88228 Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 

that the action is incorporated by 

reference under 1 CFR part 51. As a 

result, the final rule correction is being 

withdrawn. 

Lists of Subjects in 14 CFR Part 73 

Airspace, Prohibited areas, Restricted 

areas. 

The Withdrawal 

■ The FAA determined that the final 

rule correction published in the Federal 

Register on December 6, 2023 (88 FR 

84695) contains incorrect references. 

Therefore, the FAA withdraws that final 

rule correction. 

Issued in Washington, DC, on December 

15, 2023. 

Brian Konie, 

Acting Manager, Rules and Regulations 

Group. 

[FR Doc. 2023–28032 Filed 12–20–23; 8:45 am] 

BILLING CODE 4910–13–P 

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. 

SUMMARY: The Food and Drug 

Administration (FDA, the Agency, or 

we) is issuing a final rule to amend its 

regulations to implement a provision of 

the 21st Century Cures Act (Cures Act). 

This final rule allows an exception from 

the requirement to obtain informed 

consent when a clinical investigation 

poses no more than minimal risk to the 

human subject and includes appropriate 

safeguards to protect the rights, safety, 

and welfare of human subjects. The 

final rule permits an institutional 

review board (IRB) to waive or alter 

certain informed consent elements or to 

waive the requirement to obtain 

informed consent, under limited 

conditions, for certain FDA-regulated 

minimal risk clinical investigations. 

DATES: This rule is effective January 22, 

2024. 

ADDRESSES: For access to the docket to 

read background documents or 

comments received, go to https://

www.regulations.gov and insert the 

docket number found in brackets in the 

heading of this final rule into the 

‘‘Search’’ box and follow the prompts, 

and/or go to the Dockets Management 

Staff, 5630 Fishers Lane, Rm. 1061, 

Rockville, MD 20852, 240–402–7500. 

FOR FURTHER INFORMATION CONTACT: 

Lauren Milner, Office of Clinical Policy, 

Food and Drug Administration, 10903 

New Hampshire Ave., Silver Spring, MD 

20993–0002, 301–796–5514, 

lauren.milner@fda.hhs.gov. 

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 


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Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 88229 

1The 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. 

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 

Abbreviation What it means 

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. 

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 lifethreatening situations or by Presidential 

waiver for certain military operations 

when specific conditions are met 

(§ 50.23 (21 CFR 50.23)) or when the 

requirements for emergency research are 

met (§ 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 


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88230 Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 

2For 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). 

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). 

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 § 50.22, 

‘‘Exception from informed consent 

requirements for minimal risk clinical 

investigations’’ to part 50 and make 

three conforming amendments to 

§§ 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 § 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 § 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 

§ 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 § 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 § 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 § 50.22(a) 

through (e). 

• In § 50.22(a), FDA finalizes the 

criterion as proposed that the clinical 

investigation involves no more than 

minimal risk to the subjects. 

• In § 50.22(b), FDA adopts the 

criterion that was proposed at § 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 

§ 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 § 50.22(d), FDA adopts the 

criterion that was proposed at § 50.22(b) 

that states that the waiver or alteration 

will not adversely affect the rights and 

welfare of the subjects. 

• In § 50.22(e), FDA adopts the 

criterion that was proposed at § 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 

§§ 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 § 50.20, General 

requirements for informed consent, is 

revised to include reference to § 50.22 as 

one of the limited exceptions to the 

general requirements for informed 

consent. The second sentence in 

§ 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 § 50.22. 

Similarly, in part 812, Investigational 

Device Exemptions (IDEs), 

§ 812.2(b)(1)(iii) is revised to make clear 

that the investigator must obtain 

informed consent in accordance with 

part 50, which includes § 50.22. In 


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Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 88231 

addition, to simplify the current 

regulatory text, we removed the 

reference to documentation being 

waived under § 56.109(c) (21 CFR 

56.109(c)), as the relevant section of the 

regulations in part 50 (i.e., § 50.27 (21 

CFR 50.27)) refers to § 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 

§ 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 FDAregulated 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 realworld 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 § 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, 


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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 § 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 § 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 § 50.22. In general, we do not believe 

that a study involving an invasive 

procedure being used for research 


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3Certain procedures, such as blood sampling that 

involves simple venipuncture, are considered 

noninvasive for purposes of FDA’s IDE regulations 

(§ 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). 

4See also 45 CFR 164.512 (Uses and disclosures 

for which an authorization or opportunity to agree 

or object is not required). 

5Please refer to FDA’s response to comment 13 

for more information on FDA’s interpretation of the 

term ‘‘practicably.’’ 

purposes would qualify as presenting no 

more than minimal risk to subjects.3

(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 § 50.3(c) 

(21 CFR 50.3(c)), involving FDAregulated 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 § 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 

§ 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 § 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 § 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 

§ 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 § 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 § 50.22(c) 

by the research community. 

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 § 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 

§ 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 nonresearch 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 § 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. 


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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 § 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 § 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 

§ 50.24, and states that § 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 § 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 § 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 (§ 52.24(a)(5)). However, we 

disagree with the commenter’s 

conclusion that because of this 

requirement, § 50.24 is ‘‘superior’’ to the 

requirements for a waiver under § 50.22. 

Each of these provisions was developed 

to address significantly different types 

of clinical investigations. The criteria 

listed in § 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 § 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 § 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 § 50.22 

in this final rule to include a 

requirement similar to that found in 

§ 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 § 50.22(b) 

requires an IRB to find that the research 

could not practicably be carried out 


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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 §§ 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 § 50.22 

criteria. Although the commenter points 

to § 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 § 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 § 50.22 that 

the investigator obtain consent from 

subjects or LARs if feasible similar to 

the requirement in § 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 § 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 § 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 § 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 § 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 


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6 83 FR 57378 at 53781. 

7While 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. 

8Complaints 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/scienceresearch/clinical-trials-and-human-subjectprotection/reporting-complaints-related-fdaregulated-clinical-trials. 

