[Federal Register Volume 87, Number 187 (Wednesday, September 28, 2022)]
[Proposed Rules]
[Pages 58733-58752]
[FR Doc No: 2022-21088]

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Proposed Rules
                                                Federal Register
________________________________________________________________________

This section of the FEDERAL REGISTER contains notices to the public of
the proposed issuance of rules and regulations. The purpose of these
notices is to give interested persons an opportunity to participate in
the rule making prior to the adoption of the final rules.

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Federal Register / Vol. 87, No. 187 / Wednesday, September 28, 2022 /
Proposed Rules

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 50, 56, and 812

[Docket No. FDA-2021-N-0286]
RIN 0910-AI07

Protection of Human Subjects and Institutional Review Boards

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA or Agency) is proposing
to amend its regulations to modernize, simplify, and enhance the
current system for oversight of FDA-regulated human subject research.
This proposed rule, if finalized, would harmonize certain sections of
FDA's regulations on human subject protection and institutional review
boards (IRBs), to the extent practicable and consistent with other
statutory provisions, with the revised Federal Policy for the
Protection of Human Subjects (the revised Common Rule), in accordance
with the 21st Century Cures Act (Cures Act). We believe the proposed
changes, if finalized, will reduce regulatory burden on IRBs, sponsors,
and investigators. In addition, we propose related changes to the
investigational device exemption (IDE) regulations to clarify and
update the requirements for the submission of progress reports.

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 by November 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-2021-N-0286 for ``Protection of Human Subjects and Institutional
Review Boards.'' Received comments, those filed in a timely manner (see
ADDRESSES), will be placed in the docket and, except for 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,<PHONE_NUMBER>.
     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.'' The Agency 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,<PHONE_NUMBER>.
    Submit comments on information collection issues 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 ``Protection of

Human Subjects and Institutional Review Boards--21 CFR parts 50 and 56
(OMB Control Number 0910-0130)''.

FOR FURTHER INFORMATION CONTACT: With regard to the proposed rule:
Sheila Brown, Office of Clinical Policy, Food and Drug Administration,
10903 New Hampshire Ave., Silver Spring, MD 20993-0002,<PHONE_NUMBER>,
[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,<PHONE_NUMBER>,
[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. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. Human Subject Protection Requirements Under the Revised
Common Rule
    B. FDA's Current Regulatory Framework
    C. The Cures Act
    D. Need for the Regulation
IV. Legal Authority
V. Description of the Proposed Rule
    A. 21 CFR Part 50--Protection of Human Subjects
    B. 21 CFR Part 56--Institutional Review Boards
    C. 21 CFR Part 812--Investigational Device Exemptions
VI. Proposed Effective Date
VII. Preliminary Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs and Benefits
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
    A. Protection of Human Subjects and Institutional Review
Boards--Parts 50 and 56
    B. Investigational Device Exemptions--Part 812
X. Consultation and Coordination With Indian Tribal Governments
XI. Federalism
XII. Reference

I. Executive Summary

A. Purpose of the Proposed Rule

    The purpose of this proposed rule is to modernize, simplify, and
enhance the current system for oversight of FDA-regulated human subject
research. We propose to harmonize certain sections of FDA's regulations
on human subject protection (part 50 (21 CFR part 50)) and IRBs (part
56 (21 CFR part 56)), to the extent practicable and consistent with
other statutory provisions, with the revised Common Rule,\1\ in
accordance with section 3023 of the Cures Act (Pub. L. 114-255, enacted
December 13, 2016).\2\ The rule also proposes to revise FDA's
regulations on IDEs (part 812 (21 CFR part 812)) to clarify and update
the requirements for submission of progress reports for clinical
investigations of devices. We are also proposing minor technical and
editorial changes to the regulations for clarity. FDA believes that
these proposed changes, if finalized, would help ensure clarity and
enhance both human subject protection and the IRB review process. In
addition, harmonizing with the revised Common Rule would reduce
regulatory burden for IRBs, sponsors, and investigators.
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    \1\ For the purposes of this proposed rule, the phrase ``revised
Common Rule'' refers to the final rule (82 FR 7149, January 19,
2017), modified by the interim final rule that delayed the effective
date and general compliance date (83 FR 2885, January 22, 2018) and
the 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).
    \2\ The term ``harmonize,'' as used in this proposed rule means,
``harmonize to the extent practicable and consistent with other
statutory provisions,'' consistent with section 3023 of the Cures
Act.
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B. Summary of the Major Provisions of the Proposed Rule

    This proposed rule, if finalized, would amend parts 50 and 56 of
FDA's regulations. Among other things, we are proposing to: (1) revise
the content, organization, and presentation of information included in
the informed consent form and process to facilitate a prospective
subject's decision about whether to participate in the research; (2)
add new basic and additional elements of informed consent; (3) add a
provision that would allow IRBs to eliminate continuing review of
research in certain circumstances; (4) revise the IRB recordkeeping
requirements for certain determinations related to the need for
continuing review; and (5) add or modify some definitions. We are also
proposing to revise one section of part 812 regarding progress reports
submitted by investigators and sponsors to a reviewing IRB for
consistency with other revisions we are proposing to the continuing
review process in part 56.

C. Legal Authority

    The provisions under which FDA is proposing to issue this rule
include 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

    The primary quantifiable benefit of the proposed rule is a
decreased time burden to IRBs, investigators, and sponsors of clinical
trials from increased harmonization with the revised Common Rule.
Quantifiable costs include the development of informed consent
documents and additional recordkeeping burdens. The estimated
annualized cost savings of the proposed rule range from approximately
$22 to $103 million in 2018 dollars, with a central estimate of
approximately $43 million, discounted at 7 percent over 10 years. At 3
percent, estimates of annualized cost savings range from approximately
$22 to $103 million, with a central estimate of approximately $43
million. Estimated annualized costs of the proposed rule range from
approximately $0.7 million to $2.3 million, with a central estimate of
approximately $1.2 million, discounted at 7 percent. At 3 percent,
estimates of annualized costs range from approximately $0.6 million to
$2.0 million, with a central estimate of approximately $1.1 million.
The impact of the proposed provisions is analyzed in the Preliminary
Economic Analysis of Impacts for this proposed rule.

II. Table of Abbreviations/Commonly Used Acronyms in This Document

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     Abbreviation/acronym                    What it means
------------------------------------------------------------------------
Cures Act....................  21st Century Cures Act (Pub. L. 114-255).
FDA..........................  Food and Drug Administration.
IRB..........................  Institutional Review Board.
FD&C Act.....................  Federal Food, Drug, and Cosmetic Act.
FR...........................  Federal Register.
HHS..........................  Department of Health and Human Services.
IDE..........................  Investigational Device Exemption.

IND..........................  Investigational New Drug Application.
LAR..........................  Legally Authorized Representative.
NIH..........................  National Institutes of Health.
OHRP.........................  Office for Human Research Protections.
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.
WGS..........................  Whole Genome Sequencing.
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III. Background

A. Human Subject Protection Requirements Under the Revised Common Rule

    The Federal Policy for the Protection of Human Subjects, codified
by the Department of Health and Human Services (HHS) at 45 CFR part 46,
subpart A, and generally referred to as the Common Rule, sets forth
requirements for the protection of human subjects involved in research
that is conducted or supported by HHS. The Common Rule was issued in
1991 \3\ and has been adopted by other Federal Departments and
Agencies. The purpose of the Common Rule is to promote uniformity,
understanding, and compliance with human subject protections and to
create a uniform body of regulations across the Federal Departments and
Agencies.\4\ On January 19, 2017, HHS announced revisions to modernize,
strengthen, and make the Common Rule more effective. 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 the regulated community.\5\
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    \3\ 56 FR 28001, June 18, 1991.
    \4\ 80 FR 53933 at 53935, September 8, 2015.
    \5\ 82 FR 7149, January 19, 2017.
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B. FDA's Current Regulatory Framework

    FDA's regulations for the protection of human subjects at parts 50
and 56 apply to clinical investigations, as defined at current
Sec. Sec.  50.3(c) and 56.102(c), regardless of the source of funding.
These regulations, which include requirements for informed consent and
IRBs, are intended to protect the rights, safety, and welfare of
subjects involved in clinical investigations involving FDA-regulated
products.
    Prior to the most recent revision to the Common Rule, FDA's
regulations regarding the protection of human subjects were largely
consistent with the requirements in the Common Rule, with a few
exceptions generally arising from differences in FDA's mission or
statutory authority. FDA-regulated research that is HHS-conducted or
HHS-supported is subject to both HHS's and FDA's regulations. Many IRBs
review both types of research and must comply with both sets of
regulations. FDA and the Office for Human Research Protections (OHRP)
have been actively working together for many years to harmonize
regulatory requirements and guidance.

 C. The Cures Act

    On December 13, 2016, the Cures Act was signed into law with its
purpose of accelerating the discovery, development, and delivery of
21st century cures.\6\ 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.\7\ Section
3023 of the Cures Act further directs the Secretary of HHS to, as
appropriate, make modifications to those regulations, in order to,
among other things, reduce regulatory duplication and unnecessary
delays. FDA is working with other HHS Agencies in carrying out this
statutory mandate, and this proposed rule is being issued in accordance
with this provision.
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    \6\ Public Law 114-255.
    \7\ Public Law 114-255, title III, section 3023, December 13,
2016.
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D. Need for the Regulation

    As described above, FDA's regulations governing the protection of
human subjects largely have been consistent with the requirements of
the Common Rule, with a few exceptions generally due to differences in
FDA's mission and statutory authority. The revised Common Rule includes
provisions intended to strengthen the effectiveness of the human
subject protection regulations, and FDA is proposing to harmonize with
certain provisions in the revised Common Rule that are applicable to
FDA-regulated clinical investigations. For example, proposed new basic
and additional elements of informed consent, along with new
requirements for the presentation of information in the consent form,
would help facilitate a prospective subject's decision about whether to
participate in the research and facilitate the enrollment process. In
addition, FDA is proposing to harmonize with the revised Common Rule by
adding provisions that reduce burden on IRBs and that are intended to
allow IRBs to focus their resources on research that presents higher
risk, thereby enhancing human subject protection. Harmonization will
also reduce confusion and regulatory burden for the oversight of
studies that are subject to both the revised Common Rule and FDA
regulations.
    This proposed rule does not address all of the provisions contained
in the revised Common Rule. The Agency has addressed some of these
provisions in a previously issued proposed rule \8\ and is also
considering how other provisions of the revised Common Rule that are
potentially relevant to FDA-regulated research, such as provisions
related to single IRB review for cooperative research, posting of
informed consent forms, broad consent, limited IRB review, exempt
research, and public health surveillance activities, could be applied
to FDA-regulated research. FDA plans to take additional steps to
harmonize FDA's regulations with the revised Common Rule, to the extent
practicable and consistent with statutory provisions.
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    \8\ See FDA's notice of proposed rulemaking, ``Institutional
Review Board Waiver or Alteration of Informed Consent for Minimal
Risk Clinical Investigations,'' 83 FR 57378, November 15, 2018
(https://www.govinfo.gov/content/pkg/FR-2018-11-15/pdf/2018-24822.pdf).
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IV. Legal Authority

    FDA is proposing to issue this rule under the Agency's 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. Requirements for informed consent and IRB
review also help protect the rights and welfare of human subjects
involved in those clinical investigations. Section 701(a) of the FD&C
Act authorizes the Agency to issue regulations for the efficient
enforcement of the FD&C Act.
    These statutory provisions authorize FDA to issue the proposed
revisions to its regulations to enhance protection of human subjects
and the IRB review process for FDA-regulated clinical investigations.

