[Federal Register Volume 88, Number 244 (Thursday, December 21, 2023)]
[Rules and Regulations]
[Pages 88228-88249]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-27935]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 50, 312, and 812

[Docket No. FDA-2018-N-2727]
RIN 0910-AH52


Institutional Review Board Waiver or Alteration of Informed 
Consent for Minimal Risk Clinical Investigations

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA, the Agency, or we) is 
issuing a final rule to amend its regulations to implement a provision 
of the 21st Century Cures Act (Cures Act). This final rule allows an 
exception from the requirement to obtain informed consent when a 
clinical investigation poses no more than minimal risk to the human 
subject and includes appropriate safeguards to protect the rights, 
safety, and welfare of human subjects. The final rule permits an 
institutional review board (IRB) to waive or alter certain informed 
consent elements or to waive the requirement to obtain informed 
consent, under limited conditions, for certain FDA-regulated minimal 
risk clinical investigations.

DATES: This rule is effective January 22, 2024.

ADDRESSES: For access to the docket to read background documents or 
comments received, go to https://www.regulations.gov and insert the 
docket number found in brackets in the heading of this final rule into 
the ``Search'' box and follow the prompts, and/or go to the Dockets 
Management Staff, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852, 
240-402-7500.

FOR FURTHER INFORMATION CONTACT: Lauren Milner, Office of Clinical 
Policy, Food and Drug Administration, 10903 New Hampshire Ave., Silver 
Spring, MD 20993-0002, 301-796-5514, <a href="/cdn-cgi/l/email-protection#3559544047505b1b585c595b5047755351541b5d5d461b525a43"><span class="__cf_email__" data-cfemail="83efe2f6f1e6edadeeeaefede6f1c3e5e7e2adebebf0ade4ecf5">[email protected]</span></a>.

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the Final Rule
    B. Summary of the Major Provisions of the Final Rule
    C. Legal Authority
    D. Costs and Benefits
II. Table of Abbreviations/Commonly Used Acronyms in This Document
III. Background
    A. Need for the Regulation/History of This Rulemaking
    B. Summary of Comments to the Proposed Rule
    C. General Overview of the Final Rule
IV. Legal Authority
V. Comments on the Proposed Rule and FDA Response
    A. Introduction
    B. Description of General Comments and FDA Response
    C. Comments on the Proposed Waiver or Alteration Criteria
    D. Comments on Adopting the Revised Common Rule's Fifth 
Criterion for Waiver or Alteration of Informed Consent
    E. Comments on Secondary Research Involving Leftover 
Biospecimens
    F. Comments on Examples of Clinical Investigations That Would 
Meet the Waiver Criteria
    G. Comments on Requests for Guidance
    H. Comments on the Expedited Review List and IRB Continuing 
Review
    I. Comments on the Cost Savings of the Proposed Rule
    J. Comments on the Proposed Effective Date
VI. Effective Date
VII. Economic Analysis of Impacts
    A. Introduction
    B. Summary of Costs, Cost Savings, and Benefits
VIII. Analysis of Environmental Impact
IX. Paperwork Reduction Act of 1995
X. Federalism
XI. Consultation and Coordination With Indian Tribal Governments
XII. References

I. Executive Summary

A. Purpose of the Final Rule

    This final rule implements the statutory changes made to the 
Federal Food, Drug, and Cosmetic Act (FD&C Act) by the Cures Act to 
allow for a waiver or alteration of informed consent when a clinical 
investigation poses no more than minimal risk to the human subject and 
includes appropriate safeguards to protect the rights, safety, and 
welfare of human subjects. The rule will permit an IRB to waive or 
alter certain informed consent elements or to waive the requirement to 
obtain informed consent, under limited conditions, for certain minimal 
risk clinical investigations.

B. Summary of the Major Provisions of the Final Rule

    The final rule amends FDA's regulations to allow IRBs responsible 
for the review, approval, and continuing review of clinical 
investigations to approve an informed consent procedure that does not 
include or that alters certain informed consent elements, or to waive 
the requirement to obtain informed consent, for certain minimal risk 
clinical investigations. For an IRB to approve a waiver or alteration 
of informed consent requirements for minimal risk clinical 
investigations, the rule requires an IRB to find and document five 
criteria that are consistent with the revised rule entitled ``Federal 
Policy for the Protection of Human Subjects'' (the revised Common Rule 
(January 19, 2017)). FDA believes the amendment provides appropriate 
safeguards to protect the rights, safety, and welfare of the human 
subjects participating in such clinical investigations. We are also 
making conforming amendments to FDA's regulations.

C. Legal Authority

    Sections 505(i)(4) and 520(g)(3) of the FD&C Act, as amended by the 
Cures Act, in conjunction with FDA's general rulemaking authority in 
section 701(a) of the FD&C Act, serve as FDA's principal legal 
authority for this rule. In addition, the Cures Act directs the 
Secretary of the Department of Health and Human Services (HHS) to 
``harmonize differences between the HHS Human Subject Regulations and 
the FDA Human Subject Regulations,'' to the extent practicable and 
consistent with other statutory provisions.

D. Costs and Benefits

    This rule will help enable the conduct of certain minimal risk 
clinical investigations for which the requirement to obtain informed 
consent is waived or for which certain elements of informed consent are 
waived or altered.
    We expect costs in the form of affected IRBs, as well as 
investigators and sponsors of clinical investigations, reading and 
learning the rule. We also expect costs in the form of drafting new

[[Page 88229]]

waiver or alteration requests and additional recordkeeping burdens 
associated with reviewing and documenting IRB decisions on waiver or 
alteration requests. The net present value of the estimated costs of 
the rule are approximately $10.1 million, with a lower bound of 
approximately $8.1 million and an upper bound of approximately $14.0 
million, discounted at 3 percent over 10 years. At a 7 percent discount 
rate, the estimated costs of the rule are approximately $9.1 million, 
with a lower bound of approximately $7.5 million and an upper bound of 
approximately $12.4 million. The estimated annualized costs of the rule 
are approximately $1.2 million, with a lower bound of approximately 
$0.9 million and an upper bound of approximately $1.6 million, 
discounted at 3 percent over 10 years. At a 7 percent discount rate, 
the estimated annualized costs of the rule are approximately $1.3 
million, with a lower bound of approximately $1.1 million and an upper 
bound of approximately $1.8 million.
    We expect that there will be cost savings to IRBs from 
harmonization of FDA's informed consent regulations with the provision 
for waiver or alteration of informed consent for certain minimal risk 
research in the Common Rule. The estimated net present value of the 
cost savings of the rule are approximately $1.7 million, with a lower 
bound of approximately $0.9 million and an upper bound of approximately 
$3.5 million, discounted at 3 percent over 10 years. At a 7 percent 
discount rate, the estimated cost savings of the rule are approximately 
$1.4 million, with a lower bound of approximately $0.7 million and an 
upper bound of approximately $2.8 million. The estimated annualized 
cost savings of the rule are approximately $0.2 million, with a lower 
bound of approximately $0.1 million and an upper bound of approximately 
$0.4 million, discounted at 3 percent over 10 years. At a 7 percent 
discount rate, the estimated annualized costs savings of the rule are 
approximately $0.2 million, with a lower bound of approximately $0.1 
million and an upper bound of approximately $0.4 million.
    We also expect benefits in the form of healthcare advances from 
minimal risk clinical investigations that would not be performed 
without a waiver or alteration of informed consent. We cannot quantify 
all benefits that might arise from such studies because of the lack of 
relevant data available regarding the focus of these types of studies 
that will support regulatory submissions to FDA.

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

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           Abbreviation                         What it means
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Cures Act.........................  21st Century Cures Act (Pub. L. 114-
                                     255).
FDA or the Agency.................  U.S. Food and Drug Administration.
FD&C Act..........................  Federal Food, Drug, and Cosmetic
                                     Act.
HHS...............................  U.S. Department of Health and Human
                                     Services.
HIPAA Privacy Rule................  Health Insurance Portability and
                                     Accountability Act Privacy Rule (45
                                     CFR Part 160 and 45 CFR Part 164,
                                     Subparts A and E).
IDE...............................  Investigational Device Exemption.
IRB...............................  Institutional Review Board.
IVD...............................  In Vitro Diagnostic.
LAR...............................  Legally Authorized Representative.
OHRP..............................  Office for Human Research
                                     Protections.
OMB...............................  U.S. Office of Management and
                                     Budget.
PHI...............................  Protected Health Information.
PRA...............................  Paperwork Reduction Act of 1995.
RWD...............................  Real-world data.
SACHRP............................  Secretary's Advisory Committee on
                                     Human Research Protections.
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III. Background

A. Need for the Regulation/History of This Rulemaking

    In the Federal Register of November 15, 2018 (83 FR 57378), FDA 
issued a proposed rule to revise our informed consent regulations at 
part 50 (21 CFR part 50) to permit an IRB to waive or alter certain 
informed consent elements or to waive the requirement to obtain 
informed consent, under limited conditions, for certain FDA-regulated 
minimal risk clinical investigations. As described in the proposed 
rule, FDA's current regulations governing the protection of human 
subjects (parts 50 and 56 (21 CFR parts 50 and 56)) require that a 
human subject, or the subject's legally authorized representative 
(LAR), provide informed consent before the subject participates in a 
clinical investigation, and only allow exception from the general 
requirements of informed consent in certain life-threatening situations 
or by Presidential waiver for certain military operations when specific 
conditions are met (Sec.  50.23 (21 CFR 50.23)) or when the 
requirements for emergency research are met (Sec.  50.24 (21 CFR 
50.24)).
    On December 13, 2016, the Cures Act (Pub. L. 114-255) was signed 
into law. Section 3024 of the Cures Act amended sections 505(i)(4) and 
520(g)(3) of the FD&C Act (21 U.S.C. 355(i)(4) and 360j(g)(3)) to 
provide FDA with the authority to permit an exception from informed 
consent requirements when the proposed clinical testing poses no more 
than minimal risk to the human subject and includes appropriate 
safeguards to protect the rights, safety, and welfare of the human 
subject. This rule implements the statutory change by allowing an 
additional exception from the general requirements of informed consent 
for certain FDA-regulated clinical investigations.
    In addition, section 3023 of the Cures Act directs the Secretary of 
the Department of Health and Human Services (HHS) to ``harmonize 
differences between the HHS Human Subject Regulations and the FDA Human 
Subject Regulations,'' to the extent practicable and consistent with 
other statutory provisions. This rule harmonizes \1\ FDA's requirements 
for waiver or alteration of informed consent for minimal risk clinical 
investigations with the revised Common Rule's requirements under 45 CFR 
46.116(f)(3). The Common Rule has included four criteria for waiver or 
alteration of informed consent for minimal risk research since it was 
originally issued in

[[Page 88230]]

1991 (56 FR 28001, June 18, 1991). When the Common Rule was revised (82 
FR 7149, January 19, 2017),\2\ a fifth criterion was added, i.e., 
``[i]f 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'' (45 CFR 46.116(f)(3)(iii)). FDA proposed to adopt 
the four criteria from the 1991 version of the Common Rule and 
solicited comment on whether to adopt the fifth criterion (83 FR 57378, 
November 15, 2018).
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    \1\ 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.
    \2\ For the purposes of this final 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 
and general compliance date (83 FR 2885, January 22, 2018) and the 
final rule that further 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).
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    On July 25, 2017, FDA issued a guidance document entitled ``IRB 
Waiver or Alteration of Informed Consent for Clinical Investigations 
Involving No More Than Minimal Risk to Human Subjects'' (IRB Waiver or 
Alteration of Informed Consent Guidance) (82 FR 34535). This guidance 
informs sponsors, investigators, and IRBs that FDA does not intend to 
object to an IRB waiving or altering informed consent requirements, as 
described in the guidance, for certain minimal risk clinical 
investigations. In addition, the guidance informs sponsors, 
investigators, and IRBs that FDA does not intend to object to a sponsor 
initiating, or an investigator conducting, a minimal risk clinical 
investigation for which an IRB waives or alters the informed consent 
requirements as described in the guidance. FDA intends to withdraw the 
guidance after the regulations in this rule become effective.
    FDA is issuing this final rule to permit an IRB waiver or 
alteration of informed consent in limited circumstances, consistent 
with the Cures Act. We believe that this rule will both safeguard the 
rights, safety, and welfare of human subjects and enable minimal risk 
clinical investigations that may facilitate medical advances and 
promote public health. In addition, because some clinical research is 
subject to FDA and other federal requirements under the Common Rule, 
harmonization of this waiver provision should also provide clarity for 
and reduce burden on the research community.

B. Summary of Comments to the Proposed Rule

    We received fewer than 50 comment letters to the proposed rule from 
academia, IRBs, public advocacy groups, industry, trade organizations, 
public health organizations, individuals, and other organizations. FDA 
received comments on topics that included the following: (1) general 
support or opposition to the rule; (2) definitions and descriptions of 
the criteria listed in the rule; (3) adopting the fifth criterion from 
the revised Common Rule; (4) secondary research involving biospecimens; 
(5) examples of clinical investigations that might meet the proposed 
waiver criteria; (6) requests for specific and/or additional guidance 
on the rule; (7) the expedited review list and IRB continuing review; 
(8) cost savings of the proposed rule; and (9) the proposed effective 
date of the rule.

C. General Overview of the Final Rule

    In this rulemaking, FDA is finalizing its proposal to add new Sec.  
50.22, ``Exception from informed consent requirements for minimal risk 
clinical investigations'' to part 50 and make three conforming 
amendments to Sec. Sec.  50.20, 312.60, and 812.2 (21 CFR 50.20, 
312.60, and 812.2) of our current regulations to reflect the exception 
from informed consent for certain minimal risk clinical investigations. 
In addition, based on comments received on the proposed rule, FDA is 
adding the criterion at Sec.  50.22(c), which addresses clinical 
investigations involving identifiable private information or 
identifiable biospecimens. As described below, FDA changed the order of 
the criteria in Sec.  50.22 to match the order of the revised Common 
Rule's requirements for general waiver or alteration of consent (45 CFR 
46.116(f)(3)). FDA also made minor organizational and editorial changes 
to Sec.  50.22 to increase clarity and consistency with the regulatory 
text of the revised Common Rule.
    <bullet> FDA made a minor editorial change to the introductory text 
to Sec.  50.22 for clarity. Specifically, we revised the text ``or that 
waives'' to read ``or may waive.'' The regulation permits the IRB 
responsible for the review, approval, and continuing review of the 
clinical investigation to approve an informed consent procedure that 
does not include or that alters some or all of the elements of informed 
consent in Sec.  50.25(a) and (b) of FDA's current regulations, or to 
waive the requirement to obtain informed consent, provided that the IRB 
finds and documents five criteria under Sec.  50.22(a) through (e).
    <bullet> In Sec.  50.22(a), FDA finalizes the criterion as proposed 
that the clinical investigation involves no more than minimal risk to 
the subjects.
    <bullet> In Sec.  50.22(b), FDA adopts the criterion that was 
proposed at Sec.  50.22(c) and adds the word ``requested'' for clarity 
and to harmonize with the text of the revised Common Rule at 45 CFR 
46.116(f)(3)(ii) (i.e., the clinical investigation could not 
practicably be carried out without the requested waiver or alteration).
    <bullet> Based on comments received on the proposed rule (see 
section V.D. of this final rule), FDA is finalizing this rule with the 
additional criterion at Sec.  50.22(c) that states that if the clinical 
investigation involves using identifiable private information or 
identifiable biospecimens, the clinical investigation could not 
practicably be carried out without using such information or 
biospecimens in an identifiable format.
    <bullet> In Sec.  50.22(d), FDA adopts the criterion that was 
proposed at Sec.  50.22(b) that states that the waiver or alteration 
will not adversely affect the rights and welfare of the subjects.
    <bullet> In Sec.  50.22(e), FDA adopts the criterion that was 
proposed at Sec.  50.22(d) and adds ``or legally authorized 
representatives'' to the criterion (i.e., whenever appropriate, the 
subjects or legally authorized representatives will be provided with 
additional pertinent information after participation) to align with the 
revised Common Rule and to make clear to whom additional information 
may be provided.
    <bullet> Three conforming amendments to Sec. Sec.  50.20, 312.60, 
and 812.2 of our current regulations are finalized as proposed. FDA 
received no public comments on these three proposed conforming 
amendments. The introductory clause of Sec.  50.20, General 
requirements for informed consent, is revised to include reference to 
Sec.  50.22 as one of the limited exceptions to the general 
requirements for informed consent. The second sentence in Sec.  312.60, 
General responsibilities of investigators, is revised to reference part 
50 generally rather than list each specific exception to the informed 
consent requirements in part 50. This simplifies the regulatory text 
and makes it clear that the investigator is responsible for obtaining 
the informed consent of each human subject to whom the drug is 
administered in accordance with part 50, which includes Sec.  50.22. 
Similarly, in part 812, Investigational Device Exemptions (IDEs), Sec.  
812.2(b)(1)(iii) is revised to make clear that the investigator must 
obtain informed consent in accordance with part 50, which includes 
Sec.  50.22. In

[[Page 88231]]

addition, to simplify the current regulatory text, we removed the 
reference to documentation being waived under Sec.  56.109(c) (21 CFR 
56.109(c)), as the relevant section of the regulations in part 50 
(i.e., Sec.  50.27 (21 CFR 50.27)) refers to Sec.  56.109(c) and need 
not be repeated.

