Differences between the draft and final guidance

The final guidance is based on a June 2019 draft version, and includes several suggestions for diversifying study populations. The new recommendations, discussed in more detail below, include broadening study subject eligibility criteria by using real-world data to find participants and using mobile medical professionals to visit participants at their locations instead of requiring participants to visit distant clinical trial sites. The final guidance also has new information on the inclusion of racial and ethnic minorities, advancing community engagement, and making recruitment events more accessible.

Broadening eligibility criteria

First, FDA recommends diversifying clinical trials by broadening eligibility criteria to avoid the unnecessary exclusion of specific subgroups. For instance, FDA notes that in preliminary trials, investigational drugs typically lack sufficient safety data to adequately assess the risks that the drugs present to more vulnerable populations, such as pregnant women and people with organ dysfunction. As a result, those populations are often necessarily excluded from clinical trials in the earlier stages of drug development.

However, as safety data become available and dosing adjustments are made, FDA believes there should be fewer exclusions related to concomitant medications or comorbidities. Likewise, as the study drug’s safety profile improves, FDA recommends that clinical trial eligibility criteria be broadened to include those more medically complex subjects. This approach can be accomplished by narrowing the exclusion criteria in later trials to only those specific conditions that are associated with heightened safety risks. For example, where trial participation presents an unreasonable risk to participants with advanced heart failure, but not to participants with mild heart failure, only those advanced cases should be excluded.

Bridging the data gap between clinical trial population and real-world patient population

FDA also explains its view that inadequate participation of clinically relevant populations results in insufficient safety and efficacy data. Thus, clinical trial sponsors should seek to bridge the data gap between the clinical trial population and the real-world patient population by enrolling participants who reflect the characteristics of clinically relevant populations with regard to age, sex, race, and ethnicity. For example, FDA suggests that sponsors enroll infants and adolescents in confirmatory trials with adults, and enroll women and racial and ethnic minorities in numbers sufficient to allow for analysis of the study data by sex, race and ethnicity.

Using new trial designs and methodological approaches

FDA further recommends that sponsors consider various trial design and methodological approaches that will facilitate the enrollment of a broader population. Examples of such trial design considerations include:

• characterizing drug metabolism across populations that may metabolize or clear the drug differently in order to allow for dose adjustments and reduce the likelihood of unnecessary exclusion,

• using an adaptive clinical trial design to allow for pre-specified trial design changes during the trial when data become available,

• developing a broader pediatric development program, and

• including pharmacokinetic sampling to establish dosing in women who become pregnant during a trial.

The guidance also recommends utilizing enrichment, which is described as a trial design strategy involving the targeted inclusion of certain populations, with the goal of more readily demonstrating the drug’s effect.

Reducing the burden of clinical trial participation

FDA explains that along with the diversity limitations imposed by narrow eligibility criteria, certain populations may be precluded from participating in clinical studies if they face additional challenges related to their obligations in the trials. For example, trials requiring frequent clinic visits may impose a greater burden on elderly, disabled, and adolescent participants. Financial costs associated with traveling to clinic visits and taking time away from work, may also preclude certain populations from participation. The guidance explains that these barriers may be addressed by designing clinical trials to be less burdensome, including:

• reducing the frequency of clinic visits,

• considering use of electronic communication to replace in-person visits,

• using mobile medical professionals to visit and assess participants at their locations, and

• using electronic informed consent forms to permit remote trial enrollment.

FDA also suggests that trial sponsors may consider offering financial reimbursements for costs associated with trial participation to alleviate any financial burden on study participants.

Adopting more inclusive enrollment and retention policies

In line with the guidance's overall theme of broader participation, FDA suggests that clinical trial sponsors adopt enrollment and retention policies that advance inclusiveness for diverse study populations. FDA recommends public outreach and education such as working directly with communities to assess and address potential participant needs, and remaining engaged with those communities after the conclusion of the trial to continue fostering trust.

Sponsors may also consider providing cultural competency and proficiency training for clinical investigators and research staff to help facilitate trust with underrepresented communities and help decrease biased communication and behavioral practices.

Further, trial sponsors should consider expanding clinical trial sites to include geographic locations with a higher concentration of racial and ethnic minorities, making recruitment events accessible by holding them often and on weekends, and using online and social media recruitment to reach participants who do not have access to traditional referral centers.

To facilitate outreach to non-fluent English speakers, the guidance also recommends providing trial resources and documents in multiple languages and providing multilingual research staff or interpreters.

Improving the quality of clinical studies

The guidance concludes its series of practical suggestions by stating that implementing these recommendations aimed at diversity in clinical trial populations will improve the quality of clinical studies:

• by ensuring that the study populations more accurately represent the population that will ultimately use the drug,

• by allowing for the development of important safety information about the drug when used in certain populations, and

• by increasing the ability to understand the drug’s safety profile in later stages of drug development.

If you have any questions about this guidance, or clinical trial regulations more generally, please feel free to contact any of the authors listed below or the Hogan Lovells attorney with whom you regularly work.

Authored by Robert Church, Eman Al-Hassan, Heidi Gertner, and Blake Wilson