FDA lays out strategies for promoting diversity in clinical trial enrollment

Regulatory NewsRegulatory News | 09 November 2020 |  By 

The US Food and Drug Administration (FDA) is encouraging drug and biologics sponsors to broaden enrollment criteria and to avoid unnecessarily excluding participants in a final guidance document aimed at increasing the diversity of clinical trial participants.
“To further promote and protect public health, it is important that people who are in clinical trials represent the populations most likely to use the potential medical product,” FDA Commissioner Stephen M. Hahn, MD, said in a statement.
The final guidance, issued 9 November 2020, discusses ways for sponsors to include individuals with different demographic characteristics – including, sex, race, ethnicity, age and location – and non-demographic characteristics, such as those with rare diseases, organ dysfunction, comorbid conditions or disabilities. It replaces draft guidance issued in 2019. (RELATED: FDA drafts guidance on enhancing diversity in clinical trial populations, Regulatory Focus 06 June 2019)
In its Federal Register announcement of the availability of the final guidance, FDA noted that the final guidance includes more emphasis on real-world data and sending medical professionals to visit trial participants instead of requiring extensive participant travel. The agency also added more detail about including racial and ethnic minorities and fostering community engagement. The changes were made following a period of public consultation that saw 90 submissions from large pharmaceutical and research organizations and trade associations. (RELATED: Experts seek tweaks to FDA draft guidance on clinical trial diversity, Regulatory Focus 12 August 2019)
While some patients should be excluded from clinical trials because the risk of an adverse event outweighs the potential benefit to the individual, the FDA said there should be fewer exclusions among patients using concomitant medications and those with comorbidities, as well as among medically complex patients.
Additionally, the agency pointed out that patients who were commonly excluded in the past – such as older adults, children, patients at extremes of the weight range, and those with malignancies and HIV – were left out without a strong clinical or scientific justification.
“Unnecessary exclusion of such participants may lead to a failure to discover important safety information about use of the investigational drug in patients who will take the drug after approval,” the agency wrote in the final guidance. “Therefore, broadening eligibility criteria in later stages of drug development for the phase 3 population increases the ability to understand the therapy’s benefit-risk profile across the patient population likely to use the drug in clinical practice.”
Inclusive trial practices
Specifically, the FDA suggested employing inclusive trial practices, such as considering each exclusion criterion individually to determine if it is necessary to ensure safety and achieve the study objectives. For instance, if participants with advanced heart failure would face unreasonable risks by participating in the trial, sponsors could consider enrolling patients with milder disease. In that case, the exclusion criteria should specifically define the population of heart failure patients that would be excluded, the FDA said.
Sponsors can also consider eliminating or modifying certain exclusion criteria as a clinical trial moves to phase 3, rather than simply transferring protocols from the phase 2 trial.
The guidance also advises sponsors to enroll participants who reflect the characteristics of clinically relevant populations in terms of age, sex, race, and ethnicity. To meet this objective, sponsors can consider including children and adolescents in confirmatory clinical trials that involve adults; enrolling enough women in a trial to allow detection of significant sex-related differences in drug response; and including racial and ethnic minorities to identify population-specific signals.
In the guidance, FDA specifically recommends that sponsors of drugs and biologics develop a plan for the inclusion of clinically relevant populations no later than the end of the phase 2 meeting.
There are also design and methodological changes that could help promote greater diversity, according to the FDA guidance document. The agency suggested that sponsors characterize drug metabolism and clearance across populations early in clinical development to avoid later exclusions and allow for dose adjustments. Another approach would be to use a pre-specified trial design to allow for changes during the trial, including altering the study population as new data becomes available.
“Adaptive trials may also provide for broader enrollment when there is uncertainty regarding whether the drug will be safe and effective in certain populations, with an interim analysis that will enable adjustment of future enrollment based on pre-specified criteria regarding response,” the agency wrote.
Sponsors can also consider broader pediatric development from an early stage, rather than the sequential enrollment of age subgroups, as well as pharmacokinetic sampling to establish dosing in women who become pregnant during a trial. 
Non-clinical factors
The FDA also urged sponsors to consider non-clinical factors that contribute to broader trial enrollment, such as making participation less burdensome for patients.
Sponsors can consider reducing the frequency of study visits, adding flexibility by replacing physical visits with electronic communication, or using mobile medical professionals who can travel to the participant’s location.
FDA also suggested locating trial sites in places with a higher concentration of racial and ethnic minorities, and selecting health care providers and study coordinators who reflect the diversity being sought among trial participants “because participants may prefer a health care provider of their same cultural background.”
Trial sponsors should also make participants aware of any financial reimbursements for travel and lodging expenses, the agency said. Sponsors can also consider paying participants in exchange for participation in research. “FDA recognizes, however, that payment for participation may raise difficult questions that should be addressed by the [Institutional Review Board], such as how much money participants should receive, and for what participants should receive payment, such as their time, inconvenience, discomfort, or some other consideration.”
Rare diseases
In the final guidance, the FDA recognized that designing trials for rare diseases and conditions present unique challenges.
“Because rare diseases often affect small, geographically dispersed patient populations with disease-related travel limitations, special efforts may be necessary to enroll and retain these participants to ensure that a broad spectrum of the patient population is represented,” the agency wrote.
The FDA recommended that sponsors working on rare disease treatments engage patient advocacy groups, experts, and patients early in the process to aid enrollment. Another option for rare disease trials is to launch an open-label extension study with broader inclusion criteria, after early-phase studies.
Sponsors can also consider “re-enrollment” of participants in early-phase trials to later-phase trials, provided the therapy provided in the phase 1 study is not expected to change the course of the disease.
“Sponsors considering this approach should examine the potential for selection bias as the participants who better tolerated the drug and experienced more effectiveness in early phases may be disproportionally selected for a phase 3 trial, which may contribute to safety findings that are not representative of the population of patients who will use the drug if it is approved,” the agency advised.


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Tags: FDA, US

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