Cooperative Research: The ANPRM sought public comment on the
feasibility, advantages, and disadvantages of mandating that all
domestic (U.S.) sites in a study involving more than one institution
rely on a single IRB for that study. This would apply regardless of
whether the study underwent convened review or expedited review.
Further, it would only affect which IRB would be designated as the
reviewing IRB for institutional compliance with the IRB review
requirements of the Common Rule. It would not relieve any site of its
other obligations under the regulations to protect human subjects. Nor
would it prohibit institutions from choosing, for their own purposes,
to conduct additional internal ethics reviews, though such reviews
would no longer have any regulatory status in terms of compliance with
the Common Rule.
To address institutions' concerns about OHRP's practice of
enforcing compliance with the Common Rule through the institutions that
are engaged in human subjects research, the ANRPM also suggested that
appropriate accompanying changes could be made in enforcement
procedures to hold external IRBs directly accountable for compliance
with certain regulatory requirements.\106\ This change was discussed
only for U.S. sites in multi-institutional studies. The ANPRM suggested
that, in most cases, independent local IRB reviews of international
sites are appropriate because it might be difficult for an IRB in the
U.S. to adequately evaluate local conditions in a foreign country that
could play an important role in the ethical evaluation of the study.
---------------------------------------------------------------------------
\106\ 74 FR 9578 (Mar. 5, 2009). Also available at http://www.hhs.gov/ohrp/newsroom/rfc/com030509.html.
---------------------------------------------------------------------------
This issue attracted a large number of comments, and revealed
nearly evenly divided perspectives. Researchers and disease advocacy
groups tended to favor the single IRB review requirement. IRB and
institutional representatives tended to be opposed to the possible
requirement, though many indicated single IRB review should be
encouraged. Support was especially strong for single IRB review for
cooperative clinical trials for which the evaluation of a study's
social value, scientific validity, and risks and benefits, and the
adequacy of the informed consent form and process generally do not
require the unique perspective of a local IRB. Moreover, depending on
the nature of the study, FDA may not permit differences in protocols
across sites, which further bolstered commenters' views that the
requirements be harmonized across the Common Rule and FDA requirements.
Commenters reported incidences of IRBs continuously second-guessing
each other, which delayed studies to the point that subject recruitment
opportunities were foregone or lost. This problem seemed especially
critical in studies of rare diseases and cancers, which nearly always
involve multiple research sites.
Support for the use of a single IRB, however, was not restricted to
clinical trials. Several commenters cited long delays and burdensome
requirements resulting from multiple reviews of studies in the
behavioral and social sciences. In addition to the view that these
administrative requirements do not enhance protections, supporters of a
single IRB review of cooperative studies cited the frequent need for
maintaining consistency across sites, which can be degraded by multiple
reviews.
Despite support for the ANPRM suggestion, several commenters
expressed concern about making such a provision mandatory, stating that
the current regulations at Sec. __.114 currently permit the use of
joint review arrangements for cooperative research. They noted that
although this option exists, institutions might be hesitant to use it
because of liability concerns and the unwillingness of institutions or
IRBs to rely on the judgment of other institutions or IRBs. However,
several commenters expressed concern about signaling the acceptability
of a single IRB for review while allowing institutions to continue to
conduct their own ethics review, fearing that such a policy would not
correct the current situation, which tends to favor multiple reviews.
Thus, they commented that mandating a single IRB might be the only way
to achieve the goals of streamlining review while ensuring protections.
Another issue raised was the need to set clearer expectations of
the responsibilities of local IRBs that are not designated as the
central IRB. A number of commenters supporting the requirement for a
central IRB also requested that OHRP issue guidance on how to select
the IRB, responsibilities of all parties, and clarifying compliance and
enforcement policies. Several commenters also requested that OHRP
develop a template for reliance agreements to replace inter-
institutional agreements currently in use.
Those who expressed concern about the use of a single IRB said some
studies, especially in the behavioral and social sciences, might
involve significant contextual issues reflecting community norms,
standards, and practices, or local culture and customs. Use of a
distant IRB might not consider and best protect subjects based on
community norms. Others noted that such concerns can be addressed by
investigators or IRBs submitting ``points to consider'' regarding
significant contextual or cultural considerations of relevance to their
site.
A primary issue posed by those opposed to mandating use of a single
IRB in cooperative studies focused on potential loss of accountability
and increased liability for the institutions
[[Page 54044]]
where the research is conducted but where the reviewing IRB is not
located.
Streamlining Documentation Requirements for Expedited Studies:
Under the current Common Rule, investigators typically must submit the
same documents including a detailed protocol, informed consent forms,
and any other supporting documents, regardless of whether the study
will be reviewed by a convened IRB or be approved by the expedited
review process. The ANPRM suggested that although it is important to
document why research qualifies for expedited review, it is unclear
whether the time and effort expended in such preparation activities
result in increased benefit in terms of protecting subjects.
The ANPRM further suggested that standard templates for protocols
and consent forms and sample versions of those documents that are
specifically designed for use in the most common types of studies might
facilitate expedited review. Such forms would need to be carefully
designed to eliminate those elements that are of relevance only in
studies that pose greater than minimal risks and to substantially
reduce the current burden of researchers involved in producing these
documents and of the IRB members who review them. The ANPRM asked
whether there were specific changes that could be made to reduce the
burden imposed on investigators and their staffs in terms of meeting
the requirements to submit documents to an IRB, without decreasing
protections to subjects.
There were few comments on streamlining the document submission
requirements for expedited review, and there was no consensus among
those who did comment about how to achieve that goal.
Continuing Review: The ANPRM asked for public comments on
eliminating continuing review for all minimal risk studies that undergo
expedited review, unless the reviewer explicitly justifies why
continuing review would enhance protection of research subjects.
Additionally, the ANPRM suggested that, for studies initially
reviewed by a convened IRB, continuing review would not be required
after the study reaches the stage where procedures are limited to
either: (1) Analyzing data (even if it is identifiable), or (2)
accessing follow-up clinical data from procedures that subjects would
undergo as part of standard care for their medical condition or disease
(such as periodic CT scans to monitor whether the subjects' cancers
have recurred or progressed) unless specifically mandated by the IRB,.
This would be a change from the current Rules, which require at least
expedited IRB review of the activities described in (1) and (2) above.
The requirement that research involving greater than minimal risk be
reviewed by a convened IRB would not be changed from the current
system.
By eliminating the requirement for continuing review of these
activities, the ANPRM suggested that this change would allow for more
effective use of IRBs' time by enabling the IRB to focus on reviewing
information that is necessary to ensure protection of research
subjects. Requiring annual continuing review of research studies
involving only activities that are already well-documented to generally
involve no more than minimal risk may provide little if any added
protection to subjects, and it may be preferable for IRB resources to
be devoted to research that poses greater than minimal risk.
The ANPRM asked for public comment on whether it would be
appropriate to require IRBs to submit periodic reports to OHRP in the
instances in which they choose to override the default policy of no
continuing review required for the situations described above. The
information, if collected by OHRP, might be useful in developing future
guidance or revising the categories of research eligible for expedited
review.
A large majority of public comments were in favor of the suggested
revisions. Many were comfortable with continuing to allow IRBs or
reviewers the discretion to require continuing review in certain
circumstances, citing the historical position of OHRP in considering
the regulations as the floor, rather than the ceiling, for protecting
the subjects of research. Those who were opposed to the revisions cited
concerns about institutional liability, the possibility for increased
noncompliance among investigators no longer required to ``check in,''
and possible breakdowns in lines of communications between
investigators and IRBs. Others expressed concerns about how an IRB will
know that a study has ended and suggested that investigators be
required to file a notice of closure of a study.
Note that the November 10, 2010, document entitled, ``Guidance on
IRB Continuing Review of Research'' states:
OHRP is aware that many IRBs require investigators to submit
final closeout reports when a research study is completed or no
longer involves human subjects. Since the HHS regulations at 45 CFR
part 46 do not require submission of such reports, institutions are
free to decide whether and when such reports are required and what
their content should include.\107\
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\107\ Office for Human Research Protections. (2010, November
10). Identifying the Point When Continuing Review is no Longer
Necessary. Retrieved from Guidance on IRB Continuing Review of
Research: http://www.hhs.gov/ohrp/policy/continuingreview2010.html#section-k.
Commenters overwhelmingly opposed requiring IRBs to periodically
report on the instances when they (or a reviewer) elect to override the
default position of no continuing review required. The reasons for
opposition included: (1) Additional administrative burden that would
negate the reduced burden gained; (2) the possibility that requiring
such reporting would discourage IRBs/reviewers from making an override
decision; and (3) concerns that such reports would lead to OHRP second-
guessing IRB decisions and imposing compliance oversight in an extra-
regulatory decision. Several commenters suggested that OHRP could use
other means than this requirement for developing guidance and improving
educational efforts regarding expedited and continuing review.
5. Improving Harmonization
The ANPRM did not suggest any specific approaches to harmonization
but asked for public comment on a set of questions focused on: (1) The
extent to which differences in guidance on research protections from
different agencies strengthen or weaken protections for human subjects;
(2) the extent to which differences in guidance on research protections
from different agencies facilitate or inhibit the conduct of research
domestically and internationally; and (3) the desirability of all
Common Rule agencies issuing one set of guidance.
Responses to questions about the need for harmonization across
Common Rule agencies reflected widespread support for such efforts.
Several commenters acknowledged the difficulty of getting all Common
Rule agencies to agree on all issues, as each has a different mission
and research portfolio. However, they encouraged seeking harmonized
guidance whenever possible.
Regulatory Text
For the reasons set forth in the preamble, it is proposed that the
Federal Policy for the Protection of Human Subjects be amended as
follows:
PART __PROTECTION OF HUMAN SUBJECTS
__.101 To what does this policy apply?
__.102 Definitions for purposes of this policy.
[[Page 54045]]
__.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
__.104 Exempt research.
__.105 Protection of biospecimens and identifiable private
information.
__.106 [Reserved]
__.107 IRB membership.
__.108 IRB functions and operations.
__.109 IRB review of research.
__.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
__.111 Criteria for IRB approval of research.
__.112 Review by institution.
__.113 Suspension or termination of IRB approval of research.
__.114 Cooperative research.
__.115 IRB records.
__.116 General requirements for informed consent.
__.117 Documentation of informed consent.
__.118 Applications and proposals lacking definite plans for
involvement of human subjects.
__.119 Research undertaken without the intention of involving human
subjects.
__.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
__.121 [Reserved]
__.122 Use of Federal funds.
__.123 Early termination of research support: Evaluation of
applications and proposals.
__.124 Conditions.
Sec. __.101 To what does this policy apply?
(a) Except as provided in paragraph (b) of this section, and as
detailed in Sec. __.104, this policy applies to the research described
in paragraphs (a)(1) and (2) of this section. The entities that must
comply with this policy are institutions that are engaged in research
described in paragraphs (a)(1) or (2) of this section, and
institutional review boards (IRBs) reviewing research that is subject
to this policy.
(1) All research involving human subjects conducted, supported, or
otherwise subject to regulation by any Federal department or agency
that takes appropriate administrative action to make the policy
applicable to such research. This includes research conducted by
Federal civilian employees or military personnel, except that each
department or agency head may adopt such procedural modifications as
may be appropriate from an administrative standpoint. It also includes
research conducted, supported, or otherwise subject to regulation by
the Federal Government outside the United States.
