David Forster, JD, MA, CIP

In order to comply with the 21st Century Cures Act,

 FDA has released two notices of proposed rulemaking intended to harmonize the FDA institutional review board (IRB) and informed consent regulations with the Federal Policy for the Protection of Human Subjects (the “Common Rule”) to the extent possible.

 The Common Rule was revised in 2018 and the FDA notices of proposed rulemaking will harmonize the FDA regulations with the majority of those 2018 revisions. The Common Rule has been adopted by 20 federal agencies and applies to research that is conducted or supported by those agencies.

The first FDA notice of proposed rulemaking on Cooperative Research2 focuses on harmonization with the Common Rule requirement at 45 CFR 46.114(b)(1) that “Any institution located in the United States that is engaged in cooperative research must rely upon approval by a single IRB for that portion of the research that is conducted in the United States.” The FDA proposed language is virtually identical.

However, FDA has proposed differences in the exceptions to the rule. The Common Rule provides two exceptions:

The following research is not subject to this provision:

(i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe); or

(ii) Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.

While the FDA has proposed acceptance of the first exemption, it has not proposed adoption of the second and is proposing additional exceptions (items ii through iv):

Research is not subject to paragraph (b)(1) of this section if at least one of the following criteria is met:

(i) Cooperative research for which more than single IRB review is required by law (including tribal law passed by the official governing body of an American Indian or Alaska Native tribe);

(ii) Cooperative research involving a highly specialized FDA-regulated medical product for which unique, localized expertise is required;

(iii) Cooperative research on drugs that meets the exemptions from an investigational new drug application under § 312.2(b) of this chapter; or

(iv) Cooperative research on medical devices that meets the abbreviated requirements under § 812.2(b) of this chapter, or that meets the requirements for exempted investigations under § 812.2(c) of this chapter.

These different exemptions have the potential to create regulatory conflicts for research that is federally funded and thus subject to the Common Rule and FDA regulated. For instance, if an NIH-funded study qualified for the exceptions at 21 CFR 56.114(b)(2)(ii), (b)(iii), or b(iv), there would be conflicting regulatory requirements. Because the Common Rule does not include these provisions, the Common Rule would still require single IRB review unless the NIH took action under 45 CFR 46.114(b)(2)(ii) to determined that “Research for which any Federal department or agency supporting or conducting the research determines and documents that the use of a single IRB is not appropriate for the particular context.” While these regulatory conflicts create some additional regulatory burden, it will not be unmanageable for the regulated community.

If FDA adopts this requirement, sponsors will be required to use a single IRB for their US sites, whereas in the past that had been allowed but not required. Many industry sponsors have voluntarily taken this approach for some time, so disruption at the sponsor level will be minimal. For institutions and investigators, the imposition of the single IRB requirement would likely require some modifications to standard operating procedures and resources to comply, but many have already taken these steps due to the previous adoption of this requirement in the Common Rule.

In the FDA notice of proposed rulemaking on Protection of Human Subjects and IRBs,3 it is the proposed harmonization with the Common Rule requirements for informed consent documents that will most likely affect sponsors. Like the Common Rule, the FDA proposed rule would require:

(e)(1) Informed consent must begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject or legally authorized representative in understanding the reasons why one might or might not want to participate in the research. This part of the informed consent must be organized and presented in a way that facilitates comprehension.

(2) Informed consent as a whole must present information in sufficient detail relating to the research, and must be organized and presented in a way that does not merely provide lists of isolated facts, but rather facilitates the prospective subject’s or legally authorized representative’s understanding of the reasons why one might or might not want to participate.(21 CFR 50.20(e)).

FDA is proposing to include three additional elements of informed consent, which have already been included in the revised Common Rule, at sections 21 CFR 50.25(b)(7), (8), and (9). Section 50.25(b)(7) would require a statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit. Section 50.25(b)(8) would require a statement on whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions. Finally, section 50.25(b)(9) pertains to research involving biospecimens and would require that subjects be informed whether the research will (if known), or might, include whole genome sequencing (WGS).

FDA has also proposed to clarify in 21 CFR 50.27 that electronic informed consent is acceptable by adding a parenthetical statement to that effect, so that it would state, “informed consent shall be documented by the use of a written consent form approved by the IRB and signed and dated (including in an electronic format) by the subject or the subject’s legally authorized representative at the time of consent.”

FDA has also proposed not harmonizing with two elements of informed consent that were added to the Common Rule in the 2018 revisions. The first of these involves the Common Rule requirement to provide subjects with information regarding the future use of data for additional research purposes.

