[Federal Register Volume 87, Number 187 (Wednesday, September 28, 2022)]
[Proposed Rules]
[Pages 58752-58763]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2022-21089]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 56
[Docket No. FDA-2019-N-2175]
RIN 0910-AI08
Institutional Review Boards; Cooperative Research
AGENCY: Food and Drug Administration, Health and Human Services (HHS).
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA or we) is proposing to
replace current requirements for FDA-regulated cooperative research
with new requirements that would require any institution located in the
United States participating in FDA-regulated cooperative research to
rely on review and approval by a single institutional review board
(IRB) for that portion of the research that is conducted in the United
States, with some exceptions. FDA is also proposing an IRB
recordkeeping requirement for research that takes place at an
institution in which IRB oversight is conducted by an IRB that is not
operated by the institution. FDA is proposing these revisions to
streamline the IRB review process and decrease administrative burdens
and inefficiencies for investigators and IRBs without compromising
human subject protections. This proposed rule would harmonize FDA's
requirements for cooperative research and IRB records, to the extent
practicable and consistent with statutory provisions, with the
``Federal Policy for the Protection of Human Subjects'' (revised Common
Rule) and is being issued in accordance with a provision of the 21st
Century Cures Act (Cures Act).
DATES: Either electronic or written comments on the proposed rule must
be submitted by November 28, 2022. Submit written comments (including
recommendations) on the collection of information under the Paperwork
Reduction Act of 1995 (PRA) by October 28, 2022.
ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. The https://www.regulations.gov electronic filing system will accept comments until
11:59 p.m. Eastern Time at the end of November 28, 2022. Comments
received by mail/hand delivery/courier (for written/paper submissions)
will be considered timely if they are received on or before that date.
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions.'')
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2019-N-2175 for ``Institutional Review Boards; Cooperative
Research.'' Received comments, those filed in a timely manner (see
ADDRESSES), will be placed in the docket and, except for
[[Page 58753]]
those submitted as ``Confidential Submissions,'' publicly viewable at
https://www.regulations.gov or at the Dockets Management Staff between
9 a.m. and 4 p.m., Monday through Friday, 240-402-7500.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' FDA will review
this copy, including the claimed confidential information, in its
consideration of comments. The second copy, which will have the claimed
confidential information redacted/blacked out, will be available for
public viewing and posted on https://www.regulations.gov. Submit both
copies to the Dockets Management Staff. If you do not wish your name
and contact information to be made publicly available, you can provide
this information on the cover sheet and not in the body of your
comments and you must identify this information as ``confidential.''
Any information marked as ``confidential'' will not be disclosed except
in accordance with 21 CFR 10.20 and other applicable disclosure law.
For more information about FDA's posting of comments to public dockets,
see 80 FR 56469, September 18, 2015, or access the information at:
https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
Submit comments on the information collection under the Paperwork
Reduction Act of 1995 to the Office of Management and Budget (OMB) at
https://www.reginfo.gov/public/do/PRAMain. Find this particular
information collection by selecting ``Currently under Review--Open for
Public Comments'' or by using the search function. The title of this
proposed collection is Institutional Review Boards--21 CFR part 56 (OMB
Control Number 0910-0130--Revision).
FOR FURTHER INFORMATION CONTACT: With regard to the proposed rule:
David Markert, Office of Clinical Policy, Food and Drug Administration,
10903 New Hampshire Ave., Silver Spring, MD 20993, 301-796-0752,
[email protected].
With regard to the information collection: Domini Bean, Office of
Operations, Food and Drug Administration, Three White Flint North, 10A-
12M, 11601 Landsdown St., North Bethesda, MD 20852, 301-796-5733,
[email protected].
SUPPLEMENTARY INFORMATION:
Table of Contents
I. Executive Summary
A. Purpose of the Proposed Rule
B. Summary of the Major Provisions of the Proposed Rule
C. Legal Authority
D. Costs and Benefits
II. Background
A. Single IRB Review Requirements Under the Revised Common Rule
B. The National Institutes of Health (NIH) Single IRB Policy
C. The Cures Act
D. FDA's Current Regulatory Framework
E. Need for this Regulation
III. Legal Authority
IV. Description of the Proposed Rule
A. Single IRB Review Requirement for Cooperative Research
B. Exceptions to the Single IRB Review Requirement
C. Single IRB Review for Research Not Subject to Sec. 56.114(b)
D. IRB Records
V. Proposed Effective Date
VI. Preliminary Economic Analysis of Impacts
VII. Analysis of Environmental Impact
VIII. Paperwork Reduction Act of 1995
IX. Consultation and Coordination With Indian Tribal Governments
X. Federalism
XI. References
I. Executive Summary
A. Purpose of the Proposed Rule
This proposed rule would harmonize, to the extent practicable and
consistent with statutory provisions, FDA's cooperative research
requirements with the cooperative research requirements in the revised
Common Rule,\1\ which requires use of a single IRB review process for
multisite research conducted in the United States, with some
exceptions. This proposed rule would establish an IRB recordkeeping
requirement that would be harmonized, to the extent practicable and
consistent with statutory provisions, with the revised Common Rule's
IRB recordkeeping requirement for research overseen by an IRB that is
not operated by the institution where the study is conducted. FDA
believes that, in many situations, mandatory single IRB review for
multi-institutional clinical investigations would streamline the review
process and increase efficiencies for the oversight of clinical
investigations without compromising human subject protections.
Increased efficiencies may facilitate faster initiation of clinical
investigations supporting the development of new medical products to
benefit the public health. FDA also believes that, in many cases,
mandatory single IRB review for multi-institutional clinical
investigations would decrease administrative burdens created by
multiple IRB reviews for institutions, investigators, IRBs, and
sponsors. This proposed rule is being issued in accordance with section
3023 of the Cures Act (Pub. L. 114-255).
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\1\ For the purpose of this proposed rule, ``revised Common
Rule'' refers to the January 19, 2017, final rule (82 FR 7149),
which was modified by an interim final rule that delayed the
effective date and general compliance date (83 FR 2885, January 22,
2018) and a final rule that delayed the general compliance date,
while allowing use of three burden-reducing provisions for certain
research during the delay period (83 FR 28497, June 19, 2018). The
compliance date for the cooperative research provisions of the
revised Common Rule was January 20, 2020.
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B. Summary of the Major Provisions of the Proposed Rule
FDA is proposing to replace the current requirements under Sec.
56.114 ``Cooperative research'' of part 56 (21 CFR part 56) with new
regulatory text that would require any institution located in the
United States participating in cooperative research to rely on approval
by a single IRB for that portion of the research that is conducted in
the United States, with some exceptions. FDA is also proposing an IRB
recordkeeping requirement for research that takes place at an
institution in which IRB oversight is conducted by an IRB that is not
operated by the institution.
C. Legal Authority
FDA is proposing to issue this rule under sections 403, 406, 409,
412, 413, 503, 505, 510, 513-515, 520, 531-539, 541-542, 701, and 721
of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 343,
346, 348, 350a, 350b, 353, 355, 360, 360c-360e, 360j, 360hh-360pp,
360rr-360ss, 371, and 379e) and section 351 of the Public Health
Service Act (PHS Act) (42 U.S.C. 262).