(2) All clinical trials as defined by this policy, irrespective of
funding source, that meet all of the following conditions:
(i) The clinical trials are conducted by an institution that
receives support from a Federal department or agency for human subjects
research that is not excluded from this policy under Sec. __.101(b)(2)
and does not qualify for exemption in accordance with Sec. __.104;
(ii) The clinical trials are not subject to regulation by the Food
and Drug Administration; and
(iii) The clinical trials are conducted at an institution located
within the United States.\1\
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\1\ Under this provision, only 45 CFR part 46, subpart A,
applies to all clinical trials meeting the applicable conditions.
This provision does not require clinical trials to comply with the
requirements of 45 CFR part 46, subparts B, C, and D.
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(b) The following categories of activities are excluded from this
policy, and no procedural, recordkeeping, or other requirements of this
policy apply to the activities other than the conditions specified for
the relevant category or categories:
(1) The following activities are excluded because they are deemed
not to be research, as defined in Sec. __.102(l), for the purposes of
this regulation:
(i) Data collection and analysis, including the use of
biospecimens, for an institution's own internal operational monitoring
and program improvement purposes, if the data collection and analysis
is limited to the use of data or biospecimens originally collected for
any purpose other than the currently proposed activity, or is obtained
through oral or written communications with individuals (e.g., surveys
or interviews).
(ii) Oral history, journalism, biography, and historical
scholarship activities that focus directly on the specific individuals
about whom the information is collected.
(iii) Collection and analysis of data, biospecimens, or records by
or for a criminal justice agency for activities authorized by law or
court order solely for criminal justice or criminal investigative
purposes.
(iv) Quality assurance or improvement activities involving the
implementation of an accepted practice to improve the delivery or
quality of care or services (including, but not limited to, education,
training, and changing procedures related to care or services) if the
purposes are limited to altering the utilization of the accepted
practice and collecting data or biospecimens to evaluate the effects on
the utilization of the practice. This exclusion does not cover the
evaluation of an accepted practice itself.
(v) Public health surveillance activities, including the collection
and testing of biospecimens, conducted, supported, requested, ordered,
required, or authorized by a public health authority and limited to
those necessary to allow the public health authority to identify,
monitor, assess, or investigate potential public health signals or the
onset of a disease outbreak, including trends, or signals, and patterns
in diseases, or a sudden increase in injuries from using a consumer
product, or conditions of public health importance, from data, and
including those associated with providing timely situational awareness
and priority setting during the course of an event or crisis that
threatens public health, including natural or man-made disasters.
(vi) Surveys, interviews, surveillance activities and related
analyses, or the collection and use of biospecimens conducted by a
defense, national security, or homeland security authority solely for
authorized intelligence, homeland security, defense, or other national
security purposes.
(2) The following activities are excluded because they are
considered to be low-risk human subjects research, when already subject
to independent controls without application of these regulatory
requirements. These exclusions do not apply when the research includes
the collection or analysis of biospecimens. All of the following
exclusion categories apply to research subject to this policy and to
research subject to the additional requirements of 45 CFR part 46,
subparts B, C, and D, however, the exclusion at paragraph (b)(2)(i) of
this section applies only to research subject to subpart D for research
involving educational tests, or observations of public behavior when
the investigator does not participate in the activities being observed.
(i) Research, not including interventions, that involves the use of
educational tests (cognitive, diagnostic, aptitude, achievement),
survey procedures, interview procedures, or observation of public
behavior (including visual or auditory recording) uninfluenced by the
investigators, if at least one of the following criteria is met:
(A) The information is recorded by the investigator in such a
manner that human subjects cannot be identified, directly or through
identifiers linked to the subjects;
(B) Any disclosure of the human subjects' responses outside the
research would not reasonably place the subjects
[[Page 54046]]
at risk of criminal or civil liability or be damaging to the subjects'
financial standing, employability, educational advancement, or
reputation; or
(C) The research will involve a collection of information subject
to the Paperwork Reduction Act of 1995, 44 U.S.C. 3501 et seq.;
research information will be maintained on information technology that
is subject to and in compliance with section 208(b) of the E-Government
Act of 2002, 44 U.S.C. 3501 note; and all of the information collected,
used, or generated as part of the research will be maintained in a
system or systems of records subject to the Privacy Act of 1974, 5
U.S.C. 552a.
(ii) Research involving the collection or study of information that
has been or will be acquired solely for non-research activities or were
acquired for research studies other than the proposed research study,
when either of the following two criteria is met:
(A) These sources are publicly available, or
(B) The information is recorded by the investigator in such a
manner that human subjects cannot be identified, directly or through
identifiers linked to the subjects, the investigator does not contact
the subjects, and the investigator will not re-identify subjects or
otherwise conduct an analysis that could lead to creating identifiable
private information.
(iii) Research conducted by a Federal department or agency using
government-generated or government-collected information obtained for
non-research purposes (including criminal history data), if the
information originally involved a collection of information subject to
the Paperwork Reduction Act of 1995, 44 U.S.C. 3501 et seq.; the
information is maintained on information technology that is subject to
and in compliance with section 208(b) of the E-Government Act of 2002,
44 U.S.C. 3501 note; and all of the information collected, used, or
generated as part of the research is maintained in a system or systems
of records subject to the Privacy Act of 1974, 5 U.S.C. 552a.
(iv) Research as defined by this policy that involves only data
collection and analysis involving the recipient's use of identifiable
health information when such use is regulated under 45 CFR parts 160
and 164, subparts A and E, for the purposes of ``health care
operations'' or ``research'' as those terms are defined at 45 CFR
164.501 or for the purpose of ``public health activities'' as described
under 45 CFR 164.512(b).
(3) The following activities are excluded because they are
considered to be low-risk human subjects research activities that do
not meaningfully diminish subject autonomy. The following exclusion
category applies to research subject to this policy and to research
subject to the additional requirements of 45 CFR part 46, subparts B,
C, or D.
(i) The secondary research use of a non-identified biospecimen that
is designed only to generate information about an individual that
already is known, including but not limited to the development and
validation of certain tests and assays (such as research to develop a
diagnostic test for a condition using specimens from individuals known
to have the condition and those known not to have the condition),
quality assurance and control activities, and proficiency testing.
(ii) [Reserved]
(c) Department or agency heads retain final judgment as to whether
a particular activity is covered by this policy, which judgment shall
be exercised consistent with the ethical principles of the Belmont
Report.\2\
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\2\ The National Commission for the Protection of Human Subjects
of Biomedical and Behavioral Research, The Belmont Report: Ethical
Principles and Guidelines for the Protection of Human Subjects of
Research (Apr. 18, 1979).
---------------------------------------------------------------------------
(d) Department or agency heads may require additional protections
for specific research activities or classes of research activities
conducted, supported, or otherwise subject to regulation by the Federal
department or agency but not otherwise covered by this policy. Advance
public notice will be required when those additional requirements apply
to entities outside of the Federal department or agency itself.
(e) Compliance with this policy requires compliance with pertinent
federal laws or regulations that provide additional protections for
human subjects.
(f) This policy does not affect any state or local laws or
regulations that may otherwise be applicable and that provide
additional protections for human subjects.
(g) This policy does not affect any foreign laws or regulations
that may otherwise be applicable and that provide additional
protections to human subjects of research.
(h) When research covered by this policy takes place in foreign
countries, procedures normally followed in the foreign countries to
protect human subjects may differ from those set forth in this policy.
In these circumstances, if a department or agency head determines that
the procedures prescribed by the institution afford protections that
are at least equivalent to those provided in this policy, the
department or agency head may approve the substitution of the foreign
procedures in lieu of the procedural requirements provided in this
policy. Except when otherwise required by statute, Executive Order, or
the department or agency head, notices of these actions as they occur
will be published in the Federal Register or will be otherwise
published as provided in department or agency procedures.
(i) Unless otherwise required by law, department or agency heads
may waive the applicability of some or all of the provisions of this
policy to specific research activities or classes of research
activities otherwise covered by this policy provided the alternative
procedures to be followed are consistent with the principles of the
Belmont Report.\3\ Except when otherwise required by statute or
Executive Order, the department or agency head shall forward advance
notices of these actions to the Office for Human Research Protections,
Department of Health and Human Services (HHS), or any successor office,
or to the equivalent office within the appropriate Federal department
or agency, and shall also publish them in the Federal Register or in
such other manner as provided in department or agency procedures. The
waiver notice must include a statement that identifies the conditions
under which the waiver will be applied and a justification as to why
the waiver is appropriate for the research, including how the decision
is consistent with the principles in Belmont Report. Each Federal
department or agency conducting or supporting the research must
establish, on a publicly accessible federal Web site, a list of the
research for which a waiver has been issued.
---------------------------------------------------------------------------
\3\ Id.
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(j) Federal guidance on the requirements of this policy shall be
issued only after consultation, for the purpose of harmonization (to
the extent appropriate), with other Federal departments and agencies
that have adopted this policy, unless such consultation is not
feasible.
(k) Transition provisions--(1) Research initiated prior to the
compliance dates. Ongoing human subjects research in which human
subjects (as defined by this policy) were involved prior to the
compliance dates for the cited provisions need not comply with the
additional requirements of this subpart at Sec. Sec. __.101(a)(2),
__.103(e), __.104(c) through (f), __.105, __.108(a)(2), __.109(f)(2),
__.111(a)(7) and (8), __.114, __.115(a)(10) and (11), __.116, and
__.117 that became effective on [effective date of the final rule].
[[Page 54047]]
(2) Use of prior collections of biospecimens. Research involving
the use of prior collections of biospecimens that meets both of the
following criteria need not comply with the requirements of these
regulations:
(i) The biospecimens were collected for either research or non-
research purposes before the compliance date for the additional
requirements of this subpart at Sec. __.102(e)(1)(iii), and
(ii) Research use of the biospecimens occurs only after removal of
any individually identifiable information associated with the
biospecimens.
Sec. __.102 Definitions for purposes of this policy.
(a) Certification means the official notification by the
institution to the supporting Federal department or agency component,
in accordance with the requirements of this policy, that a research
project or activity involving human subjects has been reviewed and
approved by an IRB in accordance with an approved assurance.
(b) Clinical trial means a research study in which one or more
human subjects are prospectively assigned to one or more interventions
(which may include placebo or other control) to evaluate the effects of
the interventions on biomedical or behavioral health-related outcomes.
(c) Department or agency head means the head of any Federal
department or agency, for example, the Secretary, HHS, and any other
officer or employee of any Federal department or agency to whom the
authority provided to the department or agency head by these
regulations has been delegated.
(d) Federal department or agency refers to a Federal department or
agency (the department or agency itself rather than its bureaus,
offices or divisions) that takes appropriate administrative action to
make this policy applicable to the research involving human subjects it
conducts, supports, or otherwise regulates (e.g., HHS, the Department
of Defense, or the Central Intelligence Agency).
(e)(1) Human subject means a living individual about whom an
investigator (whether professional or student) conducting research:
(i) Obtains data through intervention or interaction with the
individual, and uses, studies, or analyzes the data;
(ii) Obtains, uses, studies, analyzes, or generates identifiable
private information; or
(iii) Obtains, uses, studies, or analyzes biospecimens.
(2) Intervention includes both physical procedures by which data
are gathered (e.g., venipuncture) and manipulations of the subject or
the subject's environment that are performed for research purposes.
(3) Interaction includes communication or interpersonal contact
between investigator and subject.
(4) Private information includes information about behavior that
occurs in a context in which an individual can reasonably expect that
no observation or recording is taking place, and information that has
been provided for specific purposes by an individual and that the
individual can reasonably expect will not be shared or made public
(e.g., a medical record or clinically obtained biospecimen).
(5) Identifiable private information is private information that is
individually identifiable (i.e., the identity of the subject is or may
readily be ascertained by the investigator or associated with the
information).
