Background

The Food and Drug Omnibus Reform Act of 2022 (FDORA) amended the Federal Food, Drug, and Cosmetic Act (FDCA) to require drug and device sponsors to submit diversity action plans (DAPs) for the stated purpose of increasing enrollment of subjects from historically underrepresented populations, which the agency believes will help the strength and generalizability of clinical evidence. FDORA’s DAP requirement reflected the principles outlined in FDA’s April 2022 draft guidance, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials,” which we summarized online here. FDA has now issued draft guidance on DAPs which focuses on age group, sex, race, and ethnicity demographic characteristics of the clinically relevant study populations, including the rationale for the enrollment goal and an explanation of how the diversity goals will be attained. For purposes of the latest guidance, “underrepresented populations” in terms of race and ethnicity may include participants who are Black or African American, Hispanic/Latino, Indigenous and Native American, Asian, Native Hawaiian and Other Pacific Islander, and other persons of color. For sex and age, underrepresented populations may include female participants and participants in the older adult and pediatric age groups.

Despite the draft guidance’s focus on age, sex, and racial & ethnic diversity, FDA notes at the outset that “the broader issues regarding health disparities and differential access to health care and clinical studies that may occur based on other factors, including but not limited to geographic location, gender identity, sexual orientation, socioeconomic status (SES), physical and mental disabilities, pregnancy status, lactation status, and co-morbidity.” Accordingly, FDA encourages sponsors to consider such additional factors in their DAPs, “which may support subgroup analyses.” For example, a sponsor developing a DAP “should also consider the potential that pregnant or lactating individuals with the condition or disease may use the medical product,” the draft guidance advises.

It is important to note that, when finalized, this guidance will create binding requirements on study sponsors. This is unlike most FDA guidance documents that just provide the agency’s recommendations. As background, FDORA required the agency to specify the form and manner for the submission of DAPs in guidance; thus, specifications regarding the form and manner for the submission of a DAP as described in the final guidance will have a binding effect.

Below we have summarized the draft guidance’s recommendations and requirements as they pertain to:

• which drug and device sponsors should submit DAPs;
• the types of content that should be included in a DAP, including the enrollment goals, the rationale for those goals, and metrics to meet them;
• the timeline and procedures for submission of a DAP to FDA;
• how diversity goals should be considered when conducting multinational studies; and,
• the circumstances under which FDA may grant a waiver for a DAP.

Which clinical trials require DAPs?

For drugs and biological products, FDA requires a DAP for a clinical investigation of a new drug that is being assessed in a phase 3 study (as defined in 21 CFR 312.21(c)), or as appropriate, another pivotal clinical study of a drug (other than a bioavailability or bioequivalence study).

For medical devices, FDA expects sponsors to develop a DAP for a study that is intended to serve as the primary basis for FDA’s evaluation of safety and effectiveness and benefit-risk determination, and does not intend to receive or review a DAP for other studies such as those not designed to collect definitive evidence of the safety or effectiveness of a device for a specified intended use. This applies both to significant risk studies that require an IDE application and nonsignificant risk studies that do not require an IDE application. If, however, the study is IDE-exempt (e.g., many IVD studies) a DAP is not required even if the study is intended to serve as the primary clinical evidence for a future marketing application.

The DAP requirement applies to clinical studies that commence enrollment 180 days after the publication of the final DAP guidance. Although the DAP requirement applies only to specified studies, the agency strongly recommends that sponsors develop and implement a comprehensive diversity strategy across the entire clinical development program, including in early studies, when possible.

Enrollment goals

FDA’s draft guidance explains how a DAP must include the sponsor’s enrollment goals for a clinical study, “disaggregated by the race, ethnicity, sex, and age group of the clinically relevant study population.” Sponsors must present their enrollment goals across subsets of the population with these demographic characteristics (e.g., for race: Asian, Black/African American). These demographic characteristics are summarized in Table 1 of the guidance.

The guidance recommends that enrollment goals “be informed by the estimated prevalence or incidence of the disease or condition in the U.S. intended use population for which the medical product is being studied.” Although increased enrollment (i.e., greater than proportional) of certain populations may be needed “in some cases…to elucidate potential clinically important differences in drug or medical device response between subsets of the study population,” the draft guidance adds that “a rationale must be provided for the proposed enrollment goals, including when such goals may deviate from the estimated prevalence or incidence of a disease or condition in the intended use population.”

When there is limited or no data or information available to characterize the incidence and/or prevalence of the disease or condition, or the demographic characteristics of the intended population, the draft guidance recommends that sponsors either use:

• prevalence and incidence information for the broader disease and base enrollment on the demographic characteristics of that broader disease population; or,

• goals based on general U.S. population demographics (i.e., U.S. census data).