D. Costs and Benefits
This proposed requirement for single IRB review for FDA-regulated
cooperative research as well as harmonizing, to the extent practicable
and consistent with statutory provisions, these FDA requirements
[[Page 58754]]
with the revised Common Rule should reduce the administrative and
coordination costs of conducting cooperative research by: (1) reducing
duplicative reviews; (2) facilitating an earlier start of cooperative
research; and (3) reducing the need to reconcile variability in IRB
review decisions for cooperative research conducted with a common
protocol. Reducing the costs of conducting cooperative research should
reduce the costs of FDA-regulated medical product development and
facilitate an earlier start of cooperative research, which could
contribute to a faster introduction of those products into commercial
use. Over 10 years, the annualized costs range from approximately $30
million to $134 million with a 7 percent discount rate and range from
$30 million to $127 million with a 3 percent discount rate. The
annualized net cost savings (benefits net of costs) range from $87
million to $882 million with a 7 percent discount rate and range from
$87 million to $897 million with a 3 percent discount rate.
II. Background
Table of Abbreviations/Commonly Used Acronyms in This Document
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Abbreviation/acronym What it means
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AI/AN............................. American Indian or Alaska Native.
Cures Act......................... 21st Century Cures Act.
FDA............................... Food and Drug Administration.
IRB............................... Institutional Review Board.
FD&C Act.......................... Federal Food, Drug, and Cosmetic
Act.
FR................................ Federal Register.
HHS............................... Health and Human Services.
IDE............................... Investigational Device Exemption.
IND............................... Investigational New Drug
Application.
NIH............................... National Institutes of Health.
OHRP.............................. Office for Human Research
Protections.
NSR............................... Nonsignificant Risk.
PRA............................... Paperwork Reduction Act of 1995.
OMB............................... Office of Management and Budget.
PHS Act........................... Public Health Service Act.
SACHRP............................ Secretary's Advisory Committee on
Human Research Protections.
U.S.C............................. United States Code.
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FDA is in the process of amending its regulations under 21 CFR
parts 50 and 56 on protection of human subjects and IRBs to harmonize
with the revised Common Rule, consistent with section 3023 of the Cures
Act. This proposed rule only addresses single IRB review for
cooperative research and a related IRB recordkeeping requirement. FDA
intends to undertake additional rulemaking to harmonize our regulations
with the revised Common Rule, to the extent practicable and consistent
with statutory provisions.
A. Single IRB Review Requirements Under the Revised Common Rule
The Common Rule was originally issued in 1991 (56 FR 28001, June
18, 1991). The Common Rule sets forth requirements for the protection
of human subjects involved in research that is conducted or supported
by the Department of Health and Human Services (HHS) (see 45 CFR part
46, subpart A) and other Federal Departments and Agencies. The purpose
of the Common Rule is to promote uniformity, understanding, and
compliance with human subject protections as well as to create a
uniform body of regulations across the Federal Departments and Agencies
(80 FR 53931 at 53935, September 8, 2015).
On January 19, 2017, HHS and the other Common Rule Departments and
Agencies announced revisions to modernize, strengthen, and make the
Common Rule more effective (82 FR 7149, January 19, 2017). The revised
Common Rule is intended to better protect human subjects involved in
research, while facilitating valuable research and reducing burden,
delay, and ambiguity for investigators (82 FR 7149). One of the
proposals adopted in the revised Common Rule is the requirement for
institutions located in the United States that are engaged in
cooperative research (also referred to as multi-institutional studies,
multisite studies, or multicenter studies) to use single IRB review for
that portion of the research that takes place within the United States,
with certain exceptions.\2\
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\2\ For the purpose of this proposed rule, the terms ``central
IRB'', ``single central IRB'', ``single IRB'' and ``single IRB of
record'' are synonymous and interchangeable. The terms ``site'' and
``institution'' are also intended to be synonymous and
interchangeable.
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In adopting a single IRB review requirement as part of the revised
Common Rule, HHS and the other Common Rule Departments and Agencies
agreed with those commenters on the proposed rule to revise the Common
Rule who indicated that mandated single IRB review would ultimately
decrease administrative burdens and inefficiencies for investigators
and institutions without diminishing human subject protections, while
also acknowledging that transition to the single IRB review model would
require additional time and changes to institutional policies and
structures. In addition, HHS and the other Common Rule Departments and
Agencies stated in the preamble that ``in many cases multiple IRB
approvals increase burden and frequently delay the implementation of
studies, increasing the costs of clinical trials and potentially
stalling access to new therapies.'' (82 FR 7149 at 7209.)
The revised Common Rule requires that all U.S. institutions engaged
in cooperative research rely upon a single IRB review with two
exceptions: (1) cooperative research for which more than single IRB
review is required by law (including tribal law passed by the official
governing body of an American Indian or Alaska Native (AI/AN) tribe) or
(2) research for which any Federal Department or Agency supporting or
conducting the research determines and documents that the use of single
IRB review is not appropriate for the particular context (45 CFR
46.114(b)). Under the first exception, if applicable law (including
when the official governing body of an AI/AN tribe passes a tribal law)
requires more than single IRB review for certain cooperative research,
then the revised Common Rule's requirement for single IRB review
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does not apply to such cooperative research (82 FR 7149 at 7209). In
addition, the revised Common Rule allows a Federal Department or Agency
supporting or conducting the research the flexibility to determine that
use of a single IRB is not appropriate for certain contexts, thereby
permitting additional IRB review in some circumstances (82 FR 7149 at
7209). While the revised Common Rule does not prohibit an institution
from conducting its own additional internal review, ``such reviews
would no longer have any regulatory status in terms of compliance with
the Common Rule.'' (82 FR 7149 at 7209). For cooperative research
subject to this single IRB review mandate, the reviewing IRB will be
identified by the Federal Department or Agency supporting or conducting
the research, or proposed by the lead institution subject to the
acceptance of the Federal Department or Agency supporting the research
(82 FR 7149 at 7209).
B. The National Institutes of Health (NIH) Single IRB Policy
On December 3, 2014, the NIH proposed a Draft NIH Policy, ``Use of
a Single Institutional Review Board of Record for Multisite Research,''
which stated that NIH would generally expect all domestic sites of
multisite NIH-funded studies to use a single IRB of record.\3\ In
finalizing its policy, NIH explained that, in general, public comments
on the Draft NIH Policy were supportive of NIH's goal of enhancing and
streamlining IRB review in multisite research. However, NIH also
described that some commenters, mainly academic institutions and
organizations representing them, expressed concerns about the scope of
the proposed policy, did not agree that it should become a term and
condition of funding, and pointed to the importance of local IRB
review. On the other hand, many NIH stakeholders agreed that the use of
single IRB review for multisite studies involving a single protocol
would help streamline IRB review and could help enhance protections for
human subjects (81 FR 40325 at 40326, June 21, 2016). On June 21, 2016,
NIH finalized its policy on the use of single IRB review, which is
complementary to the revised Common Rule's cooperative research
provision (81 FR 40325 at 40326). NIH's final single IRB policy went
into effect on January 25, 2018.\4\
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\3\ https://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-026.html. On January 6, 2015, NIH published a notice to inform
readers of the Federal Register about the draft policy and provide
an opportunity for comment (80 FR 511).
\4\ NOT-OD-17-076 ``Revision: Notice of Extension of Effective
Date for Final NIH Policy on Single Institutional Review Board for
Multi-Site Research,'' June 16, 2017, https://grants.nih.gov/grants/guide/notice-files/NOT-OD-17-076.html.
