Part 1: A Brief History

Are you a sponsor or working with a sponsor developing a drug or biologic product under a US IND?
[Yes] – Are you developing your phase 3 protocol?
[Yes] – Are you developing a Diversity Action Plan for your phase 3 study?

Diversity Action Plans will soon be required for phase 3 clinical trials and other pivotal studies of drugs and biological products conducted in the US. Are you ready for this requirement?

As highlighted by FDA, Diversity Action Plans are intended to increase enrollment of participants who are members of historically underrepresented populations in clinical studies to help improve the strength and generalizability of the evidence for the intended use population. To achieve this, sponsors must now develop and define specific goals for enrollment of underrepresented populations into applicable clinical studies.  The requirement to submit a Diversity Action Plan will be in force when FDA publishes final guidance for these plans. FDA took a step in that direction by issuing draft guidance in June 2024.

A Brief History:

Over the past 4 decades, the US FDA has been gradually focusing attention on participant diversity in clinical trials, dating back to the late 1980s and early 1990s with an initial focus on increasing the participation of women in clinical trials. Throughout the early 2000s, FDA’s efforts related to diversity evolved into expectations that sponsors enroll participants who reflect the demographics for clinically relevant populations with regard to age, gender, race, and ethnicity, as expounded upon in FDA’s “Guidance for Industry: Collection of Race and Ethnicity Data in Clinical Trials”, issued in 2016.

The primary aim of the 2016 Guidance was to provide a minimum standard for maintaining, collecting, and presenting data on race and ethnicity, to enable a common framework for uniformity and consistency in the collection and use of data on race and ethnicity when reported in US INDs and marketing applications submitted to FDA. However, this guidance did not explicitly address the level of participation of racial and ethnic groups (i.e., enrollment goals) in clinical trials. Instead, it directed sponsors to consult with the FDA review division for guidance related to the level of participation or the size of a trial as part of discussions of clinical trial design prior to the start of a trial.

After the 2016 Guidance, FDA approached the topic of enrollment goals for underrepresented populations in a somewhat stepwise manner, initially focusing on eligibility requirements and enrollment practices in the November 2020 “Guidance for Industry: Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs”. Referring to previous FDA and ICH guidances for inclusion of clinically relevant populations, older adult populations, pregnant women, and participants with rare diseases, this Guidance provided recommendations for developing and broadening eligibility criteria and improving recruitment that sponsors could take to increase enrollment of underrepresented populations in clinical trials.

A year and a half later, in April 2022, FDA for the first time issued guidance stating that sponsors should define enrollment goals for underrepresented racial and ethnic participants as early as practical in clinical development. The “Draft Guidance for Industry: Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials” provided recommendations to sponsors developing medical products regarding the development of a Race and Ethnicity Diversity Plan to enroll representative numbers of participants from underrepresented racial and ethnic populations in the United States. Per this draft guidance, the Diversity Plan should:

• specify underrepresented racial and ethnic populations based on assessments of the disease or condition
• define specific goals for enrollment of the identified underrepresented populations
• provide a specific plan of action to enroll and retain underrepresented racial and ethnic participants in the planned trials, with status updated regarding meeting enrollment goals.

However, at the time this draft guidance was issued in April 2022, although FDA provided recommendations regarding diversity plans, such plans were not a regulatory or statutory requirement. That changed with the passage of the Food and Drug Omnibus Reform Act of 2022 (FDORA), which added additional sections to the Federal Food, Drug, and Cosmetic Act requiring sponsors to submit Diversity Action Plans for certain clinical studies. This applies to phase 3 clinical studies, other pivotal clinical studies of a drug or biological product, and certain device studies. Thus, for the first time, submitting a diversity plan with specific enrollment goals for underrepresented populations is now a statutory requirement.

What are the Diversity Action Plan Requirements?

