FDA to Add New Diversity Requirements for Certain Clinical Studies

Industry sponsors will be required to submit diversity action plans for certain key clinical studies of drugs and devices, according to draft guidance released recently by the US Food and Drug Administration. The agency’s overarching goal is to include more participants from traditionally underrepresented groups in trials, thus broadening the generalizability of study results.

Such plans will have to include a sponsor’s rationale and goals for who it’s planning to enroll, as well as a description of how it intends to meet those goals. Though the focus is on ensuring adequate representation by age, sex, race, and ethnicity, the agency also encourages companies to consider any other factors critical to ensuring a diverse study population, including geographic location, socioeconomic status, gender identity, sexual orientation, and others.

The public can submit comments on the draft guidance—which also goes over the time line and procedures for submitting the plans and receiving feedback from the FDA as well as the process for requesting a waiver from the requirements—through September 26, 2024.

The agency has issued guidance on increasing diversity in clinical studies before and was legally required to release this latest document—which replaces prior guidance—under a mandate included in the Food and Drug Omnibus Reform Act (FDORA) of 2022.

The diversity action plans that will be required under the new guidance “may help guide sponsors toward more intentional thinking about ways to ensure that trial participants are representative of the patients who will ultimately use the products. This will improve our understanding of the disease and the medical product under study and inform the safe and effective use of those products,” Richard Pazdur, MD, director of the FDA’s Oncology Center of Excellence and director of the Office of Oncologic Diseases in the FDA’s Center for Drug Evaluation and Research, told TCTMD in a statement.

A First Step

Several clinical trialists interviewed by TCTMD viewed the new guidance as an important first step in ensuring that studies both include representative cohorts and provide results that can be applied to a broad swath of the population.

Wayne Batchelor, MD (Inova Heart and Vascular Institute, Fairfax, VA), co-chair of the steering committee for the American College of Cardiology’s Clinical Trials Research program, said “this is a very important development that’s moving us in the right direction towards improving and increasing clinical trial diversity and making sure that the safety and efficacy data that we get from both device and drug studies is more representative of the populations that will receive those drugs and devices as they roll out.”

This is important, Batchelor said, “because historically there have been certain groups who've been grossly underrepresented in clinical research, and we know that there is some heterogeneity of both drugs and devices in terms of their safety and effectiveness in different groups of patients. So it's really mission critical to ensure that the data from which we make these assessments of safety and efficacy are drawn from a diverse group of patients and a representative group that's similar to the group that's going to ultimately get those therapies.”

We have the best of intentions when a study is launched and yet . . . we keep falling into the same patterns. Michelle O’Donoghue

Michelle O’Donoghue, MD (Brigham and Women’s Hospital and Harvard Medical School, Boston, MA), a senior investigator in the TIMI Study Group, said that up until now, “the conversation has been far too abstract, where everyone recognizes the importance of improving representation from all different members of the community and clinical trials and yet we consistently see that we fall short of that when clinical trial results are being presented.

“As a clinical trialist myself, I know that we have the best of intentions when a study is launched and yet, because of perhaps our unwillingness to think outside the box and think about new ways to approach the question, we keep falling into the same patterns,” she continued. “So I think it's time that we really follow through on making concrete efforts to improve diversity within our clinical trials. And, unfortunately, so far it's been largely lip service, but hopefully this diversity action plan will be an important step in the right direction.”

Indeed, said Deepak Bhatt, MD (Icahn School of Medicine at Mount Sinai, New York, NY), this new guidance “isn't the usual sort of, ‘Oh, yeah, we'll try to get a diverse population here.’ There actually has to be submitted a diversity action plan, setting enrollment goals and how those goals will be met. So it moves it from theoretical to practical.”

Making Everyone Accountable

Generally, guidance from the FDA doesn’t contain legally enforceable requirements, the agency noted in the draft. The exception is this case applies to the “form and manner” of the submission of a diversity action plan, which will be required for sponsors—unless a waiver is granted—once the guidance is finalized.

The FDA will be required to update Congress each year with a report, which it must publish on its website, detailing which diversity action plans it received and whether studies met the enrollment goals that were specified. It remains unclear, however, what would happen if a study fell short of the stated goals.

Addressing that question, Pazdur said “tracking the data and providing transparency in regard to what’s working and what’s not, and engaging with sponsors, are the FDA’s main tools in addressing our goal to increase enrollment of members of historically underrepresented populations in clinical trials and to help improve the generalizability of evidence for the intended population that will be using the medical product.”

The trialists discussing the issue with TCTMD indicated that they think sponsors will not only abide by the new measures, but also embrace them.