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C. The Cures Act
On December 13, 2016, the Cures Act was signed into law amending
certain provisions of the FD&C Act. The Cures Act is designed to help
accelerate the discovery, development, and delivery of 21st century
cures. Section 3023 of the Cures Act directs the Secretary of HHS, to
the extent practicable and consistent with other statutory provisions,
to harmonize differences between the HHS Human Subject Regulations and
FDA's Human Subject Regulations. Section 3023 requires modifications to
the HHS and FDA Human Subject Regulations, as appropriate, to: (1)
reduce regulatory duplication and unnecessary delays; (2) modernize
such provisions in the context of multisite and cooperative research
projects; and (3) protect vulnerable populations, incorporate local
considerations, and support community engagement through mechanisms
such as consultation with local researchers and human research
protection programs. The Cures Act also requires the Secretary, as
appropriate, to ensure that human subject research that is subject to
the HHS Human Subject Regulations and to the FDA Human Subject
Regulations may: (1) use joint or shared review; (2) rely upon the
review of an independent IRB or an IRB of an entity other than the
sponsor of the research; or (3) use similar arrangements to avoid
duplication of effort (section 3023 of the Cures Act). FDA is working
with the Office for Human Research Protections (OHRP) and others in HHS
to carry out this statutory mandate.
In addition, section 3056 of the Cures Act amended section 520(g)
of the FD&C Act to remove the requirement for IRBs overseeing clinical
investigations of devices to be ``local.'' \5\ Before this statutory
change, section 520(g) of the FD&C Act required review by a local
institutional review committee (i.e., IRB) for clinical testing of a
medical device, so requiring single IRB review for clinical
investigations of devices was not possible. However, in light of this
statutory change, medical device studies may now rely on a single IRB
review process.
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\5\ On June 7, 2017, FDA amended its regulations to reflect this
statutory change (82 FR 26348).
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D. FDA's Current Regulatory Framework
FDA has historically supported efforts to reduce administrative
burden in cooperative research. Since being issued in 1981, the IRB
regulations at part 56 have provided for the voluntary use of
cooperative review in multi-institutional studies (46 FR 8958, January
27, 1981). Under current FDA regulations, institutions involved in
multi-institutional studies may use joint review, reliance upon the
review of another qualified IRB, or similar arrangements aimed at
avoiding duplication of effort.\6\ When FDA's rule, ``Protection of
Human Subjects, Standards for Institutional Review Boards for Clinical
Investigations'' was proposed, we indicated that the purpose of the
section regarding cooperative research was ``to explicitly reduce
duplicative review of multi-institutional studies'' (44 FR 47699 at
47700, August 14, 1979). In the preamble to the final rule issuing
FDA's regulations at part 56, FDA also stated that ``the purpose of
this section is to assure IRBs that FDA will accept reasonable methods
of joint review'' (46 FR 8958 at 8970). Additionally, FDA issued
guidance in 2006 intended to assist sponsors, institutions, IRBs, and
clinical investigators involved in multicenter clinical studies in
meeting the requirements of part 56 by facilitating the use of a
centralized IRB review process, especially in situations where
centralized review could improve efficiency of IRB review.\7\ The
guidance encourages the use of a centralized IRB review process and
provides recommendations regarding how to document agreements and
procedures relating to a centralized IRB review system, including those
reviews of studies at clinical trial sites not affiliated with the IRB.
The guidance also provides some examples of cooperative IRB review
models.
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\6\ 21 CFR 56.114.
\7\ See FDA's ``Guidance for Industry: Using a Centralized IRB
Review Process in Multicenter Clinical Trials'' (March 2006).
Available at: https://www.fda.gov/media/75329/download.
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E. Need for this Regulation
Although the use of a single IRB review process is already
encouraged and consistent with our regulations at Sec. 56.114, it is
voluntary. Consistent with the purpose for including the single IRB
review requirement for cooperative research in the revised Common Rule,
as described above, FDA believes that requiring single IRB review for
certain multi-institutional clinical investigations would streamline
the review process without compromising human subject protections. In
addition, as described in section II.A., FDA believes that the benefits
of requiring
[[Page 58756]]
single IRB review recognized by HHS and the other Common Rule
Departments and Agencies would also be realized for multisite, FDA-
regulated research, with some exceptions.
Institutions have been reluctant to voluntarily use single IRB
review for a variety of reasons, most of which are unrelated to whether
single IRB review is more efficient and less burdensome than multiple
local IRB reviews. A study conducted by the Clinical Trials
Transformation Initiative (CTTI) \8\ identified several perceived
barriers to the use of single IRB review, including concerns about
potential noncompliance by the single IRB, potential loss of local
context, and the quality of the single IRB's review. The study found
that the perceived barriers to single IRB review resulted from a
conflation of institutional responsibilities with the ethical review
responsibilities of the IRB, among other factors (Ref. 1).
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\8\ The Clinical Trials Transformation Initiative (CTTI) is a
public-private partnership that focuses on developing and driving
adoption of practices that will increase the quality and efficiency
of clinical trials (https://www.ctti-clinicaltrials.org/who-we-are).
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Over the years, clinical investigations have become more complex,
with increasing numbers of sites. For scientific reasons, multicenter
clinical investigations generally share a common protocol that could be
carried out at each site, or different aspects of the protocol (e.g.,
study recruitment, data coordination) could be conducted at different
sites. In either case, site-specific, local IRB reviews of such a
protocol would not be likely to provide additional human subject
protections beyond those provided by a single IRB with appropriate
expertise to evaluate the risks and benefits of the study, the adequacy
of the informed consent process and document, and local issues. In
these cases, review by multiple IRBs may lead to unnecessary additional
reviews that could delay research without providing an increase in
human subject protections. For example, when multiple IRBs are involved
in reviewing a cooperative research protocol, a change to the protocol
or informed consent document required by one site's IRB could mean that
the protocol or informed consent document would need to be resubmitted
for review to all the other sites participating in this multisite
study, resulting in significant delays in initiating the study. In
addition, multiple IRB reviews could result in recruitment differences
between sites, leading to difficulty recruiting subjects with the
condition of interest, and in some cases, an impact on the
generalizability of the study results. Furthermore, multisite clinical
investigations can generate large volumes of safety reports; however,
duplicative local IRB review of safety reports at every study site may
not improve subject safety. A single IRB may be better positioned to
review, analyze, and act upon important safety findings.
Examples of administrative burdens and review inefficiencies that
result from multiple IRB reviews as described above have also been
cited in literature. For example, Greene and Geiger identified numerous
related but distinct factors that contribute to research delays and
unnecessary costs in multicenter studies that undergo review by
multiple IRBs, including: added time for the initial review and
approval of the clinical investigation; differing requirements across
IRBs that included widely variable IRB approval processes and unique
consent forms across sites even in a ``standardized'' environment;
differing test subject recruitment procedures and participant
incentives across sites, possibly affecting response rates; and, when
additional review times and IRB requirements were involved, the
additional approval requirements consumed significant amounts of fixed
grant funds, reducing the scope of the research (Ref. 2). Several other
empirical studies have also found inefficiencies and inconsistencies
associated with multiple IRB reviews of multisite clinical
investigations (Ref. 3).
