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Abstract

Since 2016, the FDA has released various guidance documents intended to promote diversity in clinical trials—particularly regarding recruitment of trial participants—and the agency’s diversity commitments are only expected to grow. As such, entities sponsoring and designing clinical trials must be proactive in ensuring that protocol inclusion and exclusion criteria do not inadvertently exclude diverse populations (absent scientific justifications).

Moreover, as technology advancements continue to reshape the clinical trial landscape, entities should increasingly explore the use of decentralized trial models, telemedicine, and remote technology for extended outreach and inclusion of diverse populations. This article thus highlights the key takeaways of several FDA diversity-related guidance documents from 2016 onwards; outlines the potential for decentralized models and digital health technology to expand diversity in trials; and informs sponsors on the need to be aware of future guidance documents that will be released over the coming years.

Background

Individuals within in the United States differ by sex, age, race, ethnicity, location, economics, and many other characteristics, while different groups within these populations may respond to medications in different ways. For these reasons, the FDA recognizes that it is important that clinical trial inclusion criteria (explained in greater detail below) seeks representatives of the different groups who will use these medications to provide data on the safety and efficacy for these diverse groups.

The FDA’s commitment to increasing diversity in clinical trials is clear and evidenced by guidance it issued within the past decade. Indeed, since October 2016, the FDA has released various guidance documents intended to promote and increase diversity in clinical trials, and with a focus on the recruitment of diverse clinical trial participants.

The focus of the FDA’s diversity efforts is often on clinical trial participant eligibility criteria. In conducting a clinical trial, a sponsor must determine which individuals are “eligible” to participate, while determinations as to eligibility criteria are generally based on the purpose and type of the clinical trial to be performed and the investigational product. The exclusion of certain populations from a trial is often an unintended consequence of setting eligibility criteria, without scientific justification. Accordingly, FDA guidance over the years includes a focus on how to increase participant diversity.

FDA Diversity Guidance: Looking Back

October 2016 - Collection of Race and Ethnicity Data in Clinical Trials Guidance

In 2016, then FDA Commissioner, Robert Califf, MD, declared that 2016 was the “Year of Clinical Trials Diversity” and in October of that year, the FDA issued a guidance outlining expectations and recommendations regarding the standardized approach for collection and reporting of race and ethnicity data in clinical trials. The October 2016 guidance document, “Collection of Race and Ethnicity Data in Clinical Trials Guidance for Industry and Food and Drug Administration Staff,”¹ was issued in response to the Office of Management and Budget (OMB) Statistical Policy Directive 15, Revisions to the Standards for the Classification of Federal data on Race and Ethnicity. The guidance set forth FDA expectations for, and recommendations on, use of a standardized approach for collecting and reporting race and ethnicity data in submissions for clinical trials.

Further, the 2016 guidance lists the OMB categories for race and ethnicity and describes FDA's reasons for recommending the use of the categories in medical product (drugs, biologics, and devices) applications. As later discussed herein, the FDA reaffirmed its commitment to diversity and inclusion, and with respect to standards for the collection and reporting of race and ethnicity data via a 2024 draft guidance, which is intended to replace the 2016 guidance.

November 2020 - Enhancing the Diversity of Clinical Trial Populations - Eligibility Criteria, Enrollment Practices, and Trial Designs

Continuing its focus on diversity in clinical trials, in November 2020, the FDA issued a guidance document titled, “Enhancing the Diversity of Clinical Trial Populations - Eligibility Criteria, Enrollment Practices, and Trial Designs,”² which focuses on sponsors and provides four sets of recommendations that can be applied in clinical trial design to ensure participants are diverse.

In issuing the guidance, the FDA satisfied the mandate under section 610(a)(3) of the FDA Reauthorization Act of 2017 (FDARA) (21 U.S.C. 360bbb note). Consistent with the FDARA mandate, the guidance discusses: (1) broadening eligibility criteria and avoiding unnecessary exclusions for clinical trials; (2) developing eligibility criteria and improving trial recruitment so that the participants enrolled in trials will better reflect the population most likely to use the drug if it is approved, while maintaining safety and efficacy standards; and (3) applying the recommendations for broadening eligibility criteria to clinical trials of drugs intended to treat rare diseases or conditions. The guidance also notes that sponsors should design clinical trials in ways to achieve participant diversity.

