In Brief:

• FDA provides detail on the content, format, and timing of sponsors’ diversity plans.

• FDA outlines five elements that should be included in the diversity plan.

• Sponsors now have a roadmap to ensure that their diversity plans are submitted timely and contain the necessary elements to satisfy FDA.

For several years, FDA has advanced a policy of increasing diversity in clinical trial populations. During that time, FDA issued broad policy statements, as well as guidance on improved data collection and steps sponsors could take to increase enrollment of diverse participants. On April 14, FDA went one step further and released draft guidance titled, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” (Draft Guidance). The Draft Guidance is FDA’s first attempt to articulate detailed expectations for submission of a plan by trial sponsors to ensure that clinical trial diversity goals are realized. This article discusses the new recommendations in the Draft Guidance and what sponsors can expect and should consider when developing their diversity plans.

The Need for Diversity in Clinical Trials and FDA’s Increased Focus on Diversity

Racial and ethnic minorities have historically been underrepresented in biomedical research despite bearing a disproportionate disease burden for certain conditions. Obtaining clinical trial data from diverse study populations is vital to ensure that drugs, biologics, and medical devices are safe and effective for all members of the population or — if they are not — that any risks are known as early and fully as possible to prevent patient harm.

FDA began taking substantial steps to increase racial and ethnic diversity in clinical trial populations beginning in the 2010s. First, in 2010, through the Affordable Care Act, FDA established its Office of Minority Health with the goal of reducing health disparities among racial and ethnic minorities.[1] Then, in 2012, Congress passed the Food and Drug Administration Safety and Innovation Act, which directed FDA to examine racial and ethnic subgroup data in applications for drugs, biologics, and medical devices and to publish its findings.[2] In 2014, FDA issued an Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data, prioritizing the improvement of completeness and quality of demographic subgroup data, the identification of barriers to subgroup enrollment in clinical trials and development of strategies to encourage participation, and an increase in availability and transparency of subgroup data.[3] Since then, FDA has issued a number of guidance documents furthering these efforts.

Past FDA guidance on increasing diversity in clinical trials focused on data collection,[4] evaluation and reporting,[5] and strategies for enhancing all types of diversity in clinical trial populations through changes to eligibility criteria, trial design, and enrollment practices.[6] A recurrent theme is the need for sponsors to develop a plan to enroll diverse populations, which should be submitted to FDA for consideration as early as possible in the medical product development process. However, until the recent Draft Guidance, FDA had not provided detail on the content, format, or timing of sponsors’ diversity plans, leaving sponsors with little clarity on how to proceed.

The Draft Guidance Specifies the Contents of Diversity Plans

The Draft Guidance recommends submitting diversity plans for products requiring an Investigational New Drug submission (IND) or an Investigational Device Exemption (IDE) and/or for which clinical trials are intended to support marketing submissions (whether a New Drug Application (NDA), a Biologics License Application (BLA), or, for medical devices, premarket approval (PMAP), 510(k) submission, de novo classification, or humanitarian device exemption (HDE)).[7] The Draft Guidance suggests that sponsors of drug trials should submit their diversity plans as soon as practicable, but no later than when a sponsor is seeking feedback for applicable pivotal trials (usually the End-of-Phase-II meeting).[8] For devices, sponsors should submit diversity plans as part of the investigational plan included in the IDE application.[9] Sponsors should include the diversity plan in their marketing application, as well as a description of the successes and challenges of implementing it.[10]

The diversity plan should include five elements: (1) overview of the disease/condition; (2) scope of the medical product development program; (3) goals for enrollment of underrepresented racial and ethnic participants; (4) a specific plan of action to enroll and retain diverse participants; and (5) status of meeting enrollment goals (as applicable). The overview section should describe the available data on the medical condition in underrepresented racial and ethnic groups, including any disparity in the application of currently available treatment strategies among racial and ethnic populations, as well as a discussion of the similarities and differences in the studied condition associated with underrepresented racial and ethnic populations. The scope section should describe the planned trials and should outline the study design, population, endpoints, and geographic locations and summarize any applicable differential findings from clinical pharmacology studies associated with certain racial and ethnic populations. The goals section should define and justify the planned enrollment of participants from underrepresented racial and ethnic populations, including specifying the underrepresented populations, the goals for enrollment of the underrepresented population, and whether greater than proportional enrollment of certain populations is necessary to identify important differences among populations. The specific plan section should describe the operational measures that will be implemented to enroll and retain underrepresented participants in the planned trials; the specific enrollment and retention strategies, including site location and access, sustained community engagement, and reducing burdens, including the number of study-related procedures, the use of local labs and imaging, and use of telehealth; and the metrics to ensure diverse participant enrollment goals are met and actions to be taken if those goals are not met. The status section should not only discuss the current status of meeting the stated goals, but also should discuss a plan and justification for collecting data in post-marketing if the enrollment goals are not achieved.[11]

Takeaways for Trial Sponsors

Although previous FDA guidance mentioned the need for a diversity plan, sponsors now have a roadmap to ensure that their diversity plans contain the necessary elements to satisfy FDA and are submitted timely.

