The U.S. Food and Drug Administration (FDA) released further draft guidance in June 2024 to help industry stakeholders further understand the agency’s thinking on requirements for the submission of Diversity Action Plans (DAPs) under sections 505(z) and 520(g)(9) of the Federal Food Drug and Cosmetic Act. Those provisions were added by section 3602(c) of the Food and Drug Omnibus Reform Act of 2022 (FDORA), which was contained in the Consolidated Appropriations Act, 2023 (Pub. L. No. 117-328) that Congress passed in December 2022.
Shortly before this draft guidance, FDA released a report of its workshop titled “Public Workshop to Enhance Clinical Study Diversity” held in November 2023. Although the workshop report strongly encouraged sponsors to consider expanding inclusion criteria to encompass participants with mental illness, mental and intellectual disabilities and pregnancy/lactating status, the DAP draft guidance only requires enrollment goals disaggregated by race, ethnicity, sex and age group.
Under the relevant statutory provisions, study sponsors are required to file DAPs with FDA for certain clinical studies involving drugs, biological products and devices. These DAPs are designed to help improve the data FDA receives from clinical trials involving medical products, and also to aid sponsors in their efforts to increase enrollment of a broad swath of study participants who are members of groups historically underrepresented in clinical research. The guidance describes the format and content of DAPs (including the timing and process for submitting the plans) and sets out the criteria by which FDA will evaluate requests for exemptions from the statutory requirements.
What studies don’t need a DAP?
FDORA applies the DAP requirement to clinical studies for which enrollment commences 180 days from publication of the final guidance. As a result, the draft guidance mentions that clinical studies with the following characteristics do not need a DAP:
- Clinical studies of drugs with protocols submitted within 180 days following publication of the final guidance where enrollment is scheduled to begin 180 days after publication of the final guidance.
- Clinical studies of devices received by FDA in investigational device exemption (IDE) applications within 180 days after publication of the final guidance.
- Clinical studies of devices that do not require an IDE application to be submitted to FDA and that are approved by an institutional review board or independent ethics committee within 180 days after the date of publication of the final guidance.
The statute allows FDA to waive the DAP requirement if certain criteria are met. The waiver can be either a full or partial waiver, depending on the circumstances. This determination is case-specific and will depend on factors relevant to the specific study. Among the criteria are included in the determination are (1) whether the waiver is necessary based on what is known about the prevalence of the disease in the population, (2) whether conducting the study in accordance with the DAP is impracticable or (3) whether the waiver is necessary to protect public health during a public health emergency.
What studies do need a DAP?
The guidance details specific clinical studies that do need a DAP depending on the study. For drugs, a DAP is required for a clinical investigation of a new drug that is a phase 3 study or, as appropriate, is another pivotal clinical study of a drug (other than a bioavailability or bioequivalence study).
For devices, a DAP is required for all studies that are not exempt from IDE regulations. For any other studies that require an IDE application, the DAP is required to be submitted as part of that application. For qualifying studies that do not require an IDE application, a DAP must be submitted as part of a premarket notification, a request for classification or an application for premarket approval.
The FDA guidance indicates that, while there are certain studies for which a DAP would not be particularly meaningful (e.g., small studies conducted during the exploratory clinical stage), the agency expects sponsors to develop a DAP for studies that are intended to serve as the primary basis for FDA’s evaluation of safety and effectiveness and benefit–risk determination.
Which subpopulations should be included in the DAP?
Under the statute, a DAP must include details of the sponsor’s goals for enrollment (which should be disaggregated by race, ethnicity, sex and age group), the rationale for those goals and the explanation of how the sponsor is expected to meet those goals.
Enrollment goals
The enrollment goals should be informed by the estimated prevalence or incidence of the disease or condition in the domestic intended-use population for which the product is being studied. This will sometimes result in certain demographic groups having higher representation in the study’s enrollment goals. The rationale for enrollment goals should include both any explanation of these deviations from the proportions of the enrollment population from the general U.S. population as well as any methodology used to reach those conclusions.
