How to Act on FDA Guidance on Diversity Plans for Clinical Trials
In 2022, the US Food and Drug Administration (FDA) released draft guidance on diversity plans to improve enrolment and retention of underrepresented racial and ethnic minorities in clinical trials. At the end of 2023, Congress acted to make most clinical trial sponsors legally required to submit a diversity action plan to the FDA, once FDA guidance is finalized. In this newsletter, we provide an overview of the history of diversity at the FDA, highlight the key messages from the draft guidance, and review how the CCS team can help overcome some of the challenges implementing this latest guidance.
History of Diversity Efforts at the FDA
Over the past several decades, the FDA has progressively implemented a series of initiatives aimed at enhancing diversity and inclusivity in clinical trials. The journey began in 1998 with the introduction of the "Demographic Rule," a regulation mandating the inclusion of information on gender, age, and race in new drug applications (NDAs) to ensure comprehensive trial participation, safety, and effectiveness assessment. In 1999, the International Council for Harmonisation introduced the E5 guideline, emphasizing "ethnically sensitive" bridging studies for the acceptability of foreign clinical data. A pivotal moment occurred in 2012 with the passage of the Food and Drug Administration Safety and Innovation Act, prompting the FDA to review existing regulations and processes. Subsequently, the 2014 FDASIA Section 907 Action Plan was published to strengthen the collection of demographic subgroup data. In 2016, the FDA provided guidance on the Collection of Race and Ethnicity Data in Clinical Trials. Building on this foundation, the FDA issued draft guidance in 2019 to broaden eligibility criteria and increase enrollment of underrepresented populations. The culmination of these efforts led to the publication of the final guidance on Enhancing the Diversity of Clinical Trial Populations.
The Most Recent Guidance: A Shift to Accountability
With the release of its 2022 draft guidance, Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials, the Agency has signalled a continued commitment to enhancing equity in health research and healthcare.
This latest document aims to provide actionable guidance on how to create plans to enrol representative participants from underrepresented racial and ethnic populations, and specifically to improve representation of 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. While this guidance is aimed at racial and ethnic inequities in health research, it also encourages trial sponsors to include other underrepresented populations defined by demographics, such as sex, gender identity, age, socioeconomic stats, disability, pregnancy status, lactation status and co-morbidity.
This move from the FDA signals a major shift in the Agency’s approach to diversity in clinical trials. Although previous regulations, like the “Demographic Rule”, required trial sponsors to report on demographic data, they did not require changes to how trials were conducted. While this specific guidance is currently nonbinding, Congress recently created a legal requirement for most sponsors of medical and drug trials to submit diversity action plans to the FDA. So, it is reasonable to consider this as a soft launch of regulations. Diversity plans will be legally required several months after the FDA finalizes its guidance.
The recent documentation is intended to provide general guidance; it is not meant to address all issues related to improving trial enrolment of underrepresented racial and ethnic populations. However, it does provide a good starting point for understanding the core components of a strong diversity plan. The FDA guidance outlines five key elements:
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The disease overview should identify key aspects related to the pathophysiology, application of medical interventions, and health disparities within underrepresented racial and ethnic populations in the United States.
Summarize available data on pathophysiology in underrepresented racial and ethnic populations.
Address any differential application of prevention, screening, diagnostics, and treatments across racial and ethnic groups.
Discuss current understanding and evidence of similarities and differences in the disease or condition within underrepresented populations in the United States.
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Scope of Medical Development
Scope of medical development should include a concise overview of the planned trials or studies intended to validate safety, effectiveness. For drugs, this should also include dosage information that will be included in marketing submissions. This section should include:
The study's design, including population and eligibility criteria, endpoints, and expected trial locations.
Discussion of how study design is tailored to enhance the inclusion of underrepresented racial and ethnic populations.
Key pertinent findings from clinical pharmacology studies, such as pharmacokinetic, pharmacodynamic and pharmacogenomic data, that may reveal differential associations with specific racial and ethnic groups.
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The diversity plan should specify and justify goals for enrolment of underrepresented racial and ethnic participants in the trial. This should:
Identify underrepresented racial and ethnic populations based on the epidemiological work done when creating the disease overview.
Lay-out goals for enrolling underrepresented racial and ethnic participants. These goals should be related to disease epidemiology or other information that may change the impact of the intervention for underrepresented groups.
Consider how enrolment goals facilitate or hinder subgroup analyses. Oversampling (i.e., disproportionate representation) of some groups may be needed to enable adequate sample sizes for analysis.
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The diversity plan should provide a detailed description of practical steps that will be taken to enrol and retain underrepresented racial and ethnic participants in trials or studies. The plan should also detail how data collected will be used to determine safety, efficacy and drug dosage (when applicable) in underrepresented groups. Key elements include:
Descriptions of steps taken to improve accessibility of the trial, including language assistance and location considerations
Plans for ongoing engagement with underrepresented communities, such as working with patient groups, community health workers and local healthcare providers
Actions to reduce burden related to trial participation (e.g., allowing telephone vs. in-person assessment when appropriate)
Metrics to assess if enrolment goals are being met
Actionable contingency plans to improve enrolment if metrics show that enrolment goals are not being met
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The diversity plan should be updated with the status of enrolment goals as needed. If the study sponsor is unable to meet the stated enrolment goals, even with the contingency plans implemented, a plan and justification for collecting data post-marketing may be needed.
The Guidance Tells You What, But Not How.
This new guidance is an important step towards improving accountability and representation in clinical trials. The challenge is that it tells you what to do, but now how to do it. For example, the guidance says that study design should be tailored to enhance the inclusion of underrepresented racial and ethnic populations. How to do that, though, is left up to trial sponsors. This work is not simple. Effective tailoring should rely on high quality engagement with members of underrepresented communities well in advance of trial launch. This work can substantially improve recruitment by identifying modifiable factors that impact patient willingness to enrol. For example, a recent study focused on a scleroderma trial that failed to meet its recruitment goals and asked the question, what would recruitment have been if patients had been consulted earlier in the process? The authors used focus groups and quantitative preference elicitation methods from health economics to identify the key factors that influenced patient willingness to participate in the trial. They then looked at how the trial could be modified to improve enrolment. They found that small changes to the trial design, like making treatment available closer to home and reducing the cost of participating, would increase recruitment by more than 50%. These methods can be used not only to improve trial recruitment but also retention.
We Can Help
Working with experts in preference elicitation and patient and stakeholder engagement, like the CCS team, can help you demystify how to make meaningful improvements to your trial design and recruitment processes. Together we can help you have more representative trial enrolment and better evidence to support your intervention. As Congresswoman Anna Eshoo said, “fixing this issue [of underrepresentation] is not only fair and just, its good science.”