(f) Institution means any public or private entity, or department
or agency (including federal, state, and other agencies).
(g) IRB means an institutional review board established in accord
with and for the purposes expressed in this policy.
(h) IRB approval means the determination of the IRB that the
research has been reviewed and may be conducted at an institution
within the constraints set forth by the IRB and by other institutional
and federal requirements.
(i) Legally authorized representative means an individual or
judicial or other body authorized under applicable law to consent on
behalf of a prospective subject to the subject's participation in the
procedure(s) involved in the research.
(j) Minimal risk means that the probability and magnitude of harm
or discomfort anticipated in the research are not greater in and of
themselves than those ordinarily encountered in daily life or during
the performance of routine physical or psychological examinations or
tests. The Secretary of HHS will maintain guidance that includes a list
of activities considered to involve no more than minimal risk. This
list will be re-evaluated no later than every 8 years based on
recommendations from the Federal departments and agencies and the
public.
(k) Public health authority (consistent with 45 CFR 164.501) means
an agency or authority of the United States, a state, a territory, a
political subdivision of a state or territory, an Indian tribe, or a
foreign government, or a person or entity acting under a grant of
authority from or contract with such public agency, including the
employees or agents of such public agency or its contractors or persons
or entities to whom it has granted authority, that is responsible for
public health matters as part of its official mandate.
(l) Research means a systematic investigation, including research
development, testing, and evaluation, designed to develop or contribute
to generalizable knowledge. Activities that meet this definition
constitute research for purposes of this policy, whether or not they
are conducted or supported under a program that is considered research
for other purposes. For example, some demonstration and service
programs may include research activities.
Sec. __.103 Assuring compliance with this policy--research conducted
or supported by any Federal department or agency.
(a) Each institution engaged in research that is covered by this
policy, with the exception of research excluded from this policy under
Sec. __.101(b) or eligible for exemption under Sec. __.104(d), and
that is conducted or supported by a Federal department or agency shall
provide written assurance satisfactory to the department or agency head
that it will comply with the requirements of this policy. In lieu of
requiring submission of an assurance, individual department or agency
heads shall accept the existence of a current assurance, appropriate
for the research in question, on file with the Office for Human
Research Protections, HHS, or any successor office, and approved for
federalwide use by that office. When the existence of an HHS-approved
assurance is accepted in lieu of requiring submission of an assurance,
reports (except certification) required by this policy to be made to
department and agency heads shall also be made to the Office for Human
Research Protections, HHS, or any successor office. Federal departments
and agencies will conduct or support research covered by this policy
only if the institution has provided an assurance that it will comply
with the requirements of this policy, as provided in this section, and
only if the institution has certified to the department or agency head
that the research has been reviewed and approved by an IRB.
(b) The assurance shall be executed by an individual authorized to
act for the institution and to assume on behalf of the institution the
obligations imposed by this policy and shall be filed in such form and
manner as the department or agency head prescribes.
(c) The department or agency head may limit the period during which
any assurance shall remain effective or
[[Page 54048]]
otherwise condition or restrict the assurance.
(d) Certification is required when the research is supported by a
Federal department or agency and not otherwise excluded under Sec.
__.101(b), waived under Sec. __.101(i), or exempted under Sec.
__.104(d), (e), or (f)(2). Institutions shall certify that each
proposal for research covered by this Sec. __.103 has been reviewed
and approved by the IRB. Such certification must be submitted as
prescribed by the Federal department or agency component supporting the
research. Under no condition shall research covered by this Sec.
__.103 be initiated prior to receipt of the certification that the
research has been reviewed and approved by the IRB.
(e) For non-exempt research involving human subjects covered by
this policy that takes place at an institution in which IRB oversight
is conducted by an IRB that is not operated by the institution, the
institution and the organization operating the IRB shall establish and
follow procedures for documenting the institution's reliance on the IRB
for oversight of the research and the responsibilities that each entity
will undertake to ensure compliance with the requirements of this
policy (e.g., in a written agreement between the institution and the
IRB, or by implementation of an institution-wide policy directive
providing the allocation of responsibilities between the institution
and an IRB that is not affiliated with the institution).
(Approved by the Office of Management and Budget under Control Number.)
Sec. __.104 Exempt research.
(a) Unless otherwise required by department or agency heads,
research activities in which the only involvement of human subjects
will be in one or more of the categories in paragraphs (d) through (f)
of this section are not subject to the requirements of this policy,
other than those specified in the category.
(b) Use of the exemption categories for research subject to the
requirements of subparts B, C, and D. Application of the exemption
categories to research subject to the requirements of 45 CFR part 46,
subparts B, C, and D, is as follows:
(1) Subpart B. Each of the exemptions at this Sec. __.104 may be
applied to research conducted under subpart B if the conditions of the
exemption are met.
(2) Subpart C. The exemptions at this Sec. __.104 do not apply to
research conducted under subpart C, except for research aimed at a
broader population that consists mostly of non-prisoners but that
incidentally includes some number of prisoners.
(3) Subpart D. Only the exemptions at paragraphs (d)(1), (2), (4),
(e)(2), and (f)(1) and (2) of this section may be applied to research
conducted under subpart D if the conditions of the exemption are met.
(c) Federal departments and agencies shall develop a decision tool
to assist in exemption determinations. Unless otherwise required by
law, exemption determinations shall be made by an individual who is
knowledgeable about the exemption categories and who has access to
sufficient information to make an informed and reasonable
determination, or by the investigator or another individual at the
institution who enters accurate information about the proposed research
into the decision tool, which will provide a determination as to
whether the study is exempt. If the decision tool is used, further
assessment or evaluation of the exemption determination is not
required. An institution or, when appropriate, the IRB, must maintain
records of exemption determinations made for research subject to the
requirements of this policy for which the institution or IRB exercises
oversight responsibility. These records must include, at a minimum, the
name of the research study, the name of the investigator, and the
exemption category applied to the research study. Maintenance of the
completed decision tool shall be considered to fulfill this
recordkeeping requirement.
(1) For studies exempted pursuant to paragraph (d)(2) of this
section, the recordkeeping requirement will be deemed satisfied by the
published list required at paragraph (d)(2)(i) of this section.
(2) [Reserved].
(d) The following categories of exempt human subjects research
generally involve a low-risk intervention with human subjects, must be
recorded as required in paragraph (c) of this section, and do not
require application of standards for information and biospecimen
protection provided in Sec. __.105 or informed consent. Only paragraph
(d)(2) of this section allows for the collection and use of
biospecimens:
(1) Research conducted in established or commonly accepted
educational settings when it specifically involves normal educational
practices. This includes most research on regular and special education
instructional strategies, and research on the effectiveness of or the
comparison among instructional techniques, curricula, or classroom
management methods that are not likely to adversely impact students'
opportunity to learn required educational content in that educational
setting or the assessment of educators who provide instruction.
(2) Research and demonstration projects that are conducted or
supported by a Federal department or agency, or otherwise subject to
the approval of department or agency heads, and that are designed to
study, evaluate, or otherwise examine public benefit or service
programs, including procedures for obtaining benefits or services under
those programs, possible changes in or alternatives to those programs
or procedures, or possible changes in methods or levels of payment for
benefits or services under those programs.
(i) Each Federal department or agency conducting or supporting the
research and demonstration projects must establish, on a publicly
accessible federal Web site or in such other manner as the department
or agency head may prescribe, a list of the research and demonstration
projects that the Federal department or agency conducts or supports
under this provision. The research or demonstration project must be
published on this list prior to or upon commencement of the research.
(ii) [Reserved]
(3)(i) Research involving benign interventions in conjunction with
the collection of data from an adult subject through verbal or written
responses (including data entry) or video recording if the subject
prospectively agrees to the intervention and data collection and at
least one of the following criteria is met:
(A) The information obtained is recorded in such a manner that
human subjects cannot be identified directly or through identifiers
linked to the subjects; or
(B) Any disclosure of the human subjects' responses outside the
research would not reasonably place the subjects at risk of criminal or
civil liability or be damaging to the subjects' financial standing,
employability, educational advancement, or reputation.
(ii) For the purpose of this provision, benign interventions are
brief in duration, harmless, painless, not physically invasive, not
likely to have a significant adverse lasting impact on the subjects,
and the investigator has no reason to think the subjects will find the
interventions offensive or embarrassing. If these criteria are met,
such benign interventions might include research activities in which a
subject is asked to read materials, review pictures or videos, play
online games, solve puzzles, or perform cognitive tasks.
[[Page 54049]]
(iii) If the research involves deceiving the subjects regarding the
nature or purposes of the research, this exemption is not applicable
unless the subject authorizes the deception as described in paragraph
(d)(3)(iv) of this section.
(iv) For the purpose of this provision, authorized deception is
prospective agreement by the subject to participate in research where
the subject is informed that he or she will be unaware of or misled
regarding the nature or purposes of the research.
(4) Taste and food quality evaluation and consumer acceptance
studies
(i) If wholesome foods without additives are consumed, or
(ii) If a food is consumed that contains a food ingredient at or
below the level and for a use found to be safe, or agricultural
chemical or environmental contaminant at or below the level found to be
safe, by the Food and Drug Administration or approved by the
Environmental Protection Agency or the Food Safety and Inspection
Service of the U.S. Department of Agriculture.
(e) The following categories of exempt human subjects research
allow for the collection of sensitive information about human subjects,
must not involve biospecimens, must be recorded as required in
paragraph (c) of this section, and require application of standards for
information and biospecimen protection provided in Sec. __.105:
(1) Research, not including interventions, involving the use of
educational tests (cognitive, diagnostic, aptitude, achievement),
survey procedures, interview procedures, or observation of public
behavior (including visual or auditory recording), if the information
obtained is recorded in such a manner that human subjects can be
identified directly or through identifiers linked to the subjects.
(2) Secondary research use of identifiable private information that
has been or will be acquired for non-research purposes, if the
following criteria are met:
(i) Prior notice has been given to the individuals to whom the
identifiable private information pertains that such information may be
used in research; and
(ii) The identifiable private information is used only for purposes
of the specific research for which the investigator or recipient entity
requested access to the information.
(f) The following categories of exempt human subjects research
involve biospecimens or identifiable private information, must be
recorded as required in paragraph (c) of this section, require
application of standards for information and biospecimen protection as
described in Sec. __.105, and require informed consent and limited IRB
review to the extent described in each category or otherwise required
by law:
(1)(i) Storage or maintenance for secondary research use of
biospecimens or identifiable private information that have been or will
be acquired for research studies other than for the proposed research
study, or for non-research purposes, if the following criteria are met:
(A) Written consent for the storage, maintenance, and secondary
research use of the information or biospecimens is obtained in
accordance with Sec. __.116(c) and (d)(2), and the template published
by the Secretary of HHS in accordance with Sec. __.116(d)(1) must be
used. Oral consent, if obtained during the original data collection and
in accordance with Sec. __.116(c) and (d)(3), would be satisfactory
for the research use of identifiable private information initially
acquired in accordance with activities excluded from this policy under
Sec. __.101(b)(2)(i) or exempt from this policy in accordance with
Sec. __.104(d)(3) or (4), or Sec. __.104(e)(1);
(B) The reviewing IRB makes the determinations required by Sec.
__.111(a)(9).
(ii) [Reserved.]
(2)(i) Research involving the use of biospecimens or identifiable
private information that have been stored or maintained for secondary
research use, if consent for the storage, maintenance, and secondary
research use of the information and biospecimens was obtained as
detailed in paragraph (f)(1)(i)(A) of this section.
(ii) If the investigator anticipates that individual research
results will be provided to a research subject, the research may not be
exempted under this provision and must be reviewed by the IRB and
informed consent for the research must be obtained to the extent
required by Sec. __.116(a) and (b).
