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FDA Clinical Trial Diversity Action Plan Guidance – What Does it Mean?

Exploring the FDA’s new guidelines to enhance diversity in clinical trials and their impact on the pharmaceutical industry.

At its core, clinical research brings new treatments and cures to patients who need them; however, genetic variations can influence drug responses. Pharmacogenetic research has revealed substantial differences among racial and ethnic groups in how they metabolize drugs and the side effects experienced. Unfortunately, problematic race-based algorithms are still being used, which could be harming people of color.

To ensure that new medical innovations are safe and effective for all people, clinical trials must be representative of the drugs and treatments who will ultimately consume them.

Algorithms must be updated and if possible, unconscious bias removed from programming. As an industry, we are not meeting the objective for underrepresented non-white patients in clinical trials to ensure safety and efficacy. 

Today black individuals constitute 8 percent of clinical trial participants, even though they make up 13 percent of the total U.S. population. On the other hand, Hispanic and Latino individuals account for just 11 percent of participants, despite representing 19 percent of the total U.S. population.

Much has been documented as to the cause of this persistent disparity which has left underrepresented populations cynical about medicine and resistant to research. Unethical cases such as the Tuskegee Study of Untreated Syphilis in Black Men and Henrietta Lacks put a spotlight on building awareness and restoring trust. On the other hand, access issues, be it the time it takes to participate in clinical trial visits and the resulting non-medical costs which arise from transportation, and/or missing work, can impact certain races and ethnicity groups more than others.

2020: the tide turns

While the Food and Drug Association (FDA) has promoted enrollment practices intended to broaden diversity, equity and inclusion, certain groups continue to be underrepresented in many trials. In 2020, the FDA issued, and ultimately finalized, “Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices and Trial Designs Guidance for the Industry.” While non-binding, the document included numerous approaches sponsors could use to facilitate the enrollment and retent broader cross-sections of the American population.

As a follow up, the FDA issued subsequent guidance in April 2022 entitled, “Diversity Plans to Improve Enrollment of Participants from Underrepresented Racial and Ethnic Populations in Clinical Trials – Guidance for Industry.” With this document, the FDA took a major step forward to outline specific actions industry should take, specifically for phase III studies, to improve the data it receives about patients who may potentially use a medical product. Components included a comprehensive Diversity Plan for each study drug, with goals for enrollment by race, ethnicity, sex and age. Additionally, it necessitated a specific plan of action for enrolling and retaining diverse participants, such as reducing financial burden through reimbursement or providing transportation, and providing language access to participants with limited English language proficiency.

In late 2022, Congress granted FDA new authority to require Diversity Action Plans (DAPs) for certain clinical studies through FDORA, or the Food and Drug Omnibus Reform Act. FDORA instructed the FDA to issue guidance on the “form and content” of DAPs; in 2024, this came to fruition.

Taking the next step in advancing diversity in clinical trials

Today, the clinical trial space is all a buzz over the much anticipated follow up draft guidance issued by the FDA entitled, “Diversity Action Plans to Improve Enrollment of Participants from Underrepresented Populations in Clinical Studies.” Published on June 24, 2024, the draft guidance is supported by the Oncology Center of Excellence (OCE), Center for Biologics Evaluation and Research (CBER), Center for Drug Evaluation and Research (CDER), Center for Devices and Radiological Health (CDRH), Office of Minority Health and Health Equity (OMHHE), and Office of Women’s Health (OWH). 

As per regulatory requirements, the FDA will accept questions and comments on the draft guidance by the general public and regulatory teams until September 26, 2024, which is three months from the date of release. Taking advantage of the commenting period, is an excellent opportunity for the industry to weigh in on the DAP Guidance Document, which the FDA expects the industry to adopt to improve awareness and access for trials.

Within the first week of release, over 100 comments were submitted by individuals, sponsors, CROs, and various associations and foundations. Reviewing the comments provides insight into what others are feeling about the Diversity Action Plan (DAP) draft guidance.

Once the commenting period is over, the FDA will work on addressing the comments. This may take months for the FDA to review and respond to comments. Once that is done, however, all comments and the FDA responses will be published in the preamble of the Federal Register announcement when the draft will be made final.

In the FDA news release for the DAP, FDA Commissioner Robert M. Califf, M.D., expressed the importance of the draft and that it was just one step towards addressing the underrepresented populations in clinical trials. He also noted that the guidance will improve the collection of race and ethnicity data.
 