9Complaints related to research subject to HHS 

regulations may be emailed to OHRP’s Director of 

the Division of Compliance Oversight at 

complaints.ohrp@hhs.gov. More information is 

available at: https://www.hhs.gov/ohrp/complianceand-reporting/submitting-a-complaint/index.html. 

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 § 50.22. 

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 § 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 § 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 § 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 § 50.22. In addition, if changes 

are proposed to a study for which a 

waiver or alteration has been granted 

under § 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

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 § 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 § 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 § 50.22 to FDAregulated clinical investigations. In that 

guidance, we intend to include 

additional information on the types of 

research activities that may involve no 


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10We note that, in the final rule, proposed 

§ 50.22(b) is now § 50.22(d). 

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 § 50.22 to 

clinical investigations involving ‘‘nonsignificant risk’’ devices. 

2. The Waiver or Alteration Will Not 

Adversely Affect the Rights and Welfare 

of the Subjects (Proposed § 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. 

(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 § 50.22, including the 

criterion in proposed § 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 (§ 56.111(a)(7)). 

We believe that the safeguards in 

§ 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 § 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 

§ 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 § 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 wellestablished 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 

§ 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 


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88238 Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 

11We note that, in the final rule, proposed 

§ 50.22(c) is now § 50.22(b). 

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. 

(Comment 13) Several comments on 

the proposal make reference to proposed 

§ 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 § 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 § 50.22 are met. 

In addition, we agree that IRBs may 

find under § 50.22(b) (§ 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 § 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., § 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 § 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 § 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 


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Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 88239 

12We note that, in the final rule, proposed 

§ 50.22(d), as revised, is now § 50.22(e). 

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 § 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 § 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. 

(Comment 14) FDA received a few 

comments about proposed § 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 § 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 § 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 § 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 § 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 § 50.22(c). 

In adopting the fifth criterion, we are 

harmonizing the waiver criteria set forth 

in § 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 § 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 § 50.22 

applies to minimal risk clinical 

investigations involving the use of 


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88240 Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 

13The 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. 

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). 

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 § 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 § 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 FDAregulated 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. 

(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 § 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 § 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 § 50.22 for a clinical 

investigation involving identifiable 


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private information or identifiable 

biospecimens. 

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 

§ 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 

(§ 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., 

§§ 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 § 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 

§ 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 § 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 

§ 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 § 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 § 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 § 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 § 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 

§ 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 § 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 § 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. 


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(Comment 19) Several comments 

provide the example of secondary 

research on biospecimens, e.g., studies 

using leftover identifiable and/or nonidentifiable 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 FDAapproved 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 FDAregulated 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 FDAregulated 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 § 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 

§ 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 

§ 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 § 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 


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15See 63 FR 60353 at 60355. 

alteration of consent under § 50.22. 

Similarly, we decline to include 

additional restrictions in § 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 § 50.24), FDA does not believe 

minimal risk research that is reviewed 

by an IRB and found to meet the criteria 

in § 50.22 necessitates these additional 

protections. However, under § 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 § 50.22. 

With regard to excluding children and 

adults with diminished capacity from 

the types of studies that may be 

conducted under § 50.22, we believe it 

is appropriate for studies with child 

subjects to qualify for a waiver or 

alteration under § 50.22 when the IRB 

finds and documents that the criteria in 

§ 50.22 are satisfied. In addition to the 

requirements of § 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 § 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, 

§ 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 § 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 § 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 § 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, § 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. 

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 

§ 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 § 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 § 50.22 to FDAregulated 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 

§ 50.22. 

FDA believes that the structure of 

§ 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 § 50.22 

requires that the IRB responsible for the 

review, approval, and continuing review 

of a minimal risk clinical investigation 


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16See 45 CFR parts 160 and 164, subparts A and 

E. 

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. 

(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 

§ 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 § 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 § 50.22 with those set forth in 

the revised Common Rule’s general 

waiver provision, we are promoting 

consistency in the application of such 

requirements across Common Rule 

Agencies and minimizing burden to 

IRBs tasked with applying the criteria 

described in this rule to FDA-regulated 

research. 

H. Comments on the Expedited Review 

List and IRB Continuing Review 

(Comment 23) Some comments 

question the interpretation of ‘‘minimal 

risk’’ in the proposed rule in relation to 

the list of categories of research that 

may be reviewed by the IRB through an 

expedited review procedure (‘‘expedited 

review list,’’ Ref. 14). One comment 

disagrees with categories of research 

included on the expedited review list. 

Another comment notes that, while the 

expedited review list categories could 

provide some benchmarks for the types 

of research that are minimal risk, these 

applications are limited and there may 

be research that qualifies as ‘‘minimal 

risk,’’ that would not qualify for the 

expedited review procedure. 

Similarly, some comments express 

concern that the proposed rule did not 

address how FDA intends to harmonize 

with the revised Common Rule with 

respect to expedited review procedures 

and IRB continuing review. A few 

comments cite SACHRP’s 

recommendations on the expedited 

review list (Ref. 15) and note concern 

about FDA and HHS adopting them. 

These comments assert that if FDA and 

HHS adopt the SACHRP 

recommendations and FDA harmonizes 

with changes made in the revised 

Common Rule regarding expedited 

review (e.g., by permitting expedited 

review of research activities appearing 

on the expedited review list, unless the 

IRB reviewer determines that the studies 

involve more than minimal risk) would 

weaken human subject protections. 

Other comments state that human 

subject protections would be weakened 

if FDA adopts the revised Common 

Rule’s requirement that eliminates IRB 

continuing review for studies that are 

eligible for review under an expedited 

review procedure. These comments urge 

that minimal risk studies for which an 

IRB waives informed consent remain 

subject to IRB continuing review. 

(Response 23) FDA agrees with the 

comments to the extent they emphasize 

the importance of ensuring that waivers 

or alterations of informed consent under 

this rule are granted only for research 

that presents no more than minimal risk 

to the subjects. However, we do not 

agree that it is necessary to address how 

FDA intends to harmonize with the 

revised Common Rule’s expedited and 

continuing review requirements as part 

of this rulemaking, which finalizes our 

proposal to permit an IRB to approve an 

informed consent procedure that waives 

or alters certain informed consent 

elements, or to waive the requirement to 

obtain informed consent, for certain 

minimal risk investigations. FDA issued 

a separate proposed rule to amend its 

regulations at parts 50 and 56, including 

with respect to expedited and 

continuing review (87 FR 58733), and 

will consider all timely comments 

received as part of that rulemaking, 

including those related to expedited 

review and/or continuing review. We 

address below the more specific 

concerns raised by the comments in 

relation to expedited or continuing 

review. 

