Background

FDA’s rules on human subject protection govern clinical investigations under sections 505(i) and 520(j) of the Federal Food, Drug, and Cosmetic Act (FDCA), as well as studies used to support applications for research or marketing permits for FDA-regulated products. Meanwhile, the “Common Rule” applies to research supported by HHS—including by the National Institutes of Health—and by other federal agencies that apply the Common Rule to research. Although the Common Rule underwent a significant revision in 2017 (that largely took effect two years later), FDA’s human research protection rules have remained largely aligned with the elements of the original Common Rule, which dates to 1991.

As a result, in October 2018, FDA published guidance on its expectations for clinical research that is subject to both the FDA’s human subject protection regulations and HHS’ revised Common Rule. This guidance made clear that research subject to FDA rules must continue to abide by FDA’s regulations, even when they are more restrictive than the Common Rule, as we summarized online here. At that time, FDA stated its plans to propose human subject protection rules to align FDA’s human subject protection regulations with the now-revised Common Rule. Now almost 4 years later, FDA has done so.

FDA’s rules governing the “Protection of Human Subjects” are found at 21 CFR Part 50, and the rules for Institutional Review Boards (IRBs) at 21 CFR Part 56. The rules for Investigational New Drugs (INDs) are at 21 CFR Part 312 and for Investigational Device Exemptions (IDEs) are at 21 CFR Part 812. The Common Rule is located at 45 CFR Part 46.

Proposal for protection of human subjects

The first proposed rule titled “Protection of Human Subjects and Institutional Review Boards” seeks to harmonize, where possible, FDA’s human subject protection regulations and the Common Rule. The proposal provides the following table to summarize the proposed changes to 21 CFR Part 50 that would harmonize with the revised Common Rule.

Notable elements of the first proposed rule that aim to harmonize FDA rules with the revised Common Rule are listed below:

• Informed consent. FDA proposes to require that informed consent begin with a brief presentation of the key information that helps a subject understand the reasons why the subject might or might not want to participate in the research. FDA also proposes to add three new additional elements of informed consent to harmonize with the revised Common Rule. These elements would a) 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, b) require a statement on whether clinically relevant research results, including individual research results, will be disclosed to subjects, and if so, under what conditions, and c) require that subjects be informed whether research involving biospecimens will (if known), or might, include whole genome sequencing (WGS).
• “Minimal risk” informed consent waiver. FDA proposes adding an exception to the requirement for documentation of informed consent, to harmonize with the revised Common Rule at 45 CFR 46.117 (c)(1)(iii). The new provision would allow the IRB to waive documentation of informed consent for a study that presents no more than minimal risk of harm to the subjects, if the subjects or legally authorized representatives are members of a distinct cultural group or community in which signing forms is not the norm, and there is an appropriate alternative mechanism for documenting that informed consent was obtained.
  • However, the revised Common Rule also retains an exception to the requirement for documentation of informed consent at 45 CFR 46.117(c)(1)(i) for situations in which the only record linking the subject and the research would be the informed consent form and the principal risk would be potential harm resulting from a breach of confidentiality. FDA is not proposing to add this in the rulemaking because it asserts the exception is “not relevant to FDA-regulated research.”
  • The proposed rule requests comment on whether this provision is relevant to FDA-regulated research and any examples of situations when it would be useful.

Notable elements of the first proposed rule that would have FDA rules differ from the revised Common Rule are listed below:

• “Identifiable biospecimen.” Under the Common Rule, identifiers may be removed from information or biospecimens collected as part of a study and the information or specimens could then be used for some secondary research without informed consent or IRB review. Under the FDA’s proposed rule, the element of informed consent at 45 CFR 46.116(b)(9) would similarly inform subjects of that possibility when applicable. However, FDA’s proposed new element would require a description of how information or biospecimens may be used for future research or distributed to another investigator for future research, which is not limited to the two situations^[1] addressed by the statements required under the corresponding element of the revised Common Rule.