FDA requested public comment on whether its proposed new element of informed consent at § 50.25(a)(9) would provide adequate notice to potential subjects regarding the possible future research use of their information and biospecimens or if the Common Rule’s provision at 45 CFR 46.116(b)(9) is more informative. It also inquired whether the research community anticipated challenges in implementing the proposed new element and if an alternative approach could lessen those challenges.

in seeking informed consent the following information shall be provided to each subject or the legally authorized representative: … (9) One of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:

(i) A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility; or

(ii) A statement that the subject’s information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies.

FDA’s proposed new regulatory language at 21 CFR 50.25(a)(9) reads as follows:

in seeking informed consent the following information shall be provided to each subject or the legally authorized representative: … A description of how information or biospecimens may be used for future research or distributed to another investigator for future research.

FDA’s proposed language at 21 CFR 50.25(a)(9) is more open ended and will in many cases be difficult for the sponsor or investigator drafting the consent form to complete. Future research with information or biospecimens is often not contemplated when writing the protocol and informed consent form, so there would be no information to provide to the subject. The goal of this new element in the Common Rule was to let subjects know whether their information and specimens might be used for further research without their consent. FDA has attempted to improve the language by making it more open ended, but it could lead to several unintended consequences. FDA’s proposed language could result in IRBs and other parties interpreting the failure to describe future secondary research in the consent form as a prohibition on secondary research without consent, which would restrict the ability to perform that research under the current HHS regulations. Parties in research may also be concerned that the conduct of secondary research without consent could be a finding in an FDA inspection if it was not described in the consent form. Thus, reducing their ability or willingness to conduct such research.

The second element which FDA is proposing not to harmonize involves activities preparatory to research. FDA requested comment on whether its current policy adequately addresses screening, recruiting, or determining eligibility for an FDA-regulated clinical investigation, or if including the revised Common Rule provision at 45 CFR 46.116(g) would be useful for FDA-regulated clinical investigations.

The Common Rule, 45 CFR 46.116(g), includes the following requirement:

(g) Screening, recruiting, or determining eligibility. An IRB may approve a research proposal in which an investigator will obtain information or biospecimens for the purpose of screening, recruiting, or determining the eligibility of prospective subjects without the informed consent of the prospective subject or the subject’s legally authorized representative, if either of the following conditions are met:

(1) The investigator will obtain information through oral or written communication with the prospective subject or legally authorized representative, or

(2) The investigator will obtain identifiable private information or identifiable biospecimens by accessing records or stored identifiable biospecimens.

In essence, this new Common Rule requirement harmonized with the 1998 FDA Information Sheet entitled “

Screening Tests Prior to Study Enrollment

Guidance for IRBs and Clinical Investigators

FDA notes that because its definition of a “clinical investigation” is distinct from the HHS definition of “research,” it is unnecessary for it to adopt the new HHS regulatory language. However, it might not be clear to all parties involved in the conduct of research that FDA has already adopted this position through guidance. This could lead to confusion in the future for individuals trying to understand FDA’s position regarding activities preparatory to research.

Commercial sponsors and investigators who do not participate in federally-funded research will be more heavily affected by these FDA proposed regulations as they will be novel to them. Those parties should be prepared to address these new requirements if and when these revisions are implemented. IRBs, institutions, and investigators involved in the review and conduct of federally-funded research have already adopted many of these provisions in 2018 in the Common Rule, and thus will not be as affected.That said, the timeline for adoption of these proposed changes to the FDA regulations is unclear, and could take several months, or even several years.

, JD, MA, CIP is Chief Compliance Officer at WCG

21st Century Cures Act, Section 1002, Public Law 114-255. 

https://www.govinfo.gov/app/details/PLAW-114publ255

Notice of Proposed Rulemaking: Institutional Review Boards; Cooperative Research (87 FR 58752) 

https://www.federalregister.gov/documents/2022/09/28/2022-21089/institutional-review-boards-cooperative-research

Notice of Proposed Rulemaking: Protection of Human Subjects and Institutional Review Boards (87 FR 58733) 

https://www.federalregister.gov/documents/2022/11/14/2022-24689/protection-of-human-subjects-and-institutional-review-boards-and-institutional-review-boards

Code of Federal regulations Title 45 46.114 

https://www.ecfr.gov/current/title-45/subtitle-A/subchapter-A/part-46/subpart-A/section-46.114

Code of Federal Regulations Title 21 56.114(b) 

https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=56.114

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