The Promise and Perils of Diversity Action Plans for Clinical Trials

Enacted on December 29, 2022, the Food and Drug Omnibus Reform Act of 2022 (FDORA)¹ included novel provisions for advancing clinical trial diversity. Specifically, FDORA granted the US Food and Drug Administration (FDA) the statutory authority to require drug and device sponsors to submit diversity action plans (DAPs) that must specify enrollment goals by race, ethnicity, sex, and age. Although Congress had previously enacted legislation encouraging clinical trial diversity, this was the first time it required clinical trial sponsors to develop plans for advancing demographic representation. Following the FDORA mandate, the FDA revised and published draft guidance on the format and content of DAPs on June 26, 2024.²

Although the draft guidance outlines the FDA’s expectations for DAPs, it leaves important questions unanswered and underscores key legislative gaps. How is success or failure to meet enrollment diversity goals measured? Are there enforcement mechanisms or consequences for failure? Should, and how should, these goals be set in the context of multinational clinical trials? Will DAPs be available for public review, and how will their adequacy be assessed? Moreover, the guidance—and its motivating legislation, FDORA—only mandate that diversity be assessed by sex, age, race, and ethnicity, and they conflate the concepts of demographics and discrimination. We recommend several approaches to address these challenges (Table).

Table.

Concerns With Current Guidance on Diversity Action Plans (DAPs) and Recommended Solutions

Concern	Solution
Addressable within the current statute
Lacks guidance on what constitutes meeting enrollment diversity goals	Provide clear definitions of what constitutes success and/or failure
Ambiguity over US enrollment diversity goals in the context of multinational clinical trials	Set a minimum proportion for US enrollment and set enrollment diversity goals among US participants only
Does not include collection of other demographic or social determinants of health data	Outline expectations about expanded demographic and social determinants of health data collection and analysis
Assesses social construct proxies but not potentially causal factors	Include guidance on collection and analysis of factors potentially mediating enrollment or outcome disparities
Requires additional legislation
Does not require public reporting of DAPs or FDA feedback	Make DAPs and FDA feedback public and available through ClinicalTrials.gov
Absence of consequences for failing to meet enrollment diversity goals	Create enforcement and accountability mechanisms for DAPs
No obligation for enrollment diversity goals by additional demographics or social determinants of health	Expand enrollment diversity goals beyond age, sex, race, and ethnicity

Abbreviation: FDA, US Food and Drug Administration.

Key Challenges and Potential Solutions

The DAP guidance provides recommendations on how enrollment goals should be set as well as measures that should be taken to meet them. It recommends that enrollment goals be based on the US incidence or prevalence of the condition for which the medical product is intended when such data are available and on the general US population when they are not. However, given the geographic determinism of US health and health care inequities and the need to select sites that improve the likelihood of enrollee representation, the guidance should also outline methods for more geographically granular assessments of disease burden. In addition, the guidance provides no clarity about what constitutes failure to meet enrollment goals or what degree of over- or underrepresentation is considered acceptable.

Even assuming that failure is defined, what happens when it occurs? Options include requiring extending enrollment on the current trial, requiring additional trials with adequate representation before pursuing FDA approval, or additional postmarketing requirements. However, it is unclear if any of these will occur, as Congress failed to give the FDA the authority to ensure DAP goals are met. Although the FDA plans to provide feedback on DAPs, additional enforcement mechanisms appear limited. Coupled with this lack of enforceability is the lack of public transparency. Although FDA guidance recommends that sponsors publish enrollment goals, Congress did not require DAPs or FDA feedback be made publicly available, limiting accountability. Further legislation should establish enforcement mechanisms if enrollment diversity goals are not met, make publication of DAPs and FDA feedback mandatory through ClinicalTrials.gov, and expand product labels to include data on representation in the drug development program that supported the approval(s).

Beyond the statutory shortfalls, the current guidance requires DAPs to set enrollment goals by sex, age, race, and ethnicity, but omits other demographic subgroups, social determinants of health, social needs and risk factors, and their intersectionality. Although the guidance encourages (but does not require) setting enrollment goals for additional factors, such as geographic location and socioeconomic status, it provides no direction on how to collect these data. Race and ethnicity are social constructs, relevant to biology only through their association with other factors. If the intention of DAPs is to understand differences in the safety and effectiveness of investigational drugs and devices, then correlative and potentially causative factors should be measured and analyzed. An increasing body of evidence supports the conclusion that health disparities attributed to demographic differences result from interacting, intermediary factors such as socioeconomic status and structural racism.^3,4 Expanded data collection (eg, income, education, place of residence) should be required such that correlations between demographics, potentially mediating variables, and outcomes can be assessed. As trial sites will be geographically distributed, analysis of these variables is also critical for determining the impact of economic and policy changes on trial participation. Relatedly, the guidance offers no discussion on the intersectionality of demographics or how disentangling such complexity should be approached statistically. Without these measures, DAPs risk conflating demographics with discrimination (ie, race with racism). None of this is to discount the importance of demographic representation, but to clarify how DAPs can achieve their stated goals of “improv[ing] the generalizability of results across the intended patient populations... and inform[ing] the safe and effective use of the medical product for all patients.”

The guidance provides only vague directions for the 70% of active registered trials that are multinational.⁵ For these studies, standards for age and biological sex exist globally such that all participants can inform outcome data. However, statements regarding race and ethnicity in this context fail to adequately advise sponsors. The guidance states that DAPs for multinational trials “must describe participant enrollment goals for the entire study” while at the same time “account[ing] for the need to enroll a population representative of the US intended use population as part of the overall medical product development program.” Yet concepts of race and ethnicity vary within the US and do not apply globally, so how can such goals be set? Is there a minimum proportion of US participants in a multinational trial upon which the enrollment targets will be assessed? Does that proportion change if there is evidence of pharmacokinetic or pharmacodynamic (PK/PD) differences in a given demographic subpopulation? We suggest the FDA acknowledge the varying conceptions of race and ethnicity within the US and globally, clarify whether US participants are the only trial participants subject to race and ethnicity enrollment goals, establish if there is a minimum proportion of enrollment that must come from the US, and note when and how PK/PD or other evidence should modify these enrollment targets. Only through such measures can the goals of adequate representation as well as generalizable safety and efficacy be met.

Conclusions

Although FDORA and DAPs are important steps in advancing clinical trial diversity, key gaps limit their ability to meaningfully achieve demographic representation in clinical trials. Some solutions are available within the context of current legislation, whereas others require additional Congressional action. Moving forward, more granular, transparent, and enforceable policy is essential for meaningful progress toward an equitable medical research enterprise.