In the preamble to the revised Common Rule, the Common Rule
Departments and Agencies stated that they believed that merely
encouraging single IRB review would ``fail to yield substantive
positive change in the system[,]'' and, therefore, determined that
requiring single IRB review was necessary in order to increase
efficiencies in research (82 FR 7149 at 7209). FDA agrees with the
Common Rule Departments and Agencies that the benefits of single IRB
review--including a streamlined review process, reduced administrative
burdens, and increased efficiencies--are unlikely to be realized if
reliance on a single IRB for review of cooperative research remains
purely voluntary. Therefore, FDA is proposing to require single IRB
review for certain multi-institutional clinical investigations to
streamline the review process, decrease administrative burden created
by multiple IRB reviews, and reduce inefficiencies for investigators,
sponsors, institutions, and IRBs. Increased efficiencies for the
oversight of clinical investigations may facilitate faster initiation
of clinical investigations for the development of new medical products
to benefit the public health. For example, a study of the National
Cancer Institute's (NCI) single IRB (Central Institutional Review Board
or CIRB) found that the time required to reopen a trial after a
temporary closure because of a major protocol amendment was
significantly faster at CIRB-affiliated sites (less than 48 hours on
average) than at sites that used their local IRBs to implement the same
trial amendments (40.5 days on average) (Ref. 4).
Furthermore, a single IRB would provide FDA with a single focal
point for an IRB inspection for a given investigation. Inspection of a
single IRB could cover oversight of a larger number of clinical
investigation sites during a single inspection, therefore providing FDA
an opportunity to operate a more efficient IRB inspection program.
FDA recognizes, however, that there are likely to be some initial
burdens associated with use of a single IRB, rather than a local IRB
model, such as establishing reliance agreements to document
responsibilities among the various institutions participating in the
research and the reviewing IRB. While FDA agrees with the Common Rule
Departments and Agencies that mandatory single IRB review will
ultimately decrease administrative burdens and inefficiencies for much
FDA-regulated research, for some types of research, we do not believe
it is clear that the potential benefits of single IRB review outweigh
the potential associated burdens in every circumstance. Therefore, as
described below, we are proposing exceptions to the single IRB review
requirement to account for these situations.
We note that the preamble to the revised Common Rule describes that
some comments identified the importance of local IRB review as a reason
for opposing the proposed requirement for use of single IRB review (82
FR 7149 at 7208). FDA believes that attention to local issues related
to the communities where the research will take place is very important
and has provided recommendations in an FDA guidance on addressing local
aspects of IRB review when using a single IRB review process.\9\ In
general, mechanisms other than a separate local IRB review and approval
can be used to address local contextual issues, such as the local site
providing the single IRB of record with information on local context
and
[[Page 58757]]
updates, when appropriate. However, because there may be some instances
for which local IRB review may be required by law or necessary to
provide important expertise for a particular FDA-regulated clinical
investigation, FDA is also proposing under Sec. 56.114(b)(2), certain
exceptions from the proposed requirement for use of single IRB review
to account for those instances.
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\9\ See FDA's ``Guidance for Industry: Using a Centralized IRB
Review Process in Multicenter Clinical Trials'' (March 2006).
Available at: https://www.fda.gov/media/75329/download.
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FDA notes that a substantial amount of the clinical research that
FDA regulates is not subject to the revised Common Rule. Although the
Common Rule Departments and Agencies conduct and support a significant
number of multi-institutional clinical investigations involving FDA-
regulated products, the majority of such investigations are conducted
and supported by industry. FDA-regulated clinical investigations that
are funded by a Common Rule Department or Agency would also be subject
to the revised Common Rule, which requires single IRB review for
cooperative research, with certain exceptions. Because FDA's proposed
mandatory single IRB review provisions would harmonize with the
corresponding requirements under the revised Common Rule, to the extent
practicable and consistent with statutory provisions, FDA's proposal
would reduce the need for sponsors, investigators, institutions, and
IRBs to comply with differing requirements. Many institutions are
already implementing the revised Common Rule's single IRB review
requirement, which had a compliance date of January 20, 2020. In
addition, clinical investigations funded by NIH are already subject to
NIH's single IRB review policy. Thus, there should be minimal impact on
sponsors of FDA-regulated clinical investigations that are also
Federally funded.
III. Legal Authority
FDA is proposing to issue this rule under our authority to issue
regulations regarding the investigational use of drugs under section
505(i) of the FD&C Act, the investigational use of devices under
section 520(g) of the FD&C Act, and the investigational use of
biological products under section 351(a) of the PHS Act. In addition,
IRB review helps assure the quality and integrity of data from clinical
investigations relied upon in submissions to FDA regarding the safety,
effectiveness, and/or marketing of FDA-regulated products, including
submissions made pursuant to sections 403, 406, 409, 412, 413, 503,
505, 510, 513-515, 520, 531-539, 541-542, and 721 of the FD&C Act and
section 351 of the PHS Act. IRB review also helps protect the rights
and safety of human subjects involved in those clinical investigations.
Section 701(a) of the FD&C Act authorizes FDA to issue regulations for
the efficient enforcement of the FD&C Act.
FDA believes that requiring single IRB review for multi-
institutional clinical investigations as described in this proposed
rule would streamline the IRB review process, decrease administrative
burdens and inefficiencies for investigators and IRBs while maintaining
adequate human subject protections, and provide FDA an opportunity to
operate a more efficient IRB inspection program.
IV. Description of the Proposed Rule
FDA is proposing to replace the current requirements under Sec.
56.114, Cooperative research, with new regulations that would require
any institution located in the United States participating in FDA-
regulated cooperative research to rely on approval by a single IRB for
that portion of the research that is conducted in the United States,
with some exceptions. For research that takes place at an institution
in which IRB oversight is conducted by an IRB that is not operated by
the institution, FDA is also proposing a new IRB recordkeeping
requirement at Sec. 56.115, IRB records. This requirement would
clarify the documentation needed to specify the institution's reliance
on the IRB for oversight of the research and the responsibilities that
the institution, and the organization operating the IRB, will undertake
to ensure compliance with the requirements of part 56. These proposed
changes address, in part, section 3023 of the Cures Act, which requires
the Secretary of HHS to harmonize differences between the HHS Human
Subject Regulations and FDA's Human Subject Regulations, to the extent
practicable and consistent with other statutory provisions. This
proposed rule is intended to fulfill that directive with respect to
FDA's requirements for cooperative research and a related IRB
recordkeeping requirement. The differences between FDA's proposal and
the revised Common Rule are described in further detail below.
A. Single IRB Review Requirement for Cooperative Research
FDA is proposing new regulatory text at Sec. 56.114(a) to describe
cooperative research covered by these regulations as a clinical
investigation that involves more than one institution and to explain
that, in the conduct of cooperative research, each institution is
responsible for safeguarding the rights and welfare of human subjects
and for complying with these regulations. This proposed regulatory text
differs from the revised Common Rule at 45 CFR 46.114(a) by using FDA's
term ``clinical investigations,'' rather than ``projects,'' and the
term ``regulations,'' rather than ``policy.'' This language better
reflects the scope of FDA's authority and the terminology used
throughout FDA's existing human subject protection regulations.
FDA is proposing new regulatory text at Sec. 56.114(b)(1) to
require that any institution located in the United States participating
in FDA-regulated cooperative research rely on approval by a single IRB
for that portion of the research that is conducted in the United
States. This proposed regulatory text differs from the revised Common
Rule at 45 CFR 46.114(b)(1) by using FDA's term ``participating,''
rather than ``engaged.'' This language better reflects the terminology
used throughout FDA's existing human subject protection regulations.
