The US Food and Drug Administration (FDA) published a much-anticipated draft guidance that recommends more diverse patient cohorts in clinical trials and is meant to improve the data the agency receives in support of premarket applications. It broadly describes what sponsors should include in their Diversity Action Plans as mandated by Congress.
The draft guidance, released on Wednesday, details what should go into a sponsor’s Diversity Action Plan, which products require such plans, and how they should be submitted to the agency. The guidance also discusses how FDA reviewers may decide whether a sponsor can waive the Diversity Action Plan requirement. When finalized, it will replace the agency’s 2022 guidance on diversity plans for clinical trials.
The 2022 Food and Drug Omnibus Reform Act (FDORA) mandated that FDA require certain late-stage clinical trials and other pivotal studies to include Diversity Action Plans when developing medical products, including drugs, biologics and medical devices. (RELATED: FDA misses congressional deadline to update clinical trial diversity guidance, Regulatory Focus 15 February 2024)
“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,” said the guidance. “Such plans must specify ‘the sponsor’s goals for enrollment in [a] clinical study,’ ‘the sponsor’s rationale for such goals,’ and include ‘an explanation of how the sponsor intends to meet those goals.’”
Specifically, the Diversity Action Plan must include the sponsor’s rationale and patient enrollment goals based on age, ethnicity, sex, and race. It also urges sponsors to look beyond those factors to other demographic differences and consider how they may affect the product’s performance.
“In general, clinical study diversity helps ensure that clinical studies appropriately test the product in a representative sample of the product’s intended use population,” said the guidance. “Factors to consider when setting enrollment goals include demographic characteristics (e.g., race, ethnicity, sex, age group), clinical characteristics (e.g., presence of comorbidities, disease etiology), and other characteristics (e.g., access to standard preventive and diagnostic care, access to standard treatments of the clinically relevant population).”
FDA noted that the draft guidance was developed by the Oncology Center of Excellence Project Equity in collaboration with the Center for Drug Evaluation and Research (CDER), the Center for Biologics Evaluation and Research (CBER), the Center for Devices and Radiological Health (CDRH), the Office of Women’s Health (OWH), and the Office of Minority Health and Health Equity (OMHHE).
Richard Pazdur, director of the FDA’s Oncology Center of Excellence and acting director of the Office of Oncologic Diseases at CDER, said ensuring there is more clinical data that is representative of a diverse population early in clinical development programs is a priority for FDA in an agency statement.
“With FDORA, there is now a requirement for sponsors to submit diversity action plans,” he added. “These plans may help ensure that sponsors are thinking critically and intentionally about the many characteristics of the patient population they aim to treat when designing their clinical study.”
FDA Commissioner Robert Califf received a round of applause when he announced the publication of the draft guidance at the White House during a forum on clinical trials. He credited the National Institutes of Health (NIH) for leading the way and meeting the first order of clinical diversity by encouraging trials that take into account sex, age, and ethnicity, but he noted that the FDA didn’t have the same ability to force the medical product industry to follow such requirements.
“This guidance has a lot in it that we hope for, which is meeting that first-order criteria that I believe NIH has already met,” said Califf. “We’re a little behind, but I think we’re getting there.”
Califf said that as clinical trials are planned, ensuring diverse enrollment should be a key focus. He also said they need to go beyond the first order of clinical trial diversity to consider factors such as patient income levels and whether they are rural or urban.
“We want to stimulate the industry and the investigators working with industry to plan ahead on this,” said Califf. He also noted that the guidance focuses on Phase 3 clinical trials because it’s hard to ensure trial diversity in earlier phases, as cohort sizes tend to be very small.
“Access to clinical trials is something everyone should be entitled to in our opinion but 90% of what gets introduced in the clinical trials that FDA regulates turn out not to make it to market,” said Califf. “We’ve always got to keep in mind that we are doing experiments on human beings, and we have to be very respectful of the people involved but also make sure that they understand that we’re testing something, and we don’t know how effective it is at this point.”
Califf also bemoaned that “clinicians have become the financial objects” of the American healthcare system, which has become a barrier to creating meaningful relationships between healthcare providers and their patients, and ultimately is a barrier to getting more people into trials in general. He noted that trial participants have consistently stated that they tend to sign up for clinical trials at the recommendation of their physician, nurse or pharmacist, but clinicians are often not signing up patients because they are overwhelmed with their patient load.
“We all love the technology, let’s work on that, let’s make that work,” said Califf. “But we’ve got to refocus energy on that relationship and … it means that doctor is engaged with you and the full array of ways you can interact.”
“I’m optimistic that will happen because [artificial intelligence (AI)] applied to physician notes and nursing notes, for example, is going to give people a lot more time and the question is going to be are we going to use that time to advance knowledge or are we going to use that time to just say bring it out and see three times as many people in the same time.”
Once the guidance is finalized, sponsors will have 180 days before they must comply with it as they begin new clinical trials.
Initial reactions to the guidance from key stakeholders have been positive. Jeff Allen, CEO of Friends of Cancer Research (FOCR), emphasized that asking for trial diversity is nothing new for FDA, but the congressional mandate will ensure the agency can enforce a regulatory framework requiring diversity action plans.
“Implementing these plans can play a major step forward to make clinical trials more inclusive of patient populations frequently underrepresented and ensure that pivotal trials are representative of the people that will ultimately receive new therapies,” he said in a statement.
Andrew Powaleny, a spokesperson for PhRMA, told Focus the pharmaceutical industry group plans to submit comments on the draft guidance.
“While we review this draft guidance in more detail, PhRMA and our member companies have developed and voluntarily adopted the first ever industry-wide principles aimed at addressing clinical trial diversity,” he added. “We are committed to working with the FDA, patient advocacy organizations and other stakeholders across the clinical research ecosystem to encourage more diverse participation in clinical trials.”
Stakeholders can comment on the draft guidance until 25 September on www.regulations.gov under docket no. FDA-2021-D-0789.