A powerful purpose: diversity action plan objectives

The DAP is intended to document the sponsor’s rational, goals, and how they intend to meet those goals for clinical trial enrollment. The goals are to be specific and separated by age grouping, ethnicity, race, and sex. These goals must be measurable and must be included in the DAP. If the drug product or medical device is in support of a specific demographic, this demographic should be documented in the plan. The FDA strongly urges sponsors to share the strategies for meeting the DAP goals with the public.

As the draft guidance is written currently, the DAP is only required for Phase III (pivotal) clinical trials and should be submitted to the FDA at the end of phase 2 (EOP-2) meeting with the FDA. 

During Phase III, safety and efficacy of a new drug product is compared to standard treatment.  The size of the trial varies but generally falls between 300 and 3000 participants who have the disease or condition being treated. This is the largest population used prior to submitting to the FDA for approval and would allow for achieving the largest statistically diverse population while allowing for greater reporting of adverse effects, safety and efficacy. Essentially, the larger population means that the more statistically meaningful data could allow for enhanced tracking of safety and efficacy amongst underrepresented populations. 

While the draft guidance only requires the DAP for Phase III, the draft guidance also notes that the “FDA strongly recommends that sponsors develop and implement a comprehensive diversity strategy across the entire clinical development program, including in early studies, when possible.” (Lines 179 – 181 of the draft guidance.) 

The draft guidance also briefly discusses development programs such as rare diseases, which may have small pivotal studies thus limiting the ability to recruit a diverse population. In such cases, the FDA recommends using sources such as patient registries to assist in targeting participants for enrollment. While not in the draft document, the discussion of diversity and how to meet the intent of the DAP should be discussed early and often in meetings with the FDA.

Once the DAP is written, dependent on regulatory pathway and which center will be receiving it, the DAP should be submitted with the investigational application for the Phase of interest. It will be labeled as “Initial” and after FDA review and commenting any subsequent updates will be labeled with “Revised” until the DAP is approved.

In rare cases, the FDA acknowledges that it may not be possible to meet the intent of a DAP and as such would allow for a waiver to be requested. FDA will consider a waiver if the need to protect public health during a public health emergency arises, if conducting a clinical trial in accordance with the DAP would be impractical, or based on what is known or determined about the prevalence or incidence of the disease or condition in the US. 

More than a mission – a mandate?

Unlike many other FDA guidance documents, the DAP guidance, when finalized, will create an element of legally binding obligation on behalf of the study sponsor. The final guidance is expected on June 26, 2025 (nine months after the close of the Draft Guidance comment period on September 26, 2024). Studies which have enrollment commencing 180 days after this final publication will be subject to the requirements of having a Diversity Action Plan, making trials enrolling in the latter half of 2025 eligible.

There is also the opportunity for a study sponsor to submit a waiver request, should the DAP not be relevant for the particular trial.

What’s included in a clinical trial diversity action plan?

To complete a Diversity Action plan, a study sponsor must include the following:
  • Enrollment goals, disaggregated by age group, sex, race, and ethnicity of “clinically relevant study populations”: These goals should be informed by the “estimated prevalence of the disease in the U.S. intended use population for which the medical product is being tested.
  • The study sponsor’s rational for its enrollment goals: This may include background on the disease and an overview of the natural history of the condition and risk factors
  • An explanation of the sponsor’s plans for meeting its enrollment goals: These may include community engagement to create broader awareness, providing cultural competency training for investigators to build trust, but also reducing participant burden. These services may include, but are not limited to, providing dependent care, transportation assistance, flexible hours for study visits as well as reimbursements for costs incurred.
The plan, in essence, becomes a blueprint for welcoming more clinical trial participants into research. The FDA is strongly encouraging sponsors to share strategies for meeting Diversity Action Plan enrollment goals, promoting transparency by offering key information on goals and procedures on their recruitment websites and the company’s overall website.

Parting thoughts

The Diversity Action Plan guidance is focused on acknowledging health inequalities and the ability to access health care and clinical studies for the underrepresented populations and trying to improve those inequalities. By proactive planning, this will enable CROs and sponsors to work towards the same goal. Clinical study diversity ensures that the studies test the product in a representative sample group of the product’s intended use population thus ensuring safety and efficacy for the consumer. It will allow clinicians to treat their patients with more confidence knowing potential adverse effects for the demographic being treated. It’s a win-win situation for the patient and manufacturer. 


Susan Shorter has 36 years of experience in the quality field, specifically with pharmaceutical, medical device, instrument and software validation, vendor approval, and internal and external auditing. She has spent several years working in the contract laboratory compliance vector of the industry and currently is working in clinical trials software as a service vector improving patient experience and retention.

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