Recruiting underrepresented populations for phase I studies: How earlier diversity planning leads will benefit your programs later

The FDA recently released a draft guidance that outlines sponsor responsibilities for recruiting underrepresented populations for clinical trials. Under this guidance, which expands on draft guidance issued in April 2022, a study sponsor must create a diversity action plan that details enrollment goals based on participant age, ethnicity, race, and sex. Sponsors are also encouraged to consider additional factors such as comorbidities, disabilities, gender identity and sexual orientation, geographic location, pregnancy and lactation, and socioeconomic status. For multinational studies, the FDA asks sponsors to specify enrollment goals for all sites, not just those in the U.S.

In addition to setting diverse-population goals, the sponsor must also describe how those goals will be met. The FDA suggests several possible strategies, including sustained community engagement and targeted efforts to improve awareness, cultural competency training for study staff, broader inclusion criteria, the use of study sites that serve diverse populations, and the use of decentralized study elements when possible.

When this guidance is finalized, sponsors will need to submit diversity action plans in conjunction with their phase III IND applications at the latest. At Parexel we are urging drug developers to plan for diverse populations from first-in-human trials. Ensuring diversity among early-phase participants helps sponsors understand their products more fully and ensure they are optimized for real-world populations.

The importance of diverse patient populations

To be maximally effective, clinical research must reflect the diversity of the real-world populations it seeks to serve. Because genetic makeup greatly impacts a person’s response to a drug, drug efficacy and side effects can vary widely among subpopulations. If a clinical study lacks diverse participants, the resulting treatments may not be optimized for the whole population, leading to further health inequities for groups that have already experienced marginalization in health care and beyond.

Drug response is a complex interaction between extrinsic influences and intrinsic factors, including age, ethnicity, race, and sex, among other considerations. Early evaluation of these intrinsic factors can result in insights that inform future studies. For example, we’ve learned that Black patients have a higher incidence of coughing when using ACE inhibitors compared to other ethnic populations, particularly white patients. Because  early-phase ACE inhibitor studies did not evaluate drug responses based on race and ethnicity, developers were surprised by this finding in late-phase trials and had to make changes that likely resulted in longer timelines and increased costs.

Black patients’ differing reaction to ACE inhibitors was also followed by the  FDA approval of BiDil (isosorbide-hydralazine) specifically for Black people with congestive heart failure. While researchers were disappointed with the drug’s total-population performance, subgroup analysis showed that the drug had positive efficacy among Black patients. Data demonstrated a significant decrease in mortality within the subgroup and a significant reduction in first-time the hospitalizations compared to the placebo. Had BiDil not been studied among diverse patient groups, its subgroup efficacy might have gone undiscovered.

It is also important to remember that groups that are underrepresented in clinical trials may bear a disproportionate burden for certain diseases. Consider asthma, which impacts eight to nine percent of the general population in the U.S. The prevalence and incidence of asthma is notably higher, however, among Black and Indigenous people. There are also differences in severity and outcomes — the mortality rate from asthma is about twice as high among Black people as it is among white people. And over the course of a year, women are approximately three times more likely than men to be hospitalized due to asthma. Asthma prevalence is also linked to socioeconomic status, with the highest rates of asthma occurring among people living below the poverty threshold

Addressing barriers to participation

There can be multiple significant barriers to recruitment of diverse patient populations. Mitigating these challenges early in development will help improve recruitment in the later stages of drug development.

The first step to addressing barriers is understanding them. What factors might be preventing underrepresented groups from joining trials? One issue could be lack of outreach to these communities from research professionals. But there can also be community-specific considerations at play. For example, people of color may distrust the medical establishment because of historical injustices. People with lower socioeconomic status may not be able to take time off from work to participate in studies. Lack of childcare may be a barrier for women, who are statistically more likely than men in the U.S. to be stay-at-home parents.

To address these barriers, sponsors can:

• Work to build relationships within underrepresented communities. At Parexel, we’ve had success partnering with trusted local healthcare providers, community organizations, and patient advocacy groups.
• Use study sites that are geographically located within underrepresented communities and employ study staff from diverse backgrounds.
• Offer early-morning, evening, and weekend hours at sites to accommodate work and caregiving schedules.
• Provide on-site childcare or childcare reimbursement.
• Help patients arrange travel and hotel stays, if necessary.
• Ensure that protocols do not require unnecessarily burdensome visits, lab work, or other requirements.
• Ensure that protocols do not include unnecessarily restrictive inclusion or exclusion criteria. For example, in studies for multiple myeloma therapies conducted between 2006 and 2019, the percentages of Black patients who failed to meet treatment-related and hematology laboratory-related criteria were notably higher than white patients.
• Reconsider care documentation requirements. Historically, sponsors have required clinical study patients to provide medical documentation of their condition and past treatment. But because many underrepresented populations lack access to consistent health care, their records will be less complete.

Building patient diversity into early-phase research

While sponsors have the option to wait until phase III protocol approval to submit a diversity action plan, we strongly recommend recruiting underrepresented populations beginning with first-in-human trials.  Early-phase data informs future studies, making them as efficient and well-founded as possible. By implementing diversity strategies in phase I, you will build a patient community that you can draw from in later phases when their participation is critical.  It also gives sponsors, CROs and sites the opportunity to test patient engagement strategies to learn which ones work for specific patient populations and which don’t, saving valuable time and resources. 

The FDA requires sponsors to assess any data that indicates differing drug safety or efficacy associated with race or ethnicity, among other factors, which requires the collection of significant toxicokinetic, pharmacokinetic, and pharmacodynamic data from diverse patient populations. These types of data are collected intensively during earlier phases. If a sponsor waits until phase III to study patient subgroups and finds differences in response based on age, ethnicity, race, or sex, such a finding would necessitate changes in protocol design, inclusion criteria, and safety profile, leading to delays and impacts on patient safety.

Leveraging ethnobridging practices to improve diversity

In addition to removing barriers to participation for underrepresented populations, sponsors can increase study diversity through ethnobridging. This is when a clinical trial conducted in one global region enrolls specific ethnic populations to satisfy regulatory requirements in a different region. In the time since ethnobridging was addressed by ICH E5 Guidance, Parexel has conducted more than 300 ethnic sensitivity studies to compare safety, tolerability, and PK/PD among diverse populations.
Although ethnobridging can be conducted anywhere in the world, the strategy has been used most frequently in North American and European regions with large Asian populations, including Los Angeles and London. Because China and Japan require pharmacokinetic data prior to approving efficacy studies, this approach allows sponsors to enroll Asian participants in early Western-based studies while also preparing for future study approval in Asia.

The writing is on the wall

While diversity plan requirements are still draft guidance, we have increasingly seen the FDA ask sponsors for data on diverse populations, particularly in the oncology space. Regulators want to be sure that study populations reflect real-world populations. In these situations, sponsors who haven’t planned fully for diversity as part of protocol development must rush to design new studies — adding cost, extending timelines, and giving competitors the opportunity to reach market first. 

At Parexel, our philosophy on diversity planning can be summed up this way: the earlier you start, the earlier you succeed. Implementing a diversity plan in early-phase research means that the strategy is integrated into the research process from the outset, allowing sponsors to benefit from early insights that can inform each subsequent phase of research.
 

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