Sec. __.105 Protection of biospecimens and identifiable private
information.
(a) In General. Institutions and investigators conducting research
that is subject to this policy, or that is exempt from this policy
under Sec. __.104(e) or (f), involving the collection, storage, or use
of biospecimens or identifiable private information, shall implement
and maintain reasonable and appropriate safeguards as specified in
paragraph (b) of this section to protect biospecimens or identifiable
private information that they collect, obtain, receive, maintain, or
transmit for research. The safeguards shall reasonably protect against
anticipated threats or hazards to the security or integrity of the
information or biospecimens, as well as reasonably protect the
information and biospecimens from any intentional or unintentional use,
release, or disclosure that is in violation of paragraph (c) of this
section. IRB review of the safeguards required by this section is not
required, except to the extent required by Sec. __.104(f)(1).
(b) Safeguards requirements. The Secretary of HHS shall establish
and publish for public comment a list of specific measures that the
institution or investigator may implement that will be deemed to
satisfy the requirement for reasonable and appropriate safeguards. The
list will be evaluated as needed, but at least every 8 years, and
amended, as appropriate, after consultation with other Federal
departments and agencies. The institutions and investigators identified
in paragraph (a) of this section shall implement paragraph (a) of this
section by choosing either to apply the safeguards identified by the
Secretary as necessary to protect the security or integrity of and
limit disclosure of biospecimens and electronic and non-electronic
identifiable private information, or to apply safeguards that meet the
standards in 45 CFR 164.308, 164.310, 164.312, and 45 CFR 164.530(c).
For Federal departments and agencies that conduct research activities
that is or will be maintained on information technology that is subject
to and in compliance with section 208(b) of the E-Government Act of
2002, 44 U.S.C. 3501 note, if all of the information collected, used,
or generated as part of the activity will be maintained in systems of
records subject to the Privacy Act of 1974, 5 U.S.C. 552a, and the
research will involve a collection of information subject to the
Paperwork Reduction Act of 1995, 44 U.S.C. 3501 et seq., these research
activities automatically will be considered in compliance with the
Secretary's reasonable and appropriate safeguards standards, unless or
until any additional safeguards are identified by the Secretary of HHS.
(c) Limitations on use, release, and disclosure. Unless otherwise
required by law, institutions and investigators shall use or release
biospecimens or use or disclose identifiable private information
collected or maintained for research only:
(1) For human subjects research regulated by this policy;
(2) For public health purposes;
(3) For any lawful purpose with the consent of the subject; or
[[Page 54050]]
(4) For other research purposes if the institution or investigator
has obtained adequate assurances from the recipient that
(i) The recipient will implement and maintain the level of
safeguards required by paragraph (b) of this section;
(ii) Except for research that qualifies for exclusion under Sec.
__.101(b) or exemption under Sec. __.104 the releasing or disclosing
institution or investigator shall obtain documentation from the
recipient that the research has been approved under Sec. __.111 to the
extent required before releasing biospecimens or disclosing
identifiable private information; and
(iii) The recipient shall not further release the biospecimens or
disclose identifiable private information except for human subjects
research regulated by this policy, or for other purposes permitted by
this paragraph. For the purposes of this requirement, an institution or
investigator shall obtain adequate assurances through the use of a
written agreement with the recipient that the recipient will abide by
these conditions.
(d) The provisions of this section do not amend or repeal, and
shall not be construed to amend or repeal, the requirements of 45 CFR
parts 160 and 164 for the institutions or investigators, including
Federal departments or agencies, to which these regulations are
applicable pursuant to 45 CFR 160.102.
Sec. __.106 [Reserved]
Sec. __.107 IRB membership.
(a) Each IRB shall have at least five members, with varying
backgrounds to promote complete and adequate review of research
activities commonly conducted by the institution. The IRB shall be
sufficiently qualified through the experience and expertise of its
members (professional competence), and the diversity of its members,
including race, gender, and cultural backgrounds and sensitivity to
such issues as community attitudes, to promote respect for its advice
and counsel in safeguarding the rights and welfare of human subjects.
The IRB shall be able to ascertain the acceptability of proposed
research in terms of institutional commitments (including policies and
resources) and regulations, applicable law, and standards of
professional conduct and practice. The IRB shall therefore include
persons knowledgeable in these areas. If an IRB regularly reviews
research that involves a category of subjects that is vulnerable to
coercion or undue influence, such as children, prisoners, pregnant
women, physically or mentally disabled persons, or economically or
educationally disadvantaged persons, consideration shall be given to
the inclusion of one or more individuals who are knowledgeable about
and experienced in working with these categories of subjects.
(b) Each IRB shall include at least one member whose primary
concerns are in scientific areas and at least one member whose primary
concerns are in nonscientific areas.
(c) Each IRB shall include at least one member who is not otherwise
affiliated with the institution and who is not part of the immediate
family of a person who is affiliated with the institution.
(d) No IRB may have a member participate in the IRB's initial or
continuing review of any project in which the member has a conflicting
interest, except to provide information requested by the IRB.
(e) An IRB may, in its discretion, invite individuals with
competence in special areas to assist in the review of issues that
require expertise beyond or in addition to that available on the IRB.
These individuals may not vote with the IRB.
Sec. __.108 IRB functions and operations.
(a) In order to fulfill the requirements of this policy each IRB
shall:
(1) Have access to meeting space and sufficient staff to support
the IRB's review and recordkeeping duties;
(2) Prepare and maintain a current list of the IRB members
identified by name; earned degrees; representative capacity;
indications of experience such as board certifications or licenses
sufficient to describe each member's chief anticipated contributions to
IRB deliberations; and any employment or other relationship between
each member and the institution, for example, full-time employee, part-
time employee, member of governing panel or board, stockholder, paid or
unpaid consultant;
(3) Establish and follow written procedures for:
(i) Conducting its initial and continuing review of research and
for reporting its findings and actions to the investigator and the
institution;
(ii) Determining which projects require review more often than
annually and which projects need verification from sources other than
the investigators that no material changes have occurred since previous
IRB review; and
(iii) Ensuring prompt reporting to the IRB of proposed changes in a
research activity, and for ensuring that such changes in approved
research, during the period for which IRB approval has already been
given, may not be initiated without IRB review and approval except when
necessary to eliminate apparent immediate hazards to the subject.
(4) Establish and follow written procedures for ensuring prompt
reporting to the IRB; appropriate institutional officials; the
department or agency head; and the Office for Human Research
Protections, HHS, or any successor office, or the equivalent office
within the appropriate Federal department or agency of
(i) Any unanticipated problems involving risks to subjects or
others or any serious or continuing noncompliance with this policy or
the requirements or determinations of the IRB; and
(ii) Any suspension or termination of IRB approval.
(b) Except when an expedited review procedure is used (as described
in Sec. __.110), an IRB must review proposed research at convened
meetings at which a majority of the members of the IRB are present,
including at least one member whose primary concerns are in
nonscientific areas. In order for the research to be approved, it shall
receive the approval of a majority of those members present at the
meeting.
Sec. __.109 IRB review of research.
(a) An IRB shall review and have authority to approve, require
modifications in (to secure approval), or disapprove all research
activities covered by this policy that do not qualify for exemption
pursuant to Sec. __.104(d), (e), or (f)(2).
(b) An IRB shall require that information given to subjects as part
of informed consent is in accordance with Sec. __.116. The IRB may
require that information, in addition to that specifically mentioned in
Sec. __.116, be given to the subjects when in the IRB's judgment the
information would meaningfully add to the protection of the rights and
welfare of subjects.
(c) An IRB shall require documentation of informed consent or may
waive documentation in accordance with Sec. __.117.
(d) An IRB shall notify investigators and the institution in
writing of its decision to approve or disapprove the proposed research
activity, or of modifications required to secure IRB approval of the
research activity. If the IRB decides to disapprove a research
activity, it shall include in its written notification a statement of
the reasons for its decision and give the investigator an opportunity
to respond in person or in writing.
(e) An IRB shall conduct continuing review of research requiring
review by
[[Page 54051]]
the convened IRB at intervals appropriate to the degree of risk, not
less than once per year, except as described in Sec. __.109(f).
(f)(1) Unless an IRB determines otherwise, continuing review of
research is not required in the following circumstances:
(i) Research eligible for expedited review in accordance with Sec.
__.110;
(ii) Research that has progressed to the point that it involves
only one or both of the following, which are part of the IRB-approved
study:
(A) Data analysis, including analysis of identifiable private
information, or
(B) Accessing follow-up clinical data from procedures that subjects
would undergo as part of standard care for their medical condition; or
(iii) Research reviewed by the IRB in accordance with the limited
IRB review procedure described in Sec. __.111(a)(9).
(2) The IRB must receive confirmation on an annual basis that the
research is still ongoing and that no changes have been made to the
research that would require the IRB to conduct continuing review of the
research.
(g) An IRB shall have authority to observe or have a third party
observe the consent process and the research.
(Approved by the Office of Management and Budget under Control Number.)
Sec. __.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in approved
research.
(a) The Secretary of HHS, has established, and published as a
Notice in the Federal Register, a list of categories of research that
may be reviewed by the IRB through an expedited review procedure. The
Secretary will evaluate the list at least every 8 years and amend it,
as appropriate, after consultation with other federal departments and
agencies and after publication in the Federal Register for public
comment. A copy of the list is available from the Office for Human
Research Protections, HHS, or any successor office.
(b)(1) An IRB may use the expedited review procedure to review the
following:
(i) Some or all of the research appearing on the list, unless the
reviewer determines that the study involves more than minimal risk;
(ii) Minor changes in previously approved research during the
period for which approval is authorized; or
(iii) Research that is being reviewed to determine whether it
qualifies for exemption in accordance with Sec. __.104(f)(1) in order
to determine that the requirements of Sec. __.111(a)(9) are satisfied.
(2) Under an expedited review procedure, the review may be carried
out by the IRB chairperson or by one or more experienced reviewers
designated by the chairperson from among members of the IRB. In
reviewing the research, the reviewers may exercise all of the
authorities of the IRB except that the reviewers may not disapprove the
research. A research activity may be disapproved only after review in
accordance with the non-expedited procedure set forth in Sec.
__.108(b).
(c) Each IRB that uses an expedited review procedure shall adopt a
method for keeping all members advised of research proposals that have
been approved under the procedure.
(d) The department or agency head may restrict, suspend, terminate,
or choose not to authorize an institution's or IRB's use of the
expedited review procedure.
Sec. __.111 Criteria for IRB approval of research.
(a) In order to approve research covered by this policy the IRB
shall determine that all of the following requirements are satisfied:
(1) Risks to subjects are minimized:
(i) By using procedures that are consistent with sound research
design and that do not unnecessarily expose subjects to risk, and
(ii) Whenever appropriate, by using procedures already being
performed on the subjects for diagnostic or treatment purposes.
(2) Risks to subjects are reasonable in relation to anticipated
benefits, if any, to subjects, and the importance of the knowledge that
may reasonably be expected to result. In evaluating risks and benefits,
the IRB should consider only those risks and benefits that may result
from the research (as distinguished from risks and benefits of
therapies subjects would receive even if not participating in the
research). The IRB should not consider possible long-range effects of
applying knowledge gained in the research (e.g., the possible effects
of the research on public policy) as among those research risks that
fall within the purview of its responsibility.
(3) Selection of subjects is equitable. In making this assessment
the IRB should take into account the purposes of the research and the
setting in which the research will be conducted and should be
particularly cognizant of the special problems of research that
involves a category of subjects who are vulnerable to coercion or undue
influence, such as children, prisoners, pregnant women, physically or
mentally disabled persons, or economically or educationally
disadvantaged persons.