IV. Legal Authority

    Title III, section 3024 of the Cures Act amended sections 505(i)(4) 
and 520(g)(3) of the FD&C Act to provide FDA with the authority to 
permit an exception from informed consent requirements when the 
proposed clinical testing poses no more than minimal risk to the human 
subject and includes appropriate safeguards to protect the rights, 
safety, and welfare of the human subject. This statutory amendment was 
signed into law and became effective on December 13, 2016. These 
regulations reflect these statutory changes to the FD&C Act, including 
appropriate human subject protection safeguards. Thus, sections 
505(i)(4) and 520(g)(3) of the FD&C Act, as amended by section 3024 of 
the Cures Act, in conjunction with FDA's general rulemaking authority 
in section 701(a) of the FD&C Act (21 U.S.C. 371(a)), serve as our 
principal legal authority for this rule. In addition, Title III, 
section 3023 of the Cures Act provides that the Secretary of Health and 
Human Services shall ``harmonize differences between HHS Human Subject 
Regulations and FDA Human Subject Regulations'' to the extent 
practicable and consistent with other statutory provisions.

V. Comments on the Proposed Rule and FDA Response

A. Introduction

    We received fewer than 50 comment letters on the proposed rule by 
the close of the comment period. We received comments from academia, 
IRBs, public advocacy groups, industry, trade organizations, public 
health organizations, individuals, and other organizations.
    We describe and respond to the comments below. Comment summaries 
are numbered, with similar comments grouped together under the same 
number. In some cases, different issues discussed in the same comment 
letter were designated as distinct comments for purposes of our 
responses. The number assigned to each comment summary or comment topic 
is purely for organizational purposes and does not signify the 
comment's value or importance, or the order in which comments were 
received.

B. Description of General Comments and FDA Response

    FDA proposed to amend its regulations to allow the IRB responsible 
for the review, approval, and continuing review of FDA-regulated 
clinical investigations to approve an informed consent procedure that 
does not include or that alters some or all of the elements of informed 
consent set forth in Sec.  50.25(a) and (b), or that waives the 
requirement to obtain informed consent, provided that the IRB finds and 
documents that four criteria are met. FDA also solicited public comment 
on the inclusion of a fifth criterion and asked for comment on the 
types of FDA-regulated minimal risk clinical investigations for which 
sponsors would anticipate requesting a waiver or alteration of informed 
consent from the IRB.
    (Comment 1) A majority of general comments favor the Agency's 
efforts to harmonize FDA's human subject protection regulations with 
the revised Common Rule. These comments generally support the proposed 
rule because it would reduce administrative burdens on IRBs and 
researchers, reduce research costs, facilitate valuable research, or 
address public health concerns without compromising subjects' rights, 
safety, or welfare.
    Several comments express support for harmonization with the revised 
Common Rule's provision for waiver or alteration of informed consent to 
reduce burdens related to conducting certain types of research, 
including some cluster randomized or pragmatic trials, and enabling 
learning health systems, in which clinicians continually learn from 
data collected at the point of care. One comment indicates that such 
research has the potential to contribute in important ways to the 
evidence base regarding drug and device efficacy, while another 
suggests that finalizing the proposal would result in more and better 
data regarding the risks and benefits of drugs and devices in real-
world settings. An additional comment argues that a waiver of informed 
consent may be necessary and ethically justifiable for certain types of 
clinical investigations that are critical for medical advancement, 
patient care, and safety.
    Other comments support the proposal because certain minimal risk 
investigations are difficult or impossible to carry out if consent is 
required, such as certain secondary research involving biospecimens 
that may lead to important medical advances toward personalized 
medicine; research involving retrospective records reviews; and 
research involving no more than minimal risk to subjects that would not 
qualify for an exception from informed consent under Sec.  50.24 of 
FDA's current regulations because participation would not hold out a 
prospect of direct benefit to the subjects. The comments point out that 
current FDA regulations permit waivers from the requirement to obtain 
informed consent only under limited circumstances.
    (Response 1) FDA agrees that this rule will facilitate 
investigators' ability to conduct certain minimal risk clinical 
investigations that could lead to healthcare advances through 
development of products to diagnose or treat diseases or other 
conditions, without compromising subjects' rights, safety, or welfare. 
To the extent that the studies described in the comments would 
constitute FDA-regulated clinical investigations that could not be 
carried out under our current regulations, we agree that this final 
rule may help enable such research and that a waiver of informed 
consent is ethically justifiable for certain types of investigations.
    In addition, FDA expects that this final rule will reduce 
administrative burdens on IRBs and researchers and reduce research 
costs. For example, harmonization with the revised Common Rule's 
general provision for waiver or alteration of informed consent will 
allow IRBs that review minimal risk clinical research subject to both 
FDA's regulations and the revised Common Rule to use the same criteria 
for reviewing a request for a waiver or alteration of informed consent 
for a clinical investigation. This should minimize the need for 
separate processes for review of such requests.
    (Comment 2) Of the comments that oppose the proposed rule, two 
oppose it because they assert that waiving consent conflicts with 
existing ethical and international standards, such as the Belmont 
Report, the Nuremberg Code, the Declaration of Helsinki, and the 
International Covenant on Civil and Political Rights (ICCPR). Two other 
comments suggest that FDA withdraw the proposal because the underlying 
law and revised Common Rule are defective and ``against the spirit'' of 
human subject protection.
    (Response 2) FDA disagrees with the comments opposing the rule. We 
believe that the rule upholds the principles underlying existing 
ethical standards, while accounting for advances in the conduct of FDA-
regulated clinical investigations. It is also consistent with the 
obligations of the ICCPR and the U.S.' reservations, declarations, and 
understandings to the Covenant (see,

[[Page 88232]]

e.g., Ref. 1). The standards referenced in the comments emphasize the 
importance of voluntary informed consent for research participants. As 
stated in the proposed rule, obtaining informed consent from those who 
volunteer to participate in research is a fundamentally important 
principle of human subject protection. However, there are some 
situations in which important research cannot practicably be conducted 
if informed consent is required. This rule permits a waiver of consent 
in limited circumstances, consistent with the statutory amendments 
Congress made in section 3024 of the Cures Act. The waiver is only 
permitted in circumstances where the risks posed to subjects by the 
research are minimal and where an IRB has reviewed the research and 
determined, among other things, that the waiver or alteration will not 
adversely affect the rights and welfare of subjects. If research can be 
practicably carried out without a waiver of informed consent, 
investigators cannot obtain a waiver under this rule.
    Additionally, the ethical principles identified in many of the 
national and international guidelines for research conduct, such as the 
three ethical principles described in the Belmont Report (respect for 
persons, beneficence, and justice), should be considered and weighed 
within the context of a particular clinical investigation, as the 
consideration of each principle depends on multiple factors associated 
with the investigation, such as research methodologies or participant 
populations. This rule permits a waiver or alteration of consent only 
in limited circumstances where the risks posed to subjects by the 
research are very low. We believe that with the protections in place 
under this rule (including the requirement for an IRB to find and 
document that the waiver or alteration will not adversely affect the 
rights and welfare of subjects), the balance between respect for 
persons and beneficence should come out in favor of facilitating 
research that satisfies the criteria in Sec.  50.22 by permitting 
waiver or alteration of informed consent requirements to advance the 
public health. Additionally, although informed consent is a critical 
element of FDA's regulations that reflects the principle of respect for 
persons through the exercise of autonomy, we believe that the criteria 
provided in this rule also reflect the principle of respect for 
persons. For example, in a minimal risk clinical investigation for 
which an IRB waives consent, ensuring that the rights and welfare of 
subjects are not adversely affected by the waiver demonstrates respect 
for persons, as does providing additional pertinent information about 
the investigation to subjects whenever appropriate (Ref. 2).
    Finally, FDA declines to withdraw the proposed rule in response to 
the comments that disagree with section 3024 of the Cures Act and the 
revised Common Rule. The Common Rule's provisions for waiver or 
alteration of informed consent for minimal risk research have been in 
effect for over 30 years and have provided appropriate safeguards to 
protect the rights and welfare of human subjects. As noted above, FDA 
believes that this rule provides an important mechanism for conducting 
clinical investigations that will both appropriately safeguard human 
subjects and potentially lead to medical advances that serve the public 
health.
    (Comment 3) Some comments suggest that conducting research without 
informed consent would violate the U.S. Constitution or weaken 
constitutionally guaranteed rights. One comment argues that ``invasive 
procedures, interventions or intrusions'' into a person's ``body, 
cognition, or otherwise'' without consent is a violation or a potential 
violation of the Fourth, Fifth, Eighth, and Fourteenth Amendments. A 
second comment asserts that waiving consent for research involving 
physical interventions would violate the Fourth and Fifth Amendments 
and requested clarification that Constitutional rights are among the 
rights at issue when considering whether the proposed criteria for 
waiver of consent are satisfied. Another comment indicates that a 
waiver of informed consent would constitute an unwanted bodily invasion 
and that individuals have a constitutional right to privacy that 
protects them against such invasions. Other comments make general 
statements questioning the constitutionality of a waiver of informed 
consent.
    (Response 3) We disagree with comments suggesting that the rule is 
unconstitutional. With respect to the comments that make only a general 
assertion that the rule may violate the Constitution or weaken 
constitutional rights, the lack of additional detail regarding the 
grounds for this assertion makes it impossible to provide a further 
substantive response. One comment cites a Federal district court case, 
Merriken v. Cressman, 364 F. Supp. 913 (E.D. Pa. 1973), for the general 
proposition that Federal courts have applied a requirement for fully 
voluntary informed consent grounded in constitutional law to social, 
behavioral, and biomedical research. Contrary to the comment's 
assertion, however, the court did not decide in Merriken whether 
informed consent is required for participation in all research as a 
general matter. The case involved a program designed to help a school 
district identify potential drug abusers. Id. at 914. The court found 
that part of this program represented an invasion of an individual 
constitutional right to privacy that was not outweighed by the 
government's public need for the information. Id. at 918, 921. The 
court then went on to address the standard for and adequacy of consent 
to waive a constitutional right to privacy involving an invasion of the 
parent-child relationship, rather than consent to participate in FDA-
regulated minimal risk research. Merriken does not prevent FDA from 
finalizing this rule.
    Of those comments that identify particular constitutional 
Amendments or rights, none provides specific facts or a legal basis for 
their claims that the rule would violate those provisions or rights. We 
are thus unable to provide a specific response to those comments. 
However, we note that the rule does not require an IRB to waive or 
alter informed consent, nor does it require any entity, including a 
government entity, to conduct or support any research. Therefore, to 
the extent that conducting a particular clinical investigation with a 
waiver or alteration of informed consent could be viewed as interfering 
with a constitutional right, this rule does not require an IRB to grant 
such a waiver or alteration or require that the research be conducted. 
In addition, we are clarifying, as requested by one comment, that 
constitutional rights are among the rights that may be appropriate for 
an IRB to consider when determining if the criterion in Sec.  50.22(d) 
of the final rule (which requires the IRB to find that ``[t]he waiver 
or alteration will not adversely affect the rights and welfare of the 
subjects'') is satisfied.
    Finally, we note that some of the comments that question the 
constitutionality of the rule appear to be concerned about potential 
waivers of informed consent for research involving ``invasive 
procedures.'' It is important to emphasize that the provision for a 
waiver or alteration of informed consent being finalized in this rule 
is available only for clinical investigations that involve no more than 
minimal risk to the subjects and meet the other criteria in Sec.  
50.22. In general, we do not believe that a study involving an invasive 
procedure being used for research

[[Page 88233]]

purposes would qualify as presenting no more than minimal risk to 
subjects.\3\
---------------------------------------------------------------------------

    \3\ Certain procedures, such as blood sampling that involves 
simple venipuncture, are considered noninvasive for purposes of 
FDA's IDE regulations (Sec.  812.3(k) (21 CFR 812.3(k)), and 
research involving such procedures may be considered no more than 
minimal risk for the purpose of expedited review (63 FR 60353 at 
60355, November 9, 1998) (see response to Comment 20).
---------------------------------------------------------------------------

    (Comment 4) A few comments oppose the proposal because it would not 
restrict or prohibit waiver of consent for classified research, citing 
President Clinton's Memorandum of 1997 regarding classified research 
(``Clinton Memorandum,'' Ref. 3).
    (Response 4) We do not believe it is necessary to address 
classified research in this rulemaking. As noted in some of these 
comments, the Clinton Memorandum is directed to Agencies that may 
conduct or support classified research subject to the 1991 Common Rule. 
FDA's informed consent regulations apply to all clinical 
investigations, as defined in Sec.  50.3(c) (21 CFR 50.3(c)), involving 
FDA-regulated articles. FDA does not regulate research on the basis 
that it is federally conducted or supported. To the extent a Federal 
Agency conducts or supports classified research and prohibits waiver of 
informed consent for such research, FDA's new waiver provision at Sec.  
50.22 does not require any IRB to waive informed consent and thus would 
not conflict with the prohibition.
    (Comment 5) Several comments argue that waivers of informed consent 
weaken human subject protections and would allow IRBs to retreat from 
their human subject protection responsibilities. These comments also 
express concern that the proposal might decrease public trust in both 
research and healthcare providers. One comment states that no third 
parties, including IRBs, should be allowed to make decisions for study 
subjects as to what constitutes ``minimal risk.''
    (Response 5) We do not agree that providing a waiver or alteration 
of informed consent under the limited circumstances described in the 
rule would allow IRBs to retreat from their human subject protection 
responsibilities or that such waivers or alterations will decrease 
public trust in research and healthcare providers. IRBs have been 
making similar waiver and alteration decisions for research subject to 
the Common Rule since its issuance in 1991, and the comments do not 
provide evidence that such decisions have decreased overall public 
trust in either research or healthcare providers. As noted above, this 
rule provides appropriate safeguards to protect the rights, safety, and 
welfare of human subjects when consent is waived and thus waivers 
granted in accordance with Sec.  50.22 should not weaken public trust.
    We also disagree with the comment stating that IRBs should not be 
allowed to make decisions as to what research constitutes ``minimal 
risk.'' IRBs have considerable experience making ``minimal risk'' 
determinations under FDA regulations (see response to Comment 10). For 
example, IRBs have been making minimal risk determinations for decades 
to decide whether expedited review procedures may be used for certain 
categories of research (see Sec.  56.110(b)(1) (21 CFR 56.110(b)(1)); 
63 FR 60353, November 9, 1998) and when reviewing clinical 
investigations involving children as subjects (see part 50, subpart D). 
In light of this experience, we believe that IRBs are generally well-
positioned to determine what constitutes ``minimal risk'' to subjects 
when considering the details of a particular clinical investigation.
    (Comment 6) Several comments criticize the proposal as too vague 
and subjective. These comments recommend adding definitions or 
providing further description of the criteria in Sec.  50.22. They also 
recommend clarifying or providing examples of research for which a 
waiver or alteration would be allowed under the proposal in order to 
reduce the potential for inconsistency and variability in IRBs' 
decision making.
    (Response 6) We do not agree with the comments stating that this 
rule is too vague and subjective. The five criteria in Sec.  50.22 for 
a waiver or alteration of informed consent for minimal risk clinical 
investigations are harmonized with the revised Common Rule's criteria 
in 45 CFR 46.116(f)(3). We note that four of these criteria have been 
included in the Common Rule and have been successfully applied since 
the Common Rule was originally issued in 1991. The revised Common Rule 
added a fifth criterion (45 CFR 46.116(f)(3)(iii)), which corresponds 
to Sec.  50.22(c) in this rule. That fifth criterion was modeled on a 
comparable criterion in the HIPAA Privacy Rule, which requires, as a 
condition of waiver of the requirement to obtain an individual's 
authorization, that the research could not practicably be conducted 
without access to and use of protected health information (PHI) (see 82 
FR 7149 at 7224).\4\ We believe that alignment between the HIPAA 
Privacy Rule, the revised Common Rule, and part 50 will support 
consistent application of the criterion in Sec.  50.22(c) by the 
research community.
---------------------------------------------------------------------------