Additionally, FDA has noted in the guidance that an individual clinical study that is part of a larger series of clinical studies may not achieve the proportionate representation that is the goal of the DAP provisions. As long as the entire series of studies achieves the proportional representation, and the DAPs for each of the component studies reflect its place in the larger series of studies, the sponsor will have met the requirements of the statute.
The guidance allows that certain clinical studies will have a more global or regional approach instead of just examining U.S. populations. For those studies, the enrollment goals included in the DAP should not be limited to U.S.-enrolled participants and should reflect the goals for the entire study. However, the study design should account for the need to enroll a representative sample of the U.S. intended-use population.
Rationale
To meet the requirement that a DAP includes the sponsor’s rationale for its enrollment goals, the DAP must contain sufficient information and analysis for FDA to understand how the sponsor determined the enrollment goals.
The sponsor’s rationale should:
- Include any background necessary to understand the disease or condition. This can include an overview of the history of the disease and risk factors, as well as any other background information that the sponsor deems necessary to justify the enrollment goals;
- Describe the data and information about the potential differential safety and effectiveness across the clinically relevant population. For drugs, as an example, this information should include any differences in pharmacokinetics or pharmacodynamics across the relevant demographics. For devices, the information should include any differences in the various demographic groups that would impact the safety and effectiveness of the device in those populations; and
- Describe whether the study is only one of several planned studies to support a single submission, and indicate how individual studies are intended to contribute to the overall enrollment goals for the entire clinical development program.
Plan to meet goals
The DAP must also include a section detailing how the sponsor intends to meet its enrollment goals, inclusive of any enrollment and retention strategies that may include:
- Sustained community involvement
- Cultural competency and proficiency training for clinical investigators and research staff
- Language assistance for participants with limited English proficiency
- Reducing the financial and logistical burden for participants in the study
- Increasing accessibility at study sites and initiating studies in areas that serve diverse populations
- Decentralizing the study where appropriate in order to reach a broader demographic
The DAP should describe how the sponsor plans to monitor compliance with enrollment goals. Additionally, sponsors are encouraged to share their strategies for compliance with the DAP publicly on their website both as a recruiting tool for the study and also to increase public transparency with attempts to meet the statutory requirements.
When should a DAP be submitted?
The time lines for submitting a DAP are dictated by statute and differ based on the circumstances of each clinical study.
For drugs, the statute requires the DAP to be submitted as soon as practicable, but no later than the date on which the sponsor submits the protocol to FDA for the phase 3 study or other pivotal study. FDA recommends that drug sponsors submit the DAP when the sponsor is seeking feedback at the “End-Of-Phase-2 meeting.”
For devices requiring an IDE application, the DAP must be included as part of that application. For devices that do not require an IDE application, the DAP should be submitted as part of the 510(k) notification, Premarket Application or De Novo classification request.
What’s next for FDA and the industry?
While FDA’s draft guidance notes that a DAP’s enrollment goals should be informed by the estimated domestic prevalence or incidence of the disease being studied, the workshop report noted that accurate disease prevalence/incidence data across all relevant demographic groups is often unavailable. It is unclear how FDA would enforce its DAP requirement when there is little consensus on the best methods to measure prevalence/incidence consistently and accurately for certain subpopulations.
FDA has also indicated that any waivers of the DAP requirement will be rare. The draft guidance, however, does not provide insight into how FDA will analyze the merit and scope of waivers that sponsors submit. FDA’s waiver process will be especially salient for sponsors that support studies for rare diseases or diseases in which a study population is difficult to enroll. Notably, the guidance does not discuss the implications for sponsors that are denied a waiver and fail to meet enrollment goals.
FDA will accept public comments on this draft guidance until September 26, 2024. The authors of this alert will continue to follow updates in relation to the draft guidance and other related developments on clinical trial diversity within the industry. In the meantime, please do not hesitate to reach out to any of the authors for further discussion or to contact the Reed Smith lawyer with whom you regularly work.
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