(4) Informed consent will be sought from each prospective subject
or the subject's legally authorized representative, in accordance with,
and to the extent required by, Sec. __.116.
(5) Informed consent will be appropriately documented, in
accordance with, and to the extent required by, Sec. __.117.
(6) When appropriate, the research plan makes adequate provision
for monitoring the data collected to ensure the safety of subjects.
(7) When appropriate, there are adequate provisions to protect the
privacy of subjects and to maintain the confidentiality of data, in
addition to the requirements in Sec. __.105, if the IRB determines
that the standards for information and biospecimen protection in Sec.
__.105 are not sufficient to protect the privacy of subjects and the
confidentiality of data.
(8) If the investigator proposes a research plan for returning
clinically relevant results to subjects, that the plan is appropriate.
(9) For purposes of conducting the limited IRB review as required
by Sec. __.104(f)(1), the IRB need not make the determinations at
paragraphs (a)(1) through (8) of this section, and shall determine that
the following requirements are satisfied:
(i) The procedures for obtaining broad consent for storage,
maintenance, and secondary research use of biospecimens or identifiable
private information will be conducted in accordance with the
requirements of the first paragraph in Sec. __.116.
(ii) If there will be a change for research purposes in the way the
biospecimens or information are stored or maintained, that the privacy
and information protection standards at Sec. __.105 are satisfied for
the creation of any related storage database or repository.
(b) When some or all of the subjects are likely to be vulnerable to
coercion or undue influence, such as children, prisoners, pregnant
women, physically or mentally disabled persons, or economically or
educationally disadvantaged persons, additional safeguards have been
included in the study to protect the rights and welfare of these
subjects.
Sec. __.112 Review by institution.
Research covered by this policy that has been approved by an IRB
may be subject to further appropriate review and approval or
disapproval by officials of the institution. However, those
[[Page 54052]]
officials may not approve the research if it has not been approved by
an IRB.
Sec. __.113 Suspension or termination of IRB approval of research.
An IRB shall have authority to suspend or terminate approval of
research that is not being conducted in accordance with the IRB's
requirements or that has been associated with unexpected serious harm
to subjects. Any suspension or termination of approval shall include a
statement of the reasons for the IRB's action and shall be reported
promptly to the investigator, appropriate institutional officials, and
the department or agency head.
(Approved by the Office of Management and Budget under Control Number.)
Sec. __.114 Cooperative research.
(a) Cooperative research projects are those projects covered by
this policy that involve more than one institution. In the conduct of
cooperative research projects, each institution is responsible for
safeguarding the rights and welfare of human subjects and for complying
with this policy.
(b)(1) Any institution located in the United States that is engaged
in cooperative research must rely upon approval by a single IRB for
that portion of the research that is conducted in the United States.
The reviewing IRB will be selected by the Federal department or agency
supporting or conducting the research or, if there is no funding
agency, by the lead institution conducting the research.
(2) The following research is not subject to the requirements of
this provision:
(i) Cooperative research for which more than single IRB review is
required by law; or
(ii) Research for which the Federal department or agency supporting
or conducting the research determines and documents that the use of a
single IRB is not appropriate for the particular study.
(c) For research not subject to paragraph (b) of this section, an
institution participating in a cooperative project may enter into a
joint review arrangement, rely on the review of another IRB, or make
similar arrangements for avoiding duplication of effort.
Sec. __.115 IRB records.
(a) An institution, or when appropriate an IRB, shall prepare and
maintain adequate documentation of IRB activities, including the
following:
(1) Copies of all research proposals reviewed, scientific
evaluations, if any, that accompany the proposals, approved sample
consent forms, progress reports submitted by investigators, and reports
of injuries to subjects.
(2) Minutes of IRB meetings, which shall be in sufficient detail to
show attendance at the meetings; actions taken by the IRB; the vote on
these actions including the number of members voting for, against, and
abstaining; the basis for requiring changes in or disapproving
research; and a written summary of the discussion of controverted
issues and their resolution.
(3) Records of continuing review activities, including the
rationale for conducting continuing review of research that has
progressed to the point that it involves only one or both of the
following:
(i) Data analysis, including analysis of identifiable private
information, or
(ii) Accessing follow-up clinical data from procedures that
subjects would undergo as part of standard care for their medical
condition.
(4) Copies of all correspondence between the IRB and the
investigators.
(5) A list of IRB members in the same detail as described in Sec.
__.108(a)(2).
(6) Written procedures for the IRB in the same detail as described
in Sec. __.108(a)(3) and (4).
(7) Statements of significant new findings provided to subjects, as
required by Sec. __.116(b)(5).
(8) The rationale for requiring continuing review for research that
otherwise would not require continuing review as described in Sec.
__.109(f)(1).
(9) The rationale for an expedited reviewer's determination that
research appearing on the expedited review list described in Sec.
__.110(b)(1)(i) is more than minimal risk.
(10) The written agreement between an institution and an
organization operating an IRB specifying the responsibilities that each
entity will undertake to ensure compliance with the requirements of
this policy, as described in Sec. __.103(e).
(11) Records relating to exemption determinations, as described in
Sec. __.104(c).
(b) The records required by this policy shall be retained for at
least 3 years, and records relating to research that is conducted shall
be retained for at least 3 years after completion of the research. The
institution or IRB may maintain the records in printed form, or
electronically. All records shall be accessible for inspection and
copying by authorized representatives of the Federal department or
agency at reasonable times and in a reasonable manner.
(c) The institution or IRB retaining the records shall safeguard
identifiable private information contained within these records in
compliance with Sec. __.105.
(Approved by the Office of Management and Budget under Control Number.)
Sec. __.116 General requirements for informed consent.
Except as provided elsewhere in this policy, no investigator may
involve a human subject in research covered by this policy unless the
investigator has obtained the legally effective informed consent of the
subject or the subject's legally authorized representative. An
investigator shall seek such consent only under circumstances that
provide the prospective subject or the representative sufficient
opportunity to consider whether or not to participate and that minimize
the possibility of coercion or undue influence. The information that is
given to the subject or the representative shall be in language
understandable to the subject or the representative. The prospective
subject or the representative must be provided with the information
that a reasonable person would want to have in order to make an
informed decision about whether to participate, and an opportunity to
discuss that information. The information must be presented in
sufficient detail relating to the specific research, and must be
organized and presented in a way that does not merely provide lists of
isolated facts, but rather facilitates the prospective subject's or
representative's understanding of the reasons why one might or might
not want to participate. In obtaining informed consent, the
investigator must present first the information required by this
section, before providing other information, if any, to the subject or
the representative. Any informed consent form must include only the
requirements of informed consent under this section, and appendices
that include any other information provided to the subject or the
representative. If an authorization required by 45 CFR parts 160 and
164 is combined with a consent form, the authorization elements
required by 45 CFR 164.508 must be included in the consent form and not
the appendices. No informed consent, whether oral or written, may
include any exculpatory language through which the subject or the
representative is made to waive or appear to waive any of the subject's
legal rights, or releases or appears to release the investigator, the
sponsor, the institution, or its agents from liability for negligence.
[[Page 54053]]
(a) Basic elements of informed consent. Except as provided in
paragraph (c), (e), or (f) of this section, in seeking informed consent
the following information shall be provided to each subject or the
representative:
(1) A statement that the study involves research, an explanation of
the purposes of the research and the expected duration of the subject's
participation, a description of the procedures to be followed, and
identification of any procedures that are experimental;
(2) A description of any reasonably foreseeable risks or
discomforts to the subject;
(3) A description of any benefits to the subject or to others that
may reasonably be expected from the research;
(4) A disclosure of appropriate alternative procedures or courses
of treatment, if any, that might be advantageous to the subject;
(5) A statement describing the extent, if any, to which
confidentiality of records identifying the subject will be maintained;
(6) For research involving more than minimal risk, an explanation
as to whether any compensation and an explanation as to whether any
medical treatments are available if injury occurs and, if so, what they
consist of, or where further information may be obtained;
(7) An explanation of whom to contact for answers to pertinent
questions about the research and research subjects' rights, and whom to
contact in the event of a research-related injury to the subject;
(8) A statement that participation is voluntary, refusal to
participate will involve no penalty or loss of benefits to which the
subject is otherwise entitled, and the subject may discontinue
participation at any time without penalty or loss of benefits to which
the subject is otherwise entitled; and
(9) One of the following statements about any research that
involves the collection of identifiable private information:
(i) A statement that identifiers might be removed from the data and
the data that is not identifiable could be used for future research
studies or distributed to another investigator for future research
studies without additional informed consent from the subject or the
representative, if this might be a possibility; or
(ii) A statement that the subject's data collected as part of the
research, from which identifiers are removed, will not be used or
distributed for future research studies.
(b) Additional elements of informed consent. Except as provided in
paragraphs (c), (e), or (f) of this section, when appropriate, one or
more of the following elements of information shall also be provided to
each subject or the representative:
(1) A statement that the particular treatment or procedure may
involve risks to the subject (or to the embryo or fetus, if the subject
is or may become pregnant) that are currently unforeseeable;
(2) Anticipated circumstances under which the subject's
participation may be terminated by the investigator without regard to
the subject's or the representative's consent;
(3) Any additional costs to the subject that may result from
participation in the research;
(4) The consequences of a subject's decision to withdraw from the
research and procedures for orderly termination of participation by the
subject;
(5) A statement that significant new findings developed during the
course of the research that may relate to the subject's willingness to
continue participation will be provided to the subject;
(6) The approximate number of subjects involved in the study;
(7) A statement that the subject's biospecimens may be used for
commercial profit and whether the subject will or will not share in
this commercial profit;
(8) A statement regarding whether clinically relevant research
results, including individual research results, will be disclosed to
subjects, and if so, under what conditions; and
(9) An option for the subject or the representative to consent, or
refuse to consent, to investigators re-contacting the subject to seek
additional information or biospecimens or to discuss participation in
another research study.
(c)(1) Elements of informed consent for broad consent to the
storage, maintenance, and secondary research use of biospecimens or
identifiable private information. If the subject or the representative
will be asked to provide broad consent to the storage or maintenance of
biospecimens or identifiable private information, collected for either
research studies other than the proposed research or non-research
purposes, and the secondary research use of this stored material, the
information required in paragraphs (a)(2), (3), (5), and (7) and, if
applicable, (b)(7) through (9) of this section, shall be provided to
each subject, with the following additional information:
(i) A general description of the types of research that may be
conducted with information and biospecimens and the information that is
expected to be generated from the research, the types of information or
biospecimens that might be used in research, and the types of
institutions that might conduct research with the biospecimens or
information;
(ii) A description of the scope of the informed consent must be
provided, including:
(A) A clear description of the types of biospecimens or information
that were or will be collected and the period of time during which
biospecimen or information collection will occur. This may include all
biospecimens and information from the subject's medical record or other
records existing at the institution at the time informed consent is
sought; and
(B) For purposes of paragraph (c)(1)(ii)(A) of this section, the
period of time during which biospecimen or information collection will
occur cannot exceed 10 years from the date of consent. For research
involving children as subjects, that time period cannot exceed 10 years
after parental permission is obtained or until the child reaches the
legal age for consent to the treatments or procedures involved in the
research, whichever time period is shorter. The time limitations
described do not apply to biospecimens or information that initially
will be collected for research purposes.
