Earlier this week, the FDA released guidance to enable greater diversity in clinical trials through changes to eligibility criteria, enrolment practices, and trial designs.
Underrepresentation of minority groups, including but not limited to; ethnic minorities, women, people with health conditions and the elderly, has remained an unmet challenge for a considerable amount of time.
With that being said, the release of this guidance is most definitely a step in the right direction to addressing that challenge. If you’d like to learn more about the changes that have been made, we’ve summarised the guidelines below.
Broadening eligibility criteria to increase diversity in enrolment
The new guidance begins with practices that could be implemented into enrolment strategies, which could make clinical trials more inclusive and reach a broader audience. Whilst the FDA acknowledges that in some circumstances it is beneficial to exclude particular groups of people, such as excluding people with higher chances of toxicity, they have also outlined that many clinical trials simply use the same template when it comes to eligibility criteria. This leads to many trials excluding perfectly eligible groups of people, with no scientific justification.
That being said, this section speaks on how to broaden eligibility criteria in phase III clinical trials through inclusive trial practices, trial design and methodological approaches, and enrichment strategies:
Inclusive clinical trial practices
Consider eliminating or modifying the criteria to expand the study population. Clinical trials should consider which exclusion criteria are absolutely necessary, and which can be dropped or modified. For example, if those with advanced heart failure were unable to participate, would it be the same for those with a milder condition? Is it necessary to exclude all people with varying degrees of heart failure?
Question whether exclusion criteria from phase II studies are suitable for phase III. Exclusion criteria from phase II studies can be incredibly restrictive, and clinical trials should consider expanding their eligibility criteria when progressing through to phase III studies. Especially as new data from the phase II studies may eliminate exclusion criteria. For example, drug-drug interaction studies may enable those who currently take prescribed medicine to take part.
Eligibility criteria should closely mirror the population the drug aims to treat. The guidelines outline the importance of including participants of different ages, sexes, races and ethnicities. Sponsors should include a plan for the inclusion of clinically relevant populations no later than the end of phase II studies.
Trial design and methodological approaches
The FDA then outlines example approaches for the trial design and methodology that could help sponsors to increase representation in their trials:
Consider characterising drug metabolism and clearance across different populations.
Use an adaptive clinical trial design to accommodate any changes.
Consider a broader paediatric subgroup development program.
Consider pharmacokinetic sampling to allow continued participation of pregnant women.
Implementing enrichment strategies
Enrichment strategies can be used by companies to demonstrate the efficacy of a drug through targeted inclusion of specific populations. For example, a clinical trial investigating a cardiovascular drug would specifically seek to enrol participants with risk factors for cardiovascular disease. However, the FDA does reiterate that enrichment strategies should not lead to the exclusion of other populations.
Study design and conduct considerations to improve enrolment
Narrow eligibility criteria isn’t the only factor that impairs enrolment; study design and how clinical trials are conducted have an impact too. For example, clinical trials that require frequent hospital visits are open to financial and travel burdens, whilst medical mistrust can impact people’s interest in clinical trial enrolment.
The FDA provides key examples of how to improve study design and conduct to enhance enrolment:
Make trial participation less burdensome for participants. This includes the use of virtual platforms, real-time data, and adopting a more decentralised trial approach. In addition, participants should also be made aware of any financial reimbursements associated with travel that they could entitled to.
Adopt enrolment and retention practices that enhance inclusiveness. This includes public outreach and education, community engagement and strengthening relationships, use of clinical trial sites in locations with a high population of ethnic minorities, adapting recruitment event times to make them more accessible, and more.
Expand access. The FDA recognises that while they may not necessarily meet the eligibility criteria, some patients should be allowed access to clinical trials when they have a serious or life-threatening condition.
Broadening eligibility criteria and encouraging recruitment for clinical trials of investigational drugs intended to treat rare diseases or conditions
Lastly, the FDA addresses the unique recruitment challenges in clinical trials that are investigating drugs for rare diseases. As patients with rare diseases are few and far between, it can be difficult to ensure that representation goals are met.
To help minimise underrepresentation in these studies, the FDA outlined some changes in the enrolment process:
Engage with patient advocacy groups, experts and patients, early on in the drug development process. Allowing patients to have a say in the design of trials would ensure that all the active participants are committed.
Consider re-enrolment of participants from earlier phases. With limited numbers of eligible rare disease patients, it may be beneficial to re-enrol previous participants in later phases. Though, the FDA cautioned against selection bias, where patients with better tolerance to the drug would be selected to participate in further trials.
Overall, the efforts of the FDA to produce updated guidelines, specifically with aims to improve diversity and representation in clinical trials, can only result in the increase in accuracy of clinical trial data, improving quality of clinical trial data, and ultimately ensuring efficacy and safety in populations that are commonly underrepresented.