V. Description of the Proposed Rule

A. 21 CFR Part 50--Protection of Human Subjects

    We propose to revise part 50 by adding new requirements, including
revised definitions intended to enhance human subject protections.
These proposed revisions would require presentation of information in
the informed consent document to be in an organized and understandable
manner, and to include a concise and focused presentation of the key
information most likely to assist a prospective subject in
understanding the reasons why the subject might or might not want to
participate in the research. The new proposed provisions also include a
new basic element of informed consent and three new additional elements
of informed consent. New proposed definitions include the definitions
of private information, identifiable private information, and
identifiable biospecimen. FDA is also proposing to make grammatical
corrections or other editorial changes to provide clarity. Table 1
summarizes the proposed changes to part 50 that would harmonize with
the revised Common Rule.

                Table 1--Proposed Revisions to Part 50 To Harmonize With the Revised Common Rule
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                                                                     Harmonizes with revised Common Rule section
           Section No.                     FDA proposes to:                       (45 CFR part 46)
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50.3(l)..........................  Add a sentence to the            46.102(i).
                                    definition of legally
                                    authorized representative
                                    (LAR) to address situations in
                                    which there is no applicable
                                    State or local law governing
                                    who may act as a LAR.
50.3(t)..........................  Add a definition of ``written    46.102(m).
                                    or in writing'' that includes
                                    both physical and electronic
                                    formats.
50.3(u)..........................  Add a definition of ``private    46.102(e)(4).
                                    information''.
50.3(v)..........................  Add a definition of              46.102(e)(5).
                                    ``identifiable private
                                    information''.
50.3(w)..........................  Add a definition of              46.102(e)(6).
                                    ``identifiable biospecimen''.
50.20............................  Add provisions (d) and (e) for   46.116(a)(1)-(6).
                                    organizing and presenting
                                    information about the research
                                    to subjects; redesignate or
                                    make minor editorial changes
                                    to other portions of the
                                    paragraph.
50.25(a).........................  Add ``or legally authorized      46.116(b).
                                    representative'' to clarify to
                                    whom informed consent
                                    information must be provided.
50.25(a)(9)......................  Add a basic element of informed  46.116(b)(9).
                                    consent that would require a
                                    description of how information
                                    or biospecimens may be used
                                    for future research or
                                    distributed for future
                                    research.
50.25(b).........................  Add ``or the legally authorized  46.116(c).
                                    representative'' to the end of
                                    the sentence to clarify to
                                    whom informed consent
                                    information must be provided.
50.25(b)(2)......................  Add ``or legally authorized      46.116(c)(2).
                                    representative's'' to clarify
                                    that the investigator may
                                    terminate the research without
                                    the consent of the subject or
                                    the LAR.
50.25(b)(7)-(9)..................  Add three new additional         46.116(c)(7)-(9).
                                    elements of informed consent,
                                    including a statement as to
                                    how private information or
                                    biospecimens collected during
                                    the research may be used for
                                    commercial profit and whether
                                    the subject will or will not
                                    share in this commercial
                                    profit, whether clinically
                                    relevant results will be
                                    disclosed to study subjects,
                                    and for research involving
                                    biospecimens, whether the
                                    research involves whole genome
                                    sequencing.
50.25(d).........................  Add a reference to tribal law    46.116(i).
                                    of American Indian or Alaska
                                    Native tribes, to clarify that
                                    the reference to ``Federal,
                                    State, or local law'' is
                                    intended to include tribal
                                    laws; make minor editorial
                                    changes.
50.25(e).........................  Add a reference to tribal law    46.116(j).
                                    of American Indian or Alaska
                                    Native tribes, to clarify that
                                    the reference to ``Federal,
                                    State, or local law'' is
                                    intended to include tribal law.
50.27(a).........................  Add a parenthetical to provide   46.117(a).
                                    for consent forms in an
                                    electronic format and add
                                    ``informed consent'' before
                                    ``form''.
50.27(b)(1)......................  Add ``or the subject's legally   46.117(b)(1).
                                    authorized representative''
                                    (to clarify that the subject
                                    or LAR shall have the
                                    opportunity to read the
                                    informed consent form);
                                    reorder the sentences and make
                                    minor editorial changes.
50.27(b)(2)......................  Add a sentence to clarify that   46.117(b)(2)
                                    when using a short form
                                    written informed consent, the
                                    key information must be
                                    presented first to the subject
                                    before other information, if
                                    any, is provided, and add
                                    ``legally authorized
                                    representative'' in three
                                    places; reorder sentences and
                                    make minor editorial changes.
----------------------------------------------------------------------------------------------------------------

1. Definitions
    We propose to harmonize our definition of ``legally authorized
representative'' at Sec.  50.3(l) with the definition in the revised
Common Rule at 45 CFR 46.102(i), by adding a sentence to address
situations in which there is no applicable State or local law that
authorizes a LAR to provide consent on behalf of a prospective research
subject. We propose that in these circumstances, an individual
recognized by institutional policy as acceptable for providing consent
in the nonresearch context may be considered a LAR for purposes of
consenting to the subject's participation in the procedures involved in
the research.
    In addition, we propose to add several new definitions that are
used in the revised Common Rule. At Sec.  50.3(t), we propose to add
the definition of ``written or in writing,'' which would harmonize with
this definition in the revised Common Rule, at 45 CFR 46.102(m). The
definition would include both paper and electronic

formats, the latter of which are increasingly used to fulfill many of
the documentation requirements that appear throughout FDA's human
subject protection regulations. This definition would help clarify that
consent forms and related documentation (e.g., written summaries of
what is said to subjects and LARs when a short form consent is used in
accordance with Sec.  50.27(b)(2) and IRB findings required under Sec.
50.24) may be in an electronic format.
    FDA is proposing to add three new definitions for the terms
``private information,'' ``identifiable private information,'' and
``identifiable biospecimen.'' The terms ``identifiable private
information,'' and ``identifiable biospecimen'' and/or references to
biospecimens are found in new proposed elements of informed consent at
Sec.  50.25(a)(9), (b)(7), and (b)(9), and in the proposed provisions
regarding IRB continuing review at Sec.  56.109(g)(1).\9\ FDA is
proposing to add these new terms and definitions to help modernize our
regulations to reflect the changing research landscape involving, for
example, access to vast amounts of data from electronic health records
and stored biospecimens, the ability to share data and biospecimens for
research purposes, and the development of new technologies and analytic
capabilities to advance science and the public health.
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    \9\ We also note that FDA issued a proposed rule on November 15,
2018, that proposed to permit an IRB to approve an informed consent
procedure that waives or alters certain informed consent elements or
that waives the requirement to obtain informed consent for certain
minimal risk studies, when the IRB finds and documents four
criteria. The proposed rule invited comment on a fifth criterion for
IRB waiver or alteration of informed consent that was added to the
revised Common Rule at 45 CFR 46.116(f)(3)(iii) and reads, ``if the
research involves using identifiable private information or
identifiable biospecimens, the research could not practicably be
carried out without using such information or biospecimens in an
identifiable format'' (see 83 FR 57378 at 57381). The comment period
on the proposed rule is closed, and FDA is in the process of
reviewing comments received on this fifth criterion. If the proposed
rule is finalized in a form that includes the fifth criterion, the
final provision would include references to ``identifiable private
information'' and ``identifiable biospecimen''.
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    We propose to add, at Sec.  50.3(u), a definition of ``private
information'' that harmonizes with the definition of ``private
information'' in the revised Common Rule, at 45 CFR 46.102(e)(4).
Private information includes information about behavior that occurs in
a context in which an individual can reasonably expect that no
observation or recording is taking place, and information that has been
provided for specific purposes by an individual and that the individual
can reasonably expect will not be made public (e.g., a medical record).
    We propose to add, at Sec.  50.3(v), a definition of ``identifiable
private information'' to harmonize with the revised Common Rule's
definition of ``identifiable private information'' at 45 CFR
46.102(e)(5). We propose to define ``identifiable private information''
as private information for which the identity of the subject is or may
readily be ascertained by the sponsor or investigator or associated
with the information. This definition differs from the text of the
revised Common Rule provision by including information for which a
subject's identity is or may be readily ascertained by the ``sponsor''
in addition to information that is or may be readily ascertained by the
investigator. FDA would consider information for which a subject's
identity is or may be readily ascertained by members of the research
team conducting the investigation under the supervision of the
investigator to be ``identifiable private information'' under this
proposed definition.
    FDA's regulations define the terms ``sponsor'' and
``investigator,'' and they are used throughout our regulations to
describe the responsibilities that apply to certain parties involved in
FDA-regulated research. OHRP has stated in guidance that it considers
the term ``investigator'' to include ``anyone involved in conducting
the research,'' \10\ which is broader than the definition of an
``investigator'' under FDA's regulations (see, e.g., Sec.  50.3(d)).
FDA believes that information for which a subject's identity is or may
readily be ascertained by the sponsor of FDA-regulated research should
be considered identifiable; and we believe adopting such an approach
will help to harmonize the effects of the two sets of regulations.
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    \10\ See OHRP's 2008 Guidance, ``Coded Private Information or
Specimens Use in Research'', https://www.hhs.gov/ohrp/regulations-and-policy/guidance/research-involving-coded-private-information/index.html (accessed January 29, 2021).
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    We propose to add, at Sec.  50.3(w), a definition of ``identifiable
biospecimen,'' to harmonize with the revised Common Rule's definition
of ``identifiable biospecimen'' at 45 CFR 46.102(e)(6). For the same
reasons described above with respect to the definition of
``identifiable private information'', we propose to define an
identifiable biospecimen as a biospecimen for which the identity of the
subject is or may readily be ascertained by the sponsor or investigator
or associated with the biospecimen.
    The revised Common Rule also includes a provision at 45 CFR
46.102(e)(7)(i) that requires the Federal Departments and Agencies
implementing the revised Common Rule, upon consultation with
appropriate experts, to reexamine the meaning of the terms
``identifiable private information'' and ``identifiable biospecimen''
within 1 year and regularly thereafter (at least every 4 years). That
provision further provides that if appropriate and permitted by law,
these Federal Departments and Agencies may alter the interpretation of
these terms, including through the use of guidance. FDA intends to
participate in this effort with HHS and the other Federal Departments
and Agencies.
2. General Requirements for Informed Consent
    We propose to amend the general requirements for informed consent
under Sec.  50.20 to harmonize with the revised Common Rule at 45 CFR
46.116(a)(1) through (6). These requirements address the content,
organization, and presentation of information included in the consent
form and process to facilitate a prospective subject's decision about
whether to participate in the research. To this end, we propose to
redesignate our existing requirements as Sec.  50.20(a), (b), (c), and
(f) and add new paragraphs (d) and (e). New paragraph (d) would clarify
that the prospective subject or the subject's legally authorized
representative must be provided with the information that a reasonable
person would want to have to make an informed decision about whether to
participate and be given an opportunity to discuss that information.
    In new Sec.  50.20(e)(1) and (2), we propose to require that
informed consent begin with a concise and focused presentation of the
key information that is most likely to assist a prospective subject or
LAR in understanding the reasons why the subject might or might not
want to participate in the research, and that the information be
organized and presented in a way that facilitates the subject's or
LAR's comprehension.
3. Elements of Informed Consent
    We propose to add the phrase ``or legally authorized
representative'' to Sec.  50.25(a) and (b), to harmonize with the
revised Common Rule at 45 CFR 46.116(b) and (c), and to clarify to whom
informed consent information must be provided.
    We propose to add a new basic element of informed consent at Sec.
50.25(a)(9) to harmonize with the

