[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