Let’s Break Down the New FDA Guidance…

Last week, the Food and Drug Administration issued the finalized guidance about enhancing diversity in clinical trials: “Enhancing the Diversity of Clinical Trial Populations — Eligibility Criteria, Enrollment Practices, and Trial Designs.” In recognition of the ongoing challenges to representative participation in clinical trials, this guidance provides recommendations and strategies for increasing the enrollment of underrepresented populations: developing and broadening eligibility criteria, avoiding unnecessary exclusions, and improving trial recruitment so that the participants enrolled in trials will better reflect the population most likely to use the drug, while maintaining safety and efficacy.

Definition of Diversity

With the aim of enrolling a study population that more accurately reflects the population that is likely to take the drug, diversity in this guidance includes a wide range of demographic (e.g., sex, race, ethnicity, age, location of residency, socioeconomic status) and non-demographic (e.g., comorbid conditions, disabilities, range of weights and BMIs, rare diseases, polypharmacy) characteristics.

Inclusive Trials

To broaden the eligibility criteria, the following strategies can be effective:

  • Review each exclusion criterion closely to determine if it is necessary to ensure safety or achieve the study objectives. If not, consider whether it can be removed or modified to be more inclusive. The FDA provides the following examples:
    “…when exclusions are necessary because participants with impaired organ function would be placed at unreasonable risk, base the exclusions on an appropriately specific measure of organ dysfunction that does not lead to the unnecessary exclusion of participants with milder dysfunction.”
    “…if there are unreasonable risks to participants with advanced heart failure, but enrollment of those with milder disease would be appropriate, the exclusion criteria should specifically define the population of heart failure participants that should be excluded (e.g., New York Heart Association (NYHA) stage III and IV).”
  • Exclusion criteria in phase 2 studies are often more restrictive than needed when the drug makes it to phase 3 trials. However, the criteria are typically automatically transferred to the phase 3 protocol. Determine whether any of the criteria can be removed or modified to be less restrictive when reviewing the phase 3 protocol.
  • Ensure an adequate study population in terms of age, sex, race, and ethnicity to allow for appropriate data analysis to determine if there are clinically significant differences due to those characteristics.

Trial Design

Some design and methodological approaches can also facilitate enrollment of a broader population:

  • Determining drug metabolism and clearance (e.g., by age, race, organ dysfunction) early in clinical development can provide the data to inform the exclusion criteria and dose adjustment, if needed, for different populations in later trial phases.
  • Adaptive clinical trial designs have become more common, to help reduce overall trial timelines. They can allow for design changes, including modifications to the trial population, as trial data become available; for example, interim safety data might support a broader population in trials where a smaller sample was initially used due to safety concerns.
  • Avoid, when possible, the sequential enrollment of pediatric groups by age (e.g., older children first, followed by younger children), because this can delay drug development. Instead, consider a broader pediatric development program early.

Enrichment Strategies

Enrichment, when participants with specific disease or genetic characteristics are enrolled, has also become a more popular trial design given its benefits for a greater chance of demonstrating efficacy. However, broad exclusions should still be avoided. It might be beneficial to include marker-negative participants with the disease, particularly if it is expected that the drug might also be used for these people, as well as patients with varying disease severity. These participants could always be included in secondary analyses of efficacy.

Other Strategies

In addition to demographic and clinical characteristics, other considerations to improve clinical trial enrollment include those related to participant resources, such as time, cost, and travel, as well as participant confidence in the trial process itself.

To address these, consider if the number of visits can be reduced, some visits can be moved to virtual settings (e.g., mobile apps, telehealth), or home health visits can be used. Financial reimbursement could be made available to participants for travel, meals, or child care expenses.

Collaboration with community leaders and groups, patient advocacy groups, and local healthcare providers can support community outreach efforts, distribute education materials, and help instill trust in research. Insights from these groups can also be used to inform the protocol design and ensure that community concerns are considered. Provision of trial materials in multiple languages and a multilingual team will improve communication with potential participants.

Alternative recruitment strategies such as social media channels and disease support groups might reach a broader population than a traditional referral center, particularly when social distancing is important such as during the current pandemic.

Finally, consider the use of real-world data such as electronic health records and claims data to identify potential sites and participants.

Challenging But Not Impossible

We recognize that the level of diversity required to achieve a representative study population has been difficult for many studies to achieve. Success requires both strategic know-how and expert execution, as we discussed in a recent blog post. Therefore, it’s great to see the FDA provide their expert guidance for strategies that are likely to be successful, many of which we are using to support ongoing trials, including COVID-19 vaccine trials.


Schedule a demo today to learn how Trialbee’s recruitment and retention programs using real-world data such as electronic health records and claims data can support the identification and inclusion of a representative sample in your next clinical trial.

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