Per the Act, the requirements to submit a Diversity Action Plan apply to clinical studies for which enrollment begins 180 days after publication of the final guidance by FDA. FDA moved this requirement a step closer in June 2024 by issuing the Draft Guidance for Industry: Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies. This draft guidance, which replaces the previous April 2022 draft guidance noted above, is currently open for comments under FDA’s Docket Management system, with a deadline of 26 September 2024 for any comments from interested parties. Sponsors need to assume that FDA will finalize the new guidance in a timely manner, thus triggering the requirements for submission of a Diversity Action Plan for the applicable clinical trials.

Per the June 2024 Draft Guidance, a Diversity Action Plan must include:

• goals for enrollment in the clinical study, disaggregated by race, ethnicity, sex, and age group of clinically relevant study populations
• rationale for enrollment goals
• explanation of how the sponsor intends to meet enrollment goals

The Diversity Action Plan should be succinct, generally not exceeding 10 pages in length, excluding references.  For drugs and biological products, sponsor must submit the plan to the IND no later than when the sponsor submits the protocol to FDA for the applicable clinical study. FDA recommends submission of the Diversity Action Plan when a sponsor is seeking feedback regarding the clinical study design (for example, at an End-of-Phase meeting).

Sponsors should begin preparing now for the forthcoming requirement to prepare and submit a Diversity Action Plan for phase 3 and other pivotal studies.  The preparation of a Diversity Action Plan will require collaboration with an integrated team developing the protocol and overall clinical feasibility and conduct strategy. Ranging from initial feasibility questionnaire development and identification of sites that are engaged with underserved populations in their communities, to the active tracking of diversity metrics throughout the enrollment of your study, a sound operational strategy is key in positioning yourself to achieve your diversity goals for your program. Our regulatory and clinical trial feasibility experts at Rho can help you prepare Diversity Action Plans for your clinical trials.

In future blog posts, we’ll cover some considerations to develop Diversity Action Plans in compliance with FDA’s draft guidance, and we will also provide updates as FDA moves forward with finalizing the guidance and the Diversity Action Plan requirements go into effect, so check back for more information to support your pivotal clinical program.

Kevin Barber, PhD, RAC, PMP, Senior Vice President, Regulatory Strategy & Submissions, has more than 20 years of experience in regulatory affairs and product development, working for both sponsor companies and CROs, across all stages of development from pre-clinical through product launch and post-approval life cycle management. He has led the preparation and execution of integrated regulatory strategy and clinical development plans for drug, biologic, and medical device products in therapeutic areas including dermatology, nephrology, urology, women’s health, CNS/neurology, cardiovascular diseases, virology, oncology, immunology, infectious diseases, blood products, and gene therapy. Dr. Barber has significant experience preparing and filing regulatory submissions, including more than 45 US INDs and more than 40 marketing applications in the US, Canada, Europe, Latin America, Australia, and New Zealand. He also has experience with medical device and in vitro diagnostic development programs and regulatory submissions including pre-IDE meetings, IDEs, 510(k)s, and PMAs.

Genna Kingon, PhD, RAC, Senior Director, Regulatory Strategy oversees regulatory strategy and submissions management from pre-IND to post-approval, with more than a decade of experience in regulatory strategy and project management and more than 16 years of experience in scientific writing. Her experience includes leading and contributing to multidisciplinary teams for global marketing application development for submission to regulatory authorities. Dr. Kingon’s experience also includes serving as the program director leading multidisciplinary teams in the strategy, management, and development of INDs/IDEs and associated marketing application activities for a portfolio of related products. In addition, she provides regulatory and management oversight as an advisor on several programs in a variety of indications from pre-IND/IDE/CTA to marketing application submissions.

Michael Pace, PhD, Director, Global Feasibility & Study Start Up, has more than 9 years of experience within the academic and clinical research sectors, with an exclusive focus on global and strategic clinical trial feasibility within the last 4 years. He provides extensive experience in integrating critical strategic and data elements into clinical trial strategies, including but not limited to disease background, competitive trial landscapes, epidemiology, standard of care, country experience, enrollment rate assessments, and recruitment projections. Dr. Pace has strategic feasibility experience across a variety of therapeutic areas, including neurology, psychiatry, rare disease, oncology/hematological malignancies, cardiovascular, renal/metabolic, and medical device.