Some of the comments appear 

concerned that any changes to the FDA 

expedited review requirements intended 

to harmonize with the revised Common 

Rule could be perceived by the research 

community as broadening what 

qualifies as minimal risk or discourage 

determinations that a study presents 

more than minimal risk. As an initial 

matter, the revised Common Rule did 

not modify the current definition of 

‘‘minimal risk’’ that is found in HHS 

regulations (45 CFR 46.102(j)), so FDA 

regulations (§ 50.3(k)) remain consistent 

with the definition of ‘‘minimal risk’’ 

provided in the revised Common Rule. 

In addition, under FDA’s regulations at 

§ 56.110(b)(1), for research to qualify for 

expedited review, a determination must 

be made by an IRB that the proposed 

research involves no more than minimal 

risk to human subjects. In other words, 

under current FDA regulations, the 

categories of activities appearing on the 

expedited review list are not presumed 

to be minimal risk. FDA’s proposed rule 

to amend parts 50 and 56 (87 FR 58733) 

does not propose to change this. In 

addition, the revised Common Rule did 

not modify the 1998 expedited review 

list (63 FR 60364), so HHS and FDA (63 

FR 60353) maintain identical lists of 

categories of research activities that may 

be reviewed by an IRB through the 

expedited review procedure. As 

described in the revised Common Rule, 

an IRB may use the expedited review 

procedure to review studies that involve 

activities appearing on the expedited 

review list, unless the IRB reviewer 

determines that the studies involve 

more than minimal risk (see 45 CFR 

46.110(b)(1)(i)). However, OHRP has 

clarified that, until a new expedited 

review list is finalized, the entire 1998 

HHS expedited review list, including 

the ‘‘Applicability’’ section, remains in 


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Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 88245 

effect for studies subject to the revised 

Common Rule (Ref. 16). Under the 

current wording of the ‘‘Applicability’’ 

section, to be eligible for expedited 

review, research must present no more 

than minimal risk to subjects. Therefore, 

for research to qualify for expedited 

review under the revised Common Rule, 

a determination must still be made by 

an IRB that the specific circumstances of 

the proposed research involve no more 

than minimal risk to human subjects. 

Under § 50.22, as finalized in this rule, 

an IRB must find and document that the 

clinical investigation involves no more 

than minimal risk to subjects, regardless 

of whether the study falls within a 

category on the expedited review list, to 

waive or alter informed consent. 

As noted in comments, the revised 

Common Rule provision at 45 CFR 

46.109(f)(1)(i) eliminates the 

requirement for an IRB to conduct 

continuing review of research that is 

eligible for expedited review in 

accordance with 45 CFR 46.110, unless 

the IRB determines otherwise. FDA’s 

IRB continuing review requirements are 

not being revised in this rule. As 

explained above, FDA is engaged in 

separate rulemaking to amend parts 50 

and 56 to harmonize with the revised 

Common Rule in accordance with 

section 3023 of the Cures Act. As part 

of that effort, FDA proposed changes to 

eliminate the requirement for an IRB to 

conduct continuing review of research, 

unless an IRB determines otherwise, 

that has progressed to the point that it 

involves only data analysis, including 

analysis of identifiable private 

information or identifiable 

biospecimens, and/or accessing 

followup clinical data from procedures 

that subjects would undergo as part of 

clinical care. However, FDA’s proposed 

rule to amend parts 50 and 56 (87 FR 

58733) does not propose to eliminate 

continuing review of all research 

eligible for expedited review, unless the 

IRB determines otherwise, for the 

reasons described in the preamble to 

that proposed rule. FDA will take into 

account the comments urging that 

minimal risk studies for which an IRB 

waives informed consent remain subject 

to IRB continuing review as part of 

finalizing any changes to continuing 

review requirements in that separate 

rulemaking. 

As HHS evaluates and amends, as 

appropriate, its current expedited 

review list as required under 45 CFR 

46.110(a), FDA intends to participate in 

the process and will update our own 

expedited review list, as appropriate, 

and will consider if any related changes 

to our regulations are necessary. 

I. Comments on the Cost Savings of the 

Proposed Rule 

(Comment 24) Some comments 

describe support for the rule because it 

will reduce administrative burden and 

result in cost savings. Other comments 

express the view that the proposed cost 

savings of the rule are low and may not 

outweigh the negative impact of waiving 

informed consent for certain minimal 

risk studies. One comment states that, 

although the potential benefits cannot 

be fully quantified, the analysis should 

focus on some of the drawbacks of this 

rule. 

(Response 24) As discussed in section 

VII, FDA believes that this rule will 

reduce administrative burden and that 

any costs incurred are outweighed by 

non-quantifiable benefits in the form of 

healthcare advances resulting from 

research performed using a waiver or 

alteration of informed consent, as well 

as a reduction in burden for the research 

community arising from the 

harmonization of FDA’s informed 

consent regulations with the revised 

Common Rule’s provision for waiver or 

alteration of informed consent for 

certain minimal risk research. 

However, as part of developing a 

response to this comment, we 

reanalyzed the proposed rule to 

consider potential additional costs 

associated with the rulemaking. Based 

on that review, we determined that 

there are some one-time costs associated 

with reading and implementing the rule, 

which we anticipate to be small because 

the final rule is harmonized with 

Common Rule provisions with which 

the clinical research community is 

already familiar. We also determined 

that there are some annual costs 

associated with drafting and reviewing 

requests for a waiver or alteration of 

consent. In this final rule, we include a 

revised analysis of cost and cost savings 

in the Economic Analysis of Impacts 

(section VII). We also determined that 

some of these costs are associated with 

collections of information subject to 

review by the Office of Management and 

Budget (OMB) under the Paperwork 

Reduction Act of 1995 (PRA). For 

further information, see section IX. 

