FDA Proposes Rules on Informed Consent and Institutional Review Boards

On September 28, 2022, the Food and Drug Administration (FDA) published two proposed rules, seeking to amend its human subject protection regulations regarding informed consent and institutional review boards (IRBs). The proposed rules are part of FDA’s ongoing efforts, as mandated by section 3023 of the Cures Act, to harmonize its regulations on human subject protection and IRBs with the revised Federal Policy for the Protection of Human Subjects (the revised Common Rule).

The first proposed rule, Protection of Human Subjects and Institutional Review Boards, would, for FDA-regulated clinical investigations, revise the content, organization, and presentation of information required in the informed consent form (ICF), add new elements of informed consent, and eliminate continuing IRB review of research in certain circumstances. The second proposed rule, Institutional Review Boards; Cooperative Research, would require use of single IRB review for multisite research conducted in the U.S., with some exceptions. Comments on both proposed rules are due November 28, 2022.

FDA’s regulations on informed consent and IRBs (21 C.F.R. parts 50 and 56) set forth requirements related to the rights, safety, and welfare of human subjects for FDA-regulated clinical investigations. HHS’s Common Rule regulates human subject research conducted or supported by HHS and other federal departments and agencies that adopted the Common Rule.

In 2017, HHS published a final rule revising the Common Rule.[1] The revisions to the Common Rule created differences between FDA’s human subject protection regulations and the Common Rule. Because some FDA-regulated research may also be conducted or supported by HHS and thus be subject to both sets of regulations, FDA issued a guidance in October 2018 to clarify the impact of certain Common Rule revisions on FDA-regulated clinical investigations.[2]

Section 3023 of the Cures Act, which was enacted in 2016, directs the Secretary of HHS to harmonize differences between the Common Rule and FDA’s human subject regulations, to the extent practicable and consistent with other statutory provisions.[3] Consistent with this statutory mandate, FDA addressed some of the differences in a previously issued proposed rule on IRB waiver or alteration of informed consent for certain minimal risk research.[4] The proposed rules are the next step in this harmonization process, although FDA explains in the preamble to the proposed rule on informed consent and IRBs that its harmonization efforts are ongoing with respect to certain of the revised Common Rule’s provisions (e.g., provisions on the posting of informed consent forms, broad consent, limited IRB review, exempt research, and public health surveillance activities).

Through this proposed rule,[5] FDA seeks to harmonize with the revised Common Rule certain sections in FDA regulations related to informed consent, continuing review of research, expedited IRB review, and related definitions. While the proposed provisions largely track the revised Common Rule, there are a few notable exceptions.

Definitions

FDA proposes to add or modify certain definitions in its informed consent regulations, including adding three definitions for the terms “private information,” “identifiable private information,” and “identifiable biospecimen.”

• Private information: FDA proposes to define “private information” as including “information about behavior that occurs in a context in which an individual can reasonably expect that no observation or recording is taking place, and information that has been provided for specific purposes by an individual and that the individual can reasonably expect will not be made public (e.g., a medical record).”[6] FDA’s proposed definition of “private information” is the same as the definition of the term under the revised Common Rule.
• Identifiable private information: The proposed rule defines “identifiable private information” as “private information for which the identity of the subject is or may readily be ascertained by the sponsor or investigator or associated with the information.”[7] This proposed definition differs from the Common Rule — the Common Rule definition only includes information that is or may be readily ascertained by the investigator. However, FDA views its proposed definition to be consistent with the Common Rule definition because the term “investigator” under the Common Rule includes “anyone involved in conducting the research,”[8] which is broader than the definition of “investigator” under FDA regulations (e.g., 21 C.F.R. § 50.3(d)). Thus, by including information ascertainable by not just the “investigator” but also the “sponsor,” the proposed approach harmonizes with the term’s scope in the Common Rule.
• Identifiable biospecimen: Similarly, FDA proposes to define “identifiable biospecimen” as “a biospecimen for which the identity of the subject is or may readily be ascertained by the sponsor or investigator or associated with the biospecimen.”[9] For the same reasons described above, FDA considers this proposed definition to align with the definition under the revised Common Rule.

The revised Common Rule requires the definitions of “identifiable private information” and “identifiable biospecimen” to be reviewed periodically and updated as needed.[10] FDA notes that it intends to participate in this effort, but does not commit to updating the definitions in its own regulations to the extent practicable and consistent with statutory provisions. This could potentially lead to discrepancies between the Common Rule and FDA regulations, which could cause confusion among stakeholders.

Informed Consent

FDA proposes to revise the required content, organization, and presentation of information in the ICF to facilitate a prospective subject’s decision-making. For example, FDA proposes to adopt the revised Common Rule’s requirement that mandates ICFs begin with a concise and focused presentation of the key information that is most likely to assist a prospective subject in determining whether or not to participate in the clinical investigation.

