Ensuring Diversity in Clinical Trials Remains Critical

Diversity in clinical trials is critical to ensure the data generated from medical research accurately reflects the patient populations that will ultimately be using the resulting treatments, explained Corey Cutler, MD, MPH, president of American Society for Transplantation and Cellular Therapy (ASTCT), during the 2025 ASTCT and Center for International Blood and Marrow Transplant Research (CIBMTR) Tandem Meeting in Honolulu, Hawaii. The issue of diversity in medical research is particularly important in the United States, where broad demographic variations exist in terms of race, ethnicity, socioeconomic status, and genetic background.

“Notwithstanding recent events in American politics, we all understand that diversity in clinical trials remains a very important guiding principle for all of us as investigators,” Cutler said during the ASTCT and CIBMTR Tandem Meeting. “Diversity in clinical trials really ensures that data that we generate from our studies, either here in the US or abroad, is reflective of the diverse population of the United States.”

Innovation in health care and medical research. Image Credit: © elenabsl - stock.adobe.com

In June 2024, the FDA released updated draft guidance on diversity action plans, underscoring the importance of inclusive clinical trials and replacing the prior guidance issued in 2022. However, Cutler noted this guidance is no longer available on the FDA website.

“In this currently unavailable document—not kidding—the FDA recognized broader issues of health disparity and differential access to health care that underpinned the need to perform clinical trials in diverse patient populations,” Cutler said.

According to Cutler, despite the absence of this 2024 FDA guidance online, the regulatory evolution from 2022 to 2024 highlights the ongoing recognition of the importance of addressing disparities in health care access and outcomes. To further this cause, an ongoing concerted effort to perform clinical trials among diverse patient populations will be necessary.

“One way to ensure diversity is to perform multi-regional trials, which are studies that are performed in either multiple countries, geographic locations, or regulatory environments. In fact, the FDA released guidance on the conduct of multi-regional clinical trials shortly after its diversity guidelines were promulgated, and, in fact, these are still available [online],” Cutler said. “Multi-regional clinical trials are used to achieve rapid accrual goals, recognizing, as investigators, that performing these international clinical trials is difficult for several reasons.”

One such reason relates to the variations in regulatory guidelines between the FDA, the European Medicines Agency, and regulatory agencies in other countries. These disparities can impact study design, particularly regarding comparator arms in graft-versus-host disease (GVHD) trials, for example, as illustrated by the REACH trial (NCT02999087). In this trial, there were certain compounds used in European trial sites that are routinely used for chronic GVHD in European countries, while in the US, the only FDA-approved agent at the time of the REACH trial was not widely available in Europe. Such discrepancies complicate the interpretation of trial outcomes and require careful consideration when designing international studies.

“In performing these international trials, we know that there are important differences in standards of care, such as for comparator arms in GVHD therapeutic trials,” Cutler said. “Similarly, standards of care in leukemia induction can make trials difficult to interpret, as we recently learned from the BMT-CTN 1506/MORPHO trial [NCT02997202], where outcomes following an intervention were different in different areas across the world.”

In addition to regulatory challenges, socioeconomic factors play a profound role in clinical trial participation and transplant outcomes, explained Michael Verneris, MD, a pediatric hematology/oncology and bone marrow transplant physician at the University of Colorado and Children’s Hospital Colorado in Aurora. According to Verneris, studies by CIBMTR have shown that children with public insurance experience worse transplant outcomes compared to those with private insurance. Moreover, unrelated donor transplantation outcomes can be influenced by the socioeconomic status of the donor, suggesting that financial disparities extend beyond the patient and impact broader transplant success rates. Further, countries with lower health care expenditures as a percentage of gross domestic product also exhibit higher treatment-related mortality and inferior overall survival rates among patients who develop GVHD.

“Other factors that influence outcome are biological and genetic diversity, and these are critical to ensuring that novel treatments are safe and effective for all patient populations. From a genetic standpoint, solid genetic differences in the form of single nucleotide polymorphisms for the P450 enzyme family are associated with variations in the metabolism of tacrolimus,” Verneris said. “Similar associations have been found with ondansetron and voriconazole [Vfend; Pfizer], so understanding genetic diversity and how it influences our clinical trials is critical.”

