The Food and Drug Administration (FDA) has announced the release of draft guidance intended to enhance the diversity of clinical trial populations with recommended approaches to expanding eligibility criteria and increasing enrollment of underrepresented populations. Through the guidance, the agency wants to encourage the inclusion of participants in clinical trials that are reflective of the population for which the product is intended.
The FDA notes that current clinical trial recruitment strategies often exclude certain populations without strong clinical or scientific justification, such as the elderly, people with multiple conditions, and children. The guidance provides recommendations for more inclusive trial practices and designs to expand eligibility criteria and enrollment practices.
The guidance outlines several recommendations for inclusive trial practices (pg. 4):
- Examine each exclusion criteria to determine if it is necessary in assuring the safety of trial participants. If not, consider eliminating or modifying the criteria to expand the populations, and create narrow exclusion criteria to avoid unnecessary exclusions.
- Consider if criteria from phase 2 studies can be eliminated or modified to expand study population.
- Base exclusions on appropriate measure of organ dysfunction where participants with impaired organ function would be placed at risk.
- Consider the inclusion of children (ages 2 to 11) and adolescents (ages 12 to 17) in confirmatory trials.
Next, the guidance outlines trial design and methodological approach considerations (pg. 5-6):
- Consider the characterization of drug metabolism and clearance across populations that may metabolize the drug differently, in early clinical development. Early characterization of metabolism and clearance will assist in avoiding later exclusions.
- Consider using adaptive clinical trials that allow for pre-specified changes through out the trial, including the alteration of trial population. This allows for clinical trials that start with a small populations based on safety concern to later expand based on interim data.
- Consider a pediatric development program early when enrollment is justified with clear scientific rationale. Additionally, consider staggering enrollment based on age.
- Consider a broader participant group as a part of secondary efficacy and safety analyses, even when the primary analyses are narrow. The inclusion of the broad spectrum of disease severity in secondary analyses allows the study to utilize enrichment to demonstrate effectiveness and safety in a broader population, without jeopardizing the success of the primary clinical endpoint.
- Consider the inclusion of pharmacokinetic sampling in pregnant women, when appropriate and when it is possible for continued participation, in order to establish dosing in women who become pregnant during trials. This may provide information on drug metabolism across trimesters.
Finally the guidance presents other considerations to improve enrollment. Briefly, these considerations are:
- Make trial participation less burdensome (pg. 7)
- Adopt enrollment and retention practice that enhance inclusiveness (pg. 8)
- Expand access (pg. 9)
The FDA then details recommendations specific to broadening the eligibility criteria and encouraging recruitment for clinical trials intended to treat rare diseases. (pg. 9-10):
- Engage early with patient advocacy groups that are committed to finding new therapies in order to elicit their opinion on trial design considerations.
- Plan to pre-enroll participants from early-phase trial in to later-phase trials when examining the effectiveness of products for rare disease. Traditionally, early-phase participants are not eligible for phase 3 trials, but when the study population is narrow for rare diseases, re-enrolling participants may facilitate analyses of safety and efficacy.
- Make available an open-label extension extension study after early-phase studies to encourage greater participation by those who received placebo.
Comments on the draft guidance are due in 60 days, placing the deadline on or near August 6, 2019.