revised Common Rule at 45 CFR 46.116(b)(9) and enhance human subject
protections. While FDA is not proposing to use language verbatim from
the revised Common Rule for this new basic element of informed consent
at Sec.  50.25(a)(9), our proposal similarly requires the provision of
additional information to potential subjects about the possible future
use of their information or biospecimens. This information will help
subjects make informed decisions about whether to participate in a
particular clinical investigation.
    The element of informed consent in the revised Common Rule at 45
CFR 46.116(b)(9) requires that subjects be provided with one of two
statements that address research that involves the collection of
identifiable private information or identifiable biospecimens.\11\
Under the revised Common Rule, identifiers could be removed from
information or biospecimens collected as part of a study and the
information or specimens could then be used for some secondary research
without informed consent or IRB review. The element of informed consent
at 45 CFR 46.116(b)(9) would inform subjects of that possibility when
applicable.
---------------------------------------------------------------------------

    \11\ This may be either: (1) a statement that identifiers may be
removed from the identifiable private information or identifiable
biospecimens, and the information or biospecimens may be used for
future research studies or distributed to another investigator for
future research studies, without obtaining additional informed
consent from the subject or legally authorized representative if
this might be a possibility or (2) a statement that the subject's
information or biospecimens, even if the identifiers are removed,
will not be used or distributed for future research.
---------------------------------------------------------------------------

    FDA's proposed new element would require a description of how
information or biospecimens may be used for future research or
distributed to another investigator for future research. While FDA's
proposed element is not limited to the two situations addressed by the
statements required under the corresponding element of the revised
Common Rule, the research community would be able to develop informed
consent forms and processes that comply with both sets of regulations.
For example, if appropriate, an investigator may use one of the
statements provided in the revised Common Rule to satisfy FDA's
proposed requirement. When applicable, an investigator would also be
required to provide a description that conveys to subjects the possible
future use of their identifiable biospecimens or information that may
not be stripped of identifiers.
    In addition, as noted above, Congress passed the Cures Act with a
stated purpose of accelerating the discovery, development, and delivery
of 21st century cures. FDA has been working to modernize its approach
to evaluating innovative medical products as new technologies and
sources of data create new options for generating and analyzing
evidence regarding FDA-regulated products. Such technological advances
may have the potential to, for example, streamline and improve the
efficiency of clinical studies, but they may also raise new questions
in the future about the applicability of certain FDA regulatory
requirements, including requirements for informed consent. Therefore,
we are concerned about the practicability of limiting this proposed
element of informed consent to the two situations addressed by the
statements required under the Common Rule at this time. FDA's proposal
is intended to incorporate flexibility as to the description that an
investigator would provide to each subject or the legally authorized
representative to help ensure that subjects are informed regarding
possible future uses of information and biospecimens collected from
their participation in a clinical investigation as the ways in which
information and biospecimens are used relevant to FDA-regulated
products continue to evolve. We request public comment on whether FDA's
proposed new basic element of informed consent at Sec.  50.25(a)(9)
would provide adequate notice to potential subjects regarding the
possible future research use of their information and biospecimens or
whether the Common Rule's provision at 45 CFR 46.116(b)(9) would better
inform potential subjects about the possible future use of their
information and biospecimens in research. We further request public
comment on whether the research community anticipates challenges in
implementing FDA's proposed new element and whether an alternative
approach could lessen such challenges.
    FDA is proposing to add three new additional elements of informed
consent, Sec.  50.25(b)(7), (8), and (9), to harmonize with the revised
Common Rule at 45 CFR 46.116(c)(7), (8), and (9), respectively. Section
50.25(b)(7) would require a statement that the subject's biospecimens
(even if identifiers are removed) may be used for commercial profit and
whether the subject will or will not share in this commercial profit.
Section 50.25(b)(8) would require a statement on whether clinically
relevant research results, including individual research results, will
be disclosed to subjects, and if so, under what conditions. Section
50.25(b)(9) pertains to research involving biospecimens and would
require that subjects be informed whether the research will (if known),
or might, include whole genome sequencing (WGS). The preamble to the
revised Common Rule noted that WGS generates an extremely large amount
of information about people, including factors that will contribute to
their future medical conditions. The Common Rule goes on to state
``Given the unique implications of the information that can be
developed through WGS, if it is either known that a specific research
study will include this technique, or might include it, we believe that
this aspect of the research must be disclosed to prospective subjects
as part of the informed consent process.'' \12\ FDA agrees that it is
important for prospective subjects to be informed when a clinical
investigation involves or may involve WGS, and is, therefore, proposing
to add this new element.
---------------------------------------------------------------------------

    \12\ 82 FR 7149 at 7216, January 19, 2017.
---------------------------------------------------------------------------

4. References to Federal, State, or Local Law
    We propose to revise Sec.  50.25(d) and (e) by adding a reference
to tribal law passed by the official governing body of an American
Indian or Alaska Native tribe, to clarify that references to Federal,
State, or local law are intended to include tribal law. This proposed
change would harmonize FDA regulations with the revised Common Rule at
45 CFR 46.116(i) and (j).
5. Documentation of Informed Consent
    We propose to add a parenthetical to Sec.  50.27(a), to clarify
that consent forms in an electronic format are an acceptable format and
add the term ``informed consent'' before the term ``form'' to harmonize
the regulatory text with the revised Common Rule at 45 CFR 46.117(a).
    We are proposing to revise Sec.  50.27(b)(1) and (2) to include
references to a subject's legally authorized representative. We are
proposing to reorder sentences and make other changes in Sec.
50.27(b)(1) to clarify that the subject or legally authorized
representative shall have adequate opportunity to read the informed
consent form. We are proposing to revise Sec.  50.27(b)(2) to require
that the key information required by Sec.  50.20 be presented first
when using a short form written informed consent. These changes are
being proposed to better inform potential subjects about participation
in a clinical investigation, and to

harmonize with the revised Common Rule at 45 CFR 46.117(b)(1) and (2).
    FDA is not proposing to add the new provision found in the revised
Common Rule at 45 CFR 46.116(g) at this time. This provision allows
IRBs to approve a research proposal for which investigators obtain
information or biospecimens without an individual's informed consent
for the purpose of screening, recruiting, or determining eligibility of
the prospective human subject or LAR if either of the following
conditions are met: (1) the investigator will obtain information
through oral or written communication with the prospective subject or
LAR or (2) the investigator will obtain identifiable private
information or identifiable biospecimens by accessing records or stored
identifiable biospecimens.
    FDA's longstanding policy on preparatory activities to a clinical
investigation is that some specific activities are not considered to
fall within the definition of a clinical investigation, and therefore
do not require IRB review or informed consent under FDA's regulations.
For example, we generally have not considered performing a survey of
patient records at a site to determine whether the site has a
sufficient number of patients with the condition of interest for the
clinical investigation to be feasible to require informed consent and
IRB review. However, IRB review and informed consent would need to be
obtained prior to initiation of any clinical screening procedure that
is performed solely for the purpose of determining eligibility for a
clinical investigation.\13\ We request comment on whether FDA's current
policy adequately addresses screening, recruiting, or determining
eligibility for an FDA-regulated clinical investigation, or if
including the revised Common Rule provision at 45 CFR 46.116(g) would
be useful for FDA-regulated clinical investigations. Furthermore, FDA
is proposing to make grammatical corrections, updates to statutory
references, and other minor editorial changes to part 50. Throughout
part 50 a global change has been made to spell out references to ``the
act'', to conform to current Federal Register format requirements.
Table 2 contains a description of amendments that are unrelated to
harmonization with the revised Common Rule.
---------------------------------------------------------------------------

    \13\ See FDA's guidance entitled, ``Screening Tests Prior to
Study Enrollment, Guidance for Institutional Review Boards and
Clinical Investigators,'' January 1998, available at https://www.fda.gov/regulatory-information/search-fda-guidance-documents/screening-tests-prior-study-enrollment.