J. Comments on the Proposed Effective 

Date 

(Comment 25) We proposed that any 

final rule issued based on the proposed 

rule would become effective 30 days 

after its date of publication in the 

Federal Register. One comment requests 

clarification on the application of the 

effective date. Specifically, the comment 

asks whether the rule would apply only 

to clinical investigations that receive 

initial IRB approval on or after the 

effective date, or if it would apply to 

IRB review at any stage of the clinical 

investigation (e.g., initial IRB approval 

or amendments) conducted on or after 

that date. 

(Response 25) In response to this 

comment, we note that the rule will 

apply to IRB review at any stage of an 

FDA-regulated clinical investigation 

conducted on or after the effective date, 

including initial IRB approval or review 

of any changes to a previously approved 

clinical investigation. 

VI. Effective Date 

This rule is effective 30 days after the 

date of its publication in the Federal 

Register. 

VII. Economic Analysis of Impacts 

A. Introduction 

We have examined the impacts of the 

final rule under Executive Order 12866, 

Executive Order 13563, Executive Order 

14094, the Regulatory Flexibility Act (5 

U.S.C. 601–612), the Congressional 

Review Act/Small Business Regulatory 

Enforcement Fairness Act (5 U.S.C. 801, 

Pub. L. 104–121), and the Unfunded 

Mandates Reform Act of 1995 (Pub. L. 

104–4). 

Executive Orders 12866, 13563, and 

14094 direct us to assess all benefits, 

costs, and transfers of available 

regulatory alternatives and, when 

regulation is necessary, to select 

regulatory approaches that maximize 

net benefits (including potential 

economic, environmental, public health 

and safety, and other advantages; 

distributive impacts; and equity). Rules 

are ‘‘significant’’ under Executive Order 

12866 Section 3(f)(1) (as amended by 

Executive Order 14094) if they ‘‘have an 

annual effect on the economy of $200 

million or more (adjusted every 3 years 

by the Administrator of the Office of 

Information and Regulatory Affairs 

(OIRA) for changes in gross domestic 

product); or adversely affect in a 

material way the economy, a sector of 

the economy, productivity, competition, 

jobs, the environment, public health or 

safety, or State, local, territorial, or tribal 

governments or communities.’’ OIRA 

has determined that this final rule is not 

a significant regulatory action under 

Executive Order 12866 Section 3(f)(1). 

A rule is ‘‘major’’ under the 

Congressional Review Act/Small 

Business Regulatory Enforcement 

Fairness Act if it has resulted or is likely 

to result in an annual effect on the 

economy of $100 million or more or 

meets other criteria specified in the 

Congressional Review Act (5 U.S.C. 

804(2)). OIRA has determined that this 


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88246 Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 

final rule is not a major rule under the 

Congressional Review Act/Small 

Business Regulatory Enforcement 

Fairness Act. 

The Regulatory Flexibility Act 

requires us to analyze regulatory options 

that would minimize any significant 

impact of a rule on small entities. 

Because the final rule is unlikely to 

impose a substantial burden on the 

affected small entities, we certify that 

the final rule will not have a significant 

economic impact on a substantial 

number of small entities. 

The Unfunded Mandates Reform Act 

of 1995 (section 202(a)) requires us to 

prepare a written statement, which 

includes an assessment of anticipated 

impacts, before issuing ‘‘any rule that 

includes any Federal mandate that may 

result in the expenditure by State, local, 

and tribal governments, in the aggregate, 

or by the private sector, of $100,000,000 

or more (adjusted annually for inflation) 

in any one year.’’ The current threshold 

after adjustment for inflation is $177 

million, using the most current (2022) 

Implicit Price Deflator for the Gross 

Domestic Product. This final rule would 

not result in an expenditure in any year 

that meets or exceeds this amount. 

B. Summary of Costs, Cost Savings, and 

Benefits 

We expect costs in the form of 

affected IRBs, as well as investigators 

and sponsors of clinical investigations, 

reading and learning the rule. We also 

expect costs in the form of drafting new 

waiver or alteration requests, and 

additional recordkeeping burdens 

associated with reviewing and 

documenting IRB decisions on waiver or 

alteration requests. The net present 

value of the estimated costs of the rule 

are approximately $10.1 million, with a 

lower bound of approximately $8.1 

million and an upper bound of 

approximately $14.0 million, 

discounted at 3 percent over 10 years. 

At a 7 percent discount rate, the 

estimated costs of the rule are 

approximately $9.1 million, with a 

lower bound of approximately $7.5 

million and an upper bound of 

approximately $12.4 million. The 

estimated annualized costs of the rule 

are approximately $1.2 million, with a 

lower bound of approximately $0.9 

million and an upper bound of 

approximately $1.6 million, discounted 

at 3 percent over 10 years. At a 7 

percent discount rate, the estimated 

annualized costs of the rule are 

approximately $1.3 million, with a 

lower bound of approximately $1.1 

million and an upper bound of 

approximately $1.8 million. 

We also expect that there will be cost 

savings to IRBs because the time 

burdens of reviewing waiver or 

alterations requests would be reduced 

from harmonization of FDA’s informed 

consent regulations with the provision 

for waiver or alteration of informed 

consent for certain minimal risk 

research in the Common Rule. The 

estimated net present value of the cost 

savings of the rule are approximately 

$1.7 million, with a lower bound of 

approximately $0.9 million and an 

upper bound of approximately $3.5 

million, discounted at 3 percent over 10 

years. At a 7 percent discount rate, the 

estimated cost savings of the rule are 

approximately $1.4 million, with a 

lower bound of approximately $0.7 

million and an upper bound of 

approximately $2.8 million. The 

estimated annualized cost savings of the 

rule are approximately $0.2 million, 

with a lower bound of approximately 

$0.1 million and an upper bound of 

approximately $0.4 million, discounted 

at 3 percent over 10 years. At a 7 

percent discount rate, the estimated 

annualized costs savings of the rule are 

approximately $0.2 million, with a 

lower bound of approximately $0.1 

million and an upper bound of 

approximately $0.4 million. 