FDA also proposes to add a basic element of informed consent, which would require ICFs to include a description of how information or biospecimens obtained during the clinical investigation may be used or distributed for future research. Here, FDA deviates from the revised Common Rule approach. The revised Common Rule requires that subjects be provided with one of two statements in the ICF: (1) a statement that after removal of identifiers, the private information or biospecimens might be used or distributed for future research without obtaining additional informed consent; or (2) a statement that even if identifiers are removed, the subject’s information or biospecimens will not be used or distributed for future research.[11]

FDA considers its proposed approach to offer more flexibility: by requiring a “description” of future use or distribution of information or biospecimens, FDA’s new proposed basic informed consent element is not limited to the Common Rule’s two scenarios. FDA seeks comments on this proposal, specifically on whether FDA’s proposed basic element would adequately inform subjects about the possible future use of their information and biospecimens, and whether the research community anticipates challenges in implementing FDA’s proposed basic element.

The proposed rule also seeks to add three new additional informed consent elements: (1) a statement that the subject’s biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will share in this commercial profit; (2) a statement on whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions; and (3) that subjects be informed whether the research will or might include whole genome sequencing. These proposed additional elements are the same additional elements that were incorporated into the revised Common Rule.

Continuing Review of Research and Related Changes

FDA proposes to eliminate the requirement for an IRB to conduct continuing review of research, where that research has progressed to where it involves only: (1) data analysis, including analysis of identifiable private information or identifiable biospecimens; and/or (2) accessing follow-up clinical data from procedures that subjects would undergo as part of their clinical care. This proposed change tracks the revised Common Rule.

FDA is not proposing to adopt two other revised Common Rule provisions that identify circumstances in which continuing review is not required. First, FDA is not adopting the revised Common Rule provision that eliminates the requirement for continuing IRB review of research that is eligible for expedited review.[12] Even though studies eligible for expedited review involve no more than minimal risk, FDA believes that continued IRB oversight of such studies would provide meaningful protection to human subjects. Second, FDA is not proposing at this time to adopt the revised Common Rule provision that eliminates the continuing review requirement for research reviewed under the limited IRB review procedures.[13] This is because FDA has not proposed to adopt a limited IRB review process similar to that of the Common Rule. However, FDA reserves the possibility that it may take additional steps to harmonize its regulations with the Common Rule provisions on limited IRB review at a later time.

In keeping with FDA’s proposed curtailing of the continuing IRB review requirement, FDA proposes that: (1) if an IRB determines that continuing review of research is necessary when such review is otherwise not required, the IRB must maintain a record of the rationale for conducting continuing review; and (2) the medical device regulations in 21 C.F.R. part 812 be amended to require investigators and sponsors to submit progress reports to IRBs only to the extent continuing IRB review is still required.

Expedited Review

FDA proposes to maintain its language on expedited IRB review procedures, despite revisions to the corresponding provision in the Common Rule. In 1998, FDA and HHS each published a list of categories of research that may be reviewed by an IRB through an expedited review procedure, and the two lists are identical.[14] Under current FDA regulations, an IRB may use the expedited review procedure to review “some or all of the research appearing on [FDA’s expedited review] list and found by the reviewer(s) to involve no more than minimal risk.”[15] The Common Rule used to have the same wording, but the revised Common Rule now states that an IRB may use the expedited review procedure to review “some or all of the research appearing on [HHS’s expedited review] list […], unless the reviewer determines that the study involves more than minimal risk.”[16] FDA considers its existing regulations to be consistent with the revised Common Rule because a determination must still be made that the research involves no more than minimal risk in order for research to qualify for expedited review. Accordingly, FDA proposes no changes to its expedited IRB review procedures at this time.

FDA notes that the revised Common Rule requires an evaluation of the expedited review list at least every eight years and to amend the list as appropriate, after consultation with other agencies.[17] FDA states that it intends to participate in the process and will update its own expedited review list as appropriate.

Other Issues on Which FDA Seeks Comment

In addition to the issues and proposals discussed above, FDA requests comments on the following issues:

• FDA’s plan to not adopt the revised Common Rule provision that allows an IRB to approve a research proposal under which an investigator will obtain information or biospecimens without the subject’s informed consent for the purpose of screening, recruiting, or determining the eligibility of prospective subjects, provided certain conditions are met. FDA does not plan to adopt this provision due to FDA’s longstanding policy that certain preparatory activities to a clinical investigation do not fall within the definition of “clinical investigation” — and therefore do not require IRB review or informed consent under FDA’s regulations.
• FDA’s plan to not include the Common Rule exception to the requirement for documentation of informed consent for situations in which the only record linking the subject and the research would be the ICF and the principal risk would be potential harm resulting from a breach of confidentiality.
• The proposed effective date and approach to implementation to minimize disruption to ongoing research. Specifically, FDA proposes that the effective date of any final rule based on this proposed rule be 180 days from the date of publication of the final rule. Furthermore, to avoid unwarranted burden and delay to ongoing research, FDA proposes that for research initially approved by an IRB before the effective date, FDA would not require compliance with the proposed new informed consent requirements(though sponsors and investigators may voluntarily comply).