 Table 2--Proposed Revisions to Part 50 Unrelated to Harmonization With
                         the Revised Common Rule
------------------------------------------------------------------------
         Section No.                        FDA proposes to:
------------------------------------------------------------------------
50.1(a)......................  Remove specific statutory provisions in
                                final sentence and make minor wording
                                changes.
50.3(b)(20) and 50.3(j)......  Update references to certain provisions
                                of the PHS Act.
50.3(b)(16)-(19), (23).......  Clarify that citations in this section of
                                the regulatory text are to the FD&C Act.
50.3(i)......................  Add a sentence to the definition of IRB
                                to state the primary purpose of IRB
                                review is to assure the protection of
                                the rights and welfare of human
                                subjects.
50.24(a)(6)..................  Revise the citation at the end of the
                                first sentence from ``Sec.   50.25'' to
                                ``this part'' to simplify the regulatory
                                text and ensure that both the informed
                                consent procedures and document are
                                consistent with part 50.
50.25(c).....................  Add heading to conform to current Federal
                                Register format requirements.
------------------------------------------------------------------------

    We propose to modify Sec.  50.1(a) to remove the list of statutory
provisions in the final sentence because the scope of part 50 is
already described in the provision. In addition, removing these
provisions will delete certain out of date citations and eliminate the
need to update statutory references in the future. Similarly, we
propose to modify Sec.  50.3(b)(20) and (j) to remove outdated
references to certain provisions of the PHS Act. We propose to clarify
that references in Sec.  50.3(b)(16) through (19) and (23) are to
sections of the FD&C Act.
    We propose to add the following sentence, ``The primary purpose of
such review is to assure the protection of the rights and welfare of
the human subjects'' to the definition of ``institutional review
board'' at Sec.  50.3(i), to be consistent with our current definition
of IRB at Sec.  56.102(g).
    We propose to revise the citation in Sec.  50.24(a)(6) from ``Sec.
50.25'' to ``this part,'' to simplify the regulatory text, and to
clarify that both the informed consent procedures and documents for
studies conducted under Sec.  50.24 must be consistent with part 50.
    We also propose to add a heading to Sec.  50.25(c), ``Required
statement in informed consent documents for applicable clinical
trials,'' to conform to current Federal Register format requirements.

B. 21 CFR Part 56--Institutional Review Boards

    We propose to revise part 56 to modify provisions related to
continuing review, add or modify definitions, and make clarifying
editorial changes. FDA believes that these proposed changes will help
modernize, clarify, and enhance both human subject protection and the
IRB review process. Table 3 identifies sections in which FDA proposes
to harmonize our regulatory requirements with language in the revised
Common Rule.

                Table 3--Proposed Revisions to Part 56 To Harmonize With the Revised Common Rule
----------------------------------------------------------------------------------------------------------------
                                                                           Harmonizes with revised common rule
               Section No.                       FDA Proposes to:               section  (45 CFR part 46)
----------------------------------------------------------------------------------------------------------------
56.102(n)................................  Add a definition of          46.102(m).
                                            ``written or in writing''
                                            that includes both
                                            physical and electronic
                                            formats.
56.103(c)................................  Add a reference to tribal    46.101(f).
                                            law of American Indian or
                                            Alaska Native tribes to
                                            clarify that the reference
                                            to Federal, State, or
                                            local laws is intended to
                                            include tribal law; make
                                            minor editorial changes.

56.107(a)................................  Make minor changes to        46.107(a).
                                            characteristics of IRB
                                            members and the
                                            description of categories
                                            of subjects who are
                                            considered vulnerable.
56.107(b)................................  Delete Sec.   56.107(b)      46.107(a).
                                            because the requirement
                                            for IRB membership
                                            diversity would be
                                            included in Sec.
                                            56.107(a); redesignate
                                            remaining sections--see
                                            table 4.
56.108(a)(2).............................  Move IRB member list         46.108(a)(2).
                                            details from Sec.
                                            56.115(a)(5) to
                                            56.108(a)(2) and make
                                            minor editorial changes.
56.108(a)(3)(i)-(iii)....................  Make editorial changes to    46.108(a)(3)(i), (ii) and (iii).
                                            the requirements for IRB
                                            written procedures.
56.108(a)(4)(i)-(ii), 56.108(b)..........  Make editorial changes and   46.108(a)(4).
                                            redesignate the sections.
56.109(b)................................  Add ``or legally authorized  46.109(b).
                                            representatives, when
                                            appropriate'' to clarify
                                            that subjects or LARs must
                                            be given informed consent
                                            information in accordance
                                            with Sec.   50.25.
56.109(c)(3).............................  Add a new exception to the   46.117(c)(1) and (c)(1)(iii).
                                            requirement for
                                            documentation of informed
                                            consent in specific
                                            circumstances.
56.109(d)................................  Provide that LARs may also   46.117(c)(2).
                                            receive written
                                            statements, if required by
                                            the IRB, when
                                            documentation of informed
                                            consent is waived.
56.109(f)................................  Add reference to Sec.        46.109(e).
                                            56.109(g).
56.109(g)................................  Eliminate the requirement    46.109(f)(1)(iii).
                                            to conduct continuing
                                            review of research under
                                            certain circumstances.
56.110(b)................................  Remove parenthetical         46.110(b)(1)(ii).
                                            phrase, ``(of 1 year or
                                            less)''.
56.111(a)(3).............................  Revise the description of    46.111(a)(3).
                                            subjects who may be
                                            considered vulnerable.
56.111(a)(5).............................  Delete the phrase ``and to   46.111(a)(5).
                                            the extent required'' from
                                            the requirement to
                                            document informed consent
                                            in accordance with Sec.
                                            50.27.
56.111(b)................................  Revise the description of    46.111(b).
                                            subjects who are
                                            considered vulnerable.
56.115(a)(3).............................  Add a requirement to retain  46.115(a)(3).
                                            records of the rationale
                                            for continuing review of
                                            research that otherwise
                                            would not require
                                            continuing review under
                                            Sec.   56.109(g).
----------------------------------------------------------------------------------------------------------------

1. Definitions
    We are proposing to add a new definition, ``written or in
writing'', at Sec.  56.102(n), which would harmonize with the
definition in the revised Common Rule at 45 CFR 46.102(m). The new
definition would include both paper and electronic formats, the latter
of which are increasingly used to fulfill many of the documentation
requirements that appear throughout the IRB and human subject
protection regulations. Adding this definition would provide clarity to
the regulated community that IRB records may be maintained in
electronic formats.
2. Tribal Law and IRB Review
    We are proposing to add a reference to tribal law passed by the
official governing body of an American Indian or Alaska Native tribe to
clarify that the reference to Federal, State, or local laws or
regulations, is intended to include tribal law. This proposed revision
would also harmonize Sec.  56.103(c) with the revised Common Rule at 45
CFR 46.101(f).
3. IRB Membership
    We are proposing to amend Sec.  56.107(a) to harmonize with the
revised Common Rule's language at 45 CFR 46.107(a), which describes
characteristics of IRB membership. We propose deleting Sec.  56.107(b),
which requires IRBs to ensure that their membership not consist
entirely of a single gender and prohibits IRB membership from being
composed entirely of members of one profession. Section 56.107(b) is no
longer necessary because it would be subsumed into proposed Sec.
56.107(a), which would require that an IRB's membership reflects
diversity of professional qualifications, and other factors including
race, gender, and cultural backgrounds.
4. IRB Functions and Operations
    We propose moving the details about IRB membership rosters from
Sec.  56.115(a)(5) to Sec.  56.108(a)(2) and making editorial changes
to harmonize the language with the revised Common Rule at 45 CFR
46.108(a)(2). We are also proposing editorial and technical revisions
to Sec.  56.108, including redesignating some sections, to harmonize
with the revised Common Rule.
5. IRB Review of Research
    We propose adding ``or legally authorized representative, when
appropriate'' to Sec.  56.109(b), to clarify that subjects or legally
authorized representatives must be given informed consent information
in accordance with Sec.  50.25, and to harmonize with the revised
Common Rule at 45 CFR 46.109(b).
    We propose adding new Sec.  56.109(c)(3) to add an exception to the
requirement for documentation of informed consent, to harmonize with
the revised Common Rule at 45 CFR 46.117 (c)(1)(iii). The new provision
would allow the IRB to waive documentation of informed consent for a
study that presents no more than minimal risk of harm to the subjects,
if the subjects or legally authorized representatives are members of a
distinct cultural group or community in which signing forms is not the
norm, and there is an appropriate alternative mechanism for documenting
that informed consent was obtained.
    We note that the revised Common Rule also retains an exception to
the requirement for documentation of informed consent at 45 CFR
46.117(c)(1)(i) for situations in which the only record linking the
subject and the research would be the informed consent form and the
principal risk would be potential harm resulting from a breach of
confidentiality. FDA's regulations historically have not included this
same exception, and we are not proposing to add it in this rulemaking
because we do not believe it is relevant to FDA-regulated research. We
are, however, requesting comment on whether this provision is relevant
to FDA-regulated research and any examples of situations when it would
be useful.
    We propose adding ``or legally authorized representatives'' to
Sec.  56.109(d), to clarify that legally authorized representatives may
also

receive written statements about the research, if required by the IRB,
when documentation of informed consent is waived, and to harmonize with
the revised Common Rule at 45 CFR 46.117(c)(2).
    We are proposing new Sec.  56.109(g), which would eliminate the
requirement for an IRB to conduct continuing review of research, unless
an IRB determines otherwise, that has progressed to the point that it
involves only data analysis, including analysis of identifiable private
information or identifiable biospecimens, and/or accessing followup
clinical data from procedures that subjects would undergo as part of
clinical care, to harmonize with the revised Common Rule at 45 CFR
46.109(f)(1)(iii). In these circumstances, FDA believes that requiring
continuing review would generally not provide added protection to human
subjects, and therefore, would not be necessary. When the only
remaining research activities are limited to analysis of data or
biospecimens that are part of the IRB-approved study, there is little
or no risk to human subjects that would be addressed by requiring
continuing review. Furthermore, after all subjects have enrolled and
completed the protocol-specified interventions and interactions
(including required followup study visits) to support the study's
objectives, a protocol may include a long-term followup phase during
which subjects continue to be monitored as they undergo clinical care
for their medical condition or disease by their healthcare provider.
During this continued followup phase, information regarding long-term
clinical outcomes may be obtained through accessing clinical data
generated during the course of clinical care. This proposed rule would
eliminate the requirement for continuing IRB review for this followup
portion of the study, unless the IRB determines otherwise.\14\ This
proposal to eliminate the requirement for continuing IRB review in
certain circumstances would apply to FDA-regulated studies that are
ongoing on the proposed effective date (see Section VI, Proposed
Effective Date below). If any such ongoing studies were federally
conducted or supported and also subject to the pre-2018 Requirements
(see 45 CFR 46.101(l)(1), then the pre-2018 Requirements for continuing
review would continue to apply to those studies.
---------------------------------------------------------------------------