We expect benefits in the form of 

healthcare advances from minimal risk 

clinical investigations for which the 

requirements for informed consent are 

waived or altered under the final rule 

and that otherwise would not be 

conducted. We cannot quantify all 

benefits that might arise from such 

studies because of the lack of relevant 

data available regarding the focus of 

these types of studies that will support 

regulatory submissions to the Agency. 

The costs and cost savings of the rule 

are summarized in table 1. 

TABLE 1—SUMMARY OF COSTS, COSTS SAVINGS, AND DISTRIBUTIONAL EFFECTS OF THE PROPOSED RULE

[Millions $] 

Category Primary estimate Low estimate High estimate 

Units 

Notes 

Year dollars 

Discount 

rate 

(%) 

Period 

covered 

(years) 

Costs: 

Annualized Monetized millions/year ................ .............................. ........................ ........................ .................... .................... ....................

Annualized Quantified ..................................... $1.3 $1.1 $1.8 2020 7 10 

1.2 0.9 1.6 2020 3 10 

Qualitative ........................................................ .............................. ........................ ........................ .................... .................... ....................

Annualized Monetized millions/year 

Annualized ....................................................... 0.2 0.1 0.4 2020 7 10 

Quantified ........................................................ 0.2 0.1 0.4 2020 3 10 

Qualitative ........................................................ Healthcare advances stemming from minimal risk 

clinical investigations that can proceed using a 

waiver or alteration of informed consent and that 

otherwise would not have been conducted. 

.................... .................... ....................

Transfers: 

Federal Annualized ......................................... .............................. ........................ ........................ .................... .................... ....................

Monetized $millions/year ................................. .............................. ........................ ........................ .................... .................... ....................

From: To: 

Other Annualized ............................................. .............................. ........................ ........................ .................... .................... ....................

Monetized $millions/year ................................. .............................. ........................ ........................ .................... .................... ....................

From: To: 

Effects: 

State, Local or Tribal Government: 


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We have developed a comprehensive 

Economic Analysis of Impacts that 

assesses the impacts of the final rule. 

The full analysis of economic impacts is 

available in the docket for this final rule 

(Docket No. FDA–2018–N–2727) and at 

https://www.fda.gov/about-fda/reports/ 

economic-impact-analyses-fdaregulations. 

VIII. Analysis of Environmental Impact 

We have determined under 21 CFR 

25.30(h) that this action is of a type that 

does not individually or cumulatively 

have a significant effect on the human 

environment. Therefore, neither an 

environmental assessment nor an 

environmental impact statement is 

required. 

IX. Paperwork Reduction Act of 1995 

In the proposed rule, FDA stated, 

‘‘This proposed rule refers to previously 

approved collections of information 

found in FDA regulations. . . . 

Therefore, FDA tentatively concludes 

the requirements in this document are 

not subject to additional review by 

OMB.’’ In developing the final rule, 

FDA determined that there are 

information collections contained in the 

rule that are subject to review by OMB 

under the PRA (44 U.S.C. 3501–3521). 

Specifically, the final rule adds § 50.22 

to part 50 to allow IRBs responsible for 

the review, approval, and continuing 

review of clinical investigations to 

approve an informed consent procedure 

that does not include or that alters 

certain informed consent elements, or to 

waive the requirement to obtain 

informed consent, for certain minimal 

risk clinical investigations, provided the 

IRB finds and documents the criteria set 

forth in § 50.22(a)–(e). The information 

collections associated with part 50 have 

been approved in accordance with the 

PRA under OMB control number 0910– 

0130, but the additional provision at 

§ 50.22 will modify this information 

collection. We estimate the rulemaking 

will result in an annual burden increase 

of 1,102 responses and 1,102 hours from 

recordkeeping and disclosure activity 

relating to the revised regulations in 21 

CFR part 50. 

With this exception, we conclude that 

the other provisions of this rule do not 

require substantive revisions to 

information collections already 

approved under the PRA. Provisions in 

part 312 (21 CFR part 312) of FDA’s 

regulations set forth procedures for the 

conduct of clinical investigations of 

drugs and provide for the protection of 

human subjects involved in such 

investigations. Existing regulations at 

§ 312.60 describe the general 

responsibilities of investigators with 

regard to study conduct, including 

ensuring the rights, safety, and welfare 

of human subjects. As part of these 

responsibilities, the current regulations 

require that investigators obtain 

informed consent, except as provided in 

exceptions from general requirements 

(§ 50.23) and exception from informed 

consent requirements for emergency 

research (§ 50.24). This final rule, as 

noted above, adds an additional 

exception to include waiver or 

alteration of informed consent for 

minimal risk clinical investigations 

under § 50.22. Therefore, FDA made a 

conforming revision to § 312.60 to crossreference part 50 generally, rather than 

list each specific exception to the 

informed consent requirements, for 

simplicity and for accuracy of the crossreferences in the regulatory text. FDA 

does not expect changes to the 

collections of information approved 

under OMB control number 0910–0014 

as a result of this final rule. In addition, 

FDA’s existing regulations at § 812.2 

describe abbreviated requirements for 

IDEs, which require that investigators 

obtain and document informed consent 

under part 50, unless documentation is 

waived under IRB regulations at 

§ 56.109(c). This final rule amends 

§ 812.2(b)(1)(iii) to clarify that the 

investigator must obtain informed 

consent in accordance with part 50, 

which includes the new provision for 

waiver or alteration in § 50.22. The final 

rule also simplifies the regulatory text at 

§ 812.2(b)(1)(iii) by removing the crossreference to waiver of documentation of 

informed consent under § 56.109(c). The 

relevant section of the regulations in 

part 50 (i.e., § 50.27) already refers to 

§ 56.109(c), so the cross-reference to 

§ 56.109(c) need not be repeated. FDA 

does not expect any changes to the 

collections of information collection 

approved under OMB control number 

0910–0078 as a result of this final rule. 