  • In distinguishing itself from the revised Common Rule here, FDA said it is “concerned about the practicability of limiting this proposed element of informed consent to the two situations addressed by the statements required under the Common Rule at this time.”

  • Nevertheless, the proposed rule asserts that “the research community would be able to develop informed consent forms and processes that comply with both sets of regulations.”

  • FDA requests comment on whether its proposed new basic 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 whether the Common Rule’s provision at 45 CFR 46.116(b)(9) would better inform potential subjects about the possible future use of their information and biospecimens in research, as well as on whether the research community anticipates challenges in implementing FDA’s proposed new element and whether an alternative approach could lessen such challenges.

• “Identifiable private information.” FDA proposes to define “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. This definition differs from the text of the revised Common Rule provision by including information for which a subject’s identity is or may be readily ascertained by the “sponsor” in addition to information that is or may be readily ascertained by the investigator. FDA would consider these types of information to be “identifiable private information” under this proposed definition.

• Criteria for IRB approval of research. FDA is proposing to add updated language consistent with the revised Common Rule describing categories of subjects who are considered vulnerable to coercion or undue influence, specifically “...children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons.” However, purportedly to “simplify [the] regulatory text,” FDA is also proposing to delete the phrase “to the extent required by” from § 56.111(a)(5), so that the requirement would read: “Informed consent will be appropriately documented or appropriately waived, in accordance with § 50.27 of this chapter.” FDA’s proposed revision differs slightly from the revised Common Rule at 45 CFR 46.111(a)(5), which states that informed consent will be appropriately documented or appropriately waived in accordance with 45 CFR 46.117.

• Limited IRB review. FDA is not proposing to adopt provisions from the revised Common Rule related to limited IRB review at this time, including 45 CFR 46.109(f)(1)(ii), but FDA notes that it “may take additional steps to harmonize with such provisions at a later time.”

• Recordkeeping for expedited review. FDA is not proposing add the revised Common Rule’s requirement that an IRB maintain a record of the rationale for conducting continuing review for review of research found on the HHS Expedited Review List, citing how, for studies on that list, a determination must have been made that the specific circumstances of the proposed research involve no more than minimal risk to human subjects.

Investigational Device Exemption (IDE) reporting requirements

The first proposed rule would also revise the current FDA requirement that sponsors submit progress reports to all reviewing IRBs “at regular intervals, and at least yearly.” Instead, under the proposed rule, sponsors would be required to submit such progress reports to the reviewing IRB to the extent that continuing review is required by the revised Common Rule. FDA states that it “does not believe that submission of progress reports to the IRB remains necessary when continuing review of the research by the IRB is not required,” noting the proposed removal of the requirement that IRBs maintain a record of the rationale for conducting continuing review. However, the proposed rule maintains the requirement that sponsors must submit progress reports to all reviewing IRBs at regular intervals, and at least yearly.

In addition, under the proposal, sponsors of an IDE will continue to submit progress reports to FDA at regular intervals and at least yearly under § 812.150(b)(5), and as may be requested under § 812.150(b)(10), regardless whether there is continuing IRB review. Justifying this continued requirement, FDA says that it aims “to ensure the Agency receives information regarding the IDE investigation.” FDA is not proposing to amend the requirements for treatment of IDEs at § 812.36(f), which require semi-annual progress reports to both FDA and the IRB(s) until a marketing application is filed.

FDA proposes “single IRB” requirement

The second proposed rule titled “Institutional Review Boards; Cooperative Research,” proposes a requirement for single IRB review for research that is conducted in the U.S., with some exceptions. Such a requirement would align with the Common Rule and “streamline the IRB review process and decrease administrative burdens and inefficiencies for investigators and IRBs without compromising human subject protections”.

