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Stakeholders seek flexibility, greater harmonization in FDA human subject protection rules

Stakeholders seek flexibility, greater harmonization in FDA human subject protection rules

Commenters from the pharmaceutical and medical device industries, academia and medical groups urged the US Food and Drug Administration (FDA) to help ease the complexity of the informed consent process by providing more flexibility and additional harmonization between the agency’s regulations on human subject protections and the revised Common Rule, which governs research conducted or supported by the US Department of Health and Human Services.

FDA issued two proposed rules in September 2022 outlining changes to the informed consent form and allowing Institutional Review Boards (IRBs) to eliminate continuing review of research under certain circumstances. Additionally, the agency is proposing to harmonize its cooperative research requirements with those in the Common Rule, which requires a single IRB review process for multisite research in most cases. (RELATED: FDA seeks to harmonize human subject protections with revised Common Rule, Regulatory Focus 27 September 2022)

Human subject protections and IRBs

The Pharmaceutical Research and Manufacturers of America (PhRMA) called on FDA to clarify what it means by providing research subjects with “key information” at the beginning of the informed consent form. In its comments, PhRMA suggested that FDA follow the approach used in the preamble to the Revised Common Rule, which outlines five factors that would generally satisfy the requirement.

PhRMA also asked FDA to revise its proposed language requiring informed consent to include a description of how information or biospecimens may be used for future research or distributed for future research. Rather than describing a potential future use, PhRMA suggested that the agency require a statement about whether information/specimens may be used in the future. This type of change would make it clear that researchers do not need to disclose details of future research, which may be unknown at the time of the clinical trial. As currently written, the FDA requirement “might also detract from the public health by unnecessarily restricting the use of biospecimens and information—including non-identifiable biospecimens and non-identifiable information—for uses that were not, and sometimes could not be, contemplated at the time of collection,” PhRMA commented.

The Association of American Medical Colleges (AAMC) objected to FDA’s addition of this new element of informed consent requiring a description of how information or biospecimens may be used for future research. Instead, the AAMC suggested that the agency harmonize its language with the revised Common Rule. The AAMC noted that under the revised Common Rule, research subjects must be provided with one of two statements related to the collection of identifiable private information or identifiable biospecimens and whether their information and biospecimens could be identified and used for future research.

Adding a slightly different requirement from FDA would likely result in informed consent documents that are “more complicated and confusing than informative, as sponsors, institutions, and investigators attempt to both create a study-specific description regarding future research as required by the FDA and also choose one of the two required statements under the revised Common Rule,” the AAMC commented.

There was broad support for the agency’s proposal to eliminate the requirement for IRBs to conduct continuing review in situations where the research has progressed to the point that it only involves data analysis (including analysis of identifiable private information or biospecimens) and/or accessing follow-up clinical data from procedures that subjects would undergo as part of clinical care. PhRMA and the Advanced Medical Technology Association (AdvaMed) both supported the elimination of continuing review. The Association for Clinical Oncology (ASCO) also supported eliminating continuing reviews unless the IRB determines otherwise. “We agree that requiring continuing review generally would not provide added protection to human subjects.”

AdvaMed also commented on the importance of having a common definition of a research subject between the Common Rule and the FDA Rules. However, the group suggested revising the definition to specify that it refers an individual whose “identifiable biospecimen” is used with an investigational device.

“FDA has previously stated that clinical investigations using human specimens conducted in support of premarket submissions are considered human subject investigations,” AdvaMed wrote. “Clarification that a subject refers to identifiable biospecimens will focus IRBs on higher risk clinical investigation reviews. This is consistent with FDA’s stated goal in the proposed rule to allow IRBs to focus their resources on higher risk research.”

The AAMC also called on FDA to address additional areas in need of harmonization with the revised Common Rule that were not included in the two proposed rules, including the posting of informed consent forms, public health surveillance activities, exempt research, limited IRB review, and the issue of broad consent.

IRBs and cooperative research

In comments on the proposed rule on IRBs and cooperative research, PhRMA expressed support for the single IRB review of multi-site trials. However, instead of a broad list of exceptions (as spelled out in the FDA proposed rule), PhRMA suggested the use of a “limited waiver” process. The agency could issue guidance outlining the key standards for FDA’s assessment of a waiver application with illustrative examples to assist sponsors in determining if a waiver is appropriate, the group wrote.

Additionally, PhRMA called on FDA to specify that in the case of a multi-site trial, the sponsor should select the single IRB. “Omitting direction entirely from FDA’s regulations about the entity responsible for identifying the single IRB is likely to generate confusion among sites and sponsors,” PhRMA wrote. “The Proposed Rule’s silence on this issue stands in stark contrast to the Revised Common Rule’s approach, which provides that the reviewing IRB must be identified by the Federal Department or Agency supporting or conducting the research, or be proposed by the lead institution subject to the acceptance of such Department or Agency.”

The AAMC commented that it supports the increased use of single IRBs for multi-site trials, but exceptions are warranted, and the agency should take time to study the issue. Specifically, the AAMC recommended that FDA adopt a two-year implementation period prior to the effective date of the single IRB requirement to “evaluate whether additional guidance, exceptions, or flexibilities are warranted.” Additionally, the AAMC suggested that FDA and HHS establish a pilot program that would examine costs, benefits, and consequences of a single IRB model.

The University of California (UC) system, which operates 10 research-intensive campuses and six medical schools, commented that more data is needed to establish the pros and cons of a single IRB approach. The UC system comments note that single IRB review can produce a shift in burdens rather than a burden reduction. “To utilize a single IRB, study teams must learn a new IRB review process, likely including a new electronic submission system, coordinate single IRB processes and requirements at their participating institution, and maintain communication with their local IRBs,” the UC system wrote. “Variances in administrative procedures or institutional requirements at participating sites cause delays and administrative burden.”

The University of Washington Human Subjects Division commented in support of adding exceptions to the proposed single IRB requirement, including an exception for cooperative research in which the use of single IRB is unable to meet the needs of special populations and an exception for cooperative research involving five or fewer US investigational sites.