(iii) A description of the period of time during which an
investigator can continue to conduct research using the subject's
biospecimens and information described in paragraph (c)(1)(ii)(A) of
this section (e.g., a certain number of years, or indefinitely);
(iv) A statement that participation is voluntary, refusal to
participate will involve no penalty or loss of benefits to which the
subject is otherwise entitled, and that the subject may withdraw
consent, if feasible, for research use or distribution of the subject's
information or biospecimens at any time without penalty or loss of
benefits to which the subject is otherwise entitled, and information
about whom to contact in order for the subject to withdraw consent. The
statement must make clear that information or biospecimens that already
have been distributed for research use may not be retrieved;
(v) If applicable, a statement notifying the subject or the
representative that the subject or the representative will not be
informed of the details of any specific research studies that might be
conducted, including the purposes of the research, that will use the
subject's information and biospecimens;
(vi) If applicable, a statement notifying the subject or the
[[Page 54054]]
representative of the expectation that the subject's information and
biospecimens are likely to be used by multiple investigators and
institutions and shared broadly for many types of research studies in
the future, and this information and the biospecimens might be
identifiable when shared;
(vii)The names of the institution or set of institutions at which
the subject's biospecimens or information were or will be collected, to
the extent possible (in recognition that institutions might change
names or cease to exist); and
(viii) If relevant, an option for an adult subject or the
representative to consent, or refuse to consent, to the inclusion of
the subject's data, with removal of the identifiers listed in 45 CFR
164.514(b)(2)(i)(A) through (Q), in a database that is publicly and
openly accessible to anyone. This option must be prominently noted, and
must include a description of risks of public access to the data.
(2) [Reserved]
(d)(1) The Secretary of HHS will establish, and publish in the
Federal Register for public comment, templates for consent that will
contain all of the required elements of informed consent under
paragraph (c) of this section. IRB review of the broad secondary use
informed consent form obtained in accordance with paragraph (c) of this
section is required unless the consent is obtained using only this
template, without any changes.
(2) If Sec. __.104(f)(1) requires written consent, the consent for
research use of biospecimens or identifiable private information must
be documented by the use of a written consent form signed by the
subject or the representative. The template for consent for research
use established by the Secretary may serve as the written consent form.
A copy shall be given to the person signing the form.
(3) If Sec. __.104(f)(1) allows for oral consent, a subject's or
the representative's oral consent for research use of identifiable
private information must be documented such that the consent is
associated with the subject's identifiable private information. If this
requirement is met through the use of written documentation, the
subject or the representative is not required to sign the
documentation.
(4) If the subject or the representative declines to consent to the
research use of biospecimens or identifiable private information, this
must be documented appropriately.
(e)(1) Waiver or alteration of consent in research involving public
benefit and service programs conducted by or subject to the approval of
state or local officials. An IRB may approve a consent procedure that
does not include, or that alters, some or all of the elements of
informed consent set forth above, or waive the above requirement to
obtain informed consent, provided the IRB finds and documents that:
(i) The research or demonstration project is to be conducted by or
subject to the approval of state or local government officials and is
designed to study, evaluate, or otherwise examine:
(A) Public benefit or service programs;
(B) Procedures for obtaining benefits or services under those
programs;
(C) Possible changes in or alternatives to those programs or
procedures; or
(D) Possible changes in methods or levels of payment for benefits
or services under those programs; and
(ii) The research could not practicably be carried out without the
waiver or alteration.
(2) Additional criteria for waiver or alteration of consent for
biospecimens. For research involving the use of biospecimens, an IRB
may approve a consent procedure that does not include, or that alters,
some or all of the elements of informed consent set forth above, or
waive the above requirements to obtain informed consent, provided the
IRB finds and documents the criteria in paragraph (e)(1) of this
section, and the following additional criteria:
(i) There are compelling scientific reasons to conduct the
research; and
(ii) The research could not be conducted with other biospecimens
for which informed consent was obtained or could be obtained.
(3) If an individual was asked to consent to the storage or
maintenance for secondary research use of biospecimens or identifiable
private information in accordance with the requirements of this section
at paragraph (c) of this section, and refused to consent, an IRB cannot
waive consent for either the storage or maintenance for secondary
research use, or for the secondary research use, of those biospecimens
or information.
(f)(1) Waiver or alteration of consent. An IRB may approve a
consent procedure that does not include, or that alters, some or all of
the elements of informed consent set forth above, or waive the above
requirements to obtain informed consent, provided the IRB finds and
documents that:
(i) The research involves no more than minimal risk to the
subjects;
(ii) The research could not practicably be carried out without the
requested waiver or alteration;
(iii) If the research involves accessing or using identifiable
biospecimens or identifiable information, the research could not
practicably be carried out without accessing or using identifiers;
(iv) The waiver or alteration will not adversely affect the rights
and welfare of the subjects; and
(v) Whenever appropriate, the subjects will be provided with
additional pertinent information after participation.
(2) Additional criteria for waiver or alteration of consent for
research involving biospecimens. For research involving the use of
biospecimens, an IRB may approve a consent procedure that does not
include, or that alters, some or all of the elements of informed
consent set forth above, or waive the above requirements to obtain
informed consent, provided the IRB finds and documents the criteria in
paragraph (f)(1) of this section, and the following additional
criteria:
(i) There are compelling scientific reasons for the research use of
the biospecimens; and
(ii) The research could not be conducted with other biospecimens
for which informed consent was obtained or could be obtained.
(3) If an individual was asked to consent to the storage or
maintenance for secondary research use of biospecimens or identifiable
private information, in accordance with the requirements of paragraph
(c) of this section, and refused to consent, an IRB cannot waive
consent for either the storage or maintenance for secondary research
use, or for the secondary research use, of those biospecimens or
information.
(g) An IRB may approve a research proposal in which investigators
obtain, through oral or written communication or by accessing records,
identifiable private information without individuals' informed consent
for the purpose of screening, recruiting, or determining the
eligibility of prospective human subjects of research, provided that
the research proposal includes an assurance that the investigator will
implement standards for protecting the information obtained, in
accordance with and to the extent required by Sec. __.105.
(h)(1) A copy of the final version of the informed consent form for
each clinical trial conducted or supported by a Federal department or
agency must be posted by the awardee or the Federal department or
agency component conducting the trial on a publicly available federal
Web site that will be established as a repository for such informed
consent forms . The informed consent form must be posted in such form
and manner as the department or agency head may prescribe, which will
[[Page 54055]]
include at a minimum posting, in addition to the informed consent form,
the name of the clinical trial and information about whom to contact
for additional details about the clinical trial.
(2) The informed consent form must be posted on the federal Web
site within 60 days after the trial is closed to recruitment.
(i) The informed consent requirements in this policy are not
intended to preempt any applicable Federal, state, or local laws that
require additional information to be disclosed in order for informed
consent to be legally effective.
(j) Nothing in this policy is intended to limit the authority of a
physician to provide emergency medical care, to the extent the
physician is permitted to do so under applicable federal, state, or
local law.
(Approved by the Office of Management and Budget under Control Number.)
Sec. __.117 Documentation of informed consent.
(a) Except as provided in paragraph (c) of this section, and except
for research for which consent is obtained in accordance with Sec.
__.116(c), informed consent shall be documented by the use of a written
informed consent form approved by the IRB and signed by the subject or
the subject's legally authorized representative. A copy shall be given
to the person signing the informed consent form.
(b) Except as provided in paragraph (c) of this section, the
informed consent form may be either of the following:
(1) A written informed consent form that includes a form containing
only the information required by Sec. __.116, and appendices that
include any other information. The investigator shall give either the
subject or the subject's legally authorized representative adequate
opportunity to read the informed consent form before it is signed;
alternatively, this form may be read to the subject or the subject's
legally authorized representative.
(2) A short form written informed consent form stating that the
elements of informed consent required by Sec. __.116 have been
presented orally to the subject or the subject's legally authorized
representative, and that the information required by Sec. __.116 was
presented first to the subject, before other information, if any, was
provided. The IRB shall approve a written summary of what is to be said
to the subject or the representative. When this method is used, there
shall be a witness to the oral presentation. Only the short form itself
is to be signed by the subject or the representative. However, the
witness shall sign both the short form and a copy of the summary, and
the person actually obtaining consent shall sign a copy of the summary.
A copy of the summary shall be given to the subject or the
representative, in addition to a copy of the short form.
(c)(1) An IRB may waive the requirement for the investigator to
obtain a signed informed consent form for some or all subjects if it
finds any of the following:
(i) That the only record linking the subject and the research would
be the informed consent form and the principal risk would be potential
harm resulting from a breach of confidentiality. Each subject will be
asked whether the subject wants documentation linking the subject with
the research, and the subject's wishes will govern;
(ii) That the research presents no more than minimal risk of harm
to subjects and involves no procedures for which written consent is
normally required outside of the research context; or
(iii) If the subjects are members of a distinct cultural group or
community in which signing forms is not the norm, that the research
presents no more than minimal risk of harm to subjects and provided
there is an appropriate alternative mechanism for documenting that
informed consent was obtained. Documentation must include a description
as to why signing forms is not the norm for the distinct cultural group
or community.
(2) In cases in which the documentation requirement is waived, the
IRB may require the investigator to provide subjects with a written
statement regarding the research.
(3) This waiver does not apply to research for which consent is
required to be documented in accordance with Sec. __.116(d)(2), (3),
or (4).
(4) Documentation of informed consent may not be waived under
paragraphs (c)(1)(i) or (iii) of this section for research subject to
regulation by the Food and Drug Administration unless otherwise
authorized by 21 CFR 56.109(c)(1).
(Approved by the Office of Management and Budget under Control Number.)
Sec. __.118 Applications and proposals lacking definite plans for
involvement of human subjects.
Certain types of applications for grants, cooperative agreements,
or contracts are submitted to Federal departments or agencies with the
knowledge that subjects may be involved within the period of support,
but definite plans would not normally be set forth in the application
or proposal. These include activities such as institutional type grants
when selection of specific projects is the institution's
responsibility; research training grants in which the activities
involving subjects remain to be selected; and projects in which human
subjects' involvement will depend upon completion of instruments, prior
animal studies, or purification of compounds. Except for research
excluded under Sec. __.101(b), waived under Sec. __.101(i), or
exempted under Sec. __.104(d), (e), or (f)(2), no human subjects may
be involved in any project supported by these awards until the project
has been reviewed and approved by the IRB, as provided in this policy,
and certification submitted, by the institution, to the Federal
department or agency component supporting the research.
Sec. __.119 Research undertaken without the intention of involving
human subjects.
Except for research excluded under Sec. __.101(b), waived under
Sec. __.101(i), or exempted under Sec. __.104(d), (e), or (f)(2), in
the event research is undertaken without the intention of involving
human subjects, but it is later proposed to involve human subjects in
the research, the research shall first be reviewed and approved by an
IRB, as provided in this policy, a certification submitted by the
institution to the Federal department or agency component supporting
the research, and final approval given to the proposed change by the
Federal department or agency component.
Sec. __.120 Evaluation and disposition of applications and proposals
for research to be conducted or supported by a Federal department or
agency.
(a) The department or agency head will evaluate all applications
and proposals involving human subjects submitted to the Federal
department or agency through such officers and employees of the Federal
department or agency and such experts and consultants as the department
or agency head determines to be appropriate. This evaluation will take
into consideration the risks to the subjects, the adequacy of
protection against these risks, the potential benefits of the research
to the subjects and others, and the importance of the knowledge gained
or to be gained.
(b) On the basis of this evaluation, the department or agency head
may approve or disapprove the application or proposal, or enter into
negotiations to develop an approvable one.
[[Page 54056]]
Sec. __.121 [Reserved]
Sec. __.122 Use of Federal funds.
Federal funds administered by a Federal department or agency may
not be expended for research involving human subjects unless the
requirements of this policy have been satisfied.