Failure to account for these genetic differences in clinical trial design can lead to misleading data relating to drug efficacy and safety. Additionally, patient age is another variable influencing transplant outcomes, with distinct patterns observed for both acute and chronic GVHD based on recipient and donor age, according to Verneris. These biological factors must be carefully integrated into trial design to optimize treatment strategies for diverse populations.

The Value of International Research

According to John Galvin, MD, MS, MPH, lead medical director for GVHD at Incyte Pharmaceuticals for US Medical Affairs, advancements in GVHD treatment highlight the importance of conducting international studies to obtain accurate representation of diverse populations who will use the drug globally. Improvements in GVHD prophylaxis, such as the use of post-transplant cyclophosphamide and newer agents such as ruxolitinib [Jakafi; Incyte Corporation], have contributed to making transplantation safer and more accessible.

“We've had a lot of advancement in GVHD treatment over the last 10 years, starting with the approval of ibrutinib [Imbruvica; Janssen Biotech and Pharmacyclics] in 2017, and since then, multiple approved treatments in the US for refractory acute GVHD and refractory chronic GVHD,” Galvin said. “The most recent approval happened late last year with axatilimab [Niktimvo; Incyte Corporation and Syndax Pharmaceuticals].”

However, international studies in GVHD, such as REACH3 (NCT03112603), which supported the approval of ruxolitinib, and AGAVE-201 (NCT04710576), which supported the approval of axatilimab, required overcoming significant challenges, including discrepancies in standards of care, varying definitions of clinical end points, and resource constraints associated with large-scale international studies. Despite these obstacles, Galvin explained that international trials continue to offer clear advantages. Both REACH3 and AGAVE-201 were conducted across diverse health care systems, providing valuable insights into treatment effectiveness in different populations. Their international scope also facilitated faster patient enrollment, enabling more timely trial completion and regulatory approval.

However, ensuring study cohorts accurately reflect real-world patient demographics remains a challenge. Historically, US cancer trials have struggled to achieve adequate representation of minority populations. For instance, data from CIBMTR reveal that Black patients remain underrepresented in pivotal GVHD trials, despite accounting for approximately 10% of allogeneic transplant recipients in the US.

Addressing these disparities requires targeted interventions by both trial sponsors and research sites, according to Galvin. Sponsors must prioritize site selection in regions serving diverse patient populations and provide logistical support, such as travel reimbursements and childcare assistance, to facilitate trial participation. Additionally, innovative approaches like decentralized trials, virtual study visits, and home-based care can help reduce participation barriers, particularly for underrepresented groups. Research sites, in turn, should implement robust diversity monitoring metrics and integrate inclusive recruitment strategies into their trial operations.

Regulatory agencies are also playing a critical role in fostering global collaboration. The FDA's Project Orbis, initiated in 2019, exemplifies efforts to streamline international regulatory approvals. Through this initiative, the FDA collaborates with 8 other regulatory agencies, including the Therapeutic Goods Administration in Australia, the Medicines and Healthcare products Regulatory Agency in the United Kingdom, the Health Sciences Authority in Singapore, Swissmedic in Switzerland, Agência Nacional de Vigilância Sanitária in Brazil, Health Canada, the Ministry of Health in Israel, and Pharmaceuticals and Medical Devices Agency in Japan, to facilitate simultaneous drug approvals across multiple countries. Such programs are instrumental in accelerating patient access to innovative therapies worldwide, according to Galvin.

Looking to the Future

To further improve trial design and regulatory decisions, Galvin highlighted the importance of using registries such as CIBMTR and EBMT, combined with prospective observational studies, patient-reported outcomes, and biospecimen repositories, which can be integrated with advanced analytical tools and machine learning.

“There are multiple benefits to designing studies to be international at day 1, and the risks and challenges involved in these types of studies can be addressed with collaboration and innovation. We can implement new methods to improve access, and I think that there's going to be no one size fits all for a given region's issues [pertaining] to patients getting on a study, and you have to sort of fit the study design to the challenges and the resources [of] each region,” Galvin said. “When we come up with new end points and new designs, we should [make them] evidence based. I think a lot of that is going to come from better data regionally and better data for specific patient populations and specific disease groups.”