The revised Common Rule’s “single IRB” requirement mandates that U.S. institutions engaged in cooperative research rely upon a single IRB review, with two exceptions:

1. 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 (AI/AN) tribe) or
2. research for which any Federal Department or Agency supporting or conducting the research determines and documents that the use of single IRB review is not appropriate for the particular context (45 CFR 46.114(b)).

FDA proposes the same first exception, but not the second, stating that the agency does “not believe it is practicable for FDA to adopt the same regulatory text…because most of the research that FDA regulates is not conducted or supported by FDA or by any Federal Department or Agency,” and therefore, “this exception would have no applicability to the majority of FDA-regulated research.” However, FDA invites comments on whether it should add into the final rule an exception analogous to the second Common Rule exception, in order to help address potential challenges to use of a single IRB review model for FDA-regulated cooperative research.

FDA proposes specific exceptions that aim to reflect circumstances where requiring the use of a single IRB for oversight of multisite research may not be appropriate for FDA-regulated research (items 2, 3, and 4 below):

1. Cooperative research for which more than single IRB review is required by law
2. Cooperative research involving a highly specialized FDA-regulated medical product for which unique, localized expertise is required
3. Cooperative research on drugs that is exempt from the requirements for an IND application under § 312.2(b) (21 CFR 312.2(b))
4. A device investigation conducted under the abbreviated requirements at § 812.2(b) (21 CFR 812.2(b)) for a nonsignificant risk or “NSR” study, or other cooperative research on medical devices that meet requirements for exempted investigations

In addition to these four proposed specific exceptions to the single IRB requirement, FDA has requested public comment on whether the following exceptions should be included in the final rule (although the proposed exceptions below are not included in the proposed rule):

1. Cooperative research for which use of a single IRB is unable to meet the needs of specific populations
2. Cooperative research with a small number of investigational sites

FDA further requests public comment on the impact that differences in exceptions to the single IRB review requirement may have on stakeholders, and on possible approaches to avoid or minimize any potential negative effects of such differences, such as whether additional exceptions from the proposed single IRB review requirement should be included or whether providing guidance on the application of FDA’s proposed exceptions might help avoid or minimize the differences in exceptions. FDA also requests comment on whether there are unique challenges to use of a single IRB review model for FDA-regulated cooperative research that could not be addressed by FDA’s proposed exceptions.

Another difference between the proposed rule and the revised Common Rule is that the latter 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 supporting the research.” FDA says it is not practicable for FDA to propose this same requirement “because, unlike research subject to the revised Common Rule, most of the research that FDA regulates is not conducted or supported by FDA or by any Federal Department or Agency.”

The proposed rule includes a lengthy defense of the single IRB requirement, citing a Clinical Trials Transformation Initiative (CTTI) study that identified several “perceived” barriers to the use of single IRB review, including concerns about potential noncompliance by the single IRB, potential loss of local context, and the quality of the single IRB’s review. FDA defends the single IRB requirement in pointing out that the study found that the “perceived barriers to single IRB review resulted from a conflation of institutional responsibilities with the ethical review responsibilities of the IRB, among other factors.” FDA further asserts that “multiple IRB reviews could result in recruitment differences between sites, leading to difficulty recruiting subjects with the condition of interest, and in some cases, an impact on the generalizability of the study results.”

Consistent with the Common Rule, the proposed single IRB rule also establishes a recordkeeping requirement to require documentation of an institution’s reliance on an external IRB for oversight of research.

Next steps

The changes in the first proposed rule would have an effective date of 180 days after the date of publication of the final rule, and the changes in the “single IRB” proposed rule would have an effective date of one year after the date of publication of the final rule. HHS seeks comments on these proposed timeframes.

FDA invites comments on the proposed rules through November 28, 2022. If you wish to submit a comment, or have any questions on human subject protection rules or clinical trials more generally, please contact the Hogan Lovells attorney with whom you regularly work or any of the authors of this alert.

Authored by Heidi Gertner, Robert Church, Meredith Manning, and William Ferreira