6 ways to bolster FDA’s guidance for diversifying participation in clinical trials

It has been nearly 25 years since the Food and Drug Administration first issued guidance related to racial, ethnic, age, and gender populations underrepresented in clinical trials (see “Timeline: Related prior FDA guidance”). Yet it and other agency guidance and clear documentation of unequal representation have yielded little progress in improving clinical trial diversity.

The FDA’s latest draft guidance on diversity among clinical trial participants, published in April 2022, along with other efforts by the agency and other governmental entities to improve representation in clinical trials, is a welcome step forward.

Increasing the racial and ethnic diversity of clinical trial participants is a scientific and ethical imperative emerging from differences in disease causality, presentation, and progression; in access to health care; and in drug safety and effectiveness across diverse populations.

Released in tandem with a rising, long overdue industry scientific and ethical imperative for more diverse trial participation, the proposed FDA plan has the potential to be a critical propellant for more inclusive research. Within this context of renewed focus on diversity, equity and inclusion, meaningful and sustainable change should not only be mandatory but achievable. And for the first time, this FDA guidance is prescriptive in clearly telling biotech and pharmaceutical companies to come with a plan to FDA meetings.

6 ways to bolster the FDA guidance

We highlight several opportunities to enhance the already strong recommendations included in the FDA’s draft guidance to optimize the development of clinical trials that are as diverse and inclusive as possible, and thus to improve patient outcomes.

Insist on accountability. It is time to move from “should” to “must.” Rather than recommend, we feel FDA should require the development and implementation of enrollment plans centered around increasing diversity for all Phase 2 through 4 trials. In line with the NIH Diverse Trials Act of 2022, any entity seeking public funding through the National Institutes of Health and other agencies should be required to provide a clinical trial diversity plan when applying for funding.

Address health care/access disparities. Require sponsors to provide insight into how their understanding of specific disparities (access to prior treatments, genetic screening and the like) have been integrated into their proposed plans.

Define the meaning of “diverse population.” According to the new FDA guidance, a diverse population is inclusive “of all populations as defined by demographic factors such as race, ethnicity, sex, gender identity, age, pregnancy status, lactation status, and by the presence of certain clinical characteristics such as multiple comorbidities.” Given this broad definition, including nonclinical considerations such as geographical location, socioeconomic status, language, and disability, as well greater specificity related to clinical factors such as concomitant medications, genetic profiles, and organ dysfunction, is important for stakeholders to understand the safety and effectiveness of medical products in real-world settings.

Set enrollment goals. Section V of the guidance states that “Sponsors should define enrollment goals for underrepresented racial and ethnic participants as early as practicable in clinical development for a given indication.” We believe it is important to take this further: enrollment goals should be accompanied by a description of how these goals were determined, including quantitative and qualitative assessments, which helps connect enrollment goals to disease epidemiology.

Set enrollment and retention strategies. In reference to the recommended scope of the guidance, the FDA asks for a description of “specific trial enrollment and retention strategies.” This is a natural opportunity to link to additional previously published agency guidance such as “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs,” as well Section VI of the FDA’s Patient-Focused Drug Development Guidance series, “Managing Barriers to Self-Report,” which provides valuable considerations for engaging individuals from different cultures and/or with different physical, sensory, intellectual, and/or communication capabilities.

Set mistrust within a historical context. We commend the FDA’s recognition of mistrust among populations underrepresented in clinical research via this statement: “In addition, mistrust of the clinical research system may stem from historical events that adversely impacted racial and ethnic minorities, such as the unethical Tuskegee experiments.” But we are concerned that a reference to Tuskegee alone may have a detrimental and even reductionist effect by framing a long history of unethical research practices toward many underserved subpopulations, such as Indigenous and Latinx/Hispanic populations, through a single egregious study. It is important for today’s research community to recognize the multiple historical sources that have generated earned mistrust to build new, more participatory pathways to inclusive research.

Advancing inclusive research is complex, involving genomic intricacies and intersecting social drivers of health. Achieving broader diversity, equity, and inclusion in clinical trials requires nothing less than a universal commitment to diverse, equitable and inclusive research that will lead to better medical treatments for more people.

Nicholas Kenny is the chief scientific officer for Syneos Health, where Keri McDonough is vice president for medical and scientific strategy and heads the Patient Voice Consortium and Stephen Keith is a senior medical director.

Timeline: Related Prior FDA Guidance

• 1998: “Demographic Rule” Regulation in the Code of Federal Regulations (21 CFR 314.50 (d)(5)) that new drug applications (NDAs) must include information by gender (sex), age, and race for trial participation, safety, and effectiveness.

• 1999: The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use’s (ICH) E5 Ethnic Factors in the Acceptability of Foreign Clinical Data requiring  “ethnically sensitive” bridging studies necessary to extrapolate from one region to another.

• 2005: FDA’s Guidance on Data Collection of Race and Ethnicity Data in Clinical Trials requires sponsors to present a summary of safety and effectiveness data by demographic sub-groups for age, gender and race/ethnicity based on Office of Management and Budget’s Directive 15 and census.

• 2012: The Food and Drug Administration Safety and Innovation Act of 2012 mandated that FDA review the adequacy of its existing regulations and processes, develop a report addressing the extent to which demographic subgroups are included in applications submitted to FDA, and develop an action plan based on the findings to advance clinical trial diversity.

• 2014: The FDA publishes the action plan (FDASIA Section 907 Action Plan) mandated in 2012 to enhance the collection and availability of demographic subgroup data.

• 2016: The FDA publishes guidance on “Collection of Race and Ethnicity Data in Clinical Trials”

• 2019: The FDA publishes draft guidance on “Enhancing the Diversity of Clinical Trial Populations” to broaden eligibility criteria, and increase enrollment of underrepresented populations in clinical trials.

• 2020: The FDA publishes its final guidance on “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs.”

• 2022: The FDA publishes draft guidance on “Diversity Plans to Improve Enrollment of Participants From Underrepresented Racial and Ethnic Populations in Clinical Trials” to optimize the development of diverse and inclusive clinical trials.