The 21st Century Cures Act mandated that the Department of Health and Human Services (“DHHS”) “revise the DHHS Human Subject Regulations, the FDA Human Subject Regulations, and the vulnerable populations rules to reduce regulatory duplication and unnecessary delays; modernize provisions; and protect vulnerable populations, incorporate local considerations, and support community engagement.” The Common Rule (45 CFR 46) provides protection for human subjects in research carried out or supported by most federal departments and agencies (DHHS regulations). FDA maintains a distinct set of human subjects protection regulations (21 CFR Parts 50 and 56) that applies to clinical investigations of products regulated by FDA.
Following release of the Revised Common Rule in 2018, FDA published guidance to clarify how researchers and institutions should handle research subject to both the Common Rule and to FDA Regulations. This guidance document offered some clarification regarding informed consent requirements and the continuing review of research, but harmonization of DHHS and FDA regulations was not proposed at that time. On September 28, 2022, FDA issued two proposed rules to harmonize regulations on IRBs and human subject protections with the Common Rule.
One Notice of Proposed Rulemaking (NPRM) amends FDA regulations to adopt the revised 2018 Common Rule’s single IRB requirement for cooperative research in the US, with some exceptions. The other NPRM amends FDA regulations to harmonize language, requirements for informed consent, and provisions for continuing review, while also proposing to amend certain investigational device exemption (“IDE”) reporting requirements (21 CFR Part 812). The table below outlines both NPRMs and identifies the harmonized sections.
A brief summary of the proposed non-editorial changes are as follows:
| Topic | Part 56 Section Revised | Proposed Changes | Harmonizes with Revised Common Rule Section |
| Cooperative Research | 56.114 |
Any institution located in the United States (US) that is participating in cooperative research will need to rely upon approval by a single IRB for that portion of the research that is conducted in the US, with the following exceptions: (i) Cooperative research for which more than single IRB review is required by law (e.g., tribal law); (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 IND application under § 312.2(b); or (iv) Cooperative research on medical devices that meets the abbreviated requirements under § 812.2(b), or that meets the requirements for exempted investigations under § 812.2(c). |
45 CFR 46.114 |
| IRB Records | 56.115 | Not surprisingly, documentation (a reliance agreement) specifying an institution’s reliance on an external IRB for oversight of research, and the responsibilities that each entity will undertake to ensure compliance with regulatory requirements, will be required. | 45 CFR 46.103(e) and 45 CFR 46.115(a)(9) |
| Definition | 56.102(n) | Adds the definition of ‘‘written or in writing’’ that includes both physical and electronic formats. | 46.102(m) |
| IRB Membership | 56.107 | Proposes deleting § 56.107(b), which requires IRBs to ensure that their membership not consists entirely of a single gender and prohibits IRB membership from being composed entirely of members of one profession. | 46.107(a) |
| IRB Review of Research | 56.109(b) and 56.109(d) | Add ‘‘or legally authorized representatives (LARs), when appropriate’’ to clarify that subjects or LARs must be given informed consent information in accordance with § 50.25. LARs may receive written statements, if required by the IRB, when documentation of informed consent is waived. | 46.109(b) and 46.117(c)(2) |
| IRB Review of Research | 56.109(c)(3) | A new exception to requirement for documentation of informed consent in specific circumstances would allow IRB to waive documentation for a study that presents no more than minimal risk of harm to subjects, if the subjects or LARs 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 consent was obtained. | 46.117(c)(1) and (c)(1)(iii) |
| IRB Review of Research | 56.109(g) | Unless an IRB determines otherwise, eliminate requirement for continuing review of research that has progressed to the point that it involves only data analysis, including analysis of identifiable private information or identifiable biospecimens, and/or accessing follow-up clinical data from procedures that subjects would undergo as part of clinical care. | 46.109(f)(1)(iii) |
| Criteria for IRB Approval of Research | 56.111(a)(3) and (b) | Updated language consistent with the 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.’’ | 46.111(a)(3) and (b) |
| IRB Review of Research | 56.115(a)(3) | Add requirement to retain documentation of the rationale for continuing review of research that otherwise would not require continuing review under § 56.109(g). | 46.115(a)(3) |
FDA is requesting comment on several issues that arose during the development of these notices. For example:
- The revised Common Rule retained 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. Is this provision relevant to FDA-regulated research? What are examples of situations when this exception would be useful in FDA-regulated studies?
- Is it appropriate to include an exception for cooperative research for which use of a single IRB is unable to meet the needs of specific populations? Should an IRB of record be able to supplement its members’ knowledge and experience with additional information or expertise to account for these situations? What specific examples of FDA-regulated research would be affected by this exception?
- Is it appropriate to include an exception for cooperative research with a small number of investigational sites. What is an appropriate threshold?
- What impact would the differences in exceptions from the single IRB review requirement pursuant to 45 CFR 46.114(b)(2)(ii) of the revised Common Rule have on stakeholders?
The comment period for both notices closes 28 November 2022.
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