    \4\ See also 45 CFR 164.512 (Uses and disclosures for which an 
authorization or opportunity to agree or object is not required).
---------------------------------------------------------------------------

    In response to the comments recommending additional definitions or 
criteria descriptions, we note that throughout this document (for 
example, see FDA responses to comments 10, 12, 13, and 16) we address 
comments requesting the addition of specific definitions or further 
clarification for each of the criteria described in Sec.  50.22. FDA 
intends to issue further guidance to assist IRBs in applying these 
criteria to clinical investigations with additional information on the 
types of clinical investigations that may qualify for a waiver or 
alteration of consent under Sec.  50.22.
    (Comment 7) Some comments address implementation-related aspects of 
the proposed waiver or alteration provision. One comment, noting that 
subjects may already be giving consent to undergo non-research related 
patient care, questions why it would not also be appropriate to obtain 
their consent for research-related interventions at the same time. 
Another comment questions how a person reviewing hospital records would 
know a subject agreed to be in the study if consent had been waived.
    (Response 7) With respect to the comment that questions why consent 
would need to be waived if informed consent to participate in research 
could be obtained at the same time that non-research related consent 
for patient care was being obtained, FDA notes that that the 
investigation would need to be impracticable to perform without a 
waiver in order to qualify for a waiver under this final rule. As 
stated in the preamble to the proposed rule, if scientifically sound 
research can practicably be carried out using only consenting subjects, 
we believe it should be carried out without involving nonconsenting 
subjects (83 FR 57378 at 57382). Waivers or alterations of informed 
consent under Sec.  50.22 are intended for situations where it is 
impracticable to carry out the clinical investigation, as designed, 
without the waiver or alteration. There may be certain cases in which 
getting consent from a subset of individuals in the target study 
population may be possible, but the study may still be considered 
impracticable without a waiver because of obstacles \5\ to obtaining 
consent from a sufficient number of the subjects needed to carry out 
the study as designed.
---------------------------------------------------------------------------

    \5\ Please refer to FDA's response to comment 13 for more 
information on FDA's interpretation of the term ``practicably.''

---------------------------------------------------------------------------

[[Page 88234]]

    With respect to the comment that questions how a person reviewing 
hospital records would know a subject agreed to be in the study if 
consent had been waived, any person reviewing the data for purposes of 
the study would be themselves an investigator or otherwise involved in 
the investigation, and should therefore be aware that an IRB had 
approved the study, found the criteria under Sec.  50.22 were met, and 
granted a waiver of the requirement to obtain informed consent. This 
would provide that person with assurance that the subject's rights, 
safety, and welfare are protected. Additionally, in the event of 
concerns about including a particular subject or group of subjects in a 
clinical investigation for which informed consent has been waived in 
accordance with Sec.  50.22, the investigator or member of the study 
team could consult appropriate parties, such as the sponsor or the IRB, 
to address those concerns.
    (Comment 8) Two comments suggest additional requirements for 
studies in which consent is waived. One comment cites a research paper 
that assesses the legitimacy of waivers of consent for research, which 
the authors posit is ``predicated on the reasonable belief that 
potential subjects would agree if they were asked and capable of 
consent.'' The paper includes a literature review and qualitative 
assessment of studies examining participation and refusal rates in 
human subjects research (Ref. 4). From this review, the authors 
conclude that there is reason to believe that many potential 
participants would not want to be enrolled in a study for which 
informed consent is waived, if asked. The paper concludes that waivers 
of informed consent should be rare, and that IRBs and researchers must 
find out if a study is acceptable to the target population and in the 
community where the proposed research takes place. The comment states 
that ``waivers of informed consent may be granted for a population 
based on general characteristics of the population that make getting 
consent from everyone impracticable, with express acknowledgement that 
securing consent from some members of the population may be quite 
feasible and practicable, and in those cases consent must be secured.'' 
The comment notes that this approach is modeled on the exception from 
informed consent in FDA's emergency research regulations at Sec.  
50.24, and states that Sec.  50.24 is legally and ethically superior to 
the waiver provision in the proposed rule. Finally, the comment 
recommends that an additional requirement be added to the proposed 
regulations requiring that consent should be secured from individuals 
or their LARs ``when practicable.''
    A second comment suggests that, for any research for which the 
requirement to obtain informed consent would be waived under the 
provision in the proposed rule, FDA require the drafting of an ``as 
if'' consent form in language geared toward the subject's viewpoint 
before the research begins. This comment argues a precedent for this 
approach under Sec.  50.24(a)(6). It also asserts that this exercise 
would prevent practitioners from being deprived of a description of 
research interventions and would describe the intervention in language 
geared toward the viewpoint of the human subject, which may enhance 
human subject protections and promote an atmosphere of appropriate 
respect and empathy for non-consenting human subjects.
    (Response 8) With regard to the points outlined in the cited 
research paper, we agree that the acceptability of the research to 
potential participants is an important consideration for an IRB when 
determining whether to grant a waiver or alteration of informed consent 
under the final rule. FDA stated in the preamble of the proposed rule 
that, to make the finding that the waiver or alteration will not 
adversely affect the rights and welfare of the subjects, IRBs may 
consider, for example, whether the subject population in general would 
be likely to object to a waiver or alteration being granted for the 
research in question (83 FR 57378 at 57381 to 57382). However, 
individual decisions to participate in research often depend on 
different factors, such as the recruitment method used (Ref. 5) and 
health literacy (Ref. 6). Additionally, an individual's trust (or 
distrust) in their healthcare provider and/or in the institution 
conducting the research may also contribute to their willingness to 
participate (Ref. 7). Requiring IRBs to determine and researchers to 
establish that an ``appropriate majority'' of the target study 
population would choose to participate before granting a waiver of 
consent, as the article suggests, would involve accounting for the 
individualized factors underlying such decisions. This would be unduly 
burdensome and could create significant limitations or delays for 
minimal risk investigations that Sec.  50.22 is intended to facilitate. 
Given the complexities and unknowns surrounding individual reasons for 
participation or refusal to participate in minimal risk research, we 
believe that this rule strikes an appropriate balance between enabling 
important research to proceed while safeguarding the rights, safety, 
and welfare of subjects such that consent (or elements of consent) can 
be appropriately waived.
    FDA declines to adopt the commenter's suggestion to include in the 
final rule a requirement to obtain consent from individual potential 
subjects or their LARs ``when practicable.'' FDA's provision for 
exceptions from informed consent for emergency research requires, among 
other things, an investigator commitment to attempt to contact an LAR 
for each subject within the therapeutic window and, if feasible, to ask 
the LAR for consent within that window (Sec.  52.24(a)(5)). However, we 
disagree with the commenter's conclusion that because of this 
requirement, Sec.  50.24 is ``superior'' to the requirements for a 
waiver under Sec.  50.22. Each of these provisions was developed to 
address significantly different types of clinical investigations. The 
criteria listed in Sec.  50.24 are intended for research involving a 
study population with no capacity to consent, in a setting where the 
emergency circumstances require prompt action and generally provide 
insufficient time and opportunity to locate and obtain consent from 
each subject's legally authorized representative. Specifically, for 
research to qualify to be conducted under Sec.  50.24 certain 
conditions, including the following, must be satisfied: the subject is 
in a life-threatening situation; available treatments are unproven or 
unsatisfactory; participation in the research holds out the prospect of 
direct benefit to the subject; obtaining informed consent from the 
subject is not feasible because the subject cannot provide consent due 
to their medical condition; and the intervention must be administered 
before consent can be obtained from the subject's LAR. In contrast, the 
criteria for waiver or alteration of consent in Sec.  50.22 are 
intended for research in which the risk to participants is minimal and 
are not focused on research where subjects are in a life-threatening 
situation. We, therefore, conclude that revising Sec.  50.22 in this 
final rule to include a requirement similar to that found in Sec.  
50.24(a)(5) is not appropriate for the minimal risk research that would 
otherwise qualify for a waiver or alteration of informed consent under 
this final rule. In addition, the comment's suggestion that FDA require 
informed consent to be obtained from individual subjects or their LARs 
``when practicable'' could cause confusion, given that the criterion at 
Sec.  50.22(b) requires an IRB to find that the research could not 
practicably be carried out

[[Page 88235]]

without the requested waiver or alteration of consent. Including such a 
requirement would also be an unnecessary difference from the 
corresponding provision under the Common Rule at 45 CFR 46.116(f)(3), 
contrary to the harmonization goals of this rulemaking. Because 
Sec. Sec.  50.24 and 50.22 are intended for different types of research 
with different ethical considerations, we believe that differences 
between these provisions are appropriate and that both provisions 
protect the rights, safety, and welfare of study subjects through the 
requirements that must be met for approval by an IRB.
    We also decline the suggestion to require the drafting of an ``as 
if'' informed consent form (i.e., a form that would not actually be 
used to obtain consent) if an IRB waives the informed consent 
requirement for a clinical investigation that meets the Sec.  50.22 
criteria. Although the commenter points to Sec.  50.24(a)(6) as 
precedent, that provision requires IRB approval of informed consent 
procedures and an informed consent document that are to be used to 
obtain consent from a subject or LAR, when feasible. This requirement 
recognizes that some emergency research conducted under Sec.  50.24 
``may include a limited number of subjects for whom a representative is 
able to provide surrogate consent for the subject, and the treatment 
window may be such to permit such consent to be obtained.'' (60 FR 
49086 at 49095, September 21, 1995.) As explained above, FDA is not 
including a requirement in Sec.  50.22 that the investigator obtain 
consent from subjects or LARs if feasible similar to the requirement in 
Sec.  50.24(a)(5). Development of an ``as-if'' informed consent form 
that would not be used would impose additional burdens on IRBs and 
investigators without a clear benefit. For investigations in which 
informed consent is waived, we have no evidence that an ``as if'' 
consent document would provide practitioners with additional 
information or understanding of the research beyond what is available 
in the research protocol, or that this additional document would foster 
additional empathy or respect for subjects whose consent is waived. 
Additionally, we disagree that an ``as if'' informed consent form would 
increase human subject protections beyond the requirements listed in 
Sec.  50.22, such as the requirement that the waiver or alteration not 
adversely affect the rights and welfare of subjects, as well as the 
requirement that, whenever appropriate, the subjects or their LARs are 
provided with additional pertinent information after participation.
    (Comment 9) Two comments suggest tracking the cumulative effects of 
minimal risk studies on subjects who have participated in more than one 
such study and suggest establishing a centralized registry containing 
the names of all human subjects who are involved in research or 
clinical investigations, the names of the sponsor and researcher, 
whether the research is classified, and whether informed consent was 
waived or altered.
    (Response 9) We decline to adopt the suggested requirement that all 
participants in minimal risk studies be tracked and the suggestion to 
establish a centralized registry of participants in clinical 
investigations because, among other issues (e.g., the time and 
resources needed to establish and maintain a registry with appropriate 
procedures for the collection, use, and disclosure of identifiable 
information), such a registry might present additional risks regarding 
privacy and confidentiality of participant data (e.g., data leak of 
private health information, creating links between individual data that 
otherwise would not exist, increased chance of stigmatization through 
identification of individual data collected in the registry).

C. Comments on the Proposed Waiver or Alteration Criteria

    FDA proposed that, to permit a waiver or alteration of the informed 
consent requirements, the IRB must find and document that the following 
four criteria are met: (1) the clinical investigation involves no more 
than minimal risk to the subjects; (2) the waiver or alteration will 
not adversely affect the rights and welfare of the subjects; (3) the 
clinical investigation could not practicably be carried out without the 
waiver or alteration; and, (4) whenever appropriate, the subjects will 
be provided with additional pertinent information after participation.
1. The Clinical Investigation Involves No More Than Minimal Risk to the 
Subjects (Proposed Sec.  50.22(a))
    The proposed rule included, as the first criterion, that the 
clinical investigation involves no more than minimal risk to the 
subjects. ``Minimal risk'' is defined in Sec.  50.3(k) to mean that the 
probability and magnitude of harm or discomfort anticipated in the 
research are not greater in and of themselves than those ordinarily 
encountered in daily life or during the performance of routine physical 
or psychological examinations or tests.
    (Comment 10) Fewer than half of the comments reference proposed 
Sec.  50.22(a) or mention the minimal risk criterion. The majority of 
these comments support an IRB's ability to approve informed consent 
procedures that do not include or that alter some of the elements of 
informed consent, or to waive consent entirely, for minimal risk 
research. Some of these comments support the ability to waive or alter 
informed consent requirements for specific types of research they 
identify as minimal risk, including research involving clinical record 
reviews or secondary use of biospecimens, and certain cluster 
randomized trials. One comment expresses trust in IRBs' abilities to 
know when informed consent is required.
    Conversely, some comments oppose or express reservations about 
allowing waiver or alteration of consent for minimal risk studies, 
suggesting that the term ``minimal risk'' is vague, ambiguous, or 
subjective, or express other confusion about its meaning. One comment 
indicates concern that the vagueness of the term ``minimal risk'' would 
precipitate misuse of the rule. Other comments suggest that the rule 
clarify the meaning of specific terms in the definition of minimal risk 
(e.g., ``routine physical or psychological examinations or tests''). 
These comments also suggest that FDA clarify that the ``daily life'' 
risk standard in the current definition so that IRBs would know how to 
interpret the standard to avoid allowing populations that encounter 
higher risks in daily life (e.g., live in a dangerous region) to be 
exploited. Another comment raises concerns regarding the subjective 
nature of the definition of ``minimal harm'' and the potential for 
variability in IRB decisions on requests for waivers of informed 
consent.
    Several comments assert that IRBs should not be entrusted to make 
minimal risk determinations. A few comments suggest that determinations 
of risk are subjective and that only the individual subject can make a 
meaningful decision about degrees of risk and whether a particular risk 
in a study is actually minimal. Some comments express concern that IRBs 
might inappropriately grant waivers for clinical investigations that 
are greater than minimal risk, or that they may fail to appreciate both 
the nature and risks of procedures in the research studies that are 
submitted to them for review. Other comments caution that IRB members 
may have conflicts of interest that could affect their interpretation 
of the term. To support their concerns and opposition, these comments 
cite past instances in which researchers had