The guidance further advises on the following DAP enrollment goal issues.

• DAPs across multiple studies. When conducting several clinical studies to support a single marketing submission and opting to specify enrollment goals across the planned clinical studies, “a sponsor must indicate how the individual clinical studies are intended to contribute to the stated enrollment goals.” In these cases, the DAP “for each clinical study should reflect a strategy that leads to an overall proportionate representation, even though individual clinical studies may not have proportionate representation.” FDA clarifies that where individual studies may not be fully reflective of enrollment goals across all studies, sponsors should specify how enrollment goals are expected to be met across the development program and should not seek a waiver for each study.

• Rare diseases. Although representational enrollment is still necessary, FDA acknowledges that certain development programs may include a single, small pivotal study, for which “participant numbers may be small, potentially precluding the detection of any differences in safety and effectiveness across the study population, should they exist, or limiting the sponsor’s ability to conduct a robust assessment of observed differences.”

• Real-world evidence. FDA recommends utilizing appropriate available sources (e.g., certain registries that are reasonably expected to be demographically representative, publicly available epidemiological surveys, published literature, etc.) to obtain information about the estimated prevalence or incidence of the disease or condition across the affected population, by race, ethnicity, sex, and age group.

• Global studies. For multinational studies, the draft guidance says programs should be designed with consideration given to differences in disease characteristics, medical practice, and available therapies when selecting foreign study sites. FDA cautions that a DAP for a multinational study should include enrollment goals for the entire study, not just the U.S. portion.

Rationale for enrollment goals

The guidance advises that a sponsor’s DAP enrollment goals’ rationale must include “sufficient information and analysis to explain how the sponsor determined its enrollment goals,” including “information necessary to understand the disease or condition.” Among other things, a sponsor’s rationale for enrollment goals should address natural history, risk factors, and prevalence estimates for the disease. In addition, for drugs or biologics, the guidance says a DAP’s enrollment goals’ rationale should include:

• Data and information that describe the potential for differential safety and effectiveness of the investigational drug across the clinically relevant population (e.g., differences in pharmacokinetics (PK)/ [pharmacodynamics (PD)).

• Data regarding genetic differences in PK, PD, safety, or effectiveness (e.g., genetic variations, which may vary based on ancestry and that impact drug metabolism or susceptibility to adverse reactions).

• Relevancy of other population-level or individual characteristics that available data suggest have an impact on the clinical outcomes (e.g., socioeconomic status, geographic location, comorbidities).

Additionally, for medical devices, the guidance says a DAP’s enrollment goals’ rationale should include:

• Data and information that describe the potential for differential safety and effectiveness of the device across the clinically relevant populations.

• Data regarding genetic differences that may impact safety or effectiveness (e.g., genetic variations, which may vary based on ancestry, that are expected to impact clinical outcomes or susceptibility to adverse events).

• Data on relevant factors for device performance (e.g., phenotypic, anatomical, technological, or biological factors), which should be evaluated to characterize any differential effects across a diverse population by the relevant demographic characteristics; FDA notes here that “the rationale should describe how the sponsor considered the available information when setting the enrollment goals.”

• Relevancy of other population-level or individual characteristics that available data suggest may have an impact on the clinical outcomes (e.g., socioeconomic status, geographic location, comorbidities).

Measures to meet enrollment goals

The DAP must include an explanation of how the sponsor plans to meet the specified enrollment goals, including a description of the enrollment and retention strategies for the study population, with a focus on measures that address diversity and representativeness of participants enrolled in a specific clinical study. The draft guidance offers the following examples of clinical study enrollment and retention strategies:

• Sustained community engagement, including through patient advocacy groups and community organizations.

• Offering cultural competency and proficiency training for clinical investigators and research staff.

• Improving study participant awareness and knowledge of the clinical study, including language assistance.

• Reducing participant burden, including providing transportation assistance or dependent care.

• Limiting clinical study exclusion criteria, including careful selection of site locations.

• Employing Decentralized Clinical Trial tools and strategies to help reduce the number of in-person visits to clinical sites by study subjects, as FDA has previously encouraged.

The DAP should also include a description of the plan to monitor enrollment goals during the conduct of the clinical study to ensure that goals are met. We note that the recommended strategies were previously recommended by FDA in the guidance, “Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs” (Nov. 2020). The DAP guidance “strongly encourages” sponsors to share strategies for meeting DAP enrollment goals with the public, including posting key information on sponsors’ websites.