The revised Common Rule provision at 45 CFR 46.114(b)(1) also
requires the reviewing IRB to be identified by the Federal Department
or Agency \10\ supporting or conducting the research, or to be proposed
by the lead institution subject to the acceptance of the Federal
Department or Agency supporting the research. It is not practicable for
FDA to propose this same requirement because, unlike research subject
to the revised Common Rule, most of the research that FDA regulates is
not conducted or supported by FDA or by any Federal Department or
Agency. FDA's existing regulations do not require that a specific party
involved in the research select the IRB when a single IRB process is
used, and we are unaware of difficulties in selecting the IRB that
warrant requiring the single IRB always to be identified by a
particular party for all FDA-regulated research. Because FDA is not
proposing to require that a particular party identify the single IRB,
there would be no conflict for FDA-regulated research that is also
subject to the revised Common Rule requirement that the single IRB be
identified by the Federal Department or Agency supporting or conducting
the
[[Page 58758]]
research or proposed by the lead institution subject to the acceptance
of the Federal Department or Agency supporting the research. In
addition, FDA's current regulations address the assurance of IRB review
for clinical investigations of drugs and devices by an IRB that
complies with the regulations set forth in part 56. This assurance is
addressed by the responsibilities of sponsors and investigators in an
FDA-regulated clinical investigation.\11\ In general, for clinical
investigations of drugs under 21 CFR part 312, an investigator is
responsible for ensuring that there will be initial and continuing
review and approval by a qualified IRB (Sec. 312.66), and a sponsor is
responsible for obtaining a commitment from each investigator that he
or she will ensure that requirements in part 56 relating to IRB review
and approval are met (Sec. 312.53(c)(1)(vi)(d)). For clinical
investigations of medical devices, under part 812 (21 CFR part 812),
the sponsor is responsible for ensuring IRB review and approval are
obtained (Sec. 812.40). Additionally, the sponsor is required to
identify the reviewing IRB in the investigational new drug (IND)
application or an investigational device exemption (IDE) application
submitted to FDA.\12\
---------------------------------------------------------------------------
\10\ For purposes of the Common Rule, ``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., the U.S. Department of
Health and Human Services, the U.S. Department of Defense, or the
Central Intelligence Agency).'' 45 CFR 46.102(d).
\11\ See, for example, Sec. Sec. 312.53 and 312.66 (21 CFR
312.53 and 312.66), 21 CFR 320.31, and Sec. Sec. 812.40, 812.42,
812.43, and 812.110 (21 CFR 812.40, 812.42, 812.43, and 812.110).
\12\ See 21 CFR 312.23(a)(6)(iii)(b) and 812.20(b)(6).
---------------------------------------------------------------------------
B. Exceptions to the Single IRB Review Requirement
The revised Common Rule, under 45 CFR 46.114(b)(2), provides two
exceptions from the requirement under 45 CFR 46.114(b)(1) for reliance
on approval by a single IRB. The following research is excepted: (1)
cooperative research for which more than single IRB review is required
by law (including tribal law passed by the official governing body of
an AI/AN tribe) or (2) research for which any 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
context. The preamble to the revised Common Rule noted that the second
exception ``allows a federal department or agency the flexibility to
determine that the use of a single IRB is not appropriate for certain
contexts, thereby permitting additional IRB review and consideration of
local and regional variations in some circumstances'' (82 FR 7149 at
7209).
FDA is proposing new regulatory text at Sec. 56.114(b)(2) to
provide exceptions to the requirement under Sec. 56.114(b)(1) for
reliance on approval by a single IRB. FDA is proposing the same
exception as under 45 CFR 46.114(b)(2)(i) of the revised Common Rule
for circumstances in which more than a single IRB review is required by
law. However, we do not believe it is practicable for FDA to adopt the
same regulatory text as the exception at 45 CFR 46.114(b)(2)(ii)
because most of the research that FDA regulates is not conducted or
supported by FDA or by any Federal Department or Agency. Therefore,
this exception would have no applicability to the majority of FDA-
regulated research.
We also believe it would be impracticable for FDA to adopt an
analogous exception for situations in which FDA determines and
documents that the use of a single IRB is not appropriate for the
particular context. Unlike review of a research grant application that
would be submitted to a Federal Department or Agency for approval,
certain FDA-regulated research does not require a submission to FDA or
other interaction with FDA before it begins (e.g., research on drugs
that is exempt from the requirement to submit an IND application under
Sec. 312.2(b) (21 CFR 312.2(b)). If FDA were to require such research
to obtain FDA's determination and documentation that single IRB review
is not appropriate, it would add administrative burden and delay the
initiation of research, contrary to the goals of this proposed rule.
However, we seek comment below on whether FDA should consider adding an
analogous exception, in addition to other proposed exceptions, to help
address potential challenges to use of a single IRB review model for
FDA-regulated cooperative research.
After considering these issues, instead of proposing a broad
exemption that would provide for FDA to make case-by-case
determinations that use of single IRB review is not appropriate, FDA is
proposing specific exceptions that we believe reflect circumstances for
which requiring the use of a single IRB for oversight of multisite
research may not be appropriate for FDA-regulated research. In these
cases, use of single IRB review may not be adequate to provide
important expertise for a particular FDA-regulated clinical
investigation or may not increase efficiencies for the oversight of
certain clinical investigations. The intent of these proposed
exceptions is to facilitate FDA-regulated research, minimize
administrative burden, and maintain appropriate human subject
protections.
1. Cooperative Research For Which More Than Single IRB Review Is
Required By Law
The first exception to the requirement for reliance on approval by
a single IRB in the revised Common Rule at 45 CFR 46.114(b)(2)(i)
includes cooperative research for which more than single IRB review is
required by law (including tribal law passed by the official governing
body of an AI/AN tribe). FDA is proposing this same exception at Sec.
56.114(b)(2)(i).
2. Cooperative Research Involving a Highly Specialized FDA-Regulated
Medical Product
FDA is proposing, at Sec. 56.114(b)(2)(ii), an exception from the
use of single IRB review for research involving a highly specialized
FDA-regulated medical product for which unique, localized expertise is
required. For example, for certain highly specialized FDA-regulated
medical products, expertise in the use of the product may be limited to
only a few specialists at geographically dispersed locations. In such
cases, the investigators, research staff, and IRBs associated with the
investigational sites would have the critical knowledge and training
relevant to the product, and therefore, these IRBs would have the
capability to most efficiently conduct initial review and oversee the
research, while maintaining appropriate human subject protections. We
believe that mandating the use of single IRB review could be an
obstacle to initiating important research when the localized expertise
is readily available, but none of the IRBs associated with the
investigational sites can serve as the single IRB of record. FDA
believes that this proposed criterion for exception from use of single
IRB review would be met in such a case, although we expect that such
exceptions would be rare occurrences.
3. Cooperative Research on Drugs Exempt From the IND Regulations
FDA is proposing, under Sec. 56.114(b)(2)(iii), an exception from
mandatory use of single IRB review for research on drugs that is exempt
from the requirements for an IND application under Sec. 312.2(b) (21
CFR 312.2(b)). FDA does not require submission of an IND application
for certain clinical investigations of lawfully marketed drugs that
meet the criteria under Sec. 312.2(b) (see 52 FR 8797, March 19,
1987). Such studies are generally lower risk clinical investigations of
products that are lawfully marketed. Unlike clinical investigations
that are conducted under the IND requirements,
[[Page 58759]]
increased efficiencies leading to earlier initiation of clinical
investigations exempt from the IND requirements generally would not
provide the benefit of bringing new drugs or new uses of drugs to
patients sooner.
