The United States Food and Drug Administration (FDA) issued draft guidance on April 13, 2022, entitled, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” (Guidance). The purpose of the Guidance is to outline requirements for manufacturers of FDA-regulated medical products to develop a Race and Ethnicity Diversity Plan (Diversity Plan) for enrolling an adequate number of participants from underrepresented racial and ethnic populations in clinical trials of their products. Once finalized, the Guidance will directly affect life sciences companies and research institutions that sponsor clinical trials, and it will indirectly affect research sites and institutional review boards (IRBs). Comments on the Guidance are due by June 13, 2022.

This is not the FDA’s first guidance aimed at enhancing the diversity of clinical trial populations. Most recently, FDA issued guidance in November 2020 that described approaches study sponsors could take to increase diversity generally in trial enrollment. For example, while certain populations (e.g., older adults and pregnant women) are excluded from participation in many trials, such exclusions are often made without strong clinical or scientific justification and may lead to a failure to discover important safety information. In 2017 and 2016, the FDA also issued guidance on the evaluation and reporting of race and ethnic data in medical device studies and guidance on collecting and presenting race and ethnicity data in submissions to the agency, respectively.

When Should a Diversity Plan be Submitted?

The Guidance recommends that a sponsor submit a Diversity Plan for all medical products for which an Investigational New Drug (IND) application or Investigational Device Exemption (IDE) application is required or for which clinical studies are intended to support a marketing submission for a Biologics License Application, New Drug Application, or any device marketing submission. FDA will evaluate the Diversity Plan as a key part of the sponsor’s development program.

The timelines for submission vary by the type of medical product being developed.

• Drugs. Sponsors should submit the Diversity Plan as soon as possible during drug development but no later than the time when the sponsor is seeking feedback regarding the applicable pivotal trials for the drug. The Diversity Plan may be submitted as part of a milestone meeting package or a freestanding document. The sponsor should request FDA feedback on its Diversity Plan by including specific questions in a formal milestone meeting request and meeting package.
• Devices. Sponsors should submit Diversity Plans as part of the investigational plan included in the IDE application. If the sponsor wants to discuss a proposed enrollment strategy before submitting its Diversity Plan, the sponsor should follow the Q-submission process for obtaining feedback or requesting a meeting with the FDA.

What Should the Diversity Plan Contain?

The Guidance outlines specific content requirements for a Diversity Plan. Sponsors should define the enrollment goals for underrepresented racial and ethnic participants as early as possible based on the study’s objectives and outline their plans to explore the potential for differences in safety or effectiveness associated with race and ethnicity throughout the product development lifecycle. When there are data that indicate that the product may perform differentially based on factors related to race or ethnicity (e.g., pulse oximeters’ performance in populations based on skin pigmentation), the Diversity Plan should specify the study design features that will inform the safety and effectiveness of the medical product in the relevant populations.

While most of the considerations established by the FDA are scientific, sponsors and research institutions alike should note the Guidance’s discussion of potential strategies to enroll and retain a diverse trial population. A Diversity Plan will be required to describe specific enrollment and retention strategies, including site location and access (e.g., language assistance for persons with limited English proficiency, reasonable modifications for persons with disabilities, and other issues such as transportation), sustained community engagement (e.g., community advisory boards and navigators, community health workers, patient advocacy groups, local healthcare providers, etc.); and reducing burdens due to trial/study design/conduct (e.g., number/frequency of study-related procedures, use of local laboratory/imaging, telehealth). Unfortunately, this information appears only in a table and contains no further discussion, leaving sponsors largely on their own to guess about FDA’s expectations regarding this complex topic.

What Questions Remain Unanswered?

While the Guidance provides some helpful considerations for sponsors in developing a Diversity Plan, it leaves open several questions, including the following:

• Financial Costs and Reimbursement to Trial Participants. In the Background section of the Guidance, FDA discusses financial reimbursement of study participation expenses such as travel and lodging as one method to help ensure diverse trial participation. In a related footnote, FDA notes that it does not consider reimbursement of such expenses to raise issues regarding undue influence. This discussion omits any reference to subsidizing the costs of interventions that are part of the study itself, which is a key barrier to trial participation, particularly among the uninsured. While this has been the subject of Department of Health and Human Services Office of the Inspector General advisory opinions and must be evaluated by the reviewing IRB, it is unclear whether FDA has reservations about the potential for undue influence such subsidies present.
• IRB Review. FDA has issued many guidance documents pertaining to IRBs and their review of research under the FDA’s IRB regulations at 21 CFR Part 56. Less than a year ago, the HHS Secretary’s Advisory Committee on Human Research Protections (SACHRP) released recommendations that address in detail how an IRB might evaluate some of the considerations presented in this Guidance under those regulations, the Common Rule, and the Belmont Report. It is unclear why the FDA omitted any meaningful consideration of IRB review in its Guidance, but the SACHRP recommendations are nevertheless instructive for IRBs in reviewing study protocols and the Diversity Plans prepared pursuant to this Guidance.
• Impact on Investigator-Initiated Research. The Guidance states that FDA expects a Diversity Plan to be developed early on in a product’s development lifecycle but does not explicitly require it, at least for drugs, until after a sponsor seeks feedback on a pivotal trial. Investigator-initiated research – in which the investigator or her employer is the study sponsor – does not neatly fall into this framework, however. Hence, it remains to be seen whether and when FDA will expect Diversity Plans to be prepared for such research. This could depend on whether the study is conducted according to a commercial IND or a research IND for drug and biologic studies. Academic medical centers that sponsor significant numbers of clinical trials may seek further clarity on this point in any final guidance the FDA issues.
• Data From Outside the United States. Given the global nature of drug and device development, sponsors often seek to use data from studies conducted outside the U.S. in FDA submissions. It is unclear whether or how the FDA will expect Diversity Plans to account for population or condition prevalence outside the U.S., particularly when most or all of the data supporting a marketing application derives from abroad. In submitting comments on this Guidance, sponsors should consider pressing the FDA to engage with foreign regulators, such as the European Medicines Agency, to provide a more harmonized regulatory framework in line with ICH E17.

As with other FDA guidance, this Guidance is non-binding and does not have the force of law. However, the FDA repeatedly emphasizes the importance of the recommendations it puts forth in the Guidance and states that these recommendations merely clarify existing legal requirements. If a sponsor’s recruitment goals are not met despite its “best efforts,” sponsors are expected to discuss with the FDA a plan for collecting the needed data in the post-marketing setting. Therefore, sponsors and other stakeholders should consider how the Guidance may impact their clinical trials and whether to submit any comments or requests for clarification here.