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9 Nov. 2020. Food and Drug Administration issued new regulatory guidance designed to enroll clinical trial participants more representative of the populations they claim to serve. The document presents the current thinking of FDA on the issue of increasing diversity of drug and biologic clinical trial participants, and its contents are not legally binding on the agency or public.
FDA says recruiting more representative clinical trial participants of a product’s intended population is a continuing issue going back decades. One of the continuing problems facing trial sponsors is underrepresentation of ethnic minorities and women, even when drugs or biologics are being developed for a broad population. In some cases, says the agency, enrollment and exclusion criteria for clinical trials are written to recruit individuals with specific disease conditions or prevent possible adverse effects, but may arbitrarily and unintentionally exclude groups of people that may benefit from the experimental treatments.
FDA commissioner Stephen Hahn cites health care disparities of different age, sex, and ethnic groups to vaccines and therapies in development for Covid-19 as one of the reasons for the new guidance. “This difference in impact,” says Hahn in an agency statement, “illustrates why we must encourage developers of any medical product such as treatments or vaccines for Covid-19, as well as medical products more broadly, to endeavor to include diverse populations to understand their risks or benefits across all groups.”
One example cited in the document is exclusion of pregnant or lactating women from clinical trials, when preclinical or early-stage trial data do not offer guidance on adjusting doses for those individuals to reduce risk to fetuses or infants. Likewise, people with disabilities or non-English speakers may be excluded from clinical trials to prevent adverse effects from errors in using experimental therapies. Arbitrarily excluding these populations not only reduces the representativeness of the trial sample, says FDA, sponsors could also miss important safety issues with these groups.
Make extra efforts to enroll relevant participants
The FDA document encourage trial sponsors to consider more precise criteria for excluding people with certain medical conditions from trials. For example, the experimental drug or biologic may pose a risk for people with advanced heart failure, but not less severe forms of heart disease. And the agency recommends that sponsors review and where possible relax enrollment criteria for late-stage clinical trials, and not routinely impose the same criteria used in mid-stage trials. In addition, FDA calls for trial sponsors to make extra efforts to enroll clinically relevant trial participants across age, sex, race, and enthnicity, and notes that the agency will ask sponsors for a plan to include these populations particularly in later-stage trials.
FDA recommends trial sponsors take steps early on to limit unintentional exclusion of age, sex, or ethnic groups from clinical trials. For example, the document recommends better understanding of metabolic properties of candidate drugs and biologics to prevent arbitrarily excluding people in older age groups. Another step is earlier planning for pediatric patients, with phased extension of studies to younger patients as safety data from older patients become known.
In addition, gathering data on drug interactions with women who become pregnant during a trial can provide valuable insights for including pregnant women in later-stage studies. And the document urges sponsors to consider more use of adaptive clinical trials that allow for changing trial protocols as data are collected, including expanding populations in later phases when earlier data support it.
The FDA document spells out other steps trial sponsors and designers can take to increase diversity of their participants. The agency suggests broadening trial enrichment strategies that usually aim to increase participants more likely to respond to the candidate drug or biologic, with participants less likely to respond to the drug, for a fuller picture of the treatment’s effects on the target population. Likewise, FDA recommends practical steps to make trials less burdensome on participants, use more electronic data collection where possible, reasonable reimbursement of travel expenses, and more engagement by sponsors with community medical societies and leaders.
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