“The industry partners I've spoken with understand that this is a problem,” Batchelor said. “They all internally have been thinking about this and how to solve this problem and the challenge of enrolling more diverse patients into research protocols.”

There are multiple potential ways to make that happen, including amending protocol development, diversifying study committee leadership, and finding new study sites, he said. “There are ways in which we can evaluate how we're doing in interim analyses in terms of enrollment, and then we have an opportunity to, even in some cases, if necessary, cap enrollment in certain groups if they're overrepresented, and then really work on enrollment of underrepresented groups,” Batchelor specified.

Beyond that, if there still isn’t adequate representation in the initial studies, certain groups can be further evaluated in phase IV, postmarketing studies, he said.

What’s important about these diversity action plans is that they come into play during the initial phases of a clinical study, Batchelor said. “I like the fact that this is on the front end of this, and it's going to really set the stage for how we look at clinical trial enrollment moving forward.”

[The FDA guidance] moves it from theoretical to practical. Deepak Bhatt

Whether this guidance, when finalized, will induce real change is the critical question, O’Donoghue said, adding, “I like that they have essentially put sponsors on the line for defining what they consider to be appropriate representation for different groups of key interest and then also providing a rationale. Because of course the concern would be to set those benchmarks intentionally very low so that they could easily pole vault over them, so to speak.

“But,” she continued, “I think that providing justification for why your numbers may differ from what that disease state would expect to be in the community at least makes sponsors need to think about it more cogently up front.”

Bhatt noted that even though FDA guidance is not legally binding in general, that’s not necessarily a bad thing. Creating more legal hurdles for clinical trials to go forward “would ultimately hurt the cause, not help it, by just providing yet another disincentive to do large trials in the US.”

He added, though, that “every sponsor I've worked with philosophically supports the goals of ensuring representativeness in trials. I mean, aside from just it being the right thing to do, it actually is also in a sponsor's best interest to do that because then the trial results are viewed as as generalizable as possible.”

Predicted Impact

The success of this guidance is “going to come down to the implementation and follow-through and making sure that people are held accountable to the benchmarks that they put forward,” O’Donoghue said.

But, “hopefully, this is achievable, and we have seen that when a sponsor truly prioritizes achieving some of these goals that it can, in fact, be done,” she added. She pointed to use of trial sites in racially diverse neighborhoods, measures to help patients get to clinic visits or participate from their homes, efforts to raise awareness of trial opportunities in underserved communities, and enhancing diversity among trial leadership as ways to improve representation in study cohorts.

Bhatt said he was optimistic that the release of this FDA guidance will increase diversity in clinical trials moving forward, noting, however, that some of the measures needed to enhance diversity can also increase the costs of doing a trial, which has limited previous efforts.

“Maybe nobody just comes out explicitly stating that, but that's really what it is. Otherwise, I've not yet met a sponsor that wouldn't want to have a more diverse trial,” Bhatt said. “I think if we could find ways to reduce the cost of doing trials in the US and reduce some of the perceived regulatory and legal burdens, that could really help us enroll a lot more US patients of all sorts.”

Overall, though, “this is a very laudable effort,” Bhatt said. “The challenge to date has really been moving from the desire to diversify clinical trials to actually doing it, but I think this document will help spur along that process.”

All of us involved in biomedical research have got to bend over backwards to build trust in these groups that have been historically left behind in research or—even worse—taken advantage of. Wayne Batchelor

For Batchelor, the guidance is “not a complete solution, but it provides a really nice foundation off which all stakeholders, including industry sponsors, regulatory authorities, academicians, and other stakeholders involved in biomedical research, can understand how to look at this. And the document provides some very good information on what the expectation is and will be from the FDA in terms of coming up with these plans and implementing them.”

Efforts now will be focused on bringing it to fruition, he said. “Talking about [diversity is] one thing, but actually getting these things across the finish line and achieving these goals is another thing.”

Taking a broader view, Batchelor underscored the importance of reaching out to underrepresented communities when conducting clinical research. “All of us involved in biomedical research have got to bend over backwards to build trust in these groups that have been historically left behind in research or—even worse—taken advantage of and not treated with the appropriate respect and dignity that we would want all of us to have. . . . We almost have to overcompensate for that, in my opinion.”

The requirement for diversity action plans “is one small move that can help support that notion, but it's only the tip of the iceberg,” Batchelor said. “There's a lot more work that needs to be done.”

Pazdur touched on that thought as well. “We have to remember that clinical trial inequity has a long history. Some historically underrepresented populations lack trust in the medical community. Others may want to participate in clinical trials but face significant barriers,” he said. “We all still have a lot of work to do. We hope diversity action plans will help, but we can’t expect them to be the single, simple solution to this nearly century-long problem.”