4. Cooperative Research on Medical Devices That Meets the Abbreviated
Requirements or the Requirements for Exempted Investigations
To facilitate research in accordance with the statutory purpose of
section 520(g) of the FD&C Act and avoid unnecessary burden on
regulated entities, when FDA issued the IDE regulations at part 812,
FDA did not require submission of an IDE application for all categories
of device investigations (45 FR 3731 at 3735-3736, January 18, 1980). A
device investigation conducted under the abbreviated requirements at
Sec. 812.2(b) (21 CFR 812.2(b)) (a nonsignificant risk or ``NSR''
study) is deemed to have an approved IDE and, among other requirements,
cannot be an investigation of a significant risk device, as defined at
Sec. 812.3(m) (21 CFR 812.3(m)). While IRB approval is required for an
NSR study, FDA approval of an IDE application is not. Reducing the
level of regulatory controls for these investigations based on the
degree of risk was considered appropriate to avoid unnecessary burden
and delay in the approval of research without sacrificing human subject
protection (see 45 FR 3731 at 3735-3736). In accordance with Sec.
812.2(c), certain device studies are also exempt from the requirements
of part 812, with the exception of 21 CFR 812.119 (disqualification of
a clinical investigator). The exempt categories outlined at Sec.
812.2(c) include certain studies of legally marketed devices in which
the device is used in accordance with its labeled indications (see
Sec. 812.2(c)(1) and (2)), and certain studies of diagnostic devices
that present low risk to subjects (see Sec. 812.2(c)(3)). The exempt
categories also include studies of devices undergoing consumer
preference testing, testing of a modification, or testing of a
combination of two or more devices in commercial distribution, if the
testing is not for the purpose of determining safety or effectiveness
and does not put subjects at risk (Sec. 812.2(c)(4)). In addition,
Sec. 812.2(c) clarifies that investigations of the following devices
do not require an IDE: (1) a device intended solely for veterinary use;
(2) a device shipped solely for research on or with laboratory animals
and labeled in accordance with Sec. 812.5(c); and (3) a custom device
as defined in Sec. 812.3(b), unless the device is being used to
determine safety or effectiveness for commercial distribution. (See
Sec. 812.2(c)(5)-(7).)
FDA is proposing an exception from the requirement for single IRB
review under Sec. 56.114(b)(2)(iv) for research on medical devices
that meets the abbreviated requirements under Sec. 812.2(b) or that
meets the requirements for exempted investigations under Sec.
812.2(c), to the extent the exempted investigation would be subject to
part 56. This proposed exception would encompass research that presents
a lower risk to subjects and, in certain instances, may not involve a
therapeutic intervention or invasive procedure (e.g., studies of
certain diagnostic devices). The proposed exception would also
encompass research that is not focused on bringing new devices to the
market for patients. Therefore, the initial administrative burden of
establishing cooperative review agreements may not be offset by the
anticipated benefits of single IRB review efficiencies, such as
improvement in the review and handling of safety reports and faster
initiation of research that facilitates the development of new medical
products.
In developing this proposed rule, FDA also considered
recommendations provided by the Secretary's Advisory Committee on Human
Research Protections (SACHRP) to the Secretary of HHS regarding
additional categories of research that would be potentially appropriate
for exception from the requirement to use a single IRB.\13\ FDA is
requesting feedback from stakeholders on the following specific
circumstances to assist the agency in determining whether additional
exceptions to the single IRB review requirement would be warranted.
---------------------------------------------------------------------------
\13\ Secretary's Advisory Committee on Human Research
Protections: Recommendations for IRB Review: Attachment D--Granting
Exceptions for Single IRB Review for Multi-Site Research (March 13,
2018) https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-d-points-to-consider-granting-exceptions-to-requirements-for-single-institutional-review-board-review-for-multi-site-research/index.html.
---------------------------------------------------------------------------
First, FDA is requesting comment on whether it is appropriate to
include an exception for cooperative research for which use of a single
IRB is unable to meet the needs of specific populations. Such an
exception might apply, for example, to research that involves
recruiting members of a distinct patient population or community (e.g.,
cultural, religious) for which the local perspective is particularly
important if the single IRB of record is unable to obtain sufficient
supplemental information to consider that community's needs. SACHRP
recommended that this exception be considered and provided the
following example that illustrates when this exception may be
appropriate: There may be an instance where research involves ``an
intervention with pregnant women at one site and then follow-up with
the neonates at another site. Unless a single IRB had adequate
expertise in pregnant women, obstetrical practices, and neonatal
medicine, human subject protections might best be served by having the
elements relevant to pregnant women reviewed by an IRB that has
extensive expertise with that area and the elements relevant to the
neonates reviewed by a pediatric IRB.'' \14\ In this example,
particularly for obstetrical or pediatric research that involves
complex medical issues, a single obstetrical or pediatric consultant on
an IRB that mainly reviews research in adults may not have the
sufficient range of expertise necessary to review the protocol. In
these instances, utilizing an IRB with obstetrical expertise and a
separate, pediatric IRB that has extensive experience in neonatal
research may be in the best interest of the two populations of research
subjects.
---------------------------------------------------------------------------
\14\ Ibid.
---------------------------------------------------------------------------
We request comment on whether a single IRB of record would
generally be able to supplement its members' knowledge and experience
with additional information or expertise to account for these
situations, examples of FDA-regulated research for which these
circumstances would apply, and any data on the frequency of how often
this situation may occur.
FDA is also requesting comment on including an exception for
cooperative research with a small number of investigational sites.
SACHRP recommended that research involving five or fewer
investigational sites should be considered as potentially appropriate
for exception to the single IRB review requirement.\15\ FDA is
requesting feedback on whether an exception from single IRB review
might be warranted for a multisite study with a small number of sites,
what the benefits and burdens are for a multisite study with a small
number of sites, and what the appropriate threshold should be for the
number of sites involved. In addition, we request any specific data
that can be provided on the relationship between the number of sites
and the value of single IRB review.
---------------------------------------------------------------------------
\15\ Ibid.
---------------------------------------------------------------------------
In addition, FDA recognizes that situations may arise in which a
federally conducted or supported FDA-regulated
[[Page 58760]]
clinical investigation would qualify for an exception from single IRB
review under this proposed rule but would not qualify for an exception
determination issued by a Common Rule Department or Agency pursuant to
45 CFR 46.114(b)(2)(ii) of the revised Common Rule (or vice versa).
Both the revised Common Rule and FDA's proposed rule still permit use
of a single IRB for review and approval of cooperative research even if
an exception applies. However, we are requesting public comment on any
impact that such differences in exceptions from the single IRB review
requirement may have on stakeholders, and on possible approaches to
avoid or minimize any potential negative effects of such differences
for stakeholders, such as whether additional exceptions from the
proposed single IRB review requirement should be included or whether
providing guidance on the application of FDA's proposed exceptions
might help avoid or minimize any differences in exceptions.