[[Page 88236]]

reportedly misled subjects or inappropriately conducted research 
without obtaining informed consent.
    Other comments suggest that additional oversight or clarification 
regarding IRB processes is needed with regard to granting waivers of 
informed consent and the determination of minimal risk. One comment 
urges that, if waivers are allowed, the Agency revise the proposal to 
address the following: clarify the process to determine whether to 
grant and approve waivers of informed consent, require ongoing review 
of waivers to determine whether IRBs are properly defining the studies 
as minimal risk, immediately terminate any research in which medical 
interventions are withheld or are too aggressive, and provide a 
``whistleblower form'' for individuals involved in a research study to 
anonymously submit a complaint about that study to HHS. Another comment 
requests that FDA provide details about the practical application of 
the proposal, that is, how an IRB's process of determining whether to 
grant waivers of informed consent might work to remove the risk of 
variability in when and how such waivers are granted.
    Some comments express concern that studies involving records or 
data are often labeled as minimal risk, even though IRBs struggle to 
make determinations about the magnitude of the risks posed by such 
studies and whether the risks are indeed minimal. One of these comments 
notes that the ability to link various sources of personal data may 
create additional risks for study subjects. One comment indicates 
concern that, in research involving real-world data (RWD) or review of 
health records that is categorized as ``minimal risk,'' hacking or 
inadvertent sharing could put the subjects' information at risk or 
cause subjects to be at risk for losing healthcare coverage.
    (Response 10) FDA is not revising the definition of minimal risk in 
this rule. Retaining the current definition of minimal risk will avoid 
confusion in the research community and maintain harmonization with the 
revised Common Rule. The Common Rule and FDA regulations have shared 
the same definition of minimal risk since 1991,\6\ and the definition 
of minimal risk was not changed in the revised Common Rule. Because of 
the longstanding consistency in the definitions of minimal risk 
provided in both FDA regulations and the Common Rule, IRBs have 
experience in applying the term ``minimal risk'' to research involving 
human subjects, including determining when a clinical investigation 
involves no more than minimal risk. Without additional detail, it is 
not possible to determine whether the specific types of studies the 
comments identify as minimal risk would involve no more than minimal 
risk to the subjects (see also response to Comment 19). However, we 
agree with these comments' support for waiving or altering informed 
consent to facilitate minimal risk research that meets the requirements 
of Sec.  50.22.
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    \6\ 83 FR 57378 at 53781.
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    In response to comments suggesting that IRB members might have 
conflicts of interest that could affect their interpretation of the 
term ``minimal risk,'' we note that IRBs are subject to the 
requirements under Sec.  56.107 (21 CFR 56.107), including the 
requirements prohibiting participation in IRB review by a member with a 
conflict of interest, except to provide information requested by the 
IRB, under Sec.  56.107(e).
    With respect to the comment that recommends revising the rule to 
clarify the process of an IRB waiver determination and require ongoing 
review for waivers to determine the adequacy of IRBs' interpretation of 
``minimal risk,'' we note that IRBs are required to prepare and follow 
written procedures for conducting reviews of FDA-regulated clinical 
investigations (see 21 CFR 56.108(a) and 56.115(a)(6)). These written 
procedures should include an IRB's processes for reviewing requests to 
waive or alter informed consent and documenting that the criteria in 
Sec.  50.22 are satisfied. We also note that FDA inspects IRBs to 
determine whether they are reviewing and approving research in 
accordance with FDA regulations and with the IRBs' written procedures. 
We do not believe it is necessary to prescribe a particular process or 
procedure that IRBs must follow when making and documenting a waiver or 
alteration decision for a research study, or that such a process would 
result in more consistent decision making. FDA regulations provide for 
flexibility in terms of the specific contents of IRB written 
procedures, which gives IRBs the ability to establish procedures best 
suited to their own operations. Written procedures, including the 
processes IRBs follow for making certain determinations, may vary among 
institutions and IRBs because of differences in the way organizations 
are structured, the type of research studies reviewed by the IRB, 
institutional policy or administrative practices, the number of IRBs at 
the institution, affiliation with an institution, or local and State 
laws and regulations (Ref. 8).
    FDA also declines the commenter's suggestion to add to the rule a 
requirement that research be terminated that withholds or provides for 
aggressive medical intervention. Although the comment does not 
elaborate on the meaning of an ``aggressive'' medical intervention, it 
does not appear that the types of research studies the comment 
describes would qualify for a waiver or alteration under Sec.  50.22. 
In addition, if changes are proposed to a study for which a waiver or 
alteration has been granted under Sec.  50.22, and those changes 
include the addition of an investigational intervention or other 
protocol amendment that involves more than minimal risk to subjects, 
then the study, with the change, would no longer qualify for the waiver 
or alteration.\7\ With regard to the comment encouraging a process for 
HHS to receive anonymous complaints from individuals involved in a 
research study, FDA notes these processes are already in place for both 
FDA \8\ and HHS.\9\
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    \7\ While outside the scope of this rulemaking, FDA's existing 
IRB regulations at 21 CFR 56.113 provide for termination of IRB 
approval of research that is not being conducted in accordance with 
the IRB's requirements or that has been associated with unexpected 
serious harm to subjects.
    \8\ Complaints related to FDA-regulated clinical investigations 
should be reported to the Center responsible for the product 
involved. Additional information and contact information for each 
Center is available at: https://www.fda.gov/science-research/clinical-trials-and-human-subject-protection/reporting-complaints-related-fda-regulated-clinical-trials.
    \9\ Complaints related to research subject to HHS regulations 
may be emailed to OHRP's Director of the Division of Compliance 
Oversight at <a href="/cdn-cgi/l/email-protection#8be8e4e6fbe7eae2e5fff8a5e4e3f9fbcbe3e3f8a5ece4fd"><span class="__cf_email__" data-cfemail="f3909c9e839f929a9d8780dd9c9b8183b39b9b80dd949c85">[email protected]</span></a>. More information is available 
at: https://www.hhs.gov/ohrp/compliance-and-reporting/submitting-a-complaint/index.html.
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    Regarding the comment suggesting that hacking or inadvertent 
sharing of health information can create risks for subjects, such as 
losing healthcare coverage, we note that Sec.  56.111(a)(7) (21 CFR 
56.111(a)(7)) of FDA's regulations requires IRBs to determine that, 
where appropriate, adequate provisions to protect subjects' privacy and 
maintain the confidentiality of data are in place in order to approve 
FDA-regulated research. This would include research for which the IRB 
grants a waiver or alteration of consent under Sec.  50.22.
    As previously noted, FDA plans to publish guidance to assist IRBs 
in applying the criteria for waiver or alteration of informed consent 
requirements in Sec.  50.22 to FDA-regulated clinical investigations. 
In that guidance, we intend to include additional information on the 
types of research activities that may involve no

[[Page 88237]]

more than minimal risk to the subjects and therefore might qualify for 
a waiver or alteration of informed consent.
    (Comment 11) One comment, focused on device studies, warns about 
the potential for confusion and inconsistent interpretation across IRBs 
when applying the concept of ``minimal risk'' to studies of ``non-
significant risk'' devices.
    (Response 11) FDA addressed the difference between ``non-
significant risk'' and ``minimal risk'' in a 2006 guidance for IRBs, 
clinical investigators, and sponsors entitled ``Significant Risk and 
Nonsignificant Risk Medical Device Studies'' (SR/NSR Guidance; Ref. 9). 
In the SR/NSR Guidance, FDA explains that ``non-significant risk'' and 
``minimal risk'' determinations are distinct and involve different 
considerations. IRBs that review device investigations have experience 
applying FDA's regulations at parts 50, 56, and 812, and the SR/NSR 
Guidance has been in place for many years as a resource. As a result, 
IRBs should be aware that ``non-significant risk'' and ``minimal risk'' 
are different concepts that serve different regulatory purposes. Given 
this experience, we do not believe that IRBs will encounter difficulty 
applying the concept of ``minimal risk'' in Sec.  50.22 to clinical 
investigations involving ``non-significant risk'' devices.
2. The Waiver or Alteration Will Not Adversely Affect the Rights and 
Welfare of the Subjects (Proposed Sec.  50.22(b))
    The proposed rule included, as the second criterion, that the 
waiver or alteration will not adversely affect the rights and welfare 
of the subjects.\10\ FDA stated in the preamble of the proposed rule 
that, to make this finding, IRBs may consider, for example, whether the 
waiver or alteration has the potential to negatively affect the 
subjects' well-being or whether the subject population in general would 
likely object to a waiver or alteration being granted for the research 
in question (83 FR 57378 at 57381 to 57382). It would not be necessary 
for an IRB to find that obtaining informed consent would be harmful or 
contrary to the best interests of subjects in order to satisfy this 
criterion.
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    \10\ We note that, in the final rule, proposed Sec.  50.22(b) is 
now Sec.  50.22(d).
---------------------------------------------------------------------------

    (Comment 12) Several comments mention the effects of the proposed 
rule on subjects' rights and welfare. Some comments oppose the idea of 
a waiver of consent, stating that the absence or omission of informed 
consent affects the rights of subjects. Two comments assert that a 
waiver of informed consent would be unethical and in violation of 
subjects' trust because subjects would be prevented from knowing who is 
seeing or using their records, and the waiver would take away the 
subjects' choice and ability to specify how their data will be used. An 
additional comment mirrors this concern and notes the importance of 
protecting personal data.
    Two comments object to waiving consent on the grounds that doing so 
would deny subjects necessary information about the research (e.g., the 
name of the sponsor, a description of the research or research 
protocol, a description of subjects' rights, who to contact in the 
event of injury) and would deny subjects the right to object to 
participation in the research, the right to withdraw from the research, 
and the right to recourse and remedy in the event of issues or 
wrongdoing. Finally, one comment objects to the rule based, in part, on 
a lack of definitions for the term ``welfare'' and the phrase ``welfare 
of the subjects.''
    (Response 12) FDA does not agree with the comments suggesting that 
allowing for a waiver of informed consent for minimal risk clinical 
investigations in the circumstances described in Sec.  50.22, including 
the criterion in proposed Sec.  50.22(b), adversely affects the rights 
of subjects or is unethical or in violation of subjects' trust. We note 
that provisions relating to safeguarding the rights and welfare of 
subjects in clinical investigations have been included in FDA's 
regulations for decades. Section 56.107(a) of our regulations on IRB 
membership requires that each IRB be sufficiently qualified through the 
experience and expertise of its members, and the diversity of the 
members, to promote respect for its advice and counsel in safeguarding 
the rights and welfare of human subjects. We believe that an IRB 
responsible for the review, approval, and continuing review of a 
minimal risk clinical investigation that meets these membership 
requirements is capable of finding and documenting, as appropriate, 
that the waiver or alteration will not adversely affect the rights and 
welfare of subjects participating in the research. Additionally, we 
note that to approve a clinical investigation, including a clinical 
investigation for which informed consent is waived or altered under 
this rule, an IRB must find that, where appropriate, there are adequate 
provisions to protect the privacy of subjects and to maintain the 
confidentiality of data (Sec.  56.111(a)(7)).
    We believe that the safeguards in Sec.  50.22 also help to 
alleviate the comments' concerns regarding subjects' access to 
information about the research, as we anticipate that IRBs will 
consider if any study information falling within the elements listed in 
Sec.  50.25(a) or (b) should be provided to subjects. If so, the IRB 
may conclude, for example, that an alteration of certain informed 
consent elements is appropriate rather than a waiver, or that it is 
appropriate for the subjects or their LARs to be provided with 
additional pertinent information after participation (see Sec.  
50.22(e) in this rule).
    In response to the comments objecting to the waiver provision as 
unethical or adversely affecting subjects' rights, we also point to our 
response to comment 2 for discussion regarding the ethical principles 
associated with clinical research (e.g., autonomy, beneficence, 
justice) in the context of this rule. For those FDA-regulated clinical 
investigations that would meet the criteria for waiver or alteration of 
consent under Sec.  50.22, we believe that the protections in place 
under this rule are appropriate to protect the rights, safety, and 
welfare of human subjects while facilitating research to advance public 
health.
    Finally, FDA declines to include a definition of ``welfare'' or 
``welfare of the subjects'' in the final rule. We note that the 
language of ``rights and welfare of human subjects'' has a long history 
of inclusion in both FDA regulations for human subject protections and 
the Common Rule. This and similar language are also used in other well-
established guidelines on human subject research (Refs. 10 and 11). 
Given this history, FDA believes that IRBs are accustomed to applying 
the term ``welfare'' to different types of research, including minimal 
risk research.
    FDA notes that there are resources available to IRBs and the 
research community more broadly when considering human subject welfare 
in minimal risk research. For example, the Secretary's Advisory 
Committee on Human Research Protections (SACHRP), through its 
Subcommittee on Subpart A, developed several recommendations regarding 
the interpretation of the Common Rule criteria for a waiver or 
alteration of informed consent, including the criterion regarding the 
``rights and welfare'' of subjects (Ref. 2).
3. The Clinical Investigation Could Not Practicably Be Carried Out 
Without the Waiver or Alteration (Proposed Sec.  50.22(c))
    The proposed rule included, as the third criterion, that the 
clinical investigation could not practicably be carried out without the 
waiver or

[[Page 88238]]

alteration.\11\ In the preamble to the proposed rule, FDA stated that, 
if scientifically sound research can practicably be carried out using 
only consenting subjects, FDA believes it should be carried out without 
involving nonconsenting subjects. FDA also provided an example of what 
practicable means (i.e., (1) that recruitment of consenting subjects 
does not bias the science and the science is no less rigorous as a 
result of restricting it to consenting subjects or (2) that the 
research is not unduly delayed by restricting it to consenting 
subjects) (83 FR 57378 at 57382). As noted in our response to comment 
7, the emphasis is on situations where it is impracticable to carry out 
the clinical investigation, as designed, without the waiver or 
alteration, rather than on situations where it is not feasible to 
obtain informed consent from subjects.
---------------------------------------------------------------------------

    \11\ We note that, in the final rule, proposed Sec.  50.22(c) is 
now Sec.  50.22(b).
---------------------------------------------------------------------------