    \14\ However, FDA would still receive annual reports from
sponsors on the progress of such studies in accordance with 21 CFR
312.33 and 812.150(b)(5)).
---------------------------------------------------------------------------

    The revised Common Rule contains two other provisions identifying
circumstances in which continuing review would not be necessary at 45
CFR 46.109(f)(1)(i) and (ii). We are not proposing to adopt the revised
Common Rule provision at 45 CFR 46.109(f)(1)(i), which eliminates the
requirement for an IRB to conduct continuing review of research that is
eligible for expedited review in accordance with 45 CFR 46.110 unless
the IRB determines otherwise. As described below, OHRP has clarified
that, in order for research to qualify for expedited review under the
current list of research eligible for expedited review referenced in 45
CFR 46.110(a), a determination must still be made by an IRB that the
specific circumstances of the proposed research involve no more than
minimal risk to human subjects. It is not practicable for FDA to adopt
this provision because continuing review for minimal risk FDA-regulated
clinical investigations would provide meaningful protections to human
subjects participating in such investigations. For example, as a study
progresses, the analysis of risks to subjects receiving a FDA-regulated
product may change based on adverse events that occur during the course
of the study and that do not rise to the level of unanticipated
problems involving risks to human subjects or otherwise require
reporting to the IRB. Continued IRB oversight of such studies would
offer added human subject protection to those participating in such
investigations by enabling the IRB to assess whether there are any
additional risks that present more than minimal risk to participants
and require discussion and/or action. Furthermore, for clinical
investigations that are subject to both FDA's human subject regulations
and the revised Common Rule, the Common Rule provision at 45 CFR
46.109(f)(1)(i) allows an IRB to determine that continuing review of
research eligible for expedited review is required.
    Finally, we are not proposing to adopt provisions from the revised
Common Rule related to limited IRB review at this time, including 45
CFR 46.109(f)(1)(ii). As we continue to consider how other provisions
of the revised Common Rule could be applied to FDA-regulated research,
including the revised Common Rule's exemptions, we may take additional
steps to harmonize with such provisions at a later time.
    In addition, as described below, we are proposing changes to the
IDE regulations at Sec.  812.150(a)(3) and (b)(5) to align the IRB
progress reporting requirements with these proposed changes to IRB
continuing review requirements under part 56.
    We propose reordering and redesignating the remaining language in
Sec.  56.109(f), and current Sec.  56.109(g) and (h) as Sec.
56.109(g), (h), and (i), respectively.
6. Expedited Review
    FDA's current regulations under Sec.  56.110(a) state that FDA has
established, and published in the Federal Register, a list of
categories of research that may be reviewed by the IRB through an
expedited review procedure (``expedited review list'').\15\ FDA is not
proposing any changes to Sec.  56.110(a) at this time, and the
categories of research included on the expedited review list referenced
in Sec.  56.110(a) are identical to the categories of research included
on the expedited review list referenced in 45 CFR 46.110(a) (``HHS
Expedited Review List'').\16\ The revised Common Rule requires that the
Secretary evaluate the HHS expedited review list at least every 8 years
and amend it, as appropriate, after consultation with other Federal
Departments and Agencies and after publication in the Federal Register
for public comment (45 CFR 46.110(a)). We intend to participate in this
process and will update our own expedited review list, as appropriate
for FDA-regulated studies.
---------------------------------------------------------------------------

    \15\ See ``Protection of Human Subjects: Categories of Research
That May Be Reviewed by the Institutional Review Board (IRB) Through
an Expedited Review Procedure,'' 63 FR 60353, November 9, 1998.
    \16\ See ``Protection of Human Subjects: Categories of Research
That May Be Reviewed by the Institutional Review Board (IRB) Through
an Expedited Review Procedure,'' 63 FR 60364, November 9, 1998.
---------------------------------------------------------------------------

    As described in the revised Common Rule, an IRB may use the
expedited review procedure to review studies that involve activities
appearing on the expedited review list, unless the IRB reviewer
determines that the studies involve more than minimal risk (see 45 CFR
46.110(b)(1)(i)). OHRP has clarified that until a new list is
finalized, the entire 1998 HHS Expedited Review List, including the
``Applicability'' section, remains in effect for studies subject to the
revised Common Rule.\17\ Under the current wording of the
``Applicability'' section, to be eligible for expedited review research
must present no more than minimal risk to subjects. Therefore,

application of the 1998 HHS Expedited Review List means that, in order
for research to qualify for expedited review under the revised Common
Rule, a determination must still be made that the specific
circumstances of the proposed research involve no more than minimal
risk to human subjects.
---------------------------------------------------------------------------

    \17\ See OHRP, Revised Common Rule Q&As: After January 21, 2019
(the general compliance date for the revised Common Rule), is the
1998 Expedited Review List still in effect for studies subject to
the revised Common Rule?, https://www.hhs.gov/ohrp/education-and-outreach/revised-common-rule/revised-common-rule-q-and-a/index.html
(accessed August 6, 2019).
---------------------------------------------------------------------------

    Under FDA's current regulations at Sec.  56.110(b)(1), an IRB may
use the expedited review procedure to review ``[s]ome or all of the
research appearing on the list and found by the reviewer(s) to involve
no more than minimal risk.'' Because the HHS Expedited Review List,
including its ``Applicability'' section, is still in effect and lists
the same categories of research as FDA's expedited review list, IRBs
will be able to use the same procedures to review research that may be
reviewed via expedited review under the revised Common Rule and FDA's
current regulations.
    We also note that the current expedited review list (63 FR 60353,
November 9, 1998) describes categories of research that include FDA-
regulated clinical investigations that may involve more than minimal
risk. For example, Category 1 from the current expedited review list
describes clinical studies of drugs and medical devices that meet
certain conditions, including those that do not require an IND or those
for which an IDE application is not required. FDA does not believe that
all drug and device studies that do not require an IND or an IDE
application qualify as minimal risk. Given this, FDA does not presume
all clinical investigations of drugs or medical devices that do not
require an IND or an IDE application present no more than minimal risk
to subjects. Category 4 also describes clinical studies using medical
devices that may not qualify as minimal risk. Therefore, FDA is
maintaining the requirement that the reviewer determine that the
research involves no more than minimal risk and is only proposing a
minor change to the regulatory text in current Sec.  56.110(b) at this
time. We propose to remove the parenthetical phrase ``(of 1 year or
less)'' from Sec.  56.110(b)(2) to harmonize with the revised Common
Rule at 45 CFR 46.110(b)(1)(ii) because continuing review would not be
required in certain circumstances unless the IRB determines otherwise
(see Sec.  56.109(g)).
    As HHS evaluates and amends, as appropriate, its current expedited
review list as described above and as required under 45 CFR 46.110(a),
FDA intends to participate in the process and will update our own
expedited review list as appropriate and consider if any related
changes to our regulations are necessary.
7. Criteria for IRB Approval of Research
    We are proposing to add, at Sec.  56.111(a)(3) and (b), updated
language consistent with the revised Common Rule, describing categories
of subjects who are considered vulnerable to coercion or undue
influence, specifically ``. . . children, prisoners, individuals with
impaired decision-making capacity, or economically or educationally
disadvantaged persons.'' This proposal, if finalized, also would
harmonize these sections with the language in the revised Common Rule
at 45 CFR 46.111(a)(3) and (b). To simplify our regulatory text, FDA is
also proposing to delete the phrase ``to the extent required by'' from
Sec.  56.111(a)(5), so that the requirement would read ``Informed
consent will be appropriately documented or appropriately waived, in
accordance with Sec.  50.27 of this chapter.'' FDA's proposed revision
differs slightly from the revised Common Rule at 45 CFR 46.111(a)(5),
which states that informed consent will be appropriately documented or
appropriately waived in accordance with 45 CFR 46.117. We are not
proposing to include the reference to waiver of documentation as this
is addressed under Sec.  50.27.
8. IRB Review of Research
    We are proposing to add at Sec.  56.115(a)(3), language that would
require the IRB to maintain a record of the rationale for conducting
continuing review, if the IRB determines that continuing review of
research is necessary (when the research otherwise would not require
continuing review under Sec.  56.109(g)). This proposed change would
also harmonize the regulations with the language in the revised Common
Rule at 45 CFR 46.115(a)(3). The revised Common Rule includes a new
recordkeeping requirement at 45 CFR 46.115(a)(8) related to changes
made to the regulatory provision at 45 CFR 46.110(b)(1)(i) regarding
review of research found on the HHS Expedited Review List. For the
reasons described above, FDA is not proposing to make the same change
to its expedited review provision at Sec.  56.110(b)(1) and,
accordingly, is not proposing to add the related recordkeeping
requirement.
    We are proposing to revise Sec.  56.115(a)(5) by moving the details
about IRB membership rosters from that section to Sec.  56.108(a)(2),
to harmonize the language with the revised Common Rule at 45 CFR
46.115(a)(5) and 46.108(a)(2).
    Table 4 lists sections that will be moved, redesignated, or
divided, with minor editorial changes to the regulatory text in some
cases.

 Table 4--Proposed Revisions to Numbering for Regulatory Text in Part 56
------------------------------------------------------------------------
     Current section No.              Proposed revised section No.
------------------------------------------------------------------------
56.107(c)....................  56.107(b).
56.107(d)....................  56.107(c).
56.107(e)....................  56.107(d).
56.107(f)....................  56.107(e).
56.108.......................  Redesignated to begin with 56.108(a).
56.108(a)(1).................  56.108(a)(3)(i).
56.108(a)(2).................  56.108(a)(3)(ii).
56.108(a)(3).................  56.108(a)(3)(iii).
56.108(b)....................  56.108(a)(4).
56.108(c)....................  56.108(b).
56.109(f)....................  Divided into two sections, 56.109(f) and
                                (h).
56.109(g)....................  56.109(i).
56.109(h)....................  56.109(j).
------------------------------------------------------------------------

    FDA also proposes to make minor changes to the current regulatory
text and to delete outdated or unnecessary regulatory text from part 56
(see table 5). In addition, throughout part 56 a global change has been
made to spell out references to ``the act'', to conform to current
Federal Register format requirements.