Before the effective date of this final 

rule, FDA will publish a notice in the 

Federal Register announcing OMB’s 

decision to approve, modify, or 

disapprove the information collection 

provisions in this final rule. An Agency 

may not conduct or sponsor, and a 

person is not required to respond to, a 

collection of information unless it 

displays a currently valid OMB control 

number. 

X. Federalism 

We have analyzed this final rule in 

accordance with the principles set forth 

in Executive Order 13132. FDA has 

determined that the rule does not 

contain policies that have substantial 

direct effects on the States, on the 

relationship between the National 

Government and the States, or on the 

distribution of power and 

responsibilities among the various 

levels of government. Accordingly, we 

conclude that the rule does not contain 

policies that have federalism 

implications as defined in the Executive 

Order and, consequently, a federalism 

summary impact statement is not 

required. 

XI. Consultation and Coordination With 

Indian Tribal Governments 

We have analyzed this rule in 

accordance with the principles set forth 

in Executive Order 13175. We have 

determined that the rule does not 

contain policies that have substantial 

direct effects on one or more Indian 

Tribes, on the relationship between the 

Federal Government and Indian Tribes, 

or on the distribution of power and 

responsibilities between the Federal 

Government and Indian Tribes. 

Accordingly, we conclude that the rule 

does not contain policies that have 

tribal implications as defined in the 

Executive Order and, consequently, a 

tribal summary impact statement is not 

required. 

XII. References 

The following references are on 

display at the Dockets Management Staff 

(see ADDRESSES) and are available for 

viewing by interested persons between 

9 a.m. and 4 p.m., Monday through 

Friday; they are also available 

electronically at https://

www.regulations.gov. FDA has verified 

the website addresses, as of the date this 

document publishes in the Federal 

Register, but websites are subject to 

change over time. 

1. U.S. Department of State, ‘‘Fourth Periodic 

Report of the United States of America 

to the United Nations Committee on 

Human Rights Concerning the 

International Covenant on Civil and 

Political Rights’’ (December 30, 2011). 

Available at https://2009-2017.state.gov/ 

j/drl/rls/179781.htm. Accessed March 7, 

2023. 

2. Secretary’s Advisory Committee on Human 

Research Protections, 

‘‘Recommendations Related to Waiver of 

Informed Consent and Interpretation of 

‘Minimal Risk’ ’’ (January 31, 2008). 

Available at: https://www.hhs.gov/ohrp/ 

sachrp-committee/recommendations/ 

2008-january-31-letter/index.html. 

Accessed March 7, 2023. 

3. Executive Office of the President. 

Memorandum of March 27, 1997. 

‘‘Strengthened Protections for Human 

Subjects of Classified Research.’’ 62 FR 

26369 (May 13, 1997). Available at: 

https://www.federalregister.gov/ 

documents/1997/05/13/97-12699/ 

strengthened-protections-for-humanVerDate Sep<11>2014 15:43 Dec 20, 2023 Jkt 262001 PO 00000 Frm 00027 Fmt 4700 Sfmt 4700 E:\FR\FM\21DER1.SGM 21DER1

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88248 Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 

subjects-of-classified-research. Accessed 

March 22, 2023. 

4. Baker, F.X. and J.F. Merz (2018), ‘‘What 

Gives Them the Right? Legal Privilege 

and Waivers of Consent for Research,’’ 

Clinical Trials, 15(6): 579–586. Available 

at: https://journals.sagepub.com/doi/ 

10.1177/1740774518803122. Accessed 

on March 7, 2023. 

5. van Zon, S.K.R, S. Schlotens, S.A. 

Reijneveld, et al. (2016), ‘‘Active 

Recruitment and Limited Participantload Related to High Participation in 

Large Population-based Biobank 

Studies,’’ Journal of Clinical 

Epidemiology, 78: 52–62. Available at: 

https://www.sciencedirect.com/science/ 

article/pii/S0895435616300

21X?via%3Dihub. Accessed on March 7, 

2023. 

6. Kripalani, S., K. Goggins, C. Couey, et al. 

(2021), ‘‘Disparities in Research 

Participation by Level of Health 

Literacy,’’ Mayo Clinic Proceedings, 

96(2): 314–321. Available at: https://

www.mayoclinicproceedings.org/article/ 

S0025-6196(20)30856-9/fulltext. 

Accessed on March 7, 2023. 

7. Kraft, S.A., K.M. Porter, D.M. Korngiebel, 

et al. (2017), ‘‘Research on Medical 

Practices: Why Patients Consider 

Participating and the Investigational 

Misconception.’’ IRB, 39(4): 10–16. 

Available at: https://www.ncbi.nlm.

nih.gov/pmc/articles/PMC7374557/#__

ffn_sectitle. Accessed on March 7, 2023. 

8. OHRP and FDA, ‘‘Institutional Review 

Board (IRB) Written Procedures: 

Guidance for Institutions and IRBs’’ 

(May 2018). Available at: https://

www.fda.gov/regulatory-information/ 

search-fda-guidance-documents/ 

institutional-review-board-irb-writtenprocedures. Accessed on March 7, 2023. 

9. FDA, ‘‘Information Sheet Guidance for 

IRBs, Clinical Investigators, and 

Sponsors: Significant Risk and 

Nonsignificant Risk Medical Device 

Studies’’ (January 2006). Available at: 

https://www.fda.gov/regulatoryinformation/search-fda-guidancedocuments/significant-risk-andnonsignificant-risk-medical-devicestudies. Accessed on March 7, 2023. 

10. Council for International Organizations of 

Medical Sciences (CIOMS), 

‘‘International Ethical Guidelines for 

Health-related Research Involving 

Humans,’’ prepared by the Council for 

International Organizations of Medical 

Sciences in collaboration with the World 

Health Organization (2016). Available at: 

https://cioms.ch/wp-content/uploads/ 

2017/01/WEB-CIOMS-EthicalGuidelines.

pdf. Accessed on March 7, 2023. 

11. World Medical Association, ‘‘Declaration 

of Helsinki—Ethical Principles for 

Medical Research Involving Human 

Subjects’’ (October 2013). Available at: 

https://www.wma.net/policies-post/ 

wma-declaration-of-helsinki-ethicalprinciples-for-medical-researchinvolving-human-subjects/. Accessed on 

March 7, 2023. 