    (Comment 13) Several comments on the proposal make reference to 
proposed Sec.  50.22(c) or commented on the term ``practicably'' in 
this criterion. Several of the comments ask for clarification or 
additional guidance about the meaning of the term ``practicably'' in 
the proposed criterion.
    One comment asserts that there is wide variation in the way IRBs 
interpret the practicability standard. The comment continues that some 
IRBs interpret impracticable to mean that the research is impossible to 
do with consent, while other IRBs might accept investigator resistance 
to obtaining informed consent as meeting the impracticability 
threshold. This comment also recommends that practicability 
determinations be made in the context of understanding the value or 
importance of the research, and that ``impracticable'' should be 
understood to mean that the burdens of getting consent are too high, 
given the benefit, or value, promised by the research. This comment is 
one of two recommending that FDA revise its interpretation of 
``practicable'' to align with recommendations made by SACHRP in 2008 
related to waiver of informed consent and interpretation of minimal 
risk under the Common Rule (Ref. 2).
    Another comment seeks reassurance that one of the objectives of 
Sec.  50.22 is to provide IRBs with the latitude to allow a sponsor to 
have access to and utilize data and/or biospecimens that have already 
been collected without having to obtain informed consent. The comment 
encourages the inclusion of examples of minimal risk investigations to 
help IRBs understand that they have the flexibility to make real-world 
assessments of whether the research would be rendered impracticable 
because of the unavailability of subjects to give new individual 
consent.
    A final comment asks that FDA clarify the meaning of the phrase 
``unduly delayed'' in its description of the term ``practicable.'' This 
comment states that more effort should be put into finding an 
alternative to conducting research without subjects' consent.
    (Response 13) With respect to the interpretation of the term 
``practicably,'' we reiterate that the emphasis is on situations where 
it is impracticable--not necessarily impossible--to carry out the 
clinical investigation, as designed, without the waiver or alteration. 
Practicability should be assessed on a case-by-case basis considering 
the unique factors associated with the clinical investigation, such as 
its aims, its population(s), and the impact on its scientific validity 
if informed consent were required (e.g., introduction of bias). The 
relevant considerations, and the weight given to each consideration, 
should reflect the unique circumstances of the clinical investigation 
for which a waiver or alteration of informed consent is being sought.
    If an IRB finds that a clinical investigation can be practicably 
carried out using only consenting subjects, then FDA believes it should 
be carried out without involving nonconsenting subjects. However, we 
agree that, under this final rule, an IRB can approve a clinical 
investigation falling within the scope of part 50 in which 
investigators will have access to and utilize data and/or biospecimens 
that have already been collected without having to obtain informed 
consent, provided the IRB finds and documents that the criteria under 
Sec.  50.22 are met.
    In addition, we agree that IRBs may find under Sec.  50.22(b) 
(Sec.  50.22(c) in the proposed rule) that a clinical investigation 
could not practicably be carried out without a waiver or alteration of 
informed consent based on the unavailability of certain subjects in an 
investigation to give consent for a new investigation (e.g., subjects 
lost to followup), when restricting the research to the subjects 
available to provide consent would compromise the scientific or ethical 
integrity, or cause undue delay of, the investigation.
    As some comments point out, SACHRP made recommendations in 2008 
related to waivers of informed consent and the interpretation of 
minimal risk under the Common Rule, including the Common Rule waiver 
criterion that corresponds to Sec.  50.22(b). In its recommendations, 
SACHRP emphasized that the criterion ``states that the research could 
not practicably be carried out without the waiver or alteration. Put 
another way, it would not be practicable to perform the research (as it 
has been defined in the protocol by its specific aims and objectives) 
if consent was required'' (Ref. 2). SACHRP also offered the following 
concepts to help an IRB determine whether the research could not be 
practicably carried out without the waiver or alteration of consent: 
(1) the scientific validity of the research would be compromised if 
consent were required; (2) ethical concerns would be raised if consent 
were required; (3) there is a scientifically and ethically justifiable 
rationale why the research could not be conducted with a population 
from whom consent can be obtained; and (4) practicability should not be 
determined solely by considerations of convenience, cost, or speed.
    Although SACHRP's recommendations regarding the ``practicably'' 
waiver criterion were developed for research that is regulated under 
the Common Rule, they are consistent with FDA's interpretation of the 
corresponding waiver criterion in this rule (i.e., Sec.  50.22(b)). It 
thus may be appropriate for an IRB to find that a clinical 
investigation could not practicably be carried out without a waiver or 
alteration of informed consent on the grounds that ethical concerns 
would be raised if consent were required (e.g., an investigation using 
previously collected biospecimens where obtaining subjects' consent for 
secondary research use of the biospecimens may expose individuals to 
new privacy risks by linking the biospecimens with nominal identifiers 
in order to contact the individuals to seek consent). In some cases, 
these ethical concerns could justify a finding of impracticability 
under Sec.  50.22(b) even if the scientific validity of the clinical 
investigation would not be compromised by asking the individuals to 
provide informed consent.
    In addition, as stated in the preamble to the proposed rule, FDA 
interprets the term ``practicably'' in Sec.  50.22(b) to mean, for 
example, that the research is not unduly delayed by restricting it to 
consenting subjects (83 FR 57378 at 57382). The phrase ``unduly 
delayed'' refers to more than just considerations of speed. By ``unduly 
delayed,'' we mean a delay in the initiation of a clinical 
investigation that is so lengthy as to raise ethical or scientific 
concerns given the benefit, or value, potentially gained by the 
research (e.g., delaying the initiation of an investigation of a rare 
disease treatment by several years in

[[Page 88239]]

order to allow for collection of new biospecimens from consenting 
subjects with the rare disease, when biospecimens from individuals with 
the disease are available from a repository but the biospecimens have 
no accompanying current contact information). Accordingly, an IRB may 
make a finding that the research could not practicably be carried out 
without the requested waiver or alteration because requiring consent 
would unduly delay the research.
    We note that it would be inappropriate for an IRB to find that a 
clinical investigation could not practicably be carried out without a 
waiver or alteration of informed consent based solely on a clinical 
investigator being resistant to obtaining informed consent. We do not 
consider investigator resistance to obtaining informed consent to be a 
scientifically or ethically valid reason for finding under Sec.  
50.22(b) that a clinical investigation could not practicably be carried 
out without a requested waiver or alteration of informed consent.
4. Whenever Appropriate, the Subjects Will Be Provided With Additional 
Pertinent Information After Participation (Proposed Sec.  50.22(d))
    As the fourth criterion, FDA proposed that, whenever appropriate, 
the subjects will be provided with additional pertinent information 
after participation.\12\ For example, an IRB may find that information 
that had been previously withheld about the clinical investigation to 
prevent bias must be provided to subjects following their 
participation.
---------------------------------------------------------------------------

    \12\ We note that, in the final rule, proposed Sec.  50.22(d), 
as revised, is now Sec.  50.22(e).
---------------------------------------------------------------------------

    (Comment 14) FDA received a few comments about proposed Sec.  
50.22(d). Two comments cite a lack of clarity about the phrase 
``whenever appropriate'' and one asks ``when and why'' it would not be 
appropriate to provide a subject with pertinent information after the 
research has ended. One comment recommends that definitions for Sec.  
50.22(d) be included, without providing further specificity on the 
definitions to be included.
    (Response 14) For this criterion, the phrase ``whenever 
appropriate'' means that, when evaluating whether this criterion is 
met, the reviewing IRB considers factors relevant to the specific 
clinical investigation and population of the study under review to 
determine whether an investigator should provide information to the 
subjects of the minimal risk clinical investigation or to their LARs 
after participation (Ref. 2). One example where providing additional 
pertinent information after participation may be appropriate is in the 
case where some aspects of the study are not fully disclosed upfront 
because full disclosure may interfere with the purpose of the study 
(e.g., full knowledge might cause subjects to act differently than they 
naturally would during the study). In that case, withholding full 
information upfront helps to ensure subject responses are not biased. 
Providing subjects with additional pertinent information about the 
study after participation may be appropriate.
    FDA declines the recommendation that definitions in Sec.  50.22(d) 
be included, as we do not have additional information from the 
commenter regarding what specific definitions should be described. As 
noted in our responses to comments 6 and 10, we believe that IRBs are 
equipped to consider the criteria outlined in the rule, as IRBs have 
experience applying the criteria in the corresponding Common Rule 
provision for waiver or alteration of informed consent. IRBs also have 
resources available to draw upon when considering a waiver or 
alteration of informed consent for minimal risk research (Ref. 2).

D. Comments on Adopting the Revised Common Rule's Fifth Criterion for 
Waiver or Alteration of Informed Consent

    In the proposed rule, FDA explained that the revised Common Rule 
retained the same four criteria for IRB waiver or alteration of 
informed consent as were included in the 1991 version of the Common 
Rule, but added a fifth criterion, i.e., ``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'' (45 CFR 
46.116(f)(3)(iii)). FDA proposed to adopt the four criteria from the 
1991 version of the Common Rule but did not propose to adopt the fifth 
criterion at that time. Instead, FDA invited public comment on whether 
to include the fifth criterion in FDA regulations.
    (Comment 15) Several comments support including the fifth criterion 
in the final rule because it would harmonize FDA's criteria in Sec.  
50.22 for a waiver or alteration of informed consent for minimal risk 
clinical investigations with the revised Common Rule's criteria in 45 
CFR 46.116(f)(3) and would support the continued protection of human 
subjects by addressing identifiable private information and 
biospecimens. Some comments also note that adopting the fifth criterion 
is consistent with the goal of reducing administrative burden. One 
comment expresses the concern that less than complete harmonization 
would do nothing to reduce the time and effort spent training staff and 
developing multiple sets of forms and processes for review of research 
under different standards.
    Some comments maintain that inclusion of the fifth criterion is 
helpful because research involving biospecimens is an area of confusion 
and controversy and including the fifth criterion provides 
clarification of FDA's policy. One comment asserts that omission of the 
fifth criterion would contribute to the mistaken belief that FDA's 
regulations do not permit a waiver or alteration of informed consent 
for minimal risk research involving identifiable biospecimens.
    Two comments request FDA's rationale for not promulgating the fifth 
criterion if the criterion is not adopted in the final rule. Another 
comment recommends that FDA revise the definition of human subject at 
Sec.  50.3(g) to clarify the applicability of part 50 to private 
information and biospecimens. This comment also recommends that, given 
that ``identifiability is more fluid than the term implies, and 
technology is rapidly changing how data can be identified,'' FDA adopt 
a provision, similar to the revised Common Rule at 45 CFR 46.102(e)(7), 
requiring the Agency to periodically reevaluate the meaning of 
``identifiable'' and what technologies or techniques generate 
identifiable information or specimens.
    (Response 15) FDA is adopting the fifth criterion in this final 
rule. To match the structure of the revised Common Rule's general 
waiver provision (i.e., 45 CFR 46.116(f)), the fifth criterion has been 
incorporated into the codified text at Sec.  50.22(c).
    In adopting the fifth criterion, we are harmonizing the waiver 
criteria set forth in Sec.  50.22 with those set forth in the revised 
Common Rule's general waiver provision (45 CFR 46.116(f)(3)). As 
discussed in our response to comment 1, we expect that this 
harmonization will reduce administrative burdens on IRBs and 
researchers and reduce research costs. We also agree with comments 
noting that inclusion of the fifth criterion in the codified text will 
help avoid confusion regarding the applicability of Sec.  50.22 to 
minimal risk clinical investigations involving the use of private 
information or biospecimens in an identifiable format. The fifth 
criterion makes it clear that Sec.  50.22 applies to minimal risk 
clinical investigations involving the use of

[[Page 88240]]

identifiable private information or identifiable biospecimens and that 
IRBs are permitted to waive or alter informed consent for such 
investigations, provided the IRB finds and documents that the other 
criteria in Sec.  50.22 are met and that the investigation could not 
practicably be carried out without using such information or 
biospecimens in an identifiable format.
    We decline the recommendation to revise the definition of ``human 
subject'' in Sec.  50.3(g), as changes to the definition of ``human 
subject'' could have unintended effects on other sections in part 50 
beyond the scope of this rule. We also decline to adopt a provision 
that would require FDA to periodically reexamine the definitions of 
``identifiable private information'' or ``identifiable biospecimen.'' 
We note that definitions of ``identifiable private information'' and 
``identifiable biospecimen'' are included in FDA's proposed rule to 
amend part 50, Protection of Human Subjects, and part 56, Institutional 
Review Boards (87 FR 58733, September 28, 2022). Additionally, the 
revised Common Rule includes provisions at 45 CFR 46.102(e)(7)(i) and 
46.102(e)(7)(ii) that require Federal departments and Agencies 
implementing the revised Common Rule, regularly and upon consultation 
with appropriate experts, to (i) reexamine the meaning of 
``identifiable private information'' and ``identifiable biospecimen'' 
\13\ and (ii) assess whether there are analytic technologies or 
techniques that should be considered to generate identifiable private 
information or identifiable biospecimens. FDA intends to participate in 
these efforts with HHS and the other Federal departments and Agencies, 
providing input on FDA-regulated research and promoting consistent and 
appropriate interpretation of these terms across HHS and FDA human 
subject research regulations. Including a new requirement in FDA's 
regulations for FDA to consider issues relating to the meaning of 
``identifiable,'' on a periodic basis and in light of evolving 
technology, is thus unnecessary and could result in duplicative efforts 
and additional burden on the Agency without added benefit.
---------------------------------------------------------------------------

    \13\ The provision in 45 CFR 46.102(e)(7)(i) 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.
---------------------------------------------------------------------------

    (Comment 16) A few comments oppose adopting the fifth criterion. 
Two comments observe that FDA did not propose to establish a regulatory 
definition for ``identifiable.'' These comments assert that the 
definitions of the terms ``identifiable private information'' and 
``identifiable biospecimen'' in the revised Common Rule must be 
periodically reevaluated under 45 CFR 46.102(e)(7) and may change in 
the future, which could impact research involving identifiable 
biospecimens and identifiable private information in unknown ways. In 
addition, these comments maintain that the fifth criterion could lead 
to unintended negative consequences, such as investigators being 
reluctant to retain identifiers needed for quality control purposes and 
for the verification of data that may be required for FDA submissions, 
applications, and approvals. The comments also express concern that 
IRBs may be reluctant to grant waivers for research with identifiable 
biospecimens and data. Additional comments contend that the fifth 
criterion is unnecessary because it does not provide additional human 
subject protections beyond those provided by the other criteria in 
proposed Sec.  50.22, or because certain types of research (i.e., on 
biospecimens) fall outside the scope of FDA-regulated clinical 
investigations because the research does not include a ``human 
subject.'' Finally, one comment asserts that informed consent should 
never be waived for research involving identifiable private information 
or biospecimens.
    (Response 16) FDA declines to add a definition for ``identifiable'' 
in this rule. As noted in our response to comment 15, we include 
definitions of ``identifiable private information'' and ``identifiable 
biospecimen'' as part of our proposed rule to amend part 50, Protection 
of Human Subjects, and part 56, Institutional Review Boards. In that 
rule, the proposed definitions of ``identifiable private information'' 
and ``identifiable biospecimen'' harmonize with the revised Common 
Rule's definitions of these terms (45 CFR 46.102(e)(5) and (6)).
    With respect to the revised Common Rule definitions for 
``identifiable private information'' and ``identifiable biospecimen,'' 
we acknowledge that the meaning of these terms must be periodically 
reexamined pursuant to 45 CFR 46.102(e)(7) and that they may be 
interpreted differently by the Common Rule departments and Agencies in 
the future. However, we believe the commenters' concerns regarding the 
potential impact on FDA-regulated research of such periodic 
reexaminations can be addressed through FDA's involvement in the 
consultation process described in the revised Common Rule, as discussed 
in the response to comment 15. Additionally, these comments do not 
provide a basis for us to conclude that adoption of the fifth criterion 
will have unintended negative consequences for investigator retention 
of identifiers. We fully expect clinical investigators to retain the 
identifiers for private information and biospecimens when it is 
necessary to do so for quality control purposes. A failure to preserve 
the identifiers could compromise the integrity of an investigation's 
results. We do not believe clinical investigators will risk 
compromising an investigation to avoid triggering the fifth criterion 
in any research involving private information or biospecimens. Nor are 
we aware of evidence that IRBs will be reluctant to waive or alter 
informed consent for clinical investigations involving private 
information or biospecimens in an identifiable format when the waiver 
criteria are met, or that IRBs are more reluctant to waive informed 
consent for research involving identifiable private information or 
biospecimens since the fifth criterion has been adopted in the revised 
Common Rule. FDA expects IRBs to evaluate carefully each request and 
grant a waiver or alteration of informed consent only when adequately 
justified.
    We disagree with the contention that the fifth criterion is 
unnecessary because it does not provide additional human subject 
protections beyond what the other criteria provide. The fifth criterion 
respects subjects' interests in protecting the confidentiality of their 
information and biospecimens by embodying the principle that 
nonidentifiable private information and nonidentifiable biospecimens 
should be used whenever possible in clinical investigations for which 
informed consent is not obtained.\14\ Although some IRBs might consider 
these privacy interests as a part of analyzing other criteria in Sec.  
50.22, the fifth criterion requires that all IRBs consider these 
interests when determining whether to grant a waiver or alteration of 
informed consent under Sec.  50.22 for a clinical investigation 
involving identifiable

[[Page 88241]]

private information or identifiable biospecimens.
---------------------------------------------------------------------------