The Draft Guidance makes it clear that sponsors should have a detailed diversity plan in place early in the process — no later than the End-of-Phase-II meeting (before the large-scale trials of Phase III) for drugs and biologics and as part of the IDE submission for devices. To develop and submit their diversity plans on time, sponsors will have to focus on racial and ethnic diversity early in the planning process, so it is part of the overall clinical strategy and not shoehorned in later.

Sponsors should also know early on how large their participant population and demographic subpopulations will need to be to yield meaningful data and identify important differences between racial and ethnic populations. Sponsors should be prepared to “over-enroll” underrepresented populations in smaller trials to ensure statistically meaningful samples.

Perhaps the most difficult part of the diversity plan will be developing a strategy to ensure sufficient enrollment of underrepresented populations. An effective strategy should consider community outreach and burden reduction. Sponsors should analyze which types of community outreach — both with respect to locations and individuals — are most likely to yield enrollment of the desired population groups. Sponsors should also consider whether subsidizing certain costs will successfully attract more participants from underrepresented populations. In subsidizing costs, sponsors must be careful not to offer inducements in violation of informed consent or the laws relating to beneficiary inducements, including the federal Anti-Kickback Statute. FDA has stated that reimbursement of certain travel expenses and lodging do not raise concerns of undue influence,[12] and the Office of Inspector General (OIG) has issued advisory opinions stating it would not impose administrative sanctions against entities subsidizing participants’ out-of-pocket expenses, including Medicare cost-sharing obligations.[13] Twice in the last year, OIG has specifically cited the sponsor’s goal of increasing diversity among study populations to support its conclusion that it would not pursue sanctions.[14] However, sponsors should be mindful that OIG advisory opinions are limited to the proposed arrangements discussed therein and that factual differences may distinguish sponsors’ planned remuneration from those discussed in the advisory opinions. To the extent that sponsors’ plans include increased enrollment support to investigators, sponsors need to be mindful of the federal Anti-Kickback Statute and similar state laws.

Finally, given the potential difficulties of achieving sufficient diversity in study populations during the clinical phase, sponsors should consider whether and to what extent they should focus on achieving diversity goals in the post-marketing phase, when it may be more feasible to obtain sufficient data on underrepresented populations. If a sponsor intends to rely on post-marketing data, however, FDA has made it clear that the sponsor should have a detailed plan to obtain sufficient data in Phase IV studies and to justify why it could not obtain such data pre-approval.

[1] FDA Rep., FDA Action Plan to Enhance the Collection and Availability of Demographic Subgroup Data at 1 (Aug. 2014) (“Action Plan”), available at https://www.fda.gov/media/89307/download.

[2] See Section 907 of the 2012 Food and Drug Administration Safety and Innovation Act, Pub. L. No. 112-144, 126 Stat. 993, available at https://www.govinfo.gov/content/pkg/PLAW-112publ144/pdf/PLAW-112publ144.pdf.

[3] Action Plan.

[4] See FDA, Guidance for Industry and FDA Administration and Staff, Collection of Race and Ethnicity Data in Clinical Trials (Oct. 2016), available at https://www.fda.gov/media/75453/download..

[5] See FDA, Guidance for Industry and FDA Administration and Staff, Evaluation and Reporting of Age-, Race-, and Ethnicity-Specific Data in Medical Device Clinical Studies (Sept. 12, 2017), available at https://www.fda.gov/media/98686/download.

[6] See FDA, Guidance for Industry, Enhancing the Diversity of Clinical Trial Populations—Eligibility Criteria, Enrollment Practices, and Trial Designs (Nov. 2020), available at https://www.fda.gov/media/127712/download.

[7] Draft Guidance at 5.

[8] Id.at 5-6.

[9] Id. at 6.

[10] Id.

[11] See id. at 7-9.

[12] Draft Guidance at 4 n.12.

[13] See OIG Adv. Op. No. 22-05 (Mar. 16, 2022); OIG Adv. Op. No. 21-17 (Nov. 19, 2021); OIG Adv. Op. No. 21-13 (Oct. 4, 2021); OIG Adv. Op. No. 17-02 (July 7, 2017); OIG Adv. Op. No. 16-13 (Dec. 20, 2016); OIG Adv. Op. No. 15-07 (June 4, 2015).

[14] See OIG Adv. Op. No. 22-05 at 7 (Mar. 16, 2022) (”[T]he cost-sharing subsidies that would be offered under the Proposed Arrangement appear to be a reasonable means to facilitate enrollment of a socioeconomically diverse set of subjects by removing a potential financial barrier to participation in the Study.”); OIG Adv. Op. No. 21-13 at 7 (Oct. 4, 2021) (“The coinsurance subsidies offered under the Proposed Arrangement appear to be a reasonable means to facilitate enrollment of a diverse set of subjects by removing a potential financial barrier to participation in the Study.”).