12. FDA, ‘‘Guidance on Informed Consent for 

In Vitro Diagnostic Device Studies Using 

Leftover Human Specimens that are Not 

Individually Identifiable’’ (April 2006). 

Available at: https://www.fda.gov/ 

regulatory-information/search-fdaguidance-documents/guidanceinformed-consent-in-vitro-diagnosticdevice-studies-using-leftover-humanspecimens-are-not. Accessed on March 

7, 2023. 

13. FDA, ‘‘Guidance for Industry and FDA 

Staff: In Vitro Diagnostic (IVD) Device 

Studies—Frequently Asked Questions’’ 

(June 2010). Available at: https://

www.fda.gov/regulatory-information/ 

search-fda-guidance-documents/in-vitrodiagnostic-ivd-device-studies-frequentlyasked-questions. Accessed March 7, 

2023. 

14. OHRP, ‘‘Protection of Human Subjects: 

Categories of Research That May Be 

Reviewed by the Institutional Review 

Board (IRB) Through an Expedited 

Review Procedure,’’ 63 FR 60364, 

November 9, 1998. 

15. SACHRP, Recommendation to the 

Secretary of HHS, ‘‘Recommendations on 

the Expedited Review List’’ (December 

12, 2017). Available at: https://

www.hhs.gov/ohrp/sachrp-committee/ 

recommendations/attachment-adecember-12-2017/index.html. Accessed 

on March 7, 2023. 

16. OHRP, ‘‘Revised Common Rule Q&As’’ 

(December 2021). Available at: https://

www.hhs.gov/ohrp/education-andoutreach/revised-common-rule/revisedcommon-rule-q-and-a/index.html. 

Accessed on March 7, 2023. 

List of Subjects 

21 CFR Part 50 

Human research subjects, Prisoners, 

Reporting and recordkeeping 

requirements, Safety. 

21 CFR Part 312 

Drugs, Exports, Imports, 

Investigations, Labeling, Medical 

research, Reporting and recordkeeping 

requirements, Safety. 

21 CFR Part 812 

Health records, Medical devices, 

Medical research, Reporting and 

recordkeeping requirements. 

Therefore, under the Federal Food, 

Drug, and Cosmetic Act, the Public 

Health Service Act, and under authority 

delegated to the Commissioner of Food 

and Drugs, 21 CFR parts 50, 312, and 

812 are amended as follows: 

PART 50—PROTECTION OF HUMAN 

SUBJECTS 

■ 1. The authority citation for part 50 is 

revised to read as follows: 

Authority: 21 U.S.C. 321, 343, 346, 346a, 

348, 350a, 350b, 352, 353, 355, 360, 360c– 

360f, 360h–360j, 371, 379e, 381; 42 U.S.C. 

216, 241, 262. 

■ 2. In § 50.20 revise the first sentence 

to read as follows: 

§ 50.20 General requirements for informed 

consent. 

Except as provided in §§ 50.22, 50.23, 

and 50.24, no investigator may involve 

a human being as a subject in research 

covered by these regulations unless the 

investigator has obtained the legally 

effective informed consent of the subject 

or the subject’s legally authorized 

representative. * * * 

■ 3. Add § 50.22 to subpart B to read as 

follows: 

§ 50.22 Exception from informed consent 

requirements for minimal risk clinical 

investigations. 

The IRB responsible for the review, 

approval, and continuing review of the 

clinical investigation described in this 

section may approve an informed 

consent procedure that does not include 

or that alters some or all of the elements 

of informed consent set forth in 

§ 50.25(a) and (b), or may waive the 

requirement to obtain informed consent, 

provided the IRB finds and documents 

the following: 

(a) The clinical investigation involves 

no more than minimal risk to the 

subjects; 

(b) The clinical investigation could 

not practicably be carried out without 

the requested waiver or alteration; 

(c) If the clinical investigation 

involves using identifiable private 

information or identifiable 

biospecimens, the clinical investigation 

could not practicably be carried out 

without using such information or 

biospecimens in an identifiable format; 

(d) The waiver or alteration will not 

adversely affect the rights and welfare of 

the subjects; and 

(e) Whenever appropriate, the subjects 

or legally authorized representatives 

will be provided with additional 

pertinent information after 

participation. 

PART 312—INVESTIGATIONAL NEW 

DRUG APPLICATION 

■ 4. The authority citation for part 312 

continues to read as follows: 

Authority: 21 U.S.C. 321, 331, 351, 352, 

353, 355, 360bbb, 371; 42 U.S.C. 262. 

■ 5. Revise § 312.60 to read as follows: 

§ 312.60 General responsibilities of 

investigators. 

An investigator is responsible for 

ensuring that an investigation is 

conducted according to the signed 

investigator statement, the 

investigational plan, and applicable 

regulations; for protecting the rights, 

safety, and welfare of subjects under the 

investigator’s care; and for the control of 

drugs under investigation. An 


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Federal Register / Vol. 88, No. 244 / Thursday, December 21, 2023 / Rules and Regulations 88249 

investigator shall obtain the informed 

consent of each human subject to whom 

the drug is administered, in accordance 

with part 50 of this chapter. Additional 

specific responsibilities of clinical 

investigators are set forth in this part 

and in parts 50 and 56 of this chapter. 

PART 812—INVESTIGATIONAL 

DEVICE EXEMPTIONS 

■ 6. The authority citation for part 812 

is revised to read as follows: 

Authority: 21 U.S.C. 331, 351, 352, 353, 

355, 360, 360c–360f, 360h–360j, 360hh– 

360pp, 360rr–360ss, 360bbb–8b, 371, 372, 

374, 379e, 381, 382; 42 U.S.C. 216, 241, 262. 

■ 7. Revise § 812.2 (b)(1)(iii) to read as 

follows: 

§ 812.2 Applicability. 

* * * * * 

(b) * * * 

(1) * * * 

(iii) Ensures that each investigator 

participating in an investigation of the 

device obtains from each subject under 

the investigator’s care, informed consent 

in accordance with part 50 of this 

chapter. 