    \14\ In adopting this criterion, the preamble to the revised 
Common Rule stated: ``This criterion was modeled on the comparable 
criterion in the HIPAA Privacy Rule, which requires as a condition 
of waiver of the requirement to obtain an individual's authorization 
that the research could not practicably be conducted without access 
to and use of protected health information. The principle embodied 
in this additional proposed criterion was that nonidentified 
information should be used whenever possible in order to respect 
subjects' interests in protecting the confidentiality of their data 
and biospecimens'' (see 82 FR 7149 at 7224).
---------------------------------------------------------------------------

    In response to the comment suggesting that the fifth criterion is 
unnecessary because ``biospecimen research'' does not involve a human 
subject and thus does not meet the definition of ``clinical 
investigation,'' we disagree. The comment points to FDA's definition of 
``human subject'' in Sec.  50.3(g) (``Human subject means an individual 
who is or becomes a participant in research, either as a recipient of 
the test article or as a control. A subject may be either a healthy 
human or a patient.''). We note that FDA's existing IDE regulations 
(Sec.  812.3(p)) refer specifically to specimens in the definition of 
``subject'' (i.e., ``Subject means a human who participates in an 
investigation, either as an individual on whom or on whose specimen an 
investigational device is used or as a control.''). FDA's IDE 
regulations cross-reference part 50 with respect to requirements for 
obtaining informed consent (see, e.g., Sec. Sec.  812.2(b)(1)(iii) and 
812.100), and the Agency's longstanding position is that FDA-regulated 
device investigations using biospecimens are subject to informed 
consent requirements under part 50 (Refs. 12 and 13). Additionally, as 
the comment itself subsequently points out, the inclusion of this 
criterion may be helpful to biospecimen research by providing clarity 
on this issue.
    We also do not agree that informed consent should never be waived 
for clinical investigations involving private information or 
biospecimens in an identifiable format. Such research plays an 
important role in the discovery and development of innovative medical 
products, and it may not be practicable to perform the research if 
investigators are required to obtain informed consent from the 
individuals associated with the private information or biospecimens. 
Without the possibility of a waiver of informed consent, scientific 
progress in many therapeutic areas could be slowed. We believe that the 
criteria for obtaining a waiver or alteration of informed consent in 
Sec.  50.22 (including, for example, that ``[t]he waiver or alteration 
will not adversely affect the rights and welfare of the subjects''), in 
conjunction with the requirement in Sec.  56.111(a)(7) that requires 
IRBs, in order to approve research, to determine that ``[w]here 
appropriate, there are adequate provisions to protect the privacy of 
subjects and to maintain the confidentiality of data,'' adequately 
protect the privacy of individuals while not unduly inhibiting research 
that could benefit the public health.

E. Comments on Secondary Research Involving Leftover Biospecimens

    A few public comments address the applicability of Sec.  50.22 to 
secondary research involving previously collected human biospecimens.
    (Comment 17) One comment points out that FDA has an existing 
policy, the ``Guidance on Informed Consent for In Vitro Diagnostic 
Device Studies Using Leftover Human Specimens that are Not Individually 
Identifiable'' (Leftover Specimen Guidance; Ref. 12), that addresses 
the use, without informed consent, of nonidentifiable leftover human 
specimens in certain in vitro diagnostic (IVD) device investigations. 
This comment recommends incorporating key elements of section IV of the 
Leftover Specimen Guidance into Sec.  50.22(a) to clarify when IRBs may 
waive informed consent for IVD device investigations that use 
nonidentifiable leftover human specimens. The comment specifically 
proposes adding a new paragraph to Sec.  50.22(a) that would identify 
IVD device investigations meeting these key elements as examples of 
clinical investigations that involve no more than minimal risk to 
subjects.
    (Response 17) We decline the commenter's suggestion to add a new 
paragraph to Sec.  50.22(a) that would include key elements of section 
IV of the Leftover Specimen Guidance as examples of clinical 
investigations that involve no more than minimal risk to the subjects 
because such a change would create unnecessary differences between the 
revised Common Rule's general waiver provision (i.e., 45 CFR 46.116(f)) 
and Sec.  50.22. Such differences could cause confusion for IRBs that 
review and approve clinical research under both sets of regulations.
    We believe that most IVD device investigations falling within the 
scope of the policy described in section IV of the Leftover Specimen 
Guidance will satisfy the criteria at Sec.  50.22. However, to the 
extent that there are IVD device investigations that fall within the 
scope of the Leftover Specimen Guidance but do not satisfy the waiver 
criteria in Sec.  50.22, FDA is retaining the Leftover Specimen 
Guidance at this time to help avoid potential disruption to IVD device 
investigations as IRBs gain experience implementing the new waiver 
provision in Sec.  50.22 for FDA-regulated clinical investigations.
    (Comment 18) Two comments support the proposal, noting that it 
would facilitate research on residual biospecimens (e.g., archived 
pathology biospecimens) that is critical for developing new biomarkers 
for use in diagnosing and measuring the progress of disease in a 
patient. These comments remark that seeking informed consent 
retrospectively from the patients from whom the biospecimens and 
related clinical data were obtained during the course of routine care 
or for other research purposes may be very difficult or even impossible 
because, for example, the patients cannot be located. Both comments 
note that FDA recognized the challenges that obtaining informed consent 
can pose for secondary biospecimen research in the Leftover Specimen 
Guidance, which indicates that FDA intends to exercise enforcement 
discretion with regard to the use, without informed consent, of 
leftover biospecimens in IVD device studies in certain circumstances. 
However, the comments assert that the guidance does not go far enough 
because it is only guidance and it does not apply to minimal risk 
secondary research use of biospecimens that are individually 
identifiable.
    (Response 18) FDA agrees that clinical investigations involving the 
use, without informed consent, of previously collected biospecimens and 
related clinical data can play an important role in the development of 
new medical products, provided that the rights, safety, and welfare of 
the subjects from whom the data and/or biospecimens were obtained are 
adequately protected. For example, leftover biospecimens are frequently 
used in feasibility studies and studies to characterize the performance 
of new IVD devices. In addition, banked leftover biospecimens can be a 
source for unique and possibly rare specimens in sufficient quantity to 
permit the rapid completion of IVD device investigations that would be 
very difficult to conduct in a reasonable timeframe without these 
specimens. This rule addresses the minimal risk secondary research use 
of biospecimens that are individually identifiable by permitting IRBs 
to waive or alter informed consent for a clinical investigation 
involving the use of such specimens if they find and document that the 
waiver criteria in Sec.  50.22 have been satisfied.

F. Comments on Examples of Clinical Investigations That Would Meet the 
Waiver Criteria

    In the proposed rule, FDA solicited additional public input on the 
types of FDA-regulated clinical investigations for which sponsors would 
anticipate requesting a waiver or alteration of informed consent from 
the IRB. Several respondents provide examples of the types of studies 
for which sponsors would anticipate requesting a waiver or alteration 
of informed consent.

[[Page 88242]]

    (Comment 19) Several comments provide the example of secondary 
research on biospecimens, e.g., studies using leftover identifiable 
and/or non-identifiable human biospecimens, as the type of minimal risk 
clinical investigations for which sponsors would anticipate requesting 
a waiver or alteration of informed consent from the IRB.
    One comment provides the hypothetical example of an investigator 
who wants to use archived prostate cancer biospecimens and clinical 
data for a study of a new molecular marker of response to treatment for 
which the investigator anticipates submitting an application to FDA. 
The comment includes the caveat that the investigator could use the 
archived biospecimens with 10 years of clinical data but for the 
ability to obtain informed consent from patients. The comment concludes 
that, while this kind of research would offer tremendous potential to 
advance medical care, it would not be possible under the existing FDA 
regulations. The comment cites this study as an example of the type of 
study that would be appropriate for a waiver of informed consent under 
the proposed rule.
    Several comments suggest that studies including RWD would exemplify 
of the type of studies that would benefit from the proposed 
regulations. One comment describes several examples of minimal risk 
research including RWD, such as: (1) minimal risk studies that involve 
previously collected biospecimens and/or data from prior studies, with 
the safeguard that subjects' personal data must remain protected from 
public disclosure; retrospective or prospective use of de-identified 
subject data collected in registries (e.g., nested studies 
supplementing registry data); (2) use of de-identified electronic 
health record, claims, or provider data in analyses of RWD; and (3) 
studies using residual de-identified biospecimens collected during 
routine clinical practice. This comment also suggests that FDA state 
that consent can be waived or modified in postapproval studies 
(including registries) where the only research activity is the 
collection of anonymized standard-of-care data from subjects' medical 
records.
    One comment provides an example of ``minimal risk emergency 
research'' that does not hold out the prospect of direct benefit to the 
subjects as a type of study where requesting a waiver or alteration of 
informed consent would be anticipated. The comment suggests that 
sponsors may want to study FDA-approved products where the use of the 
product is no more than minimal risk. As an example, this comment cites 
a clinical investigation for a new indication for an approved 
diagnostic device utilizing ultrasound for the diagnosis of lower 
extremity venous thromboses being studied for the detection of cerebral 
thromboses in an acute, pre-hospital setting, i.e., immediately after 
head injury. The comment suggests that an approved ultrasound device 
could be deployed in the field (provided its use would not delay 
transport or adversely affect emergency care), and the data from the 
ultrasound device would not be used to guide clinical management of 
injured individuals, who would undergo definitive and proven diagnostic 
testing for cerebral blood clots after arrival in the hospital. The 
comment concludes that results from the ultrasound device could be 
compared to the definitive scan at a later time to determine its 
effectiveness in diagnosing cerebral thromboses.
    Finally, several comments request that FDA provide specific 
examples of the types of clinical investigations intended to be covered 
by the rule, while one comment argues that instances in which informed 
consent is difficult or impossible to obtain in minimal risk clinical 
investigations would be rare and that many common examples used to 
illustrate minimal risk research are unlikely to qualify as clinical 
investigations.
    (Response 19) FDA appreciates the efforts of those commenters 
responding to our request for examples of FDA-regulated clinical 
investigations for which sponsors would anticipate requesting a waiver 
or alteration of informed consent from the IRB. To the extent that the 
studies described in the comments would be considered FDA-regulated 
clinical investigations, we agree that some of the examples appear to 
be of the type for which we would anticipate sponsors might request a 
waiver or alteration of informed consent (e.g., research involving 
previously collected data and biospecimens, certain studies involving 
FDA-approved or cleared products). However, we decline to state that 
certain types of clinical investigations will necessarily meet the 
criteria under Sec.  50.22 for a waiver or alteration of informed 
consent. It is the responsibility of the reviewing IRB to determine, on 
a case-by-case basis considering the unique factors associated with the 
clinical investigation for which a waiver or alteration of informed 
consent is being sought, whether the criteria under Sec.  50.22 are 
met. As previously noted, FDA plans to issue guidance with additional 
information on the types of FDA-regulated clinical investigations that 
may qualify for a waiver or alteration of informed consent under Sec.  
50.22.
    (Comment 20) Several comments generally support the proposed rule, 
but ask FDA to place additional restrictions on, or limit the types of 
studies eligible for, such a waiver or alteration. Some comments 
suggest that the Agency place limitations on waivers or alterations of 
informed consent, such as limiting the duration of the research to 1 
year or less or limiting the number of occurrences in which a waiver of 
consent can be used for any individual to one. Some of these comments 
also recommend precluding waivers or alterations of consent for a 
variety of research activities, including research involving 
interventions or invasive procedures, behavior modifications, the 
introduction of energy into the human body, and data collection from an 
individual's body or behavior in a private space. Two comments suggest 
that a notice be published in the Federal Register identifying the 
conditions under which the waiver or alteration would be applied, as 
well as additional information about the research such as the intended 
duration and number of human subjects in the study, a justification for 
why the waiver is appropriate for the research, a description of how 
the criteria in proposed Sec.  50.22 were satisfied, and how the 
decision is consistent with the principles of the Belmont Report. 
Another comment asks that FDA limit the minimal risk research that 
could be considered for a waiver or alteration of informed consent to 
observational studies only. This comment also requests that, in order 
to protect the interests of participants, FDA require that notice be 
provided to study participants, either on an individual basis or 
publicly where the research is conducted, outlining the period the 
study was conducted, the purpose of the study, and the potential 
benefits of the study.
    Other comments oppose permitting a waiver of informed consent for 
certain types of research, such as studies involving RWD and those 
being conducted in learning healthcare systems, use of specimens 
without consent, or studies in certain research populations, such as 
children or adults of diminished capacity.
    A final comment states that waivers or alterations of informed 
consent should never be permitted for interventions on human subjects.
    (Response 20) FDA does not agree with the comments suggesting that 
we limit the duration or number of studies that may be eligible for a 
waiver or

[[Page 88243]]

alteration of consent under Sec.  50.22. Similarly, we decline to 
include additional restrictions in Sec.  50.22 with respect to a waiver 
or alteration of informed consent for specific categories of research 
(e.g., research involving behavior modifications or research involving 
RWD). We do not believe imposing such limitations or restrictions would 
provide additional protections for the rights, safety, and welfare of 
human subjects beyond those provided by the criteria listed in this 
rule and believe that these restrictions may serve to stifle innovation 
and advancements in research.
    We also do not agree with the comments stating that individual or 
public notice should be required for every minimal risk clinical 
investigation conducted with a waiver of informed consent. While FDA 
regulations provide for community consultation and public disclosure in 
the context of the exception from informed consent requirements for 
emergency research (see Sec.  50.24), FDA does not believe minimal risk 
research that is reviewed by an IRB and found to meet the criteria in 
Sec.  50.22 necessitates these additional protections. However, under 
Sec.  50.22(e), IRBs may find that additional pertinent information 
must be provided to subjects or their LARs after participation for the 
clinical investigation to qualify for a waiver or alteration of 
informed consent under Sec.  50.22.
    With regard to excluding children and adults with diminished 
capacity from the types of studies that may be conducted under Sec.  
50.22, we believe it is appropriate for studies with child subjects to 
qualify for a waiver or alteration under Sec.  50.22 when the IRB finds 
and documents that the criteria in Sec.  50.22 are satisfied. In 
addition to the requirements of Sec.  50.22, other requirements in 
FDA's regulations are intended to ensure that the rights and welfare of 
child subjects are adequately protected. For example, to approve a 
clinical investigation involving children as subjects, the IRB must 
determine that the clinical investigation meets the requirements of 
part 50, subpart D, Additional Safeguards for Children in Clinical 
Investigations (see 21 CFR 50.50 and 56.109(h)). Similarly, FDA 
regulations at Sec.  56.111(b) require that additional safeguards be 
included in studies to protect the rights and welfare of subjects 
likely to be vulnerable to coercion or undue influence. Further, Sec.  
56.111(a)(3) requires IRBs to make an assessment that the selection of 
subjects for any clinical investigation is equitable, including that 
the IRB ``should be particularly cognizant of the special problems of 
research involving vulnerable populations.''
    FDA believes that IRBs can appropriately determine whether the 
criteria in Sec.  50.22 are satisfied for research involving vulnerable 
populations, including children and adults with diminished capacity. 
FDA encourages IRBs to carefully consider the anticipated risks of the 
investigation as they might specifically affect vulnerable populations 
included in the proposed research when making findings regarding the 
``minimal risk'' criterion in Sec.  50.22(a).
    Finally, we do not agree that a waiver or alteration of informed 
consent should never be allowed for interventions on human subjects as 
part of a minimal risk clinical investigation. We note that the 
definition of minimal risk included in FDA's regulations at Sec.  
50.3(k) is identical to the definition of minimal risk found in the 
revised Common Rule at 46 CFR 46.102(j). The current definition of 
minimal risk in both FDA regulations and in the revised Common Rule 
states that minimal risk means ``the probability and magnitude of harm 
or discomfort anticipated in the research are not greater in and of 
themselves than those ordinarily encountered in daily life or during 
the performance of routine physical or psychological examinations or 
tests'' (emphasis added, Sec.  50.3(k) and 45 CFR 46.102(j)). Under 
both FDA's regulations and the revised Common Rule, minimal risk 
studies that may be reviewed by an IRB through an expedited review 
procedure can include studies that require the collection of blood 
samples by finger stick, heel stick, ear stick, or venipuncture under 
certain conditions.\15\ Thus, both the revised Common Rule and FDA's 
regulations allow for some interventions to the human body as part of 
minimal risk research; nothing in this rule changes the current 
paradigm. In instances where minimal risk research involves 
interventions to the human body, we think this rule strikes an 
appropriate balance between respect for persons and facilitating 
research.
---------------------------------------------------------------------------