  Table 5--Proposed Minor Changes to or Deletion of Regulatory Text in
                                 Part 56
------------------------------------------------------------------------
         Section No.                        FDA proposes to:
------------------------------------------------------------------------
56.102(b)(17)................  Remove outdated reference to the PHS Act,
                                add corresponding FD&C Act reference.
56.102(l)....................  Replace outdated references to sections
                                of the PHS Act.
56.103(a)....................  Delete the reference to 21 CFR part 813,
                                which was removed from FDA's regulations
                                in 1997.
56.109(h) (now 56.109(j))....  Delete the second sentence referring to
                                pediatric studies that were ongoing on
                                April 30, 2001, because it is no longer
                                needed.
56.110(b)....................  Changed reference to Sec.   56.108(c) to
                                Sec.   56.108(b) because of
                                redesignating of sections.
56.110(c)....................  Changed ``which'' to ``that'' in two
                                places.
56.115(a)(6).................  Revise the citation to written procedure
                                provisions to reflect redesignating.
56.121(c)....................  Delete ``in the Federal Register,''
                                because notices may now be posted on the
                                FDA website.
56.122.......................  Modify section title from ``revocation''
                                to ``disqualification,'' and clarify
                                that disqualification of an IRB is also
                                disclosable to the public.
------------------------------------------------------------------------

9. Disqualification of an IRB or Institution
    We are proposing to revise Sec.  56.121(c) by deleting the phrase
``in the Federal Register'' from the last sentence. This proposed
change would clarify that FDA is not limited to publishing
disqualification notices in the Federal Register but may use other
available and appropriate methods to apprise the public of IRB
disqualification actions. For example, FDA now routinely posts such
information on the Agency's website.\18\
---------------------------------------------------------------------------

    \18\ https://www.fda.gov/ScienceResearch/SpecialTopics/RunningClinicalTrials/ComplianceEnforcement/default.htm.
---------------------------------------------------------------------------

10. Public Disclosure of Information Regarding Disqualification
    We are proposing to revise Sec.  56.122 by modifying the section
title to change ``revocation'' to ``disqualification,'' and clarify
that FDA's determination of disqualification of an IRB, as well as an
institution, is disclosable to the public under 21 CFR part 20.

C. 21 CFR Part 812--Investigational Device Exemptions

    We are proposing to revise Sec.  812.150(a)(3), that requires
investigators to submit progress reports on the investigation to the
sponsor, the monitor, and the reviewing IRB at regular intervals, but
in no event less often than yearly. The proposed revisions would
provide that such progress reports must be submitted to the reviewing
IRB to the extent that continuing review is required by part 56.
Elsewhere in this document, FDA is proposing to revise part 56 to
eliminate the requirement for IRB continuing review of research under
certain circumstances, and FDA does not believe that submission of
progress reports to the IRB remains necessary when continuing review of
the research by the IRB is not required. This proposed revision to
Sec.  812.150(a)(3) is intended to provide consistency between the
continuing review requirements under part 56 and the requirements for
submission of IDE progress reports to the IRB.
    We also propose revising Sec.  812.150(b)(5), which currently
provides, among other things, that sponsors must submit progress
reports to all reviewing IRBs at regular intervals, and at least
yearly. For the same reasons described above regarding Sec.
812.150(a)(3), FDA is proposing to require sponsors to submit such
progress reports to the reviewing IRB to the extent that continuing
review is required by part 56. The sponsors of an IDE will continue to
submit progress reports to FDA at regular intervals and at least yearly
under Sec.  812.150(b)(5), and as may be requested under Sec.
812.150(b)(10), regardless of whether there is continuing IRB review.
FDA is proposing to maintain this reporting requirement for continued
oversight of investigations that require submission of an IDE
application to ensure the Agency receives information regarding the IDE
investigation. The proposed rule maintains the requirement that
sponsors of treatment IDEs submit semi-annual and annual progress
reports to all reviewing IRBs and FDA in accordance with Sec. Sec.
812.36(f) and 812.150(b)(5).
    FDA is not proposing to amend the requirements for treatment IDEs
at Sec.  812.36(f), which require semi-annual progress reports to both
FDA and the IRB(s) until a marketing application is filed. After filing
of a marketing application, Sec.  812.36(f) requires progress reports
to be submitted at least annually in accordance with the IDE
regulations at Sec.  812.150(b)(5). Our proposed changes to Sec.
812.150(b)(5) would require progress reports to be submitted to
reviewing IRBs to the extent that continuing review is required by part
56. As such, after filing of a marketing application, submission of
annual progress reports for a treatment IDE to the reviewing IRB would
be required only to the extent that continuing review is required under
part 56.

VI. Proposed Effective Date

    FDA is proposing that the effective date of any final rule that
issues based on this proposal would be 180 days from the date of
publication of the final rule to allow the regulated community time to
prepare to implement the proposed changes. FDA requests comment on this
timeframe.
    In addition, FDA's goal is to minimize disruption to FDA-regulated
studies that are ongoing when the proposed new requirements would
become effective, and we are proposing an implementation strategy to
address research initially approved by an IRB before the proposed
effective date. For these studies, FDA would not intend to enforce
compliance with the following proposed provisions:
     proposed new Sec.  50.20(d) through (e), which would,
among other things, require informed consent to begin with a concise
and focused presentation of ``key information'' and would require
informed consent information to be organized and presented in certain
ways;
     the proposed new basic and additional elements of informed
consent at Sec.  50.25(a)(9) and (b)(7) through (9); and
     the proposed revision to Sec.  50.27(b)(2), which would
require the key information required by Sec.  50.20 to be presented
first to the subject or the subject's legally authorized representative
when informed consent information is provided orally and documented
using a short form.
    This approach reflects FDA's concern that, for research an IRB has
approved before the proposed effective date, revising the already
approved informed consent form and process to comply with the
provisions identified above could cause unwarranted burden and, in some
cases, delay research. However, nothing in this proposal would prevent
sponsors and investigators from

updating the consent forms for research that was approved before the
proposed effective date to comply with the above-listed provisions. We
request comment on this proposed approach.

VII. Preliminary Economic Analysis of Impacts

A. Introduction

    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.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because estimated cost savings of the proposed rule are
greater in magnitude than estimated costs, and because we do not expect
the effects of the rule to affect entities by size, 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. 1),
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 $158 million, using the most current (2020) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.

B. Summary of Costs and Benefits

    If finalized, the proposed rule would: (1) revise content,
organization, and presentation of the information included in the
informed consent form and process to facilitate a prospective subject's
decision about whether to participate in a clinical investigation; (2)
add new basic and additional elements of informed consent; (3) add a
provision allowing IRBs to eliminate continuing review of some
research; (4) revise IRB recordkeeping requirements for certain
determinations related to the need for continuing review; and (5) add
or modify some definitions. The rule also proposes to revise FDA's
regulations IDEs (part 812) to clarify and update the requirements for
submission of progress reports for clinical investigations of devices.
    The proposed rule would harmonize certain aspects of FDA's
regulations on IRBs and informed consent processes, to the extent
practicable and consistent with statutory provisions, with the
requirements of the revised Common Rule in accordance with section 3023
of the Cures Act. The proposed rule should reduce the costs of
conducting clinical investigations by harmonizing informed consent and
certain continuing review processes for FDA-regulated research with the
revised Common Rule. The proposed rule will also generate costs that we
estimate will be relatively smaller than expected cost savings in the
form of additional time spent learning the rule, developing new
informed consent documents in line with the rule, and revised
recordkeeping requirements related to continuing review. We also expect
qualitative benefits that we do not estimate explicitly due to data
limitations, including increased efficiency of clinical investigations
and medical product development and improved human subject knowledge by
providing subjects with clearer clinical investigation information.
Table 6 summarizes our estimates of the annualized costs and annualized
benefits (in the form of cost savings) of the proposed rule.
    The benefits of the proposed rule take the form of quantified net
cost savings (cost savings minus costs) and qualitative benefits. We
estimate that the benefits of the proposed rule are approximately $68
million annually in 2018 dollars, with a lower bound of approximately
$22 million and an upper bound of approximately $249 million,
discounted at 7 percent over 10 years. When discounted at 3 percent,
estimated benefits are approximately $68 million annually, with a lower
bound of approximately $22 million and an upper bound of approximately
$249 million. We also expect quantitative benefits in the form of cost
savings from increased efficiency in medical product innovation and in
the form of improved human subject knowledge. We estimate that the
costs of the proposed rule are approximately $1.4 million annually in
2018 dollars, with a lower bound of approximately $0.7 million and an
upper bound of approximately $3.0 million, discounted at 7 percent over
10 years. When discounted at 3 percent, estimated costs are
approximately $1.3 million annually, with a lower bound of
approximately $0.6 million and an upper bound of approximately $2.6
million. These estimates are summarized in table 6.

                                     Table 6--Summary of Benefits, Costs and Distributional Effects of Proposed Rule
                                                                       [millions$]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                          Primary       Low        High    ------------------------------------
               Category                  estimate    estimate    estimate      Year      Discount     Period                      Notes
                                                                              dollars    rate (%)     covered
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits:
    Annualized Monetized millions/year         $68         $22        $249        2018           7          10  Benefits are Cost Savings.
                                                68          22         249        2018           3          10  Benefits are Cost Savings.
    Annualized Quantified.............  ..........  ..........  ..........  ..........           7  ..........
                                                                                3
                                       -----------------------------------------------------------------------------------------------------------------

    Qualitative.......................  Increased efficiency in medical
                                        product innovation and improved
                                        human subject knowledge by
                                        providing subjects with clearer
                                        information regarding clinical
                                                  investigations.

--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized $millions/            1.4         0.7         3.0        2018           7          10
     year.                                     1.3         0.6         2.6        2018           3          10
    Annualized Quantified.............  ..........  ..........  ..........  ..........           7  ..........
                                                                                3
                                       -----------------------------------------------------------------------------------------------------------------
    Qualitative.......................

--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized Monetized        ..........  ..........  ..........  ..........           7  ..........
     $millions/year.                                                                             3
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
                                       -----------------------------------------------------------------------------------------------------------------
    Other Annualized Monetized          ..........  ..........  ..........  ..........           7  ..........
     $millions/year.                                                                             3
                                       -----------------------------------------------------------------------------------------------------------------
    From/To...........................  From:
                                        To:
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects:
    State, Local or Tribal Government:
    Small Business:
    Wages:
    Growth:
--------------------------------------------------------------------------------------------------------------------------------------------------------

    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. 1) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

VIII. 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.

IX. Paperwork Reduction Act of 1995

    This proposed rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-3521).
A description of these provisions is given in the Description sections
of this document with an estimate of the recordkeeping and third-party
disclosure burden associated with the proposed rule. 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.