Sec. __.123 Early termination of research support: Evaluation of
applications and proposals.
(a) The department or agency head may require that Federal
department or agency support for any project be terminated or suspended
in the manner prescribed in applicable program requirements, when the
department or agency head finds an institution has materially failed to
comply with the terms of this policy.
(b) In making decisions about supporting or approving applications
or proposals covered by this policy the department or agency head may
take into account, in addition to all other eligibility requirements
and program criteria, factors such as whether the applicant has been
subject to a termination or suspension under paragraph (a) of this
section and whether the applicant or the person or persons who would
direct or has/have directed the scientific and technical aspects of an
activity has/have, in the judgment of the department or agency head,
materially failed to discharge responsibility for the protection of the
rights and welfare of human subjects (whether or not the research was
subject to federal regulation).
Sec. __.124 Conditions.
With respect to any research project or any class of research
projects the department or agency head of either the conducting or the
supporting Federal department or agency may impose additional
conditions prior to or at the time of approval when in the judgment of
the department or agency head additional conditions are necessary for
the protection of human subjects.
DEPARTMENT OF HOMELAND SECURITY
6 CFR Part 46
List of Subjects in 6 CFR Part 46
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of Homeland
Security proposes to add 6 CFR part 46, as set forth at the end of the
common preamble of this document.
PART 46--PROTECTION OF HUMAN SUBJECTS
Sec.
46.101 To what does this policy apply?
46.102 Definitions for purposes of this policy.
46.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
46.104 Exempt research.
46.105 Protection of biospecimens and identifiable private
information.
46.106 [Reserved]
46.107 IRB membership.
46.108 IRB functions and operations.
46.109 IRB review of research.
46.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
46.111 Criteria for IRB approval of research.
46.112 Review by institution.
46.113 Suspension or termination of IRB approval of research.
46.114 Cooperative research.
46.115 IRB records.
46.116 General requirements for informed consent.
46.117 Documentation of informed consent.
46.118 Applications and proposals lacking definite plans for
involvement of human subjects.
46.119 Research undertaken without the intention of involving human
subjects.
46.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
46.121 [Reserved]
46.122 Use of Federal funds.
46.123 Early termination of research support: Evaluation of
applications and proposals.
46.124 Conditions.
Authority: 5 U.S.C. 301; Pub. L. 107-296, sec. 102, 306(c); Pub.
L. 108-458, sec. 8306.
Reginald Brothers,
Under Secretary for Science and Technology, DHS.
DEPARTMENT OF AGRICULTURE
7 CFR Part 1c
List of Subjects in 7 CFR Part 1c
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of
Agriculture proposes to revise 7 CFR part 1c, as set forth at the end
of the common preamble of this document.
PART 1c--PROTECTION OF HUMAN SUBJECTS
Sec.
1c.101 To what does this policy apply?
1c.102 Definitions for purposes of this policy.
1c.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
1c.104 Exempt research.
1c.105 Protection of biospecimens and identifiable private
information.
1c.106 [Reserved]
1c.107 IRB membership.
1c.108 IRB functions and operations.
1c.109 IRB review of research.
1c.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
1c.111 Criteria for IRB approval of research.
1c.112 Review by institution.
1c.113 Suspension or termination of IRB approval of research.
1c.114 Cooperative research.
1c.115 IRB records.
1c.116 General requirements for informed consent.
1c.117 Documentation of informed consent.
1c.118 Applications and proposals lacking definite plans for
involvement of human subjects.
1c.119 Research undertaken without the intention of involving human
subjects.
1c.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
1c.121 [Reserved]
1c.122 Use of Federal funds.
1c.123 Early termination of research support: Evaluation of
applications and proposals.
1c.124 Conditions.
Authority: 5 U.S.C. 301.
Catherine Woteki
Under Secretary for Research, Education, and Economics, USDA.
DEPARTMENT OF ENERGY
10 CFR Part 745
List of Subjects in 10 CFR Part 745
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of Energy
proposes to revise 10 CFR part 745, as set forth at the end of the
common preamble of this document.
PART 745--PROTECTION OF HUMAN SUBJECTS
Sec.
745.101 To what does this policy apply?
745.102 Definitions for purposes of this policy.
745.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
745.104 Exempt research.
745.105 Protection of biospecimens and identifiable private
information.
745.106 [Reserved]
745.107 IRB membership.
745.108 IRB functions and operations.
745.109 IRB review of research.
745.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
[[Page 54057]]
745.111 Criteria for IRB approval of research.
745.112 Review by institution.
745.113 Suspension or termination of IRB approval of research.
745114 Cooperative research.
745.115 IRB records.
745.116 General requirements for informed consent.
745.117 Documentation of informed consent.
745.118 Applications and proposals lacking definite plans for
involvement of human subjects.
745.119 Research undertaken without the intention of involving human
subjects.
745.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
745.121 [Reserved]
745.122 Use of Federal funds.
745.123 Early termination of research support: Evaluation of
applications and proposals.
745.124 Conditions.
Authority: 5 U.S.C. 301; 42 U.S.C. 7254.
Elizabeth Sherwood-Randall,
Deputy Secretary of Energy.
NATIONAL AERONAUTICS AND SPACE ADMINISTRATION
14 CFR Part 1230
List of Subjects in 14 CFR Part 1230
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the National Aeronautics
and Space Administration proposes to revise 14 CFR part 1230, as set
forth at the end of the common preamble of this document.
PART 1230--PROTECTION OF HUMAN SUBJECTS
Sec.
1230.101 To what does this policy apply?
1230.102 Definitions for purposes of this policy.
1230.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
1230.104 Exempt research.
1230.105 Protection of biospecimens and identifiable private
information.
1230.106 [Reserved]
1230.107 IRB membership.
1230.108 IRB functions and operations.
1230.109 IRB review of research.
1230.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
1230.111 Criteria for IRB approval of research.
1230.112 Review by institution.
1230.113 Suspension or termination of IRB approval of research.
1230.114 Cooperative research.
1230.115 IRB records.
1230.116 General requirements for informed consent.
1230.117 Documentation of informed consent.
1230.118 Applications and proposals lacking definite plans for
involvement of human subjects.
1230.119 Research undertaken without the intention of involving
human subjects.
1230.120 Evaluation and disposition of applications and proposals
for research to be conducted or supported by a Federal department or
agency.
1230.121 [Reserved]
1230.122 Use of Federal funds.
1230.123 Early termination of research support: Evaluation of
applications and proposals.
1230.124 Conditions.
Authority: 5 U.S.C. 301.
Richard S. Williams,
Chief Health and Medical Officer.
DEPARTMENT OF COMMERCE
15 CFR Part 27
List of Subjects in 15 CFR Part 27
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of Commerce
proposes to revise 15 CFR part 27, as set forth at the end of the
common preamble of this document.
PART 27--PROTECTION OF HUMAN SUBJECTS
Sec.
27.101 To what does this policy apply?
27.102 Definitions for purposes of this policy.
27.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
27.104 Exempt research.
27.105 Protection of biospecimens and identifiable private
information.
27.106 [Reserved]
27.107 IRB membership.
27.108 IRB functions and operations.
27.109 IRB review of research.
27.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
27.111 Criteria for IRB approval of research.
27.112 Review by institution.
27.113 Suspension or termination of IRB approval of research.
27.114 Cooperative research.
27.115 IRB records.
27.116 General requirements for informed consent.
27.117 Documentation of informed consent.
27.118 Applications and proposals lacking definite plans for
involvement of human subjects.
27.119 Research undertaken without the intention of involving human
subjects.
27.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
27.121 [Reserved]
27.122 Use of Federal funds.
27.123 Early termination of research support: Evaluation of
applications and proposals.
27.124 Conditions.
Authority: 5 U.S.C. 301.
James Hock,
Chief of Staff, Department of Commerce.
SOCIAL SECURITY ADMINISTRATION
20 CFR Part 431
List of Subjects in 20 CFR Part 431
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Social Security
Administration proposes to add 20 CFR part 431, as set forth at the end
of the common preamble of this document.
PART 431--PROTECTION OF HUMAN SUBJECTS
Sec.
431.101 To what does this policy apply?
431.102 Definitions for purposes of this policy.
431.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
431.104 Exempt research.
431.105 Protection of biospecimens and identifiable private
information.
431.106 [Reserved]
431.107 IRB membership.
431.108 IRB functions and operations.
431.109 IRB review of research.
431.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
431.111 Criteria for IRB approval of research.
431.112 Review by institution.
431.113 Suspension or termination of IRB approval of research.
431.114 Cooperative research.
431.115 IRB records.
431.116 General requirements for informed consent.
431.117 Documentation of informed consent.
431.118 Applications and proposals lacking definite plans for
involvement of human subjects.
431.119 Research undertaken without the intention of involving human
subjects.
431.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
431.121 [Reserved]
431.122 Use of Federal funds.
431.123 Early termination of research support: Evaluation of
applications and proposals.
431.124 Conditions.
[[Page 54058]]
Authority: 5 U.S.C. 301; 42 U.S.C. 289(a).
Carolyn W. Colvin,
Acting Commissioner of Social Security.
AGENCY FOR INTERNATIONAL DEVELOPMENT
22 CFR Part 225
List of Subjects in 22 CFR Part 225
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Agency for
International Development proposes to revise 22 CFR part 225, as set
forth at the end of the common preamble of this document.
PART 225--PROTECTION OF HUMAN SUBJECTS
Sec.
225.101 To what does this policy apply?
225.102 Definitions for purposes of this policy.
225.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
225.104 Exempt research.
225.105 Protection of biospecimens and identifiable private
information.
225.106 [Reserved]
225.107 IRB membership.
225.108 IRB functions and operations.
225.109 IRB review of research.
225.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
225.111 Criteria for IRB approval of research.
225.112 Review by institution.
225.113 Suspension or termination of IRB approval of research.
225.114 Cooperative research.
225.115 IRB records.
225.116 General requirements for informed consent.
225.117 Documentation of informed consent.
225.118 Applications and proposals lacking definite plans for
involvement of human subjects.
225.119 Research undertaken without the intention of involving human
subjects.
225.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
225.121 [Reserved]
225.122 Use of Federal funds.
225.123 Early termination of research support: Evaluation of
applications and proposals.
225.124 Conditions.
Authority: 5 U.S.C. 301.
Wade Warren,
Senior Deputy Assistant Administrator for Global Health, U.S. Agency
for International Development.
DEPARTMENT OF JUSTICE
28 CFR Part 46
AG Order No. 3553-2015
List of Subjects in 28 CFR Part 46
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of Justice
proposes to revise 28 CFR part 46, as set forth at the end of the
common preamble of this document.
PART 46--PROTECTION OF HUMAN SUBJECTS
Sec.
46.101 To what does this policy apply?
46.102 Definitions for purposes of this policy.
46.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
46.104 Exempt research.
46.105 Protection of biospecimens and identifiable private
information.
46.106 [Reserved]
46.107 IRB membership.
46.108 IRB functions and operations.
46.109 IRB review of research.
46.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
46.111 Criteria for IRB approval of research.
46.112 Review by institution.
46.113 Suspension or termination of IRB approval of research.
46.114 Cooperative research.
46.115 IRB records.
46.116 General requirements for informed consent.
46.117 Documentation of informed consent.
46.118 Applications and proposals lacking definite plans for
involvement of human subjects.
46.119 Research undertaken without the intention of involving human
subjects.
46.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
46.121 [Reserved]
46.122 Use of Federal funds.
46.123 Early termination of research support: Evaluation of
applications and proposals.
46.124 Conditions.
Authority: 5 U.S.C. 301; 28 U.S.C. 509-510.