We also specifically request comment on whether there are unique
challenges to use of a single IRB review model for FDA-regulated
cooperative research that could not be addressed by FDA's proposed
exceptions. For any challenges identified, we seek comment on whether
additional exceptions should be included to address them. For example,
should FDA consider including an exception analogous to the revised
Common Rule's exception at 45 CFR 46.114(b)(2)(ii)? As explained above,
we do not believe it is practicable to rely on a broad exemption that
would provide for FDA to make case-by-case determinations that use of
single IRB review is not appropriate for the particular context as the
only means for excepting FDA-regulated cooperative research--other than
research for which more than single IRB review is required by law--from
the proposed new requirement. The Agency also believes that situations
in which use of a single IRB might not be appropriate and in which none
of FDA's proposed exceptions apply would be rare. However, we seek
comment on whether including an exception that provides for FDA to
determine and document that single IRB review is not appropriate for
the particular context, in addition to the exceptions FDA has proposed,
could help address any such situations and any negative impacts of
differences between FDA's proposed exceptions and exceptions available
under the revised Common Rule to a Common Rule Department or Agency
supporting or conducting cooperative research.
Lastly, FDA is requesting comment on the proposed exceptions and
any other criteria that should be considered when assessing whether an
exception to the use of single IRB review might be warranted. We also
encourage the public to provide examples of any additional types of
FDA-regulated clinical investigations that they believe should qualify
for such an exception. To help stakeholders comply with these proposed
requirements, if finalized, FDA intends to update our guidance on using
a centralized IRB review process in multicenter clinical trials.\16\
---------------------------------------------------------------------------
\16\ See FDA's ``Guidance for Industry: Using a Centralized IRB
Review Process in Multicenter Clinical Trials'' (March 2006).
Available at: https://www.fda.gov/media/75329/download.
---------------------------------------------------------------------------
C. Single IRB Review for Research Not Subject to Sec. 56.114(b)
FDA is proposing new regulatory text at Sec. 56.114(c) to specify
that an institution participating in cooperative research that is not
subject to the requirement for single IRB review at Sec. 56.114(b) may
enter into a joint review arrangement, rely on the review of another
IRB, or make similar arrangements for avoiding duplication of effort.
This proposed regulatory text differs from the revised Common Rule at
45 CFR 46.114(c) by use of the term ``research,'' rather than
``project.'' We believe that the term ``research'' better reflects the
terminology used throughout FDA's existing human subject protection
regulations. In addition, we note that, even if one of the proposed
exceptions under Sec. 56.114(b)(2) applies to a study, use of single
IRB review would still be permitted under this proposed provision.
In some cases, FDA-regulated clinical investigations are also
Federally conducted or supported and, thus, subject to the revised
Common Rule. It is possible that such studies could fit within a
proposed exception from FDA's proposed requirement for use of single
IRB review but may be required under the revised Common Rule to use
single IRB review. In these instances, proposed Sec. 56.114(c) would
still permit use of a single IRB for review and approval of the
cooperative research.
D. IRB Records
FDA is proposing new regulatory text at Sec. 56.115(a)(8) to
require documentation of an institution's reliance on an external IRB
for oversight of research. FDA is proposing to require, for research
that takes place at an institution in which IRB oversight is conducted
by an IRB that is not operated by the institution, the institution, or
where appropriate the IRB, must retain documentation specifying 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 part 56 (e.g., in a written agreement between
the institution and the IRB, 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,
or as set forth in a research protocol). This proposed provision is
consistent with the revised Common Rule's requirements at 45 CFR
46.103(e) and 45 CFR 46.115(a)(9). This proposed requirement is
necessary for documenting compliance with part 56 to provide a record
for FDA's oversight and compliance purposes.
V. Proposed Effective Date
FDA is proposing that any final rule that may issue based on this
proposal become effective 1 year after the final rule is published in
the Federal Register to allow the FDA-regulated community that is not
subject to the revised Common Rule's single IRB review requirement
appropriate time to prepare to implement FDA's proposed single IRB
review requirement. FDA is proposing that any such final rule would
apply to FDA-regulated cooperative research initially approved by an
IRB on or after the proposed effective date. Therefore, ongoing
cooperative research that is initially approved by an IRB prior to the
proposed effective date would be permitted, but not required, to use a
single IRB review process, consistent with FDA's current regulations at
Sec. 56.114.
VI. Preliminary Economic Analysis of Impacts
We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, the Regulatory Flexibility Act (5
U.S.C. 601-612), and the Unfunded Mandates Reform Act of 1995 (Pub. L.
104-4). Executive Orders 12866 and 13563 direct us to assess all costs
and benefits of available regulatory alternatives and, when regulation
is necessary, to select regulatory approaches that maximize net
benefits (including potential economic, environmental, public health
and safety, and other advantages; distributive impacts; and equity).
This proposed rule has been designated an economically significant
regulatory action as defined by Executive Order 12866.
[[Page 58761]]
The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because small entities affected by this proposed rule would
incur net cost savings, we propose to certify that the rule, if
finalized, will not have a significant economic impact on a substantial
number of small entities. However, as discussed in the Preliminary
Economic Analysis of Impacts (Ref. 5), there is a lack of high quality,
comprehensive data regarding the number of small and very small
institutions associated with IRBs, as defined by revenue. We have
prepared an initial regulatory flexibility analysis and are seeking
comment on the data and assumptions used in that analysis.
The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to 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 $165 million, using the most current (2020) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
result in an expenditure in any year that meets or exceeds this amount.
The proposed rule, if finalized, would require any institution
located in the United States participating in FDA-regulated cooperative
research to rely on approval by a single IRB for that portion of the
research that is conducted in the United States, with some exceptions.
The proposed rule would harmonize, to the extent practicable and
consistent with statutory provisions, FDA's requirements for
cooperative research with the requirements of the revised Common Rule
in accordance with section 3023 of the Cures Act. This proposed rule
should reduce the administrative and coordination costs of conducting
FDA-regulated cooperative research by: (1) reducing duplicative
reviews; (2) facilitating an earlier start of cooperative research; and
(3) reducing the need to reconcile variability in IRB review decisions
for cooperative research conducted with a common protocol. Reducing the
costs of conducting cooperative research should reduce the costs of
FDA-regulated medical product development and facilitate an earlier
start of cooperative research, which could contribute to a faster
introduction of those products into commercial use. Table 1 summarizes
our estimate of the annualized costs and the annualized benefits of the
proposed rule, if finalized.
Table 1--Summary of Benefits and Costs of the Proposed Rule
[$millions]
--------------------------------------------------------------------------------------------------------------------------------------------------------
Units
------------------------------------
Category Primary Low High Period Notes
estimate estimate estimate Year Discount covered
dollars rate (%) (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
Annualized Monetized $millions/ $453 $117 $1,016 2017 7 10 Benefits are cost savings.
year. 457 117 1,024 2017 3 10 Benefits are cost savings
Annualized Quantified............. .......... .......... .......... .......... .......... .......... ........................................
-----------------------------------------------------------------------------------------------------------------
Qualitative....................... Greater consumer satisfaction and
producer profits from reduced
medical product development costs
and faster commercial
introduction.
-----------------------------------------------------------------------------------------------------------------
Costs:
Annualized Monetized $millions/ 78 30 134 2017 7 10 ........................................
year. 74 30 127 2017 3 10 ........................................
Annualized Quantified............. .......... .......... .......... .......... .......... .......... ........................................
-----------------------------------------------------------------------------------------------------------------
Qualitative....................... Education, training, liability
coverage, providing local context
information, and loss of funding
to relying IRBs.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
Federal Annualized Monetized .......... .......... .......... .......... .......... .......... ........................................
$millions/year.
-----------------------------------------------------------------------------------------------------------------
From:
To:
-----------------------------------------------------------------------------------------------------------------
Other Annualized Monetized .......... .......... .......... .......... .......... .......... ........................................