Examples of FDA recommendations to sponsors on how to improve diversity include:

• Sponsors should work to ensure that eligibility criteria serve the goal of having a representative sample of the population for whom the drug has been developed and examine each exclusion criterion to determine whether it is needed to help assure the safety of trial participants or to achieve the study objectives.
• Sponsors should enroll participants who reflect the characteristics of clinically relevant populations with regard to age, sex, race, and ethnicity and can seek to do so via (1) inclusion of children and adolescents in confirmatory clinical trials involving adults when appropriate, (2) inclusion of women in adequate numbers to allow for analysis by sex, and (3) inclusion of racial and ethnic minorities and the analysis of clinical trial data by race and ethnicity.
• Broadening eligibility criteria using enrichment strategies³ and should work to make trial participation less burdensome for participants. The FDA highlights use of telemedicine in trials and states: “During the study design phase, consider the recruitment challenges that may occur because of the planned visit schedule and difficulties with accessibility (including for individuals with disabilities) to trial sites: reduce the frequency of study visits to those needed to appropriately monitor safety and efficacy, and consider whether flexibility in visit windows is possible and whether electronic communication (e.g., telephone/mobile telephone, secured electronic mail, social media platforms) or digital health technology tools can be used to replace site visits and provide investigators with adequate real-time data. Consider the use of mobile medical professionals, such as nurses and phlebotomists, to visit participants at their locations instead of requiring participants to visit distant clinical trial sites.”⁴
• Adopt enrollment and retention practices that enhance inclusiveness. Sponsors should implement more inclusive strategies for public outreach and education, including incorporating patient-focused research into clinical trial design.

April 2022 - Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials

Following the November 2020 guidance, in April 2022, the FDA released the draft guidance titled “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials Guidance for Industry.”⁵ The guidance recommends sponsors develop a Race and Ethnicity Diversity Plan to assist in enrolling underrepresented racial and ethnic populations in clinical trials.

Specifically, the draft guidance expands on the 2016 guidance and provides recommendations to sponsors on the approach for developing a Race and Ethnicity Diversity Plan “to enroll representative numbers of participants from underrepresented racial and ethnic populations in the United States, such as Black or African American, Hispanic/Latino, Indigenous and Native American, Asian, Native Hawaiian and Other Pacific Islanders, and other persons of color, in clinical trials.”⁶

The draft guidance contains a table with suggested elements of a diversity plan and outlines the content of such plans, which includes:

• Sponsors should define enrollment goals for underrepresented racial and ethnic participants as early as practicable.
• The plan should describe the planned assessment of 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.⁷

Food and Drug Omnibus Reform Act of 2022

Many of the recommendations in the April 2022 draft guidance are identical to the requirements set forth in the FDORA. At the end of 2022, as part of the Consolidated Appropriations Act, Congress passed the FDORA, which requires sponsors to submit diversity action plans to the Secretary of the Department of Health and Human Services (HHS) for any Phase III or other pivotal drug study and most device studies.

The requirement for diversity plans in the FDORA include identifying enrollment goals for subsets of the population by group, sex, racial and ethnic characteristics, rationale for these enrollment goals, and any relevant strategies on how the sponsor plans on how to reach those enrollment goals. Pursuant to FDORA, the FDA must issue updated draft guidance on Diversity Action Plans.

Recent FDA Guidance and Action – January 2024 Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products

In January 2024, the FDA released the draft guidance document “Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products Guidance for Industry.”⁸ The guidance was mandated as part of FDORA regarding the collection of race and ethnicity data in clinical trials. Once finalized, this guidance will replace the 2016 FDA guidance regarding collection of race and ethnicity data.

The guidance provides that using standard terminology for race and ethnicity helps ensure that data are collected and reported consistently in submissions to the FDA. The agency’s recommended approach is based on the OMB Statistical Policy Directive No. 15 (Policy Directive 15) and was developed in accordance with section 4302 of the Affordable Care Act; HHS Implementation Guidance on Data Collection Standards for Race, Ethnicity, Sex, Primary Language, and Disability Status; and the 25 Food and Drug Administration Safety and Innovation Act (FDASIA) Section 907 Action Plan.⁹

The draft guidance provides recommendations on: (1) meeting the requirements set forth in the 1998 final rule regarding presentation of demographic data in investigational new drug applications and new drug applications; (2) the collection of race and ethnicity data in biologics license applications and medical device applications; and (3) addressing the FDASIA Section 907 Action Plan to improve the completeness and quality of demographic data collection and reporting.¹⁰

The FDA recommends that trial participants be requested to self-report race and ethnicity information, with participants being permitted to designate a multiracial identity. While such data may be available in a trial participant’s medical record, the FDA states that race and ethnicity should not be assigned by the study team conducting the trial and recommends that investigators and/or other clinical study staff verify the accuracy of the information provided in the medical record with the study participant.¹¹

