The U.S. Food and Drug Administration (FDA) issued a long-anticipated draft guidance on June 26, 2024, entitled "Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies" (Draft Guidance). This Draft Guidance replaces and rewrites the draft guidance issued in April of 2022 (2022 Diversity Plan Draft Guidance), which only recommended the voluntary submission of diversity plans to enroll representative numbers of participants from underrepresented racial and ethnic populations in clinical trials.
The Draft Guidance was required to be issued by the Food and Drug Omnibus Reform Act of 2022 (FDORA), which amended portions of the Federal Food, Drug, and Cosmetic Act to make the submission of Diversity Action Plans mandatory in certain clinical investigations of drugs and medical devices. FDORA required FDA to issue the Draft Guidance by the end of December 2023 – better late than never! – and FDA must finalize the Draft Guidance no later than nine months after closing the comment period on the Draft Guidance (now the end of June 2025). FDORA's Diversity Action Plan requirements will become effective 180 days after the Draft Guidance is finalized.
FDORA required that the Draft Guidance address a number of topics relating to Diversity Action Plans. While the Draft Guidance in many instances tracks and provides technical information required by the statute, we summarize below key policy points and other new information it contains.
Clinical Studies Requiring Diversity Action Plans
Sponsors are required by FDORA to submit a Diversity Action Plan for the following studies:
- Phase 3 or pivotal studies of drugs, including biological products licensed under section 351 of the Public Health Service Act that are regulated as drugs.
- Medical device studies that are not exempt from the Investigational Device Exemption (IDE) regulations pursuant to 21 CFR 812.2(c).
Importantly, the Draft Guidance recognizes that many studies requiring an IDE (and thus a Diversity Action Plan under FDORA) are early-phase exploratory studies and that a Diversity Action Plan for those studies may not be particularly meaningful. While FDA strongly encourages sponsors to implement a diversity strategy throughout each clinical development program, including in early studies, FDA only intends to receive and review Diversity Action Plans for medical device studies that are designed to collect definitive evidence of the safety and effectiveness of a device. FDA is thus effectively proposing not to enforce the FDORA requirements for early-phase device studies, although it does not say so explicitly.
For medical device studies requiring an IDE application and for applicable drug studies, the Diversity Action Plan would be submitted as part of the relevant IDE application or Investigational New Drug application. For devices requiring an IDE but not requiring an IDE application – i.e., nonsignificant risk device studies subject to abbreviated IDE requirements – Diversity Action Plans must be submitted in any premarket notification, request for classification, or application for premarket approval. Many trials studying digital health technologies and in vitro diagnostics (soon to include laboratory-developed tests, at least pending court challenge) will follow this latter pathway.
What Should a Diversity Action Plan Contain?
The policy goals of the Diversity Action Plan requirements are fundamentally to improve the generalizability of study results and to detect clinically important differences across populations. Diversity Action Plans should be developed with these goals in mind. FDORA and the Draft Guidance require that enrollment targets be disaggregated by the race, ethnicity, sex, and age group demographic characteristics of the clinically relevant population. The Draft Guidance also encourages sponsors to consider other factors impacting clinical trial diversity, including geographic location, gender identity, sexual orientation, socioeconomic status, physical and mental disabilities, pregnancy status, lactation status, and co-morbidities, where relevant. In the Draft Guidance, FDA cites other guidance documents that sponsors should reference regarding the collection of many of these other types of data.
Diversity Action Plans should include the rationale for the proposed enrollment goals and a description of how the sponsor intends to meet those goals. Sponsors should assess available data that may indicate the potential for a medical product to have different responses in certain demographic groups and should be informed by the estimated prevalence or incidence of the disease or condition for which the medical product is being studied. When there are data that indicate that the product may perform differentially, it may be necessary to increase the proportional enrollment of a certain population to evaluate outcomes of interest or other clinically relevant factors in that group. If prevalence or incidence data are derived from non-publicly available sources (e.g., electronic health records or private registries), sponsors should provide the rationale for the approach, a synopsis of the analysis used, and citations for the data source(s).
In cases where a sponsor conducts several clinical studies for the sample product subject to Diversity Action Plan requirements, each clinical study should have an enrollment goal that reflects a strategy leading to overall proportionate representation, even if individual studies contain disproportionate representation.
In contrast to the 2022 Diversity Plan Draft Guidance, this Draft Guidance specifically addresses multi-national trials. A Diversity Action Plan for a multi-national clinical study must describe participant enrollment goals for the entire study and should not be limited to U.S.-enrolled participants. Additionally, the overall study design, including the selection of study sites, should account for the need to enroll a population representative of the U.S.-intended use population.
Strategies for Diverse Enrollment
The Draft Guidance discusses potential strategies sponsors should consider to enroll and retain a diverse trial population. In addition to the strategies mentioned in the 2022 Diversity Plan Draft Guidance – improving access to the clinical study through site location, language assistance, modifications for persons with disabilities, and transportation; sustained community engagement; and reducing participant burden by considering the number and frequency of visits and the use of local laboratories, imaging, and telehealth – this Draft Guidance proffers additional strategies, including providing cultural competency and proficiency training for clinical investigators and research staff. The Draft Guidance also highlights the role of clinical study decentralization when appropriate and references recent guidance on this topic entitled "Decentralized Clinical Trials for Drugs, Biological Products, and Devices" (May 2023).
Finally, like the 2022 Diversity Plan Draft Guidance, this Draft Guidance suggests providing trial participants with dependent care and reimbursing other participation costs. While these measures help to reduce participant burdens and increase retention, they should be closely examined for compliance with other state and federal beneficiary inducement and anti-kickback laws. The U.S. Department of Health and Human Services Office of Inspector General has issued several favorable advisory opinions finding specific cost-sharing subsidies to be reasonable means of promoting enrollment in clinical studies, although the facts of each advisory opinion vary.
In addition, the Draft Guidance asks Sponsors to describe plans to monitor enrollment goals during the study to ensure the goals are met. The Draft Guidance does not name specific ramifications for failure to meet an enrollment target, but it states that a sponsor would be expected to provide a mitigation plan in a status report if it does not expect to meet its stated enrollment goals. A mitigation strategy may include collecting the needed data in the post-marketing setting, as suggested in the 2022 Diversity Plan Draft Guidance.
Waivers, Modifications, and Publicity
FDORA provides that FDA may grant full or partial waivers of the Diversity Action Plan requirements. However, the Draft Guidance emphasizes that waivers will rarely be granted. For example, FDA generally does not intend to waive the requirement to submit a Diversity Action Plan even if the disease or condition under study is relatively homogenous with respect to race, ethnicity, sex, or age group. Rather, it expects sponsors in those cases to indicate in their rationale supporting their enrollment goals why the targeted population is homogenous.
After submission of the initial Diversity Action Plan, sponsors may submit modifications, as permitted by FDORA. FDA describes a process for submitting Diversity Action Plan modifications for both drug and device studies.
Finally, as required by FDORA, the Draft Guidance discusses the public posting of key information about studies' Diversity Action Plans by sponsors. The Draft Guidance strongly encourages sponsors to post key information from their Diversity Action Plans on their websites in consumer-friendly language and link to a recruitment website or to the study's listing on clinicaltrials.gov for studies that remain open to recruitment.
Sponsors, including both product manufacturers and sponsors of investigator-initiated research, should consider how the Draft Guidance may impact their clinical trials and whether to submit any comments or requests for clarification here. Stakeholder comments are due by September 26, 2024.
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