Sally Quillian Yates,
Deputy Attorney General.
DEPARTMENT OF LABOR
29 CFR Part 21
List of Subjects in 29 CFR Part 21
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Social Security
Administration proposes to add 29 CFR part 21, as set forth at the end
of the common preamble of this document.
PART 21--PROTECTION OF HUMAN SUBJECTS
Sec.
21.101 To what does this policy apply?
21.102 Definitions for purposes of this policy.
21.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
21.104 Exempt research.
21.105 Protection of biospecimens and identifiable private
information.
21.106 [Reserved]
21.107 IRB membership.
21.108 IRB functions and operations.
21.109 IRB review of research.
21.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
21.111 Criteria for IRB approval of research.
21.112 Review by institution.
21.113 Suspension or termination of IRB approval of research.
21.114 Cooperative research.
21.115 IRB records.
21.116 General requirements for informed consent.
21.117 Documentation of informed consent.
21.118 Applications and proposals lacking definite plans for
involvement of human subjects.
21.119 Research undertaken without the intention of involving human
subjects.
21.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
21.121 [Reserved]
21.122 Use of Federal funds.
21.123 Early termination of research support: Evaluation of
applications and proposals.
21.124 Conditions.
[[Page 54059]]
Authority: 5 U.S.C. 301; 29 U.S.C. 551.
Christopher P. Lu,
Deputy Secretary of Labor.
DEPARTMENT OF DEFENSE
32 CFR Part 219
List of Subjects in 32 CFR Part 219
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of Defense
proposes to revise 32 CFR part 219, as set forth at the end of the
common preamble of this document.
PART 219--PROTECTION OF HUMAN SUBJECTS
Sec.
219.101 To what does this policy apply?
219.102 Definitions for purposes of this policy.
219.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
219.104 Exempt research.
219.105 Protection of biospecimens and identifiable private
information.
219.106 [Reserved]
219.107 IRB membership.
219.108 IRB functions and operations.
219.109 IRB review of research.
219.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
219.111 Criteria for IRB approval of research.
219.112 Review by institution.
219.113 Suspension or termination of IRB approval of research.
219.114 Cooperative research.
219.115 IRB records.
219.116 General requirements for informed consent.
219.117 Documentation of informed consent.
219.118 Applications and proposals lacking definite plans for
involvement of human subjects.
219.119 Research undertaken without the intention of involving human
subjects.
219.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
219.121 [Reserved]
219.122 Use of Federal funds.
219.123 Early termination of research support: Evaluation of
applications and proposals.
219.124 Conditions.
Authority: 5 U.S.C. 301.
Patricia L. Toppings,
OSD Federal Register Liaison, Officer, Department of Defense.
DEPARTMENT OF EDUCATION
34 CFR Part 97
List of Subjects in 34 CFR Part 97
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of Education
proposes to amend 34 CFR part 97 as follows:
PART 97--PROTECTION OF HUMAN SUBJECTS
0
1. The authority citation for part 97 continues to read as follows:
Authority: 5 U.S.C. 301; 20 U.S.C. 1221e-3, 3474.
0
2. Subpart A is revised as set forth at the end of the common preamble
of this document.
Subpart A--Federal Policy for the Protection of Human Subjects
(Basic ED Policy for Protection of Human Research Subjects)
Sec.
97.101 To what does this policy apply?
97.102 Definitions for purposes of this policy.
97.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
97.104 Exempt research.
97.105 Protection of biospecimens and identifiable private
information.
97.106 [Reserved]
97.107 IRB membership.
97.108 IRB functions and operations.
97.109 IRB review of research.
97.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
97.111 Criteria for IRB approval of research.
97.112 Review by institution.
97.113 Suspension or termination of IRB approval of research.
97.114 Cooperative research.
97.115 IRB records.
97.116 General requirements for informed consent.
97.117 Documentation of informed consent.
97.118 Applications and proposals lacking definite plans for
involvement of human subjects.
97.119 Research undertaken without the intention of involving human
subjects.
97.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
97.121 [Reserved]
97.122 Use of Federal funds.
97.123 Early termination of research support: Evaluation of
applications and proposals.
97.124 Conditions.
Arne Duncan,
Secretary of Education.
DEPARTMENT OF VETERANS AFFAIRS
38 CFR Part 16
List of Subjects in 38 CFR Part 16
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of Veterans
Affairs proposes to revise 38 CFR part 16, as set forth at the end of
the common preamble of this document.
PART 16--PROTECTION OF HUMAN SUBJECTS
Sec.
16.101 To what does this policy apply?
16.102 Definitions for purposes of this policy.
16.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
16.104 Exempt research.
16.105 Protection of biospecimens and identifiable private
information.
16.106 [Reserved]
16.107 IRB membership.
16.108 IRB functions and operations.
16.109 IRB review of research.
16.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
16.111 Criteria for IRB approval of research.
16.112 Review by institution.
16.113 Suspension or termination of IRB approval of research.
16.114 Cooperative research.
16.115 IRB records.
16.116 General requirements for informed consent.
16.117 Documentation of informed consent.
16.118 Applications and proposals lacking definite plans for
involvement of human subjects.
16.119 Research undertaken without the intention of involving human
subjects.
16.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
16.121 [Reserved]
16.122 Use of Federal funds.
16.123 Early termination of research support: Evaluation of
applications and proposals.
16.124 Conditions.
[[Page 54060]]
Authority: 5 U.S.C. 301; 38 U.S.C. 501, 7331, 7334.
Robert L. Nabors II,
Chief of Staff, U.S. Department of Veterans Affairs,
ENVIRONMENTAL PROTECTION AGENCY
40 CFR Part 26
List of Subjects in 40 CFR Part 26
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Environmental
Protection Agency proposes to amend 40 CFR part 26 as follows:
PART 26--PROTECTION OF HUMAN SUBJECTS
0
1. The authority citation for part 26 continues to read as follows:
Authority: 5 U.S.C. 301; 7 U.S.C. 136a(a) and 136w(a)(1); 21
U.S.C. 346a(e)(1)(C); sec. 201, Pub. L. 109-54, 119 Stat. 531.
0
2. Subpart A is revised as set forth at the end of the common preamble
of this document.
Subpart A--Basic EPA Policy for Protection of Subjects in Human
Research Conducted or Supported by EPA
Sec.
26.101 To what does this policy apply?
26.102 Definitions for purposes of this policy.
26.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
26.104 Exempt research.
26.105 Protection of biospecimens and identifiable private
information.
26.106 [Reserved]
26.107 IRB membership.
26.108 IRB functions and operations.
26.109 IRB review of research.
26.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
26.111 Criteria for IRB approval of research.
26.112 Review by institution.
26.113 Suspension or termination of IRB approval of research.
26.114 Cooperative research.
26.115 IRB records.
26.116 General requirements for informed consent.
26.117 Documentation of informed consent.
26.118 Applications and proposals lacking definite plans for
involvement of human subjects.
26.119 Research undertaken without the intention of involving human
subjects.
26.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
26.121 [Reserved]
26.122 Use of Federal funds.
26.123 Early termination of research support: Evaluation of
applications and proposals.
26.124 Conditions.
A. Stanley Meiburg,
Acting Deputy Administrator.
DEPARTMENT OF HEALTH AND HUMAN SERVICES
45 CFR Part 46
List of Subjects in 45 CFR Part 46
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of Health
and Human Services proposes to amend 45 CFR part 46 as follows:
PART 46--PROTECTION OF HUMAN SUBJECTS
0
1. The authority citation for part 46 is revised to read as follows:
Authority: 5 U.S.C. 301; 42 U.S.C. 289.
0
2. Subpart A is revised as set forth at the end of the common preamble
of this document.
Subpart A--Basic HHS Policy for Protection of Human Research
Subjects
Sec.
46.101 To what does this policy apply?
46.102 Definitions for purposes of this policy.
46.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
46.104 Exempt research.
46.105 Protection of biospecimens and identifiable private
information.
46.106 [Reserved]
46.107 IRB membership.
46.108 IRB functions and operations.
46.109 IRB review of research.
46.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
46.111 Criteria for IRB approval of research.
46.112 Review by institution.
46.113 Suspension or termination of IRB approval of research.
46.114 Cooperative research.
46.115 IRB records.
46.116 General requirements for informed consent.
46.117 Documentation of informed consent.
46.118 Applications and proposals lacking definite plans for
involvement of human subjects.
46.119 Research undertaken without the intention of involving human
subjects.
46.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
46.121 [Reserved]
46.122 Use of Federal funds.
46.123 Early termination of research support: Evaluation of
applications and proposals.
46.124 Conditions.
Sylvia M. Burwell,
Secretary, HHS.
NATIONAL SCIENCE FOUNDATION
45 CFR Part 690
List of Subjects in 45 CFR Part 690
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the National Science
Foundation proposes to revise 45 CFR part 690, as set forth at the end
of the common preamble of this document.
PART 690--PROTECTION OF HUMAN SUBJECTS
Sec.
690.101 To what does this policy apply?
690.102 Definitions for purposes of this policy.
690.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
690.104 Exempt research.
690.105 Protection of biospecimens and identifiable private
information.
690.106 [Reserved]
690.107 IRB membership.
690.108 IRB functions and operations.
690.109 IRB review of research.
690.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
690.111 Criteria for IRB approval of research.
690.112 Review by institution.
690.113 Suspension or termination of IRB approval of research.
690.114 Cooperative research.
690.115 IRB records.
690.116 General requirements for informed consent.
690.117 Documentation of informed consent.
690.118 Applications and proposals lacking definite plans for
involvement of human subjects.
690.119 Research undertaken without the intention of involving human
subjects.
690.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
690.121 [Reserved]
690.122 Use of Federal funds.
690.123 Early termination of research support: Evaluation of
applications and proposals.
690.124 Conditions.
[[Page 54061]]
Authority: 5 U.S.C. 301.
Lawrence Rudolph,
General Counsel.
DEPARTMENT OF TRANSPORTATION
49 CFR Part 11
List of Subjects in 49 CFR Part 11
Human research subjects, Reporting and record-keeping requirements,
Research.
For the reasons stated in the preamble, the Department of
Transportation proposes to revise 49 CFR part 11, as set forth at the
end of the common preamble of this document.
PART 11--PROTECTION OF HUMAN SUBJECTS
Sec.
11.101 To what does this policy apply?
11.102 Definitions for purposes of this policy.
11.103 Assuring compliance with this policy--research conducted or
supported by any Federal department or agency.
11.104 Exempt research.
11.105 Protection of biospecimens and identifiable private
information.
11.106 [Reserved]
11.107 IRB membership.
11.108 IRB functions and operations.
11.109 IRB review of research.
11.110 Expedited review procedures for certain kinds of research
involving no more than minimal risk, and for minor changes in
approved research.
11.111 Criteria for IRB approval of research.
11.112 Review by institution.
11.113 Suspension or termination of IRB approval of research.
11.114 Cooperative research.
11.115 IRB records.
11.116 General requirements for informed consent.
11.117 Documentation of informed consent.
11.118 Applications and proposals lacking definite plans for
involvement of human subjects.
11.119 Research undertaken without the intention of involving human
subjects.
11.120 Evaluation and disposition of applications and proposals for
research to be conducted or supported by a Federal department or
agency.
11.121 [Reserved]
11.122 Use of Federal funds.
11.123 Early termination of research support: Evaluation of
applications and proposals.
11.124 Conditions.
Authority: 5 U.S.C. 301.
Anthony R. Foxx,
Secretary of Transportation.
[FR Doc. 2015-21756 Filed 9-2-15; 11:15 am]
BILLING CODE 4150-36-P