* * * * * 

Dated: December 1, 2023. 

Robert M. Califf, 

Commissioner of Food and Drugs. 

[FR Doc. 2023–27935 Filed 12–20–23; 8:45 am] 

BILLING CODE 4164–01–P 

DEPARTMENT OF HOMELAND 

SECURITY 

Coast Guard 

33 CFR Parts 3, 100, 165 

[Docket Number USCG–2023–0970] 

RIN 1625–AA00 

Coast Guard Sector Sault Sainte Marie; 

Sector Name Conforming Amendment 

AGENCY: Coast Guard, DHS. 

ACTION: Final rule. 

SUMMARY: The rule makes nonsubstantive changes to Coast Guard 

regulations in association with a change 

in the Coast Guard’s internal 

organization. The purpose of this rule is 

to reflect that U.S. Coast Guard Sector 

Sault Sainte Marie has been renamed 

U.S. Coast Guard Sector Northern Great 

Lakes. This rule will have no 

substantive effect on the regulated 

public. 

DATES: This rule is effective without 

actual notice December 21, 2023. For 

the purposes of enforcement, actual 

notice will be used from December 1, 

2023, until December 21, 2023. 

ADDRESSES: To view documents 

mentioned in this preamble as being 

available in the docket, go to https://

www.regulations.gov, type USCG–2023– 

0970 in the search box and click 

‘‘Search.’’ Next, in the Document Type 

column, select ‘‘Supporting & Related 

Material.’’ 

FOR FURTHER INFORMATION CONTACT: If 

you have questions about this rule, call 

or email Chief Warrant Officer Charles 

Palmer, U.S. Coast Guard; telephone 

906–253–2462, email Charles.b.palmer@

uscg.mil. 

SUPPLEMENTARY INFORMATION: 

I. Table of Abbreviations 

AOR Area of responsibility 

CFR Code of Federal Regulations 

COTP Captain of the Port 

DHS Department of Homeland Security 

FR Federal Register 

NPRM Notice of Proposed Rulemaking 

OCMI Officer in Charge of Marine 

Inspections 

OFCO Operating Facility Change Order 

SAR Search and Rescue 

§ Section 

U.S.C. United States Code 

II. Background Information and 

Regulatory History 

For the last several years, the Coast 

Guard has sought to better align the 

names of its assets to correspond to the 

area of responsibility which they serve. 

Review of the missions and 

engagements within the northern Great 

Lakes region highlighted that ‘‘Sector 

Sault Sainte Marie’’ alone did not 

adequately capture the breadth and 

range of Coast Guard operations and 

relationships throughout the region. The 

Coast Guard has approved the name 

change to U.S. Coast Guard Sector 

Northern Great Lakes to acknowledge 

the long-standing commitment to all 

communities of the region and to 

reaffirm the multi-mission support that 

the Coast Guard provides to ensure 

safety at sea and enhanced maritime 

governance. The geographic boundaries 

of Sector Northern Great Lakes are not 

changing, and its office is not moving 

from Sault Sainte Marie, MI. 

We did not publish a notice of 

proposed rulemaking (NPRM) before 

this final rule. The Coast Guard finds 

that this rule is exempt from notice and 

comment rulemaking requirements 

under 5 U.S.C. 553(b)(A) because the 

changes it makes are conforming 

amendments involving agency 

organization. The Coast Guard also finds 

good cause exists under 5 U.S.C. 

553(b)(B) for not publishing an NPRM 

because the changes will have no 

substantive effect on the public and 

notice and comment are therefore 

unnecessary. For the same reasons, the 

Coast Guard finds good cause exists 

under 5 U.S.C. 553(d)(3) to make the 

rule effective fewer than 30 days after 

publication in the Federal Register. 

III. Legal Authority and Need for Rule 

The Coast Guard is issuing this rule 

under authority in 14 U.S.C. 504(a)(2), 

as delegated at 33 CFR 1.05–1(h), to 

issue regulations necessary to 

implement technical, organizational, 

and conforming amendments and 

corrections to rules, regulations, and 

notices. 

On November 06, 2023, the Coast 

Guard issued Operating Facility Change 

Order (OFCO) No. 037–23 which 

changed the official unit name of U.S. 

Coast Guard Sector Sault Sainte Marie 

to U.S. Coast Guard Sector Northern 

Great Lakes. The previous name of 

Sector Sault Sainte Marie is described 

and reflected in regulations, which also 

contain contact details and other 

references to Sector Sault Sainte Marie. 

These conforming amendments update 

those regulations so that they contain 

current information. 

Under 14 U.S.C. 504(a)(2), the 

Commandant of the Coast Guard has the 

authority to establish and prescribe the 

purpose of Coast Guard Shore 

establishments. This authority has been 

delegated to the Chief of the Coast 

Guard’s Office of Regulations and 

Administrative Law under 33 CFR 1.05– 

1(h). 

IV. Discussion of the Rule 

OFCO No. 037–23, issued November 

06, 2023, changed the official unit name 

of U.S. Coast Guard Sector Sault Sainte 

Marie to U.S. Coast Guard Sector 

Northern Great Lakes. The November 

2023 OFCO did not change the area of 

responsibility (AOR). The AOR of U.S. 

Coast Guard Sector Northern Great 

Lakes is identical to that of what was 

U.S. Coast Guard Sector Sault Sainte 

Marie. All authorities and 

responsibilities previously assigned to 

Commander, U.S. Coast Guard Sector 

Sault Sainte Marie have been assigned 

to Commander, U.S. Coast Guard Sector 

Northern Great Lakes. Additionally, all 

authorities that were vested in the 

Commander, U.S. Coast Guard Sector 

Sault Sainte Marie as it pertains to the 

COTP, the OCMI, the Federal On Scene 

Coordinator, the Federal Maritime 

Security Coordinator, and the Search 

and Rescue Coordinator, have been 

assigned to Commander, U.S. Coast 

Guard Sector Northern Great Lakes. This 

rule does not change any sector, OCMI, 

or COTP zone boundary lines, nor does 


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