With respect to participant self-reporting, similar to the 2016 guidance and to remain consistent with OMB Policy Directive 15, the FDA recommends using a two-question format for requesting race and ethnicity information, with the ethnicity question preceding the question about race:

1. Are you Hispanic/Latino or not Hispanic/Latino?

2. What is your race?

With respect to race, the FDA recommends the following, minimum, choices be offered: American Indian or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific Islander; and White.¹² The FDA also encourages sponsors to provide detailed breakdowns when multiple responses are selected or at a minimum to note that “more than one race” was reported. Where appropriate, the FDA recommends using more-detailed categories by geographic region to provide sponsors flexibility in characterizing race and ethnicity.

Moving Forward: The Use of Decentralized Clinical Trials (DCTs) and Digital Health Technology

As the emphasis on encouraging diverse populations to participate in clinical trials increases, sponsors should use all tools available to them to help increase diverse recruitment. One such tool is the use of DCTs (either a wholly or partially decentralized model) for sponsors to help fulfill these obligations. In May 2023, the FDA released the draft guidance “Decentralized Clinical Trials for Drugs, Biological Products, and Devices - Guidance for Industry, Investigators, and Other Stakeholders”¹³ regarding the implementation of DCTs.

DCTs are clinical trials in which some or all trial-related activities occur at locations other than traditional clinical trial sites. In the 2023 DCT guidance, FDA recognizes that use of decentralized elements, such as conducting follow-up visits in a participant’s home or via telemedicine, increases the convenience of such activities for research participants and can assist in diversity efforts.

A key element in the draft guidance centers around sponsor responsibilities for striving toward diversity and inclusiveness in their trial populations. The guidance specifies that sponsors engaging in outreach through local health care institutions may facilitate recruitment of participants in areas where there are limited or no traditional clinical trial sites that may increase diversity.

The focus on diversity is highlighted by a press release announcing the guidance, which specifically highlights the value of DCTs in regard to enhancing diversity. In the release, Commissioner Califf stated:

Additionally, in the design of clinical trials, including DCTs, sponsors should consider the incorporation and use of digital health/telemedicine technologies in trials. The FDA has provided guidance on use of such technologies in clinical trials and notes their usefulness in reaching diverse populations previously not easily accessible.¹⁴

Looking Ahead: What Sponsors Need to Know

Sponsors should be aware that the FDA’s focus on expanding diversity in clinical trials will not disappear any time soon. Instead, we expect the FDA’s focus on the issue to only intensify.

As a result, we recommend sponsors do their best to comply with FDA recommendations outlined in this article and in the FDA’s guidance documents. Even though the recent FDA documents are purely draft documents, sponsors should aim to comply with these recommendations so they are better prepared to comply with the final guidance when it is released.

Finally, sponsors should be aware that additional final guidance is likely to be announced over the next few years, including final guidance regarding diversity action plans. Sponsors must be ready to quickly implement these recommendations.

References

1. See FDA Guidance Document “Collection of Race and Ethnicity Data in Clinical Trials Guidance for Industry and Food and Drug Administration Staff “ October 2016”; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/collection-race-and-ethnicity-data-clinical-trials

2. See FDA Guidance Document “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry” November 2020; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/enhancing-diversity-clinical-trial-populations-eligibility-criteria-enrollment-practices-and-trial

3. Enrichment is a trial design strategy in which there is a targeted inclusion of certain populations, with the goal of more readily demonstrating the effect, if any, of the drug. See Id.

4. See Id.

5. See FDA draft Guidance “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials Guidance for Industry” April 2020; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/diversity-plans-improve-enrollment-participants-underrepresented-racial-and-ethnic-populations

6. See Id.

7. See Id.

8. See FDA draft Guidance “Collection of Race and Ethnicity Data in Clinical Trials and Clinical Studies for FDA-Regulated Medical Products Guidance for Industry” January 2024; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/collection-race-and-ethnicity-data-clinical-trials-and-clinical-studies-fda-regulated-medical

9. See Id.

10. See Id.

11. See Id.

12. See Id.

13. See FDA draft Guidance “Decentralized Clinical Trials for Drugs, Biological Products, and Devices - Guidance for Industry, Investigators, and Other Stakeholders” May 2023; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/decentralized-clinical-trials-drugs-biological-products-and-devices.

14. See FDA Guidance “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations” December 2023; https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations; See FDA Digital Health Technologies (DHTs) for Drug Development, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/digital-health-technologies-remote-data-acquisition-clinical-investigations.