Proposed Rule on IRB Review for Cooperative Research

Through this proposed rule,[18] FDA seeks to mandate single IRB review for clinical investigations involving more than one institution in the U.S., i.e., cooperative research, with some exceptions. There are several places where the proposed rule departs from the revised Common Rule.

Rationale and Background

Under current FDA regulations, single IRB review for cooperative research is voluntary.[19] Despite FDA policies encouraging single IRB review,[20] FDA has observed that institutions (i.e., sites) have been reluctant to voluntarily use single IRB review, for reasons such as fear of losing local context and concerns regarding quality of review. FDA notes that decentralized IRB reviews for multisite studies carry administrative burdens and inefficiencies, while single IRB review would streamline the review process and increase efficiencies for oversight without compromising — and potentially benefiting, in certain circumstances — protection for human subjects.

The revised Common Rule already requires all U.S. institutions engaged in cooperative research that are subject to the Common Rule (i.e., that are engaged in research that is supported or funded by a participating federal department or agency) to rely on single IRB review, subject to two exceptions.[21] NIH has similarly adopted a policy that single IRB review generally will be used for multisite research funded by NIH.[22]

Proposals

FDA proposes to replace its current regulatory provision on voluntary use of single IRB review for multisite studies with a new mandatory requirement. Under FDA’s proposal, any institution located in the U.S. participating in FDA-regulated cooperative research must rely on approval by a single IRB for that portion of the research that is conducted in the United States, subject to four exceptions. FDA’s proposal deviates from the revised Common Rules in two significant ways.

First, while the revised Common Rule requires the reviewing IRB to be identified by the federal department or agency supporting or conducting the research, or to be proposed by the lead institution subject to the acceptance of the federal department or agency,[23] FDA does not propose a similar requirement for single IRB selection. In support of this approach, FDA explains that it would not be practicable for FDA to assume this responsibility given that most FDA-regulated research is not conducted by or supported by FDA or any federal department or agency. Although FDA says it is unaware of difficulties in selecting a single IRB that warrants requiring the IRB always be identified by a particular party, the lack of specificity could create challenges under a mandatory single IRB framework.

Second, while the revised Common Rule provides two exceptions to the single IRB review requirement, FDA proposes a different approach. Under the revised Common Rule, the single IRB review requirement does not apply to: (1) cooperative research for which more than single IRB review is required by law; or (2) cooperative 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.[24] FDA proposes to adopt the first exception under the revised Common Rule. But instead of adopting an analogous version of the second — which FDA believes could increase administrative burden — FDA proposes three exceptions that it believes better reflect circumstances for which requiring single IRB review may not be appropriate:

• Cooperative research involving a highly specialized FDA-regulated medical product for which unique, localized expertise is required. FDA neither defines “highly specialized medical product” or “unique, localized expertise,” nor explains which entity would be responsible for determining whether the exception applies. In the preamble to the proposed rule, FDA states that it expects this exception would be a “rare occurrence.”[25]
• Cooperative research on drugs exempt from Investigational New Drug Application (IND) regulations.
• Cooperative research on medical devices that meets the abbreviated requirements or the requirements for exempted investigations.

FDA also proposes to add regulatory text to clarify that if institutions participating in cooperative research are not required to use single IRB review under the proposed rule (e.g., ex-U.S. sites participating in cooperative research), they may still enter into a joint review arrangement, rely on the review of another IRB, or make similar arrangements for avoiding duplication of effort. This generally tracks the corresponding provision under the revised Common Rule.

Finally, FDA proposes a new IRB recordkeeping requirement. For research that takes place at an institution in which IRB oversight is conducted by an IRB not operated by the institution, the institution, or where appropriate the IRB, must retain documentation specifying the institution’s reliance on the IRB and the responsibilities each entity will undertake to ensure compliance with 21 C.F.R. part 56. This proposed requirement is consistent with the revised Common Rule.

The proposed effective date is one year after the publication of the final rule. FDA proposes to apply any new requirements to FDA-regulated cooperative research initially approved by an IRB on or after the proposed effective date.

Issues on Which FDA Seeks Comment

FDA requests comments on the following issues:

• Whether FDA should adopt an exception analogous to the revised Common Rule, under which FDA determines and documents that the use of a single IRB is not appropriate for the particular context.
• Whether it is appropriate to include an exception for cooperative research for which a single IRB is unable to meet the needs of specific populations. And relatedly, whether a single IRB would generally be able to supplement its members’ knowledge and experience with additional information or expertise to account for this situation, and any data on the frequency of how often this situation may occur.
• Whether FDA should include an exception for cooperative research with a small number of sites.
• Any impact of the discrepancies between FDA’s proposed rule and the revised Common Rule regarding exceptions to the use of single IRB review. And relatedly, possible approaches to avoid or minimize potential negative effects of the differences.
• Whether there are unique challenges to the use of single IRB review for FDA-regulated cooperative research that could not be addressed by FDA’s proposed exceptions.
• Whether there are any other criteria that should be considered when assessing whether an exception applies.

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