Timeline & procedure for submitting DAPs to FDA

Once the DAP requirements take effect 180 after the publication of the final guidance, the sponsors of studies for drugs and biologics must submit the required DAP to the relevant IND application as soon as practicable, but no later than the date the sponsor submits the protocol to FDA for the phase 3 study or other pivotal study. However, FDA recommends submission of the DAP when a sponsor is seeking feedback regarding the applicable clinical study for the drug (typically at the End-Of-Phase 2 meeting). Following submission of an initial DAP, a sponsor may, as appropriate, submit modifications, but with a “Summary of Modifications and Justification” section that outlines the modifications to the DAP and provide the rationale for such changes.

For device clinical studies that require an IDE application to be submitted to FDA, the DAP must be included in the IDE application. Sponsors of studies for which submission of an IDE application is not required should submit DAPs as part of the device’s premarket notification (510(k)), PMA application, or De Novo classification request, as applicable. The draft guidance advises that when FDA’s feedback on specific questions is necessary to guide product development and/or preparation of a submission before submitting a DAP in an IDE or in a marketing submission, the sponsor should follow the Q-submission process for obtaining feedback or requesting a meeting with FDA.

Waivers

The draft guidance suggests that FDA will waive the DAP submissions requirement in “rare instances,” and states that submission of a DAP will be possible in most cases. Appropriateness of a waiver is a “case-specific determination and will depend on factors relevant to a specific development program.” The guidance spells out the following statutory criteria against which FDA will evaluate whether a waiver is appropriate:

1. Prevalence: a waiver is necessary based on what is known or what can be determined about the prevalence or incidence in the U.S. of the disease or condition for which the new drug or device is under development.

2. Impracticability: conducting a clinical investigation in accordance with a Diversity Action Plan would otherwise be impracticable.

3. Public Health Emergency: waiver is necessary to protect public health during a PHE.

FDA emphasizes in the draft guidance that it does not intend to waive the requirement to submit a DAP “even if the disease or condition under study is relatively homogenous with respect to race, ethnicity, sex, or age group.” Elsewhere in the guidance, FDA also suggests that development programs including a single small pivotal study (e.g., rare diseases) may not necessarily warrant a waiver. Sponsors must submit requests for a waiver (if warranted) as early as feasible, and no later than 60 days before the DAP is required for submission. FDA may grant a full waiver from the requirement to submit a DAP or may grant a partial waiver for any requirement of a DAP.

Enforcement and postmarketing requirements

The draft guidance does not describe what, if any, tools FDA will use to enforce submission of DAPs, or what actions FDA will take if a clinical trial diverges from the submitted DAP. In August 2023, FDA released draft guidance describing strategies that clinical trial sponsors can utilize post-approval to enhance safety and efficacy data for populations that may have been underrepresented in premarket studies, which we analyzed at the time online here. There, FDA suggested it would use postmarketing requirements and postmarketing commitments to ensure that relevant subpopulation data is collected if certain patient populations were not adequately represented in premarket clinical trials for drugs and biologics.

The absence of relevant subpopulation data from the pivotal trial may potentially inform product labeling discussions between sponsors and the agency.

Next steps

As described above, the DAP requirement will apply to clinical studies that commence enrollment 180 days after the publication of the final DAP guidance. FDA has also provided specific circumstances in which it does not expect DAPs to be submitted even for studies submitted within that timeframe. That said, we recommend that sponsors consider engaging with agency even before the finalization of the draft guidance to consider which modifications to their clinical development infrastructure will be required to meet DAP requirements.

In announcing the draft guidance, FDA Commissioner Robert M. Califf said the agency’s draft guidance is “one of many ongoing efforts — to address the participation of underrepresented populations in clinical trials to help improve the data we have about patients who will use the medical products if approved.” Indeed, the move came as the White House kicked off a public forum on clinical trials on June 26. And FDA announced last week the publication of a report on topics discussed at the 2-day virtual public workshop “Public Workshop to Enhance Clinical Study Diversity,” which was held Nov. 29-30, 2023. Recordings and presentations from the workshop are available online here, and our analysis of the workshop is online here.

On the legislative front, U.S. Reps. Raul Ruiz (D-CA) and Rep. Larry Bucshon (R-IN) introduced last month the Clinical Trial Modernization Act that would incentivize trial diversity in a number of ways, including allowing HHS to issue grants or enter into contracts to support education and recruitment for trials studying diseases that have a disproportionate impact on underrepresented populations.

FDA seeks comments on the draft guidance through September 26, 2024.