Sponsors of clinical trials that will be submitted to the FDA should develop and submit a Race and Ethnicity Diversity Plan to the agency early in clinical development, the FDA recommended in draft guidance released April 13.

The draft guidance – Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials – recommends a plan be submitted for medical products for which an Investigational New Drug (IND) Application submission is required and/or for which clinical studies are intended to support a marketing submission under section 351(a) of the Public Health Service Act for a standalone Biologics License Application (BLA), or under 505(b)(1) or 505(b)(2) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) for a New Drug Application (NDA). The FDA also recommends a plan for medical products for which an Investigational Device Exemption (IDE) is required and/or for which clinical studies are intended to support a device marketing submission, whether a premarket notification (510(k)), premarket approval application, a De Novo classification request or a humanitarian device exemption application.

The FDA will evaluate the “plan as an important part of the sponsor’s development program.”

“The U.S. population has become increasingly diverse and ensuring meaningful representation of racial and ethnic minorities in clinical trials for regulated medical products is fundamental to public health,” FDA Commissioner Robert Califf said in announcing the guidance. “Going forward, achieving greater diversity will be a key focus throughout the FDA to facilitate the development of better treatments and better ways to fight diseases that often disproportionately impact diverse communities.”

While the guidance focuses specifically on racial and ethnic demographic characteristics of study populations, the FDA advises sponsors to seek diversity in clinical trial enrollment beyond populations defined by race and ethnicity, including other underrepresented populations defined by demographics such as sex, gender identity, age, socioeconomic status, disability, pregnancy status, lactation status and co-morbidity.

“The FDA encourages sponsors to also submit plans that help ensure the adequate participation of relevant and underrepresented populations and analyses of data collected from clinically relevant subpopulations,” the guidance said.

While sponsors may discuss their strategy to enroll a diverse study population at any time throughout the medical product’s development, the guidance recommends that:

• For drugs, sponsors should submit the plan to the relevant IND application as soon as practicable during drug development but no later than when a sponsor is seeking feedback regarding the applicable pivotal trial(s) for the drug (often at the end of Phase 2 meeting). The Plan can be submitted to the IND as part of a milestone meeting package, or on its own. Sponsors should request FDA feedback on the plan by including specific questions in a formal milestone meeting request and meeting package.
• For devices, sponsors should submit their plan as part of the investigational plan included in the IDE application. To discuss a proposed enrollment strategy before submitting the plan to the IDE or for clinical studies not conducted under an IDE, a sponsor should follow the Q-submission process for obtaining feedback or requesting a meeting with FDA.
• For IND, IDE, or Q-submissions containing a plan, sponsors should alert the FDA by marking the submission with “RACE AND ETHNICITY DIVERSITY PLAN” in large, bolded type in the cover letter. FDA may request that sponsors provide periodic updates to specific components of the plan throughout medical product development.
• Sponsors should include the plan in the marketing application for the medical product as well as a description of the successes and challenges in implementing it.

Regarding the content of the plan, the guidance recommended:

