The FDA's recent draft guidance on diversity action plans (DAPs) is poised to reshape clinical trial enrollment, mandating that sponsors strive for greater representation of underrepresented populations. This initiative, stemming from the 2022 Food and Drug Omnibus Reform Act (FDORA), seeks to address historical disparities in clinical research, ensuring that treatments are effective and safe for all patient subgroups. However, the guidance introduces several challenges for pharmaceutical companies and raises questions about its practical implementation and potential impact.
Establishing Enrollment Goals: A Complex Calculation
A key aspect of the draft guidance is the requirement for sponsors to set enrollment goals for clinical studies, disaggregated by race, ethnicity, sex, and age group. These goals should ideally be based on the estimated prevalence of the relevant disease in the U.S. intended use population. However, determining accurate prevalence estimates can be difficult, as highlighted by David Peloquin, a partner at Ropes & Gray. "In many cases, it will be difficult to arrive at a prevalence estimate for a condition in the U.S.," Peloquin notes, emphasizing the limitations and potential biases of available data sources like registries and electronic health records.
For multi-regional clinical trials, the guidance stipulates that enrollment goals should align with the U.S. intended use population, even for ex-U.S. sites. This poses logistical challenges, given the lack of uniformity in population descriptors across the globe. The FDA acknowledges these difficulties, stating that "the lack of uniformity across the globe in the use of population descriptors such as race and ethnicity may pose challenges when setting enrollment goals for international sites."
Measures to Meet Enrollment Goals: Decentralization and Beyond
The draft guidance suggests various measures to help sponsors meet their diversity enrollment goals. One notable recommendation is the use of decentralized study designs, which can potentially reach underrepresented groups by reducing geographical and socioeconomic barriers. Decentralized trials can enroll rural populations that live far from academic medical centers.
Consequences of Missing Enrollment Goals: An Unanswered Question
A significant uncertainty revolves around the consequences for sponsors who fail to meet their enrollment goals. Sarah Blankstein, counsel at Ropes & Gray, points out that the draft guidance does not explicitly address this issue. "The draft guidance doesn’t answer the question of what happens when enrollment goals are missed," Blankstein states. While the statutory requirement focuses on submitting the DAP, the FDA has various tools at its disposal, including post-marketing requirements (PMRs) and post-marketing commitments (PMCs), to collect additional data on underrepresented subgroups post-approval. There are 55 recent examples of FDA requiring post-marketing studies to obtain additional data in diverse populations that weren’t sufficiently represented in studies prior to approval.
The Impact of the Presidential Election: A Cloud of Uncertainty
The upcoming presidential election adds another layer of complexity. President-elect Trump has been critical of certain diversity, equity, and inclusion (DEI) efforts, raising the possibility of a less rigorous version of the DAP guidance being finalized. While the FDA faces a statutory deadline to finalize the guidance, the content and stringency of the final version remain uncertain.
Waivers and Data Privacy: Additional Considerations
The draft guidance allows for waivers from DAP requirements in certain circumstances, such as when the prevalence of the disease is well-known. However, the FDA has indicated that waivers will be infrequent, even for rare diseases. This approach has drawn criticism from industry groups, who argue for a more flexible approach.
Data privacy is another critical consideration. Sponsors must comply with U.S. state and ex-U.S. privacy laws, such as the GDPR in the EU, when collecting information to satisfy DAP requirements. These laws often treat race and ethnicity information as sensitive data, requiring additional notices, consents, and opt-out options.
The FDA's draft guidance on clinical trial diversity represents a significant step towards ensuring equitable representation in clinical research. However, its implementation poses numerous challenges for pharmaceutical companies, requiring careful planning, data collection, and compliance with evolving regulations. As the industry awaits the final guidance, stakeholders must navigate the complexities of setting enrollment goals, implementing effective measures, and addressing potential consequences for non-compliance.