    \15\ See 63 FR 60353 at 60355.
---------------------------------------------------------------------------

G. Comments on Requests for Guidance

    Several comments specifically request that FDA issue guidance on 
topics related to the proposed rule.
    (Comment 21) A few comments request clarification and guidance to 
ensure that IRBs apply the criteria in Sec.  50.22 appropriately and 
consistently. As noted above, several commenters request additional 
guidance to clarify the terms ``minimal risk'' and ``practicability.'' 
Others specifically ask for guidance on the applicability of a waiver 
for studies comparing the effectiveness of FDA-approved products to 
help IRBs understand and apply the criteria consistently.
    One comment requests that detailed guidance on the types of 
clinical investigations that would and would not qualify for the waiver 
of informed consent be issued simultaneously with the final rule. This 
comment expresses the concern that clinical investigators will 
inappropriately seek, and IRBs inappropriately will grant, waivers of 
informed consent for clinical investigations that involve greater than 
minimal risk to subjects after FDA finalizes the proposed rule. The 
comment cites studies that, according to the comment, were 
inappropriately characterized as minimal risk by researchers and states 
that researchers have often mischaracterized the nature of their 
studies involving human subjects and minimized the risks of the 
procedures involved in the research in an effort to avoid the 
requirements for obtaining and documenting the informed consent of the 
human subjects.
    One comment requests guidance on the relationship and interplay 
between the new waiver criterion (i.e., the fifth criterion) and the 
minimal risk criterion and on what kind of information IRBs should seek 
to make the determination that research, if carried out with 
identifiable private information or biospecimens, qualifies as minimal 
risk.
    (Response 21) Throughout this document we provide clarification of 
specific terms and phrases that are used in this rule. As discussed in 
section V.C, many of the terms used in Sec.  50.22 have longstanding 
definitions in both the Common Rule and FDA's regulations (e.g., 
``minimal risk''). Therefore, FDA is not making further modifications 
to these terms and definitions in the final rule. We plan to issue 
guidance to assist IRBs in applying the criteria for waiver or 
alteration of informed consent requirements in Sec.  50.22 to FDA-
regulated clinical investigations. In that guidance, we intend to 
provide additional information on the types of FDA-regulated minimal 
risk clinical investigations that we anticipate would satisfy the 
criteria for a waiver or alteration of informed consent under Sec.  
50.22.
    FDA believes that the structure of Sec.  50.22, requiring IRBs to 
find and document that applicable criteria are met, provides 
appropriate safeguards to protect the rights, safety, and welfare of 
human subjects. We note that Sec.  50.22 requires that the IRB 
responsible for the review, approval, and continuing review of a 
minimal risk clinical investigation

[[Page 88244]]

find and document that the applicable criteria are met, not the 
researcher or sponsor of the clinical investigation. FDA believes that 
IRBs understand their obligations to review research to ensure the 
protection of the rights and welfare of human subjects and are capable 
of appropriately applying these criteria to minimal risk clinical 
investigations.
    (Comment 22) One comment requests that FDA provide clarification or 
advisory text for sponsors, investigators, and IRBs to carefully 
consider the specific data elements to be collected as part of research 
to determine the applicability of the HIPAA Privacy Rule 
requirements.\16\ This comment suggests that, although retrospective 
collection of anonymized data or research on anonymized biospecimens 
obtained in a previous research study would not typically require 
consent under the HIPAA Privacy Rule, many low-risk, retrospective, 
postmarket clinical followup studies may require collection of PHI and, 
therefore, may still require subject authorization under the HIPAA 
Privacy Rule. This comment recommends that FDA and HHS work together to 
determine the potential impact of the multiple consent requirements in 
the Common Rule, part 50, and the HIPAA Privacy Rule on the collection 
and use of RWD, and consider developing guidance on when privacy 
requirements apply.
---------------------------------------------------------------------------

    \16\ See 45 CFR parts 160 and 164, subparts A and E.
---------------------------------------------------------------------------

    (Response 22) FDA agrees that the protection of human subjects' 
privacy when participating in clinical investigations is important, 
including when the investigation uses data collected as part of 
clinical care. We note that the criteria for IRB approval of research 
in our current regulations at Sec.  56.111(a)(7) require that, to 
approve research, IRBs determine that ``[w]here appropriate, there are 
adequate provisions to protect the privacy of subjects and to maintain 
the confidentiality of data.'' This provision requires IRBs to review 
clinical investigations to ensure that appropriate privacy safeguards 
are in place to protect human subjects involved in FDA-regulated 
clinical investigations.
    Applicability of the HIPAA Privacy Rule to clinical investigations 
covered by Sec.  50.22 is outside the scope of this rulemaking. 
However, we note that the standards laid out in both the HIPAA Privacy 
Rule and the Common Rule have coexisted for many years. Accordingly, 
FDA believes that IRBs have experience considering both rules when 
reviewing minimal risk research. By harmonizing the waiver criteria set 
forth in Sec.  50.22 with those set forth in the revised Common Rule's 
general waiver provision, we are promoting consistency in the 
application of such requirements across Common Rule Agencies and 
minimizing burden to IRBs tasked with applying the criteria described 
in this rule to FDA-regulated research.

H. Comments on the Expedited Review List and IRB Continuing Review

    (Comment 23) Some comments question the interpretation of ``minimal 
risk'' in the proposed rule in relation to the list of categories of 
research that may be reviewed by the IRB through an expedited review 
procedure (``expedited review list,'' Ref. 14). One comment disagrees 
with categories of research included on the expedited review list. 
Another comment notes that, while the expedited review list categories 
could provide some benchmarks for the types of research that are 
minimal risk, these applications are limited and there may be research 
that qualifies as ``minimal risk,'' that would not qualify for the 
expedited review procedure.
    Similarly, some comments express concern that the proposed rule did 
not address how FDA intends to harmonize with the revised Common Rule 
with respect to expedited review procedures and IRB continuing review. 
A few comments cite SACHRP's recommendations on the expedited review 
list (Ref. 15) and note concern about FDA and HHS adopting them. These 
comments assert that if FDA and HHS adopt the SACHRP recommendations 
and FDA harmonizes with changes made in the revised Common Rule 
regarding expedited review (e.g., by permitting expedited review of 
research activities appearing on the expedited review list, unless the 
IRB reviewer determines that the studies involve more than minimal 
risk) would weaken human subject protections. Other comments state that 
human subject protections would be weakened if FDA adopts the revised 
Common Rule's requirement that eliminates IRB continuing review for 
studies that are eligible for review under an expedited review 
procedure. These comments urge that minimal risk studies for which an 
IRB waives informed consent remain subject to IRB continuing review.
    (Response 23) FDA agrees with the comments to the extent they 
emphasize the importance of ensuring that waivers or alterations of 
informed consent under this rule are granted only for research that 
presents no more than minimal risk to the subjects. However, we do not 
agree that it is necessary to address how FDA intends to harmonize with 
the revised Common Rule's expedited and continuing review requirements 
as part of this rulemaking, which finalizes our proposal to permit an 
IRB to approve an informed consent procedure that waives or alters 
certain informed consent elements, or to waive the requirement to 
obtain informed consent, for certain minimal risk investigations. FDA 
issued a separate proposed rule to amend its regulations at parts 50 
and 56, including with respect to expedited and continuing review (87 
FR 58733), and will consider all timely comments received as part of 
that rulemaking, including those related to expedited review and/or 
continuing review. We address below the more specific concerns raised 
by the comments in relation to expedited or continuing review.
    Some of the comments appear concerned that any changes to the FDA 
expedited review requirements intended to harmonize with the revised 
Common Rule could be perceived by the research community as broadening 
what qualifies as minimal risk or discourage determinations that a 
study presents more than minimal risk. As an initial matter, the 
revised Common Rule did not modify the current definition of ``minimal 
risk'' that is found in HHS regulations (45 CFR 46.102(j)), so FDA 
regulations (Sec.  50.3(k)) remain consistent with the definition of 
``minimal risk'' provided in the revised Common Rule. In addition, 
under FDA's regulations at Sec.  56.110(b)(1), for research to qualify 
for expedited review, a determination must be made by an IRB that the 
proposed research involves no more than minimal risk to human subjects. 
In other words, under current FDA regulations, the categories of 
activities appearing on the expedited review list are not presumed to 
be minimal risk. FDA's proposed rule to amend parts 50 and 56 (87 FR 
58733) does not propose to change this. In addition, the revised Common 
Rule did not modify the 1998 expedited review list (63 FR 60364), so 
HHS and FDA (63 FR 60353) maintain identical lists of categories of 
research activities that may be reviewed by an IRB through the 
expedited review procedure. 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)). However, OHRP has clarified that, until a 
new expedited review list is finalized, the entire 1998 HHS expedited 
review list, including the ``Applicability'' section, remains in

[[Page 88245]]

effect for studies subject to the revised Common Rule (Ref. 16). 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, for research to qualify for expedited review 
under the revised Common Rule, 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. Under Sec.  50.22, as 
finalized in this rule, an IRB must find and document that the clinical 
investigation involves no more than minimal risk to subjects, 
regardless of whether the study falls within a category on the 
expedited review list, to waive or alter informed consent.
    As noted in comments, the revised Common Rule provision at 45 CFR 
46.109(f)(1)(i) 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. 
FDA's IRB continuing review requirements are not being revised in this 
rule. As explained above, FDA is engaged in separate rulemaking to 
amend parts 50 and 56 to harmonize with the revised Common Rule in 
accordance with section 3023 of the Cures Act. As part of that effort, 
FDA proposed changes to 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. However, FDA's 
proposed rule to amend parts 50 and 56 (87 FR 58733) does not propose 
to eliminate continuing review of all research eligible for expedited 
review, unless the IRB determines otherwise, for the reasons described 
in the preamble to that proposed rule. FDA will take into account the 
comments urging that minimal risk studies for which an IRB waives 
informed consent remain subject to IRB continuing review as part of 
finalizing any changes to continuing review requirements in that 
separate rulemaking.
    As HHS evaluates and amends, as appropriate, its current expedited 
review list 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 will consider if any related changes to our 
regulations are necessary.

I. Comments on the Cost Savings of the Proposed Rule

    (Comment 24) Some comments describe support for the rule because it 
will reduce administrative burden and result in cost savings. Other 
comments express the view that the proposed cost savings of the rule 
are low and may not outweigh the negative impact of waiving informed 
consent for certain minimal risk studies. One comment states that, 
although the potential benefits cannot be fully quantified, the 
analysis should focus on some of the drawbacks of this rule.
    (Response 24) As discussed in section VII, FDA believes that this 
rule will reduce administrative burden and that any costs incurred are 
outweighed by non-quantifiable benefits in the form of healthcare 
advances resulting from research performed using a waiver or alteration 
of informed consent, as well as a reduction in burden for the research 
community arising from the harmonization of FDA's informed consent 
regulations with the revised Common Rule's provision for waiver or 
alteration of informed consent for certain minimal risk research.
    However, as part of developing a response to this comment, we 
reanalyzed the proposed rule to consider potential additional costs 
associated with the rulemaking. Based on that review, we determined 
that there are some one-time costs associated with reading and 
implementing the rule, which we anticipate to be small because the 
final rule is harmonized with Common Rule provisions with which the 
clinical research community is already familiar. We also determined 
that there are some annual costs associated with drafting and reviewing 
requests for a waiver or alteration of consent. In this final rule, we 
include a revised analysis of cost and cost savings in the Economic 
Analysis of Impacts (section VII). We also determined that some of 
these costs are associated with collections of information subject to 
review by the Office of Management and Budget (OMB) under the Paperwork 
Reduction Act of 1995 (PRA). For further information, see section IX.

J. Comments on the Proposed Effective Date

    (Comment 25) We proposed that any final rule issued based on the 
proposed rule would become effective 30 days after its date of 
publication in the Federal Register. One comment requests clarification 
on the application of the effective date. Specifically, the comment 
asks whether the rule would apply only to clinical investigations that 
receive initial IRB approval on or after the effective date, or if it 
would apply to IRB review at any stage of the clinical investigation 
(e.g., initial IRB approval or amendments) conducted on or after that 
date.
    (Response 25) In response to this comment, we note that the rule 
will apply to IRB review at any stage of an FDA-regulated clinical 
investigation conducted on or after the effective date, including 
initial IRB approval or review of any changes to a previously approved 
clinical investigation.

VI. Effective Date

    This rule is effective 30 days after the date of its publication in 
the Federal Register.

VII. Economic Analysis of Impacts

A. Introduction

    We have examined the impacts of the final rule under Executive 
Order 12866, Executive Order 13563, Executive Order 14094, the 
Regulatory Flexibility Act (5 U.S.C. 601-612), the Congressional Review 
Act/Small Business Regulatory Enforcement Fairness Act (5 U.S.C. 801, 
Pub. L. 104-121), and the Unfunded Mandates Reform Act of 1995 (Pub. L. 
104-4).
    Executive Orders 12866, 13563, and 14094 direct us to assess all 
benefits, costs, and transfers 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). Rules are ``significant'' under Executive Order 12866 
Section 3(f)(1) (as amended by Executive Order 14094) if they ``have an 
annual effect on the economy of $200 million or more (adjusted every 3 
years by the Administrator of the Office of Information and Regulatory 
Affairs (OIRA) for changes in gross domestic product); or adversely 
affect in a material way the economy, a sector of the economy, 
productivity, competition, jobs, the environment, public health or 
safety, or State, local, territorial, or tribal governments or 
communities.'' OIRA has determined that this final rule is not a 
significant regulatory action under Executive Order 12866 Section 
3(f)(1).
    A rule is ``major'' under the Congressional Review Act/Small 
Business Regulatory Enforcement Fairness Act if it has resulted or is 
likely to result in an annual effect on the economy of $100 million or 
more or meets other criteria specified in the Congressional Review Act 
(5 U.S.C. 804(2)). OIRA has determined that this

[[Page 88246]]

final rule is not a major rule under the Congressional Review Act/Small 
Business Regulatory Enforcement Fairness Act.
    The Regulatory Flexibility Act requires us to analyze regulatory 
options that would minimize any significant impact of a rule on small 
entities. Because the final rule is unlikely to impose a substantial 
burden on the affected small entities, we certify that the final rule 
will not have a significant economic impact on a substantial number of 
small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires 
us to prepare a written statement, which includes an assessment of 
anticipated impacts, before issuing ``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 $177 
million, using the most current (2022) Implicit Price Deflator for the 
Gross Domestic Product. This final rule would not result in an 
expenditure in any year that meets or exceeds this amount.

