Pharma has recognised that there is a problem with diversity in clinical trials, but has so far struggled to successfully achieve real change. Ben Hargreaves covers how the US FDA has updated its guidance documents to demand that trial sponsors must make diversity a part of their planning.

Clinical trials have long had a problem with ensuring sufficient diversity. Fundamentally, there has been an issue where the importance of diversity was not recognised and properly understood. The necessity to reflect the general population where the treatment will be used did not feature as a concern, despite it being essential to understand the efficacy of a treatment. There are also equally important questions over ethics and access that have become a more pressing conversation.

With greater diversity accepted as the path forward for clinical trials, regulators are being challenged to put forward steps within their powers to encourage action by the industry. The Food and Drug Omnibus Reform Act (FDORA) of 2022 required the US FDA to create guidance that would see drug and device manufacturers submit diversity action plans. Within these plans would be an outline of how these manufacturers would include diverse groups of trial participants for late-stage trials. In June, the FDA released its draft guidance and opened its document to comments within 90 days of its publication.

“Generating data for a broader and more representative population early in the clinical development programme is among the FDA’s priorities to bring innovative medical products to the public […] 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,” said Richard Pazdur, director of the FDA’s Oncology Center of Excellence.

The importance of establishing a regulatory necessity to consider diversity in the creation of clinical trials is evident, after the finding that diversity in clinical trials had actually declined in recent years.

Thinking intentionally

The stated aim of the draft guidance is to assist clinical trial sponsors conducting studies involving drugs, biological products, and medical devices to meet the requirements for the submission of diversity action plans. The aim of diversity action plans is to increase the enrolment of participants who are members of historically underrepresented populations in clinical studies, thereby improving the strength and generalisability of the evidence for the intended use population.

In the draft guidance, the FDA outlines that this is particularly important when the specific population bears a disproportionate burden in certain conditions or diseases relative to their proportional representation in the general population. The American Society of Hematology provides the example of multiple myeloma, which disproportionately affects African American or Black individuals, as they are twice as likely to contract this type of cancer compared to their white counterparts. Despite this, in the US, Black patients have lower survival rates, and enrolment in clinical trials stood at 5%, despite accounting for 20% of patients.

As part of the guidance, the FDA explains that sponsors should consider whether certain demographic groups may have a different response to the medical product being tested. The agency noted that responses could differ over efficacy, safety, or presentation of the disease or condition. As part of its advice, the FDA outlined that sponsors may need to increase the proportional representation of certain populations in studies to evaluate outcomes of interest or other clinically relevant factors in that group.

In terms of what the diversity action plan must include, the FDA outlined three requirements:

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

Welcoming change

The reaction to the release of the draft guidance was broadly positive. Congresswoman Anna Eshoo, the sponsor of the Diverse and Equitable Participation in Clinical Trials (DEPICT) Act, which created a requirement for manufacturers to show how they would include diverse populations in clinical trials, welcomed the release of the guidance. In her response, she stated: “Clinical trials have failed to achieve a level of diversity that reflects the American population for decades. I applaud the FDA’s steps to implement my legislation to address this inequality and look forward to the agency finalising guidance on the Diversity Action Plans to ensure clinical trials are representative of all Americans.”

Patient organisations also had their say, with the Association for Clinical Oncology and Friends of Cancer Research releasing an open letter in response to the draft guidance. Within their statement, the organisations said: “The recommendations in each of the draft guidance documents aim to maximise the generalisability of clinical trial results, while also maintaining the safety of clinical trial participants. Broadening eligibility criteria will allow for the inclusion of more diverse patient populations on trials, which will lead to the collection of trial data that is relevant to the real-world population of patients that will use the FDA-approved therapies.”

Together, the organisations complemented the “very thorough and thoughtful guidance documents,” adding that they were already looking ahead to implementing the criteria in cancer clinical trials.

Challenges to implementation?

In the Friends of Cancer Research’s individual response to the draft guidance, the organisation notes that a complexity for the industry is in how to successfully implement diversity action plans once created. The guidance itself acknowledges that there are areas beyond the control of the life sciences industry that will play a role in whether certain populations may be eligible to participate in research studies. This can be for a number of reasons, such as the availability of healthcare in certain regions or the treatment population being small to begin with, as in rare diseases.

Pre-empting such difficulties, the FDA recommended that the sponsors invest in community-facing strategies that would encourage a sufficiently diverse patient population. However, in response, the patient organisation stated: “Whether those methods are sufficient to suitably enrol and retain new research populations also remains to be seen, or if different therapeutic areas will face bigger challenges in this area than others, and how/if FDA’s policies will adapt from there.”

With the guidance now out for comment until the end of September, there will be a period where these potential challenges can be addressed. Once the guidance is finalised, trial sponsors will have 180 days to conform to the regulation. As such, the update to guidance represents another concrete step to ensure that diversity must be a consideration for trial sponsors. The hope is that, in the coming years, this will be represented in diversity statistics that show consistent improvements to better reflect the US population in clinical trials.