A. Protection of Human Subjects and Institutional Review Boards--Parts
50 and 56 (OMB Control Number 0910-0130)

    Description: Provisions in part 50 provide for the protection of
human subjects involved in FDA-regulated clinical investigations.
Provisions in part 56 set forth requirements for the composition,
operation, and responsibilities of an IRB. IRBs serve in an oversight
capacity by reviewing, among other things, informed consent documents
and protocols for FDA-regulated studies to make findings required to
approve research and document IRB actions. If finalized, the proposed
rule would revise FDA's current regulations in parts 50 and 56 related
to informed consent, waiver of documentation of informed consent, and
IRB continuing review.
1. Proposed Changes to Informed Consent Requirements (Part 50)
    Under FDA's existing regulations at part 50, investigators must
obtain informed consent of subjects or their LARs before involving
subjects in an FDA-regulated clinical investigation, typically through
written consent forms reviewed and approved by an IRB and signed by the
subject or LAR. FDA's current regulations at Sec. Sec.  50.23 and 50.24
provide for exceptions from the requirement to obtain informed consent
in certain narrow circumstances. The information collections associated
with development, IRB approval, and documentation of informed consent
in compliance with FDA's existing regulations at Sec. Sec.  50.25 and
50.27 are currently approved under OMB control number 0910-0130.

    The proposed rule, if finalized, would revise provisions at
Sec. Sec.  50.20, 50.25, and 50.27 regarding the content, organization,
and presentation of information in the informed consent. Proposed Sec.
50.20(e) would require informed consent to begin with a concise and
focused presentation of the key information that is most likely to
assist a prospective subject or legally authorized representative in
understanding the reasons why one might or might not want to
participate in the research. This part of informed consent would have
to be organized and presented in a way that facilitates comprehension.
The proposed rule would also add a new basic element of informed
consent at proposed Sec.  50.25(a)(9) and three new additional elements
of informed consent at proposed Sec.  50.25(b)(7) through (9). Finally,
the proposed rule would revise Sec.  50.27(b)(2) to clarify that when a
short form is used to document that the required elements of informed
consent have been presented orally to the subject or LAR, the key
information required by proposed Sec.  50.20 must be presented first to
the subject or LAR. These proposed changes to FDA's informed consent
requirements would help ensure that prospective subjects receive and
understand information important to choosing whether to participate in
a clinical investigation.
2. Proposed Changes to Requirements for IRB Waiver of Documentation of
Informed Consent and Continuing Review (Part 56)
    FDA's existing regulations at Sec.  56.109(c) provide for an IRB to
waive the requirements for documentation of informed consent in some
circumstances. To harmonize with the revised Common Rule, proposed
Sec.  56.109(c)(3) would allow an IRB to waive documentation of
informed consent in an additional circumstance: if the IRB finds that
the research presents no more than minimal risk of harm to the
subjects, the subjects or LARs are members of a distinct cultural group
or community in which signing forms is not the norm, and there is an
appropriate alternative mechanism for documenting that informed consent
was obtained. IRBs are already required to maintain adequate
documentation of their activities under FDA regulations at Sec.
56.115, including minutes of IRB meetings and records of continuing
review activities. Those existing recordkeeping requirements are part
of the information collection currently approved under OMB control
number 0910-0130. We believe that proposed Sec.  56.109(c)(3)
represents an unusual circumstance that would affect a limited number
of IRBs and thus introduce minimal change in burden associated with IRB
recordkeeping.
    FDA is also proposing changes to its requirements for continuing
review to harmonize with the revised Common Rule, which are intended to
reduce burden on IRBs and allow them to focus their resources on
research that presents higher risk. Under proposed Sec.  56.109(g),
unless an IRB determines otherwise, continuing review of research is
not required for research that has progressed to the point that it
involves only one or both of the following, which are part of the IRB-
approved study: (1) data analysis, including analysis of identifiable
private information or identifiable biospecimens or (2) accessing
followup clinical data from procedures that subjects would undergo as
part of clinical care. In these circumstances, FDA believes that
requiring continuing review would generally not provide added
protection to human subjects, and, therefore, would not be necessary.
If an IRB chooses to conduct continuing review for research that meets
these criteria, the rationale for doing so must be documented according
to proposed Sec.  56.115(a)(3).
    Description of Respondents: Respondents to the information
collections include investigators that develop written informed consent
materials for submission to an IRB and that present this informed
consent information to subjects participating in FDA-regulated clinical
investigations (table 7) and IRBs that review and approve FDA-regulated
clinical investigations (table 8).
    We estimate the burden of the information collection as follows:

                                                  Table 7--Estimated Third-Party Disclosure Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                  Number of
                                                  Number of      disclosures    Total  annual
                21 CFR section                   respondents         per         disclosures         Average burden  per disclosure         Total hours
                                                                 respondent
--------------------------------------------------------------------------------------------------------------------------------------------------------
50.20(e), 50.25, and 50.27--development of              4,122               1           4,122  2.5......................................          10,305
 written consent materials for submission to
 IRB.
50.25 and 50.27--disclosure of consent                  4,122             200         824,400  0.5 (30 minutes).........................         412,200
 information to subjects.
                                              ----------------------------------------------------------------------------------------------------------
    Total....................................  ..............  ..............  ..............  .........................................         422,505
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with the information collection.

    Based on our review of information from ClinicalTrials.gov (https://clinicaltrials.gov/; accessed on March 8, 2018), we estimate that
there are 4,122 new FDA-regulated clinical investigations per year.
Table 7, row 1 provides our estimate of the annual burden respondents
will incur for developing written consent materials for new clinical
investigations. We do not anticipate that investigators will revise
informed consent forms and processes to reflect the proposed revisions
to Sec. Sec.  50.20(e), 50.25, and 50.27 for ongoing clinical trials
that are approved by an IRB before the proposed effective date of the
rule, and therefore, our estimate reflects burden we attribute to new
clinical investigations. If the proposed rule is finalized, we estimate
that for each new clinical investigation, one investigator will spend a
total of 2.5 hours to develop written consent materials to submit for
IRB approval in connection with a new clinical investigation to satisfy
proposed and existing requirements under Sec. Sec.  50.20(e), 50.25,
and 50.27 (table 7, row 1), including existing requirements already
accounted for under OMB control number 0910-0130. This new total
estimated time includes 0.5 hours for developing a written informed
consent form or the written summary of what is said to the subject as
required under Sec.  50.27(b)(2) in order to comply with the proposed
new requirements at Sec. Sec.  50.20(e), 50.25(a)(9) and (b)(7) through
(9), and 50.27(b)(2).
    The information collection approved under OMB control number 0910-
0130 pertains to developing and documenting informed consent in
accordance with Sec. Sec.  50.25 and 50.27 and includes burden
attributable to development and approval by an IRB of a site-specific
informed consent document, and the documentation of informed consent,
but

does not currently account for subsequent presentation of the informed
consent information to subjects. We address this third-party disclosure
in table 7, row 2, and seek its inclusion under control number 0910-
0130, to ensure clarity regarding the PRA approval status of the
presentation of informed consent information to individual subjects in
all FDA-regulated clinical investigations to which Sec. Sec.  50.25 and
50.27 apply. Our ability to provide a precise estimate for this burden
is limited by the significant variability in the size of clinical
investigations, which can range from a few subjects to tens of
thousands, and which thus affects the estimated average number of
responses per respondent. In accordance with PRA regulations (5 CFR
1320 at 1320.8(b)(3)(iii)), we provide our estimate in table 7, row 2
of the annual average burden and invite comment on this estimate.

                                                   Table 8--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                  Number of
                21 CFR section                    Number of      records per    Total  annual      Average  burden per  recordkeeping       Total hours
                                                recordkeepers   recordkeeper       records
--------------------------------------------------------------------------------------------------------------------------------------------------------
56.109(c)(3)--Waiver of documentation of                   25               1              25  0.25 (15 minutes)........................            6.25
 informed consent when subjects are members
 of a distinct cultural group in which
 signing forms is not the norm, research is
 no more than minimal risk, and appropriate
 mechanism for documenting that informed
 consent was obtained.
56.115(a)(3)--Documentation of rationale when             500               1             500  0.25 (15 minutes)........................             125
 conducting continuing review of research
 that otherwise would not require continuing
 review.
                                              ----------------------------------------------------------------------------------------------------------
    Total....................................  ..............  ..............  ..............  .........................................          131.25
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with the information collection.

    We estimate that one percent of IRBs (25) will review one study
annually to determine whether the subjects or their LARs are members of
a distinct cultural group or community in which signing forms is not
the norm, such that the IRB may waive documentation of informed consent
under proposed Sec.  56.109(c)(3). We believe these IRBs are likely to
document the findings required to approve the waiver in IRB meeting
minutes (Sec.  56.115(a)(2)), although they could be documented
elsewhere in IRB records. We estimate that this recordkeeping will
require 15 minutes to complete, as reflected in table 8, row 1.
    We estimate that 500 IRBs will review one study annually that will
be subject to the proposed requirement under Sec.  56.115(a)(3) to
document the IRB's rationale for conducting continuing review of
research that otherwise would not require continuing review under
proposed Sec.  56.109(g). We estimate that the associated documentation
will require 15 minutes to complete, as reflected in table 8, row 2.

B. Investigational Device Exemptions--Part 812 (OMB Control Number
0910-0078)

    Description: Provisions in part 812 set forth procedures for the
conduct of clinical investigations of devices and provide for the
protection of human subjects involved in such investigations. Under
FDA's existing regulations at Sec.  812.150(a)(3) and (b)(5), sponsors
and investigators of device investigations are required, among other
things, to submit progress reports to reviewing IRBs at regular
intervals, but in no event less often than yearly. The proposed rule
would revise Sec.  812.150(a)(3) and (b)(5) to require that such
progress reports on clinical investigations of devices be submitted to
the reviewing IRB to the extent that continuing review is required by
part 56. Therefore, the proposed change would eliminate the need to
submit progress reports to the reviewing IRB for non-significant risk
and significant risk device studies when continuing review is no longer
required under part 56. The proposed revisions to part 812 are intended
to provide consistency between the proposed continuing review
requirements under part 56 and the requirements for submission of IDE
progress reports to IRBs.
    Description of Respondents: Respondents to the information
collection are investigators for and sponsors of clinical
investigations of devices.

