FDA recommends the submission of a Plan for all medical products for which an IND submission is required or for which clinical studies are intended to support a marketing submission under section 351(a) of the PHSA, or under 505(b)(1) or 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for an NDA. A Plan is also recommended for medical products for which an IDE is required or for which clinical studies are intended to support a device marketing submission (i.e., a 510(k) premarket notification, a PMA application, a De Novo classification request, or an HDE application).

FDA’s recommendations arrive at a time in which several bills focused at clinical trial diversity have been recently introduced in Congress. Although the proposed bills take a variety of approaches, at least one pending bill directs FDA to issue regulations requiring sponsors to submit diversity plans to the agency and mandate post approval surveillance for sponsors who fall short of diverse enrollment goals. In issuing this draft guidance, FDA has articulated an ambitious framework in the absence of legislative action or notice and comment rulemaking that aims to make clinical trial sponsors take more intentional steps towards achieving research diversity in their studies.

The draft guidance builds upon the November 2020 final guidance, “Enhancing the Diversity of Clinical Trial Populations: Eligibility Criteria, Enrollment Practices, and Trial Designs,” and the October 2016 final guidance, “Collection of Race and Ethnicity Data in Clinical Trials.” In these previous documents, FDA provided recommendations to sponsors on strategies to increase enrollment of underrepresented racial and ethnic populations, collect and present race and ethnicity data to the agency, and develop and submit a plan to address the inclusion of clinically relevant populations for discussion with the agency.

FDA cites health care access inequities, racism, and historical mistrust of the clinical research system as reasons for the absence of underrepresented racial and ethnic populations in clinical research. Notably, FDA also highlights that “increasing reliance” on small studies, intermediate endpoints, and other methods to expedite approval of medical products underscores the “importance of prospectively defining the approach to generating data for a broader and more diverse population early in the development program.”

The draft guidance outlines the content of five elements recommended for inclusion in the Plan:

• Scope of Medical Product Development Program. Sponsors should describe the planned trials for the program. This section of the Plan would include outlines of the proposed studies and how the inclusion of underrepresented racial and ethnic populations would be addressed.

• • Where data indicate that the product may perform differently across the population based on racial and ethnic factors, the Plan should specify study design features that will support analyses to inform the safety and effectiveness of the product in relevant racial and ethnic populations.

• Defined Enrollment Goals. Sponsors should define enrollment goals for underrepresented racial and ethnic participants based on the epidemiology of the disease and a priori information that may impact outcomes across racial and ethnic groups. The authors note that in some cases greater than proportional enrollment of certain populations may be needed to study potential important differences.

• Specific Enrollment and Retention Strategies. The Plan should detail the specific plan of action and strategies to enroll and retain diverse participants throughout the trial, including site selection and access considerations, community engagement efforts, and plans to reduce access burdens due to the design and conduct of the study.

• Status of Meeting Enrollment Goals. As the Plan is updated and the study proceeds, sponsors will also discuss the status of the enrollment goals with FDA. If the enrollment goals are not met, sponsors may be expected to discuss a plan and justification for collecting relevant data in the post-marketing setting.

The Plan should also outline the sponsor’s proposed approach to collecting data to explore the potential differences in the drug’s safety and effectiveness associated with racial and ethnic backgrounds throughout the product’s life cycle, and plans for pediatric studies that include racial and ethnically diverse populations as part of the medical product development program.

Although the guidance document is directed at enrollment of underrepresented ethnic and racial groups, the authors also encourage sponsors to create plans to ensure adequate enrollment of other relevant and underrepresented populations defined by demographics (e.g., sex, gender identity, disability, pregnancy status). It is not clear whether future guidance documents may be issued to more strongly recommend the inclusion of diversity plans for these other populations.

Timeline

FDA will consider the Plan “as an important part of the sponsor’s development program.” For drug sponsors, FDA recommends that sponsors submit and discuss the Plan with FDA as soon as practicable, but no later than the End of Phase 2 meeting in which the sponsor seeks feedback regarding the applicable pivotal trial(s) for the drug. Sponsors are also expected to submit a formal meeting request to FDA to discuss the Plan at the time of submission. For devices, sponsors should submit the Plan as part of the investigation plan included in the IDE application, or if an IDE submission is not required because the device is non-significant,[1] then the Plan may be submitted to FDA in a Q-submission. Notably, the guidance document does not advise sponsors of non-significant risk device studies, who may not otherwise interact with the agency prior to the marketing application, whether it is recommended to present the Plan to FDA in a Q-submission prior initiating the trial.

Sponsors should also include the Plan in the marketing application for the medical product along with a description of the successes and challenges in implementing it.

When finalized, the draft guidance will be non-binding, which raises the question as to whether FDA will take action against sponsors who fail to submit a Plan. Nonetheless, it announces to industry that FDA intends to more closely scrutinize the makeup of study populations throughout the clinical development program for drugs and devices. The comment period for the draft guidance will close on June 13, 2022.