[Federal Register Volume 88, Number 244 (Thursday, December 21, 2023)]
[Rules and Regulations]
[Pages 88228-88249]
[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,<PHONE_NUMBER>, [email protected].

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

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

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.
     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).
     In Sec.  50.22(a), FDA finalizes the criterion as proposed
that the clinical investigation involves no more than minimal risk to
the subjects.
     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).
     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.
     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.
     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.
     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

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,

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

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

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

    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

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

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 [email protected]. More information is available
at: https://www.hhs.gov/ohrp/compliance-and-reporting/submitting-a-complaint/index.html.
---------------------------------------------------------------------------

    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

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

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

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

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

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.

    (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

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.
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    \15\ See 63 FR 60353 at 60355.
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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

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