$millions/year.
-----------------------------------------------------------------------------------------------------------------
From:
To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
State, Local or Tribal Government: None.............................................................................................................
Small Business: None................................................................................................................................
Wages: None.........................................................................................................................................
Growth: None........................................................................................................................................
--------------------------------------------------------------------------------------------------------------------------------------------------------
We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. The full
preliminary analysis of economic impacts is available in the docket for
this proposed rule (Ref. 5) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.
VII. Analysis of Environmental Impact
We have determined under 21 CFR 25.30(h) 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.
[[Page 58762]]
VIII. Paperwork Reduction Act of 1995
This proposed rule contains information collection provisions that
are subject to review by OMB under the PRA (44 U.S.C. 3501-3521). A
description of these provisions is given in the Description section of
this section with an estimate of the annual recordkeeping burden.
Included in the estimate is the time for reviewing instructions,
searching existing data sources, gathering and maintaining the data
needed, and completing and reviewing each collection of information.
FDA invites comments on these topics: (1) whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) 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 technology.
Title: Institutional Review Boards--21 CFR part 56 (OMB Control
Number 0910-0130--Revision).
Description: The proposed rule, if finalized, would add Sec.
56.115(a)(8) to require, for FDA-regulated research that takes place at
an institution in which IRB oversight is conducted by an IRB that is
not operated by the institution, documentation specifying the
institution's reliance on the IRB for oversight of the research and the
responsibilities each entity will undertake to ensure compliance with
part 56 (``IRB reliance agreements''). This might be accomplished in a
written agreement between the institution and the IRB, 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, or as set forth in a research
protocol. This proposed recordkeeping requirement is necessary for
documenting compliance with part 56 to provide a record for FDA's
oversight and compliance purposes in cases when IRB oversight is not
conducted by an IRB that is operated by the institution (e.g.,
cooperative research).
Description of Respondents: Respondents to the information
collection are IRBs that review and approve clinical investigations
regulated by FDA.
We estimate the burden of the information collection as follows:
Table 2--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Average burden
21 CFR part 56--Institutional Review Boards Number of records per Total annual per Total hours
recordkeepers recordkeeper records recordkeeping
--------------------------------------------------------------------------------------------------------------------------------------------------------
56.115(a)(8); Required Documentation............................... 2,520 10 25,200 15 378,000
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
There are approximately 2,520 IRBs that review FDA-regulated
research. We estimate that most IRBs will need to set up 10 IRB
reliance agreements and that each agreement will require an average of
15 hours to complete.
To ensure that comments on information collection are received, OMB
recommends that written comments be submitted through reginfo.gov (see
ADDRESSES). All comments should be identified with the title of the
information collection.
In compliance with the PRA (44 U.S.C. 3407(d)), FDA has submitted
the information collection provisions of this proposed rule to OMB for
review. These requirements will not be effective until FDA obtains OMB
approval. FDA will publish a notice concerning OMB approval of these
requirements in the Federal Register.
IX. Consultation and Coordination With Indian Tribal Governments
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the rule does not contain policies that would have a
substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. We solicit comments from tribal officials
on any potential impact on Indian Tribes from this proposed action.
X. Federalism
We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. We have determined that
the proposed rule does not contain policies that 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. Accordingly,
we conclude that the rule does not contain policies that have
federalism implications as defined in the Executive order and,
consequently, a federalism summary impact statement is not required.
XI. References
The following references marked with an asterisk (*) are on display
at the Dockets Management Staff (see ADDRESSES) and are available for
viewing by interested persons between 9 a.m. and 4 p.m., Monday through
Friday; they also are available electronically at https://www.regulations.gov. References without asterisks are not on public
display at https://www.regulations.gov because they have copyright
restriction. Some may be available at the website address, if listed.
References without asterisks are available for viewing only at the
Dockets Management Staff. FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.
1. Flynn K.E, C.L. Hahn, J.M. Kramer, et al. (2013), ``Using Central
IRBs for Multicenter Clinical Trials in the United States,'' PLOS
ONE 8(1): e54999.
2. Greene, S.M. and A.M. Geiger (2006), ``A Review Finds that
Multicenter Studies Face Substantial Challenges but Strategies Exist
to Achieve Institutional Review Board Approval,'' Journal of
Clinical Epidemiology 59 (2006) 784-790.
3. Check D.K., K.P. Weinfurt, C.B. Dombeck, et.al. (2013), ``Use of
Central Institutional Review Boards for Multicenter Clinical Trials
in the United States: A Review of the Literature,'' Clinical Trials
10: 560-567.
4. Massett, H.A., S.L. Hampp, J.L. Goldberg, et al. (2018),
``Meeting the Challenge: The National Cancer Institute's Central
Institutional Review Board for Multi-Site Research,'' Journal of
Clinical Oncology 36(8): 819-824.
[[Page 58763]]
5. *FDA, Preliminary Economic Analysis of Impacts, Docket No. FDA-
2019-N-2175, available at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.
List of Subjects in 21 CFR Part 56
Human research subjects, Reporting and recordkeeping requirements,
Safety.
Therefore, under authority delegated to the Commissioner of Food
and Drugs, we propose that 21 CFR part 56 be amended as follows:
PART 56--INSTITUTIONAL REVIEW BOARDS
0
1. The authority citation for part 56 is revised to read as follows:
Authority: 21 U.S.C. 321, 343, 346, 346a, 348, 350a, 350b, 351,
352, 353, 355, 360, 360c-360f, 360h, 360i, 360j, 360hh-360pp, 360rr-
360ss, 371, 379e, 381; 42 U.S.C. 216, 241, 262.
0
2. Revise Sec. 56.114 to read as follows:
Sec. 56.114 Cooperative research.
(a) Cooperative research covered by these regulations is a clinical
investigation that involves more than one institution. In the conduct
of cooperative research, each institution is responsible for
safeguarding the rights and welfare of human subjects and for complying
with these regulations.
(b)(1) Any institution located in the United States that is
participating in cooperative research must rely upon approval by a
single IRB for that portion of the research that is conducted in the
United States.
(2) Research is not subject to paragraph (b)(1) of this section if
at least one of the following criteria is met:
(i) Cooperative research for which more than single IRB review is
required by law (including tribal law passed by the official governing
body of an American Indian or Alaska Native tribe);
(ii) Cooperative research involving a highly specialized FDA-
regulated medical product for which unique, localized expertise is
required;
(iii) Cooperative research on drugs that meets the exemptions from
an investigational new drug application under Sec. 312.2(b) of this
chapter; or
(iv) Cooperative research on medical devices that meets the
abbreviated requirements under Sec. 812.2(b) of this chapter, or that
meets the requirements for exempted investigations under Sec. 812.2(c)
of this chapter.
(c) For research not subject to paragraph (b) of this section, an
institution participating in cooperative research may enter into a
joint review arrangement, rely on the review of another IRB, or make
similar arrangements for avoiding duplication of effort.
0
3. Amend Sec. 56.115 by adding paragraph (a)(8) to read as follows:
Sec. 56.115 IRB records.
(a) * * *
(8) For research that takes place at an institution in which IRB
oversight is conducted by an IRB that is not operated by the
institution, documentation specifying 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 part (e.g., in a written agreement between the institution and the
IRB, 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, or as set forth
in a research protocol).
* * * * *
Dated: September 23, 2022.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2022-21089 Filed 9-27-22; 8:45 am]
BILLING CODE 4164-01-P