64 - A LAR(ge) Problem: Review Approaches to Approving Enrollment of Adults Requiring Surrogate Consent

Background:  IRBs/REBs are often called upon to evaluate whether subjects unable to consent for themselves may be enrolled in research. In the absence of federal regulations – and in a large IRBs/REBs reviewing across country and cultural borders – institution-specific policies and review approaches are necessary to assess inclusion of this vulnerable population. .

Program

Description:  In 2021, a project was initiated to: (1) provide common guidance for all IRB members when considering inclusion of adults requiring consent by legally authorized representative (LAR), (2) permit greater flexibility in permitting enrollment of this population, and (3) standardize the IRB/REBs’ rationales for LAR determinations. After obtaining input from IRB/REB chairs, board members, and staff, we consulted U.S. and Canadian regulations, ICH Good Clinical Practice, and research on ethical inclusion of subjects who require consent by LAR. We then developed Canadian- and U.S.-specific reviewer guidance materials (identical except for greater than minimal risk research with no direct benefit, reflecting language in TCPS2 Article 3.9(d)) and conducted training during IRB/REB meetings. Cross-border studies were purposely directed to boards that review under both Canadian and U.S. regulations. Finally, we evaluated the program’s impact on board determinations regarding the acceptability of consent by LAR by main reasons for approval or disapproval.

Program

Assessment:  Overall, the program successfully brought formal methodology but also identified areas of further discussion: LAR determinations were generally consistent regardless of regulatory framework for first-in-human studies (disapproved), minimal risk studies, and greater than minimal risk studies with a clear prospect of direct benefit (both generally approved). As expected, the majority of discordance (>90%) between U.S. and Canadian LAR determinations was observed in studies presenting greater than minimal risk with no clear prospect of direct benefit, but with the potential to generate generalizable knowledge about the subject’s condition.

Unexpectedly, our findings suggested that U.S. and Canadian panels interpreted “prospect of direct benefit” differently: U.S. panels were more open to the prospect of hypothetical benefit and prioritized the principle of Justice to permit inclusion of this vulnerable population even if the health condition of interest was not directly related to cognitive function. Conversely, Canadian panels typically excluded subjects requiring consent by LAR unless prior studies of the investigational intervention showed definitive evidence of direct benefit, ascribing a higher importance to the principle of Beneficence.

Limitations: Our sample comprised primarily industry-sponsored pharmaceutical clinical trials and reviews from a single commercial IRB that reviews U.S.- and Canadian-based research only. Consequently, the findings may not be applicable to ethical review of research in other jurisdictions. In addition, because we did not anticipate differences in interpretations of direct benefit, we did not explicitly collect data on this topic. Further study will be required to substantiate these initial insights.

Discussion:  The most interesting outcome of our program analysis was not its success but rather the apparent differences between our U.S. and Canadian panels in evaluating “prospect of direct benefit.” Anecdotally, U.S. panels were also more likely to identify a subject’s LAR as an important safeguard, whereas Canadian panels were more skeptical that LARs will prioritize subjects’ best interests. Whether these correlations stem from cultural or regulatory differences or are purely coincidental, our findings suggest that institutional guidance on interpreting “direct benefit” and appropriate safeguards could assist IRBs/REBs when reviewing research involving vulnerable populations, including those requiring consent by LAR.