FDA Leads the Charge for Diversity in Clinical Trials

It’s long been a concern for scientists and regulators that drugs are intended for use by anyone but are predominantly tested on one group – white men. This could change because of legislation introduced in the U.S. requiring Diversity Action Plans for late-stage trials, reports Richard Staines.

While diversity in the workplace is an economic and moral issue, experts argue that diversity in clinical trials is a scientific problem as well as a moral one.

The U.S. government-run National Institutes of Health has its own National Institute on Minority Health and Health Disparities, which aims to address this very issue. According to the institute, many trials have historically relied on white male study participants, a shortcoming that may create gaps in understanding of diseases and conditions.

Recruiting patients from diverse backgrounds can help to inform how different patients may experience diseases and therapies. This can be based on several factors including age, biological sex, pregnancy status, life experiences, healthy or unhealthy lifestyle choices, environmental conditions, genetic variation, and geographic ancestry, or underlying medical problems.

Research has shown that there are still biases within the clinical trial process despite the interventions from health authorities. For example, an NIH report cites an FDA summary of clinical trials conducted between 2015 and 2019 that shows non-Hispanic white populations compose 78% of participants enrolled in U.S. trial sites, even though they comprise 61% of the country’s population.

Women are also under-represented in clinical trials, with one study finding they make up between 29% and 34% of participants at Phase 1 trials funded by the pharmaceutical industry. This is because of exclusion criteria for older people at this stage of clinical development: with many such trials excluding those under 45, younger women are less willing to take part during their childbearing years.

Diversity Action Plans

So what does this mean for companies conducting clinical trials? Diversity Action Plans apply to Phase 3 clinical studies of drugs, biological products, and devices, for which recruitment commenced 180 days after publication on the FDA’s final guidance.

At the time of writing the draft guidance mandated by the Food and Drug Omnibus Reform Act (FDORA) is overdue, although reports suggest the regulator is close to publishing the next draft.

The original law required the guidance to be published no later than a year after the law was passed on December 29, 2022. Final guidance is due no later than nine months after a consultation on that draft has closed.

Further information published by the FDA have outlined the elements of a diversity plan. These include a disease overview outlining prevalence and distribution across subgroups, backed by an overview of the studies in the clinical development programme.

They should also include enrolment goals across relevant groups and measures to enrol and retain participants from the relevant population. The FDA is not alone with its concern about disparities in clinical research: in March the UK’s Department of Health and Social Care published a plan to prevent unfair biases that can occur throughout the life cycle of medical devices. This includes R&D and testing, to approval, deployment, and post-market monitoring, as well as in the use of devices once deployed.

As part of the action plan, the Medicines and Healthcare products Regulatory Agency (MHRA) now requests that approval applications for new medical devices describe how they will address bias.

Specific guidance has been updated for the NHS to highlight potential limitations of pulse oximeter devices with darker skin tones, and the National Institute for Health and Care Research (NIHR) is currently accepting funding applications for research into smarter oximeters.

While legislation such as this has implications during the clinical trial process, it’s been broadly welcomed by the scientific community, although the legislation has forced the notoriously conservative pharma industry start to rethink its approach to ensuring diversity in large scale trials.

Harder Stance from FDA

Even without the legislation the FDA has been taking a harder stance on diversity through its existing regulatory procedures.

A commonly cited example is the PD-1 cancer drug Tyvyt (sintilimab) from Innovent/Eli Lilly, which the FDA rejected because the trial data came from China alone. The ruling followed concerns raised by the FDA’s Oncologic Drugs Advisory Committee about conducting trials in one country only instead of in several different countries and populations.

While there is inevitably resistance to further additions to the already rigorous list of requirements in clinical trial protocols there are clear benefits to improving diversity too – better patient engagement, improved trust in the drug development and medicines in general and more innovative science.

There’s also the likelihood that enrolment goals will be different for rare diseases, due to their prevalence in the population and certain racial or ethnic groups. This is covered in the guidance issued so far by the FDA, which states the need to justify the enrolment goals in a trial based on epidemiology of the disease.

Catherine Pickering, Chief Executive Officer, of iOnctura welcomed the focus on under-represented groups: “There are many benefits to diversity in clinical trials for society, it gives the medical community and patients confidence that medicines have been thoroughly tested and that we know as much about how they interact with different patient groups as possible.

Meanwhile, Richard Philipson, Chief Medical Officer from Calliditas Therapeutics, said: "By actively recruiting diverse participants in clinical trials, the pharmaceutical industry can demonstrate its commitment to serving all populations equitably. This inclusivity fosters trust and confidence in the medications and treatments developed."

John Maher, Chief Scientific Officer at Leucid, concluded: "Inclusive clinical trials are the foundation of equitable healthcare. By embracing diversity, we can bridge gaps in treatment accessibility and improve health outcomes for all.”

He noted that it’s now up to leaders in the industry to proactively address the issue.

 “As leaders in biopharma, we must actively promote diversity in clinical trials to ensure that our medicines are effective across diverse populations. It's not just about science; it's about equity."