Wien, 14.06.2023 – Text: Catarina Carrão
Historically, there has been an underrepresentation of people from diverse groups in clinical trials, which has created gaps in the understanding of treatment safety and effectiveness across different populations.
For example, certain demographic characteristics such as sex, age, race, and ethnicity, can have an impact on how a person responds to a therapeutic product; similarly, non-demographic characteristics such as socioeconomic status and residential patterns (rural vs. urban), as well as certain disease comorbidities and disabilities can influence the applicability of a medical product1.
Therefore, these sub-groups should also be included in clinical trials where appropriate. At the same time, certain populations are often excluded from trials without strong clinical or scientific justification (e.g., the elderly, those at the extremes of the weight range, individuals with organ dysfunction, those with malignancies or certain infections such as HIV, and children).
FDA point of view
According to the U.S. Food and Drug Administration (FDA) guidance on enhancing diversity in clinical trial populations, failure to include complex participants in a development program may lead to a failure to discover important safety information about the use of the investigational product in patients who will take it after approval2. As such, broadening eligibility criteria when appropriate, maximizes the generalizability of trial results and the ability to understand the therapy’s benefit-risk profile across the patient population that will likely use the drug in real world clinical practice, without jeopardizing patient safety.
With this in mind, the FDA issued a guidance with approaches that sponsors can take to increase enrollment of underrepresented populations in clinical trials3. One of those approaches is to broaden eligibility criteria by adopting enrichment strategies in clinical trial design, in which there is a targeted inclusion of certain populations with the goal of more readily demonstrating the effect of the drug – if there is one.
The enrichment of a clinical trial population may increase the trial’s potential to show an effect – if one exists, by ensuring that participants have a particular severity of a disease, a particular subset of a disease, or particular genetic markers. Additionally, prognostic enrichment enrolls participants who are more likely to reach study endpoints, or to have a disease of greater severity, reducing the size of a trial necessary to show an effect. Furthermore, predictive enrichment includes participants with a specific characteristic (e.g., genetic, pathophysiologic) who may be more likely to respond to an intervention.
Since, enrichment does not usually exclude demographic groups; the FDA encourages the use of such strategies to increase the potential of a trial to detect an effect of the investigational product. In addition, the FDA advises to include a reasonable sample of participants who have the disease, but do not meet the prognostic or predictive enrichment characteristics pre-specified in the clinical trial.
It is recommended that sponsors examine each exclusion criterion to determine if it is needed to help assure the safety of trial participants or to achieve the study objectives when developing clinical trial protocols. If not, then eliminating or modifying the criteria to expand the study population, as well as tailoring the exclusion criteria as narrowly as possible to avoid unnecessary limits to the study population, should be considered.
Furthermore, sponsors should reflect whether criteria from phase 2 studies — which may be more restrictive and are often transferred to phase 3 protocols — can be eliminated or modified to avoid unnecessary limits on the study population. Also, sponsors should base exclusions on an appropriate measure of organ dysfunction that does not lead to the unnecessary exclusion of certain populations; and, consider including children (ages 2 to 11 years) and adolescents (ages 12 to 17 years) in confirmatory clinical trials involving adults, when appropriate2,3.
Beyond the limitations in participation imposed by narrow eligibility criteria, potential participants may face additional challenges in clinical trial enrollment, and additionally limit the diversity of the study.
How can sponsors make clinical trials less burdensome in order to engage more patients?
The FDA recommends reducing the frequency of in-person study visits and be flexible with visit times; while also enlisting medical professionals that can visit participants instead of requiring patients to visit distant clinical trial sites. Also, electronic communication tools and digital health technologies, where appropriate, are encouraged by the FDA in order to engage and retain clinical trial participants.
In conclusion, factors such as race, ethnicity, sex, gender identity, age, socioeconomic status, disability, and comorbidity have been neglected in clinical trials, often without strong justification. As such, gathering a diverse clinical trial population will contribute to a more accurate assessment of a product’s safety and efficacy; and we should aim to broaden the eligibility criteria and avoid unnecessary exclusions in our clinical studies.
1 Mathilda Fienkeng, A. C., Zaida Recinos-Vasquez, Monique Carter. Enhancing diversity in clinical trial populations: An agency-industry perspective. Regulatory Focus – Regulatory Affairs Professional Society https://www.raps.org/news-and-articles/news-articles/2022/12/enhancing-diversity-in-clinical-trial-populations (2023).
2 FDA. Enhancing the Diversity of Clinical Trial Populations – Eligibility Criteria, Enrollment Practices, and Trial Designs Guidance for Industry DRAFT GUIDANCE. Center for Drug Evaluation and Research (CDER), Center for Biologics Evaluation and Research (CBER) https://www.fda.gov/media/127712/download (2020).
3 FDA. Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs Final Guidance. U.S. FDA https://www.fda.gov/media/168352/download (2023).