B. Summary of Costs, Cost Savings, and Benefits

    We expect costs in the form of affected IRBs, as well as 
investigators and sponsors of clinical investigations, reading and 
learning the rule. We also expect costs in the form of drafting new 
waiver or alteration requests, and additional recordkeeping burdens 
associated with reviewing and documenting IRB decisions on waiver or 
alteration requests. The net present value of the estimated costs of 
the rule are approximately $10.1 million, with a lower bound of 
approximately $8.1 million and an upper bound of approximately $14.0 
million, discounted at 3 percent over 10 years. At a 7 percent discount 
rate, the estimated costs of the rule are approximately $9.1 million, 
with a lower bound of approximately $7.5 million and an upper bound of 
approximately $12.4 million. The estimated annualized costs of the rule 
are approximately $1.2 million, with a lower bound of approximately 
$0.9 million and an upper bound of approximately $1.6 million, 
discounted at 3 percent over 10 years. At a 7 percent discount rate, 
the estimated annualized costs of the rule are approximately $1.3 
million, with a lower bound of approximately $1.1 million and an upper 
bound of approximately $1.8 million.
    We also expect that there will be cost savings to IRBs because the 
time burdens of reviewing waiver or alterations requests would be 
reduced from harmonization of FDA's informed consent regulations with 
the provision for waiver or alteration of informed consent for certain 
minimal risk research in the Common Rule. The estimated net present 
value of the cost savings of the rule are approximately $1.7 million, 
with a lower bound of approximately $0.9 million and an upper bound of 
approximately $3.5 million, discounted at 3 percent over 10 years. At a 
7 percent discount rate, the estimated cost savings of the rule are 
approximately $1.4 million, with a lower bound of approximately $0.7 
million and an upper bound of approximately $2.8 million. The estimated 
annualized cost savings of the rule are approximately $0.2 million, 
with a lower bound of approximately $0.1 million and an upper bound of 
approximately $0.4 million, discounted at 3 percent over 10 years. At a 
7 percent discount rate, the estimated annualized costs savings of the 
rule are approximately $0.2 million, with a lower bound of 
approximately $0.1 million and an upper bound of approximately $0.4 
million.
    We expect benefits in the form of healthcare advances from minimal 
risk clinical investigations for which the requirements for informed 
consent are waived or altered under the final rule and that otherwise 
would not be conducted. We cannot quantify all benefits that might 
arise from such studies because of the lack of relevant data available 
regarding the focus of these types of studies that will support 
regulatory submissions to the Agency. The costs and cost savings of the 
rule are summarized in table 1.

                                Table 1--Summary of Costs, Costs Savings, and Distributional Effects of the Proposed Rule
                                                                      [Millions $]
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                                           Units
                                                                                          ---------------------------------------
               Category                  Primary estimate   Low estimate    High estimate                               Period             Notes
                                                                                               Year       Discount     covered
                                                                                             dollars      rate (%)     (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs:
    Annualized Monetized millions/year  .................  ..............  ..............  ...........  ...........  ...........
    Annualized Quantified.............               $1.3            $1.1            $1.8         2020            7           10  ......................
                                                      1.2             0.9             1.6         2020            3           10  ......................
    Qualitative.......................  .................  ..............  ..............  ...........  ...........  ...........
    Annualized Monetized millions/year
    Annualized........................                0.2             0.1             0.4         2020            7           10  ......................
    Quantified........................                0.2             0.1             0.4         2020            3           10  ......................
                                       ---------------------------------------------------
    Qualitative.......................  Healthcare advances stemming from minimal risk     ...........  ...........  ...........  ......................
                                        clinical investigations that can proceed using a
                                        waiver or alteration of informed consent and that
                                        otherwise would not have been conducted.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Transfers:
    Federal Annualized................  .................  ..............  ..............  ...........  ...........  ...........  ......................
    Monetized $millions/year..........  .................  ..............  ..............  ...........  ...........  ...........  ......................
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    Other Annualized..................  .................  ..............  ..............  ...........  ...........  ...........  ......................
    Monetized $millions/year..........  .................  ..............  ..............  ...........  ...........  ...........  ......................
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Effects:
    State, Local or Tribal Government:..................................................................................................................
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[[Page 88247]]

    We have developed a comprehensive Economic Analysis of Impacts that 
assesses the impacts of the final rule. The full analysis of economic 
impacts is available in the docket for this final rule (Docket No. FDA-
2018-N-2727) 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

    In the proposed rule, FDA stated, ``This proposed rule refers to 
previously approved collections of information found in FDA 
regulations. . . . Therefore, FDA tentatively concludes the 
requirements in this document are not subject to additional review by 
OMB.'' In developing the final rule, FDA determined that there are 
information collections contained in the rule that are subject to 
review by OMB under the PRA (44 U.S.C. 3501-3521). Specifically, the 
final rule adds Sec.  50.22 to part 50 to allow IRBs responsible for 
the review, approval, and continuing review of clinical investigations 
to approve an informed consent procedure that does not include or that 
alters certain informed consent elements, or to waive the requirement 
to obtain informed consent, for certain minimal risk clinical 
investigations, provided the IRB finds and documents the criteria set 
forth in Sec.  50.22(a)-(e). The information collections associated 
with part 50 have been approved in accordance with the PRA under OMB 
control number 0910-0130, but the additional provision at Sec.  50.22 
will modify this information collection. We estimate the rulemaking 
will result in an annual burden increase of 1,102 responses and 1,102 
hours from recordkeeping and disclosure activity relating to the 
revised regulations in 21 CFR part 50.
    With this exception, we conclude that the other provisions of this 
rule do not require substantive revisions to information collections 
already approved under the PRA. Provisions in part 312 (21 CFR part 
312) of FDA's regulations set forth procedures for the conduct of 
clinical investigations of drugs and provide for the protection of 
human subjects involved in such investigations. Existing regulations at 
Sec.  312.60 describe the general responsibilities of investigators 
with regard to study conduct, including ensuring the rights, safety, 
and welfare of human subjects. As part of these responsibilities, the 
current regulations require that investigators obtain informed consent, 
except as provided in exceptions from general requirements (Sec.  
50.23) and exception from informed consent requirements for emergency 
research (Sec.  50.24). This final rule, as noted above, adds an 
additional exception to include waiver or alteration of informed 
consent for minimal risk clinical investigations under Sec.  50.22. 
Therefore, FDA made a conforming revision to Sec.  312.60 to cross-
reference part 50 generally, rather than list each specific exception 
to the informed consent requirements, for simplicity and for accuracy 
of the cross-references in the regulatory text. FDA does not expect 
changes to the collections of information approved under OMB control 
number 0910-0014 as a result of this final rule. In addition, FDA's 
existing regulations at Sec.  812.2 describe abbreviated requirements 
for IDEs, which require that investigators obtain and document informed 
consent under part 50, unless documentation is waived under IRB 
regulations at Sec.  56.109(c). This final rule amends Sec.  
812.2(b)(1)(iii) to clarify that the investigator must obtain informed 
consent in accordance with part 50, which includes the new provision 
for waiver or alteration in Sec.  50.22. The final rule also simplifies 
the regulatory text at Sec.  812.2(b)(1)(iii) by removing the cross-
reference to waiver of documentation of informed consent under Sec.  
56.109(c). The relevant section of the regulations in part 50 (i.e., 
Sec.  50.27) already refers to Sec.  56.109(c), so the cross-reference 
to Sec.  56.109(c) need not be repeated. FDA does not expect any 
changes to the collections of information collection approved under OMB 
control number 0910-0078 as a result of this final rule.
    Before the effective date of this final rule, FDA will publish a 
notice in the Federal Register announcing OMB's decision to approve, 
modify, or disapprove the information collection provisions in this 
final rule. An Agency may not conduct or sponsor, and a person is not 
required to respond to, a collection of information unless it displays 
a currently valid OMB control number.

X. Federalism

    We have analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, we conclude that the rule 
does not contain policies that have federalism implications as defined 
in the Executive Order and, consequently, a federalism summary impact 
statement is not required.

XI. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this rule in accordance with the principles set 
forth in Executive Order 13175. We have determined that the rule does 
not contain policies that have substantial direct effects 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. Accordingly, we 
conclude that the rule does not contain policies that have tribal 
implications as defined in the Executive Order and, consequently, a 
tribal summary impact statement is not required.

XII. References

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

1. U.S. Department of State, ``Fourth Periodic Report of the United 
States of America to the United Nations Committee on Human Rights 
Concerning the International Covenant on Civil and Political 
Rights'' (December 30, 2011). Available at https://2009-2017.state.gov/j/drl/rls/179781.htm. Accessed March 7, 2023.
2. Secretary's Advisory Committee on Human Research Protections, 
``Recommendations Related to Waiver of Informed Consent and 
Interpretation of `Minimal Risk' '' (January 31, 2008). Available 
at: https://www.hhs.gov/ohrp/sachrp-committee/recommendations/2008-january-31-letter/index.html. Accessed March 7, 2023.
3. Executive Office of the President. Memorandum of March 27, 1997. 
``Strengthened Protections for Human Subjects of Classified 
Research.'' 62 FR 26369 (May 13, 1997). Available at: https://
www.federalregister.gov/documents/1997/05/13/97-12699/strengthened-
protections-for-human-

[[Page 88248]]

subjects-of-classified-research. Accessed March 22, 2023.
4. Baker, F.X. and J.F. Merz (2018), ``What Gives Them the Right? 
Legal Privilege and Waivers of Consent for Research,'' Clinical 
Trials, 15(6): 579-586. Available at: https://journals.sagepub.com/doi/10.1177/1740774518803122. Accessed on March 7, 2023.
5. van Zon, S.K.R, S. Schlotens, S.A. Reijneveld, et al. (2016), 
``Active Recruitment and Limited Participant-load Related to High 
Participation in Large Population-based Biobank Studies,'' Journal 
of Clinical Epidemiology, 78: 52-62. Available at: https://www.sciencedirect.com/science/article/pii/S089543561630021X?via%3Dihub. Accessed on March 7, 2023.
6. Kripalani, S., K. Goggins, C. Couey, et al. (2021), ``Disparities 
in Research Participation by Level of Health Literacy,'' Mayo Clinic 
Proceedings, 96(2): 314-321. Available at: https://www.mayoclinicproceedings.org/article/S0025-6196(20)30856-9/
fulltext. Accessed on March 7, 2023.
7. Kraft, S.A., K.M. Porter, D.M. Korngiebel, et al. (2017), 
``Research on Medical Practices: Why Patients Consider Participating 
and the Investigational Misconception.'' IRB, 39(4): 10-16. 
Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374557/#__ffn_sectitle. Accessed on March 7, 2023.
8. OHRP and FDA, ``Institutional Review Board (IRB) Written 
Procedures: Guidance for Institutions and IRBs'' (May 2018). 
Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/institutional-review-board-irb-written-procedures. Accessed on March 7, 2023.
9. FDA, ``Information Sheet Guidance for IRBs, Clinical 
Investigators, and Sponsors: Significant Risk and Nonsignificant 
Risk Medical Device Studies'' (January 2006). Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/significant-risk-and-nonsignificant-risk-medical-device-studies. 
Accessed on March 7, 2023.
10. Council for International Organizations of Medical Sciences 
(CIOMS), ``International Ethical Guidelines for Health-related 
Research Involving Humans,'' prepared by the Council for 
International Organizations of Medical Sciences in collaboration 
with the World Health Organization (2016). Available at: https://cioms.ch/wp-content/uploads/2017/01/WEB-CIOMS-EthicalGuidelines.pdf. 
Accessed on March 7, 2023.
11. World Medical Association, ``Declaration of Helsinki--Ethical 
Principles for Medical Research Involving Human Subjects'' (October 
2013). Available at: https://www.wma.net/policies-post/wma-declaration-of-helsinki-ethical-principles-for-medical-research-involving-human-subjects/. Accessed on March 7, 2023.
12. FDA, ``Guidance on Informed Consent for In Vitro Diagnostic 
Device Studies Using Leftover Human Specimens that are Not 
Individually Identifiable'' (April 2006). Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-informed-consent-in-vitro-diagnostic-device-studies-using-leftover-human-specimens-are-not. Accessed on March 7, 2023.
13. FDA, ``Guidance for Industry and FDA Staff: In Vitro Diagnostic 
(IVD) Device Studies--Frequently Asked Questions'' (June 2010). 
Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/in-vitro-diagnostic-ivd-device-studies-frequently-asked-questions. Accessed March 7, 2023.
14. OHRP, ``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.
15. SACHRP, Recommendation to the Secretary of HHS, 
``Recommendations on the Expedited Review List'' (December 12, 
2017). Available at: https://www.hhs.gov/ohrp/sachrp-committee/recommendations/attachment-a-december-12-2017/index.html. Accessed 
on March 7, 2023.
16. OHRP, ``Revised Common Rule Q&As'' (December 2021). Available 
at: https://www.hhs.gov/ohrp/education-and-outreach/revised-common-rule/revised-common-rule-q-and-a/index.html. Accessed on March 7, 
2023.

List of Subjects

21 CFR Part 50

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

21 CFR Part 312

    Drugs, Exports, Imports, Investigations, Labeling, Medical 
research, 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, the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR parts 50, 312, and 812 are 
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, 371, 379e, 381; 42 U.S.C. 216, 
241, 262.


0
2. In Sec.  50.20 revise the first sentence to read as follows:


Sec.  50.20  General requirements for informed consent.

    Except as provided in Sec. Sec.  50.22, 50.23, and 50.24, no 
investigator may involve a human being as a subject in research covered 
by these regulations unless the investigator has obtained the legally 
effective informed consent of the subject or the subject's legally 
authorized representative. * * *

0
3. Add Sec.  50.22 to subpart B to read as follows:


Sec.  50.22  Exception from informed consent requirements for minimal 
risk clinical investigations.

    The IRB responsible for the review, approval, and continuing review 
of the clinical investigation described in this section may approve an 
informed consent procedure that does not include or that alters some or 
all of the elements of informed consent set forth in Sec.  50.25(a) and 
(b), or may waive the requirement to obtain informed consent, provided 
the IRB finds and documents the following:
    (a) The clinical investigation involves no more than minimal risk 
to the subjects;
    (b) The clinical investigation could not practicably be carried out 
without the requested waiver or alteration;
    (c) If the clinical investigation involves using identifiable 
private information or identifiable biospecimens, the clinical 
investigation could not practicably be carried out without using such 
information or biospecimens in an identifiable format;
    (d) The waiver or alteration will not adversely affect the rights 
and welfare of the subjects; and
    (e) Whenever appropriate, the subjects or legally authorized 
representatives will be provided with additional pertinent information 
after participation.

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

0
4. The authority citation for part 312 continues to read as follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360bbb, 371; 
42 U.S.C. 262.

0
5. Revise Sec.  312.60 to read as follows:


Sec.  312.60  General responsibilities of investigators.

    An investigator is responsible for ensuring that an investigation 
is conducted according to the signed investigator statement, the 
investigational plan, and applicable regulations; for protecting the 
rights, safety, and welfare of subjects under the investigator's care; 
and for the control of drugs under investigation. An

[[Page 88249]]

investigator shall obtain the informed consent of each human subject to 
whom the drug is administered, in accordance with part 50 of this 
chapter. Additional specific responsibilities of clinical investigators 
are set forth in this part and in parts 50 and 56 of this chapter.

PART 812--INVESTIGATIONAL DEVICE EXEMPTIONS

0
6. The authority citation for part 812 is revised to read as follows:

    Authority: 21 U.S.C. 331, 351, 352, 353, 355, 360, 360c-360f, 
360h-360j, 360hh-360pp, 360rr-360ss, 360bbb-8b, 371, 372, 374, 379e, 
381, 382; 42 U.S.C. 216, 241, 262.

0
7. Revise Sec.  812.2 (b)(1)(iii) to read as follows:


Sec.  812.2  Applicability.

* * * * *
    (b) * * *
    (1) * * *
    (iii) Ensures that each investigator participating in an 
investigation of the device obtains from each subject under the 
investigator's care, informed consent in accordance with part 50 of 
this chapter.
* * * * *

    Dated: December 1, 2023.
Robert M. Califf,
Commissioner of Food and Drugs.
[FR Doc. 2023-27935 Filed 12-20-23; 8:45 am]
BILLING CODE 4164-01-P


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