                                    Table 9--Estimated Annual Third-Party Disclosure Burden Under 21 CFR Part 812 \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of
                       21 CFR Part 812; IDEs                            Number of     disclosures per    Total annual   Average  burden    Total hours
                                                                       respondents       respondent      disclosures    per  disclosure
--------------------------------------------------------------------------------------------------------------------------------------------------------
812.150; reports for non-significant risk studies..................               1                1                1                6                6
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital or operating and maintenance costs associated with the information collection.

    We characterize burden associated with progress reports under Sec.
812.150 that are submitted from clinical investigators and sponsors to
reviewing IRBs as a disclosure burden. As noted above, the proposed
changes to Sec.  812.150(a)(3) and (b)(5) would eliminate the need to
submit progress reports to reviewing IRBs for non-significant risk and
significant risk devices studies when continuing review is no longer
required under part 56. Therefore, there is no additional burden, and
FDA believes these proposed changes may reduce the number of progress
reports submitted to reviewing IRBs for device studies that progress to
a point where continuing review is no longer required.
    We maintain our current estimate of one report annually for non-
significant risk device studies that do not require submission of an
IDE application to FDA, and that preparing the report requires 6 hours,
as approved under OMB control number 0910-0078. We note however, this
is a longstanding estimate and invite comment specifically with regard
to the number of progress reports sponsors and investigators anticipate
submitting annually to reviewing IRBs and the burden associated with
progress reports

under Sec.  812.150 for non-significant risk studies. We do not
specifically estimate burden for progress reports to reviewing IRBs for
significant risk studies under OMB control number 0910-0078 and
therefore invite comment here on how, if at all, the proposed changes
would affect the number of progress reports sponsors and investigators
anticipate submitting annually to reviewing IRBs and overall burden for
these significant risk studies.
    To ensure that comments on information collection are received, OMB
recommends that written comments be submitted through https://www.reginfo.gov/public/do/PRAMain (see Addresses). All comments should
be identified with the title of the information collection.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3407(d)), we have submitted the information collection provisions of
this proposed rule to OMB for review. These information collection
requirements will not be effective until FDA publishes a final rule,
OMB approves the information collection requirements, and the rule goes
into effect. FDA will announce OMB approval of these requirements in
the Federal Register.

X. 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. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.

XI. 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.

XII. Reference

    The following reference is on display at the Dockets Management
Staff (see ADDRESSES) and is available for viewing by interested
persons between 9 a.m. and 4 p.m., Monday through Friday; it is also
available electronically at https://www.regulations.gov. FDA has
verified the website address, as of the date this document publishes in
the Federal Register, but websites are subject to change over time.

1. FDA, Preliminary Economic Analysis of Impacts, Docket No. FDA-
2021-N-0286, available at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

List of Subjects

21 CFR Part 50

    Human research subjects, Prisoners, Reporting and recordkeeping
requirements, Safety.

21 CFR Part 56

    Human research subjects, Reporting and recordkeeping requirements,
Safety.

21 CFR Part 812

    Health records, Medical devices, Medical research, Reporting and
recordkeeping requirements.

    Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 50,
56, and 812 be amended as follows:

PART 50--PROTECTION OF HUMAN SUBJECTS

0
1. The authority citation for part 50 is revised to read as follows:

    Authority:  21 U.S.C. 321, 343, 346, 346a, 348, 350a, 350b, 352,
353, 355, 360, 360c-360f, 360h-360j, 360hh-360pp, 360rr-360ss, 371,
379e, 381; 42 U.S.C. 216, 241, 262.

0
2. In part 50, remove the words ``the act'' and add in their place
``the Federal Food, Drug, and Cosmetic Act'' wherever they appear.
0
3. In Sec.  50.1, revise the last sentence of paragraph (a) to read as
follows:

Sec.  50.1   Scope.

    (a) * * * Compliance with these parts is intended to protect the
rights and safety of human subjects involved in such investigations.
* * * * *
0
4. In Sec.  50.3:
0
a. Remove and reserve paragraph (a);
0
b. Amend paragraphs (b)(16) through (19) by adding ``of the Federal
Food, Drug, and Cosmetic Act'' at the end of each sentence;
0
c. Amend paragraph (b)(20) by removing ``section 358 of the Public
Health Service Act'' and adding in its place ``section 534 of the
Federal Food, Drug, and Cosmetic Act'';
0
d. Revise paragraphs (i), (j), and (l); and
0
e. Add paragraphs (t) through (w).
    The revisions and additions read as follows:

Sec.  50.3   Definitions.

* * * * *
    (i) Institutional review board (IRB) means any board, committee, or
other group formally designated by an institution to review biomedical
research involving humans as subjects, and to approve the initiation of
and conduct periodic review of such research. The primary purpose of
such review is to assure the protection of the rights and welfare of
the human subjects. The term has the same meaning as the phrase
institutional review committee as used in section 520(g) of the Federal
Food, Drug, and Cosmetic Act.
    (j) Test article means any drug (including a biological product for
human use), medical device for human use, human food additive, color
additive, electronic product, or any other article subject to
regulation under the Federal Food, Drug, and Cosmetic Act or under
section 351 of the Public Health Service Act (42 U.S.C. 262).
* * * * *
    (l) Legally authorized representative means an individual or
judicial or other body authorized under applicable law to consent on
behalf of a prospective subject to the subject's participation in the
procedure(s) involved in the research. If there is no applicable law
addressing this issue, legally authorized representative means an
individual recognized by institutional policy as acceptable for
providing consent in the non-research context on behalf of the
prospective subject to the subject's participation in the procedure(s)
involved in the research.
* * * * *
    (t) Written or in writing means writing on a tangible medium (e.g.,
paper) or in an electronic format.
    (u) Private information includes information about behavior that
occurs in a context in which an individual can reasonably expect that
no observation or recording is taking place, and information that has
been provided for specific purposes by an individual and that the
individual can reasonably expect will not be made public (e.g., a
medical record).
    (v) Identifiable private information is private information for
which the

identity of the subject is or may readily be ascertained by the sponsor
or investigator or associated with the information.
    (w) Identifiable biospecimen is a biospecimen for which the
identity of the subject is or may readily be ascertained by the sponsor
or investigator or associated with the biospecimen.
0
5. Revise Sec.  50.20 to read as follows:

Sec.  50.20   General requirements for informed consent.

    Except as provided in Sec. Sec.  50.23 and 50.24:
    (a) Before involving a human subject in research covered by these
regulations, the investigator shall obtain the legally effective
informed consent of the subject or the subject's legally authorized
representative.
    (b) An investigator shall seek informed consent only under
circumstances that provide the prospective subject or the legally
authorized representative sufficient opportunity to discuss and
consider whether or not to participate and that minimize the
possibility of coercion or undue influence.
    (c) The information that is given to the subject or the legally
authorized representative shall be in language understandable to the
subject or the legally authorized representative.
    (d) The prospective subject or the legally authorized
representative must be provided with the information that a reasonable
person would want to have in order to make an informed decision about
whether to participate, and an opportunity to discuss that information.
    (e)(1) Informed consent must begin with a concise and focused
presentation of the key information that is most likely to assist a
prospective subject or legally authorized representative in
understanding the reasons why one might or might not want to
participate in the research. This part of the informed consent must be
organized and presented in a way that facilitates comprehension.
    (2) Informed consent as a whole must present information in
sufficient detail relating to the research, and must be organized and
presented in a way that does not merely provide lists of isolated
facts, but rather facilitates the prospective subject's or legally
authorized representative's understanding of the reasons why one might
or might not want to participate.
    (f) No informed consent may include any exculpatory language
through which the subject or the legally authorized representative is
made to waive or appear to waive any of the subject's legal rights, or
releases or appears to release the investigator, the sponsor, the
institution, or its agents from liability for negligence.

Sec.  50.24   [Amended]

0
6. In Sec.  50.24, in paragraph (a)(6), remove ``Sec.  50.25'' at the
end of the first sentence and add in its place ``this part''.
0
7. In Sec.  50.25:
0
a. Revise paragraphs (a) introductory text and (a)(3);
0
b. Add paragraph (a)(9);
0
c. Revise paragraphs (b) introductory text and (b)(1), (2), and (5);
0
d. Add paragraphs (b)(7) through (9);
0
e. Add a heading to paragraph (c); and
0
f. Revise paragraphs (d) and (e).
    The additions and revisions read as follows:

Sec.  50.25   Elements of informed consent.

    (a) Basic elements of informed consent. In seeking informed
consent, the following information shall be provided to each subject or
legally authorized representative:
* * * * *
    (3) A description of any benefits to the subject or to others that
may reasonably be expected from the research.
* * * * *
    (9) A description of how information or biospecimens may be used
for future research or distributed to another investigator for future
research.
    (b) Additional elements of informed consent. When appropriate, one
or more of the following elements of information shall also be provided
to each subject or legally authorized representative:
    (1) A statement that the particular treatment or procedure may
involve risks to the subject (or to the embryo or fetus, if the subject
is or may become pregnant) that are currently unforeseeable.
    (2) Anticipated circumstances under which the subject's
participation may be terminated by the investigator without regard to
the subject's or legally authorized representative's consent.
* * * * *
    (5) A statement that significant new findings developed during the
course of the research that may relate to the subject's willingness to
continue participation will be provided to the subject.
* * * * *
    (7) A statement that the subject's biospecimens (even if
identifiers are removed) may be used for commercial profit and whether
the subject will or will not share in this commercial profit;
    (8) A statement regarding whether clinically relevant research
results, including individual research results, will be disclosed to
subjects, and if so, under what conditions; and
    (9) For research involving biospecimens, whether the research will
(if known) or might include whole genome sequencing (i.e., sequencing
of a human germline or somatic specimen with the intent to generate the
genome or exome sequence of that specimen).
    (c) Required statement in informed consent documents for applicable
clinical trials. *
    (d) Preemption. The informed consent requirements in these
regulations are not intended to preempt any applicable Federal, State,
or local laws (including tribal law passed by the official governing
body of an American Indian or Alaska Native tribe) that require
additional information to be disclosed in order for informed consent to
be legally effective.
    (e) Emergency medical care. Nothing in these regulations is
intended to limit the authority of a physician to provide emergency
medical care to the extent the physician is permitted to do so under