• Sponsors should define enrollment goals for underrepresented racial and ethnic participants as early as practicable in clinical development for a given indication. “These enrollment goals should be based in part on the pre-specified protocol objectives of the investigation. While in many cases race- and/or ethnicity-defined populations may be genetically heterogenous such that analyses to characterize differential effects due to pharmacogenomic variability may be difficult to discern, the plan should begin with an assessment of any data that may indicate the potential for a medical product to have differential safety or effectiveness associated with race or ethnicity.”
• For drug development, as applicable to the particular drug, the collection of sufficient pharmacokinetic (PK), pharmacodynamic (PD) and pharmacogenomic data from a diverse population is strongly encouraged to inform analyses of drug exposure and response.
• For devices, data on the relevant factors for device performance (e.g., phenotypic, anatomical or biological) should be collected to inform any differential effects across a diverse population. “For example, variations in skin pigmentation exist across diverse populations and it is known that skin pigmentation can affect the performance of certain devices,” the guidance said. “For studies of such devices (e.g., pulse oximeters), skin pigmentation data in a diverse population would be a relevant attribute to collect to inform the assessment of any differential effects.”
• The plan should describe the planned assessment of race and ethnicity in addition to other covariates with known potential to affect the safety and effectiveness of the medical product. In particular, for drugs, covariates with known potential to affect PK and PD should be assessed in order to aid exposure-response analyses and to inform safe and effective dosing regimens across the intended patient population, as applicable. For devices, device performance may be impacted by factors associated with race (e.g., the ability of a device to detect skin cancer based on skin pigmentation).
• When there are data that indicate that the medical product may perform differentially across the population based on factors associated with race or ethnicity, the plan should specify the study design features that will support analyses that will inform the safety and effectiveness of the medical product in the relevant racial and ethnic populations. “In some cases, increased (i.e., greater than proportional) enrollment of certain populations may be needed to elucidate potential important differences. When there are no data that indicate that race or ethnicity will impact safety or effectiveness, it is nonetheless appropriate that enrollment reflects the epidemiology of the disease,” the guidance said. The FDA also recognized that enrollment based on epidemiology alone may not be sufficient to detect any differences in safety and effectiveness or make such inferences; however, consistent representative enrollment may provide opportunities for pooling data to evaluate outcomes by race and ethnicity.
• The plan should outline the sponsor’s plan to collect data to explore the potential for differences in safety and/or effectiveness associated with race and ethnicity throughout the entire development life cycle of the medical product and not just during the pivotal trial(s) or studies.
• “In certain situations, it may be challenging to set an enrollment goal based on the epidemiology of the disease due to limited data to characterize the incidence and/or prevalence of the disease across diverse racial/ethnic populations (e.g., diseases that are defined by the presence of a rare molecular aberration),” the guidance said. The FDA encouraged sponsors to leverage various data sources (e.g., published literature and real-world data) to set enrollment goals; if this is not feasible, it may be appropriate to set the enrollment goal based on demographics in the overall population with the disease or condition.
• The plan should include the clinical pediatric studies that are planned for inclusion as part of the pediatric development of the medical product.

The recommended elements of a plan are:

• Overview of the disease/condition – describe available data on the pathophysiology of the disease or condition in underrepresented racial and ethnic populations. As appropriate, describe any differential application or use of currently available prevention, screening or diagnostic strategies and treatments, across racial and ethnic populations. Discuss the current understanding of and available evidence supporting any similarities and/or differences in the disease or condition under study that are associated with the underrepresented racial and ethnic populations in the United States.
• Scope of medical product development program – briefly describe the planned trials or studies that will support the medical product’s safety, effectiveness and, if a drug, dosage in a future marketing submission. Outline the following: study design, study population (including study eligibility criteria), endpoints, and the expected geographic locations of the trials or studies and how these aspects of the trial or study may specifically address inclusion of underrepresented racial and ethnic populations and as applicable, summarize any differential findings from clinical pharmacology studies (PK /PD data, pharmacogenomics) that may be associated with certain racial and ethnic populations and/or other relevant information.
• Goals for enrollment of underrepresented racial and ethnic participants – define and provide justification for the planned enrollment of subjects from underrepresented racial and ethnic populations. Specify underrepresented racial and ethnic populations. Specify goals for enrollment of underrepresented racial and ethnic subjects (e.g., based on the epidemiology of the disease and/or based on a priori information that may impact outcomes across racial and ethnic groups; and where appropriate, leverage pooled data sources or use demographic data in general population). In some cases, increased (i.e., greater than proportional) enrollment of certain populations may be needed to elucidate potential important differences.
• Specific plan of action to enroll and retain diverse subjects – describe in detail the operational measures that will be implemented to enroll and retain underrepresented racial and ethnic subjects in the planned trial(s) or studies, and the planned use of data to characterize safety, efficacy and optimal dosage in these subjects, when applicable. Describe specific trial enrollment and retention strategies, including but not limited to: 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.); reducing burdens due to trial/study design/conduct (e.g., number/frequency of study-related procedures, use of local laboratory/imaging, telehealth). Describe metrics to ensure that diverse participant enrollment goals are achieved and specify actions to be implemented during the conduct of the trial(s) or studies if planned enrollment goals are not met.
• Status of meeting enrollment goals (as applicable) – as the diversity plan is updated (when applicable), discuss the status of meeting enrollment goals. “If the sponsor is not able to achieve enrollment goals despite best efforts, discuss a plan and justification for collecting data in the post-marketing setting,” the guidance recommended.

The draft guidance was developed by the FDA Oncology Center of Excellence’s Project Equity, which aims to ensure that the data submitted to the agency for approval of oncology medical products adequately reflects the demographic representation of participants for whom the medical products are intended. As the guidance applies to all medical products, the Center for Drug Evaluation and Research, the Center for Biologics Evaluation and Research and the Center for Devices and Radiological Health also contributed to the collaborative effort.