The FDA recently developed a requirement for a “Race and Ethnicity Diversity Plan” for Investigational New Drug Applications.1 The goal is to ensure clinical trials adequately enroll historically underrepresented racial and ethnic backgrounds in the United States. The challenge of enrolling adequate proportions of patients based on race, ethnicity, sex, age, and socioeconomic status is well documented.2–5 By ensuring adequate representation across various disease states, the FDA hopes to better characterize the efficacy and safety outcomes associated with the use of pharmaceuticals. The approach to achieving this will be multifaceted, requiring collaboration between the FDA, study sponsors, healthcare facilities and providers, patient advocacy groups, and others. In this commentary, we propose community oncology center partnerships as one cornerstone of the solution.
Racial and ethnic minorities are underrepresented in oncology research despite disproportionate disease burden. Up to 20% of pharmaceuticals have effects that differ depending on race and ethnicity.6,7 Underrepresentation of minority populations in clinical trials has been demonstrated in several studies; one study found that African Americans account for 12.1% of the US cancer population, yet only 2.9% of patients enrolled in pharmaceutical company–sponsored cancer clinical trials were African American.8,9 Study site selection is one reason for this. The concentration of trials in academic institutions impacts the populations represented in trials. Given that up to 80% of oncology care is provided in the community, including these sites in trials is important.10
In multiple myeloma (MM), long-term proteasome inhibitor (PI)–based therapy improves outcomes.11 Attaining long-term proteasome treatment is challenging due to treatment-related toxicity and administrative burden.12 Ixazomib is an oral PI approved by the FDA in combination with lenalidomide and dexamethasone (IRd) for patients with MM who have received at least one prior line of therapy, with similar approvals granted around the world.13–16 IRd has shown a significant progression-free survival benefit in patients with relapsed/refractory MM, with limited additional toxicity compared with placebo + lenalidomide/dexamethasone.17
US MM-6 is an ongoing phase IV, prospective, interventional clinical trial (ClinicalTrials.gov identifier: NCT03173092) assessing whether induction with any bortezomib-based regimen followed by an in-class transition to an ixazomib-based regimen can prolong PI-based treatment in patients with newly diagnosed MM ineligible for transplant. The study is being conducted in community oncology centers with broad inclusion/exclusion criteria in order to optimize recruitment of underrepresented populations and to mimic real-world management.18
In total, 22 US community oncology centers enrolled 141 patients. Median age was 73 years (range, 48–90 years); 58% are male; and 18% identified as African American, 2% as Asian, and 9% as Hispanic. The International Staging System (ISS) disease stage was classified as I, II, or III in 26%, 41%, and 31% of patients, respectively. A total of 29% of patients had a calculated baseline creatinine clearance (CrCl) of <60 mL/min. As of October 17, 2022, median follow-up was 26.8 months. Median duration of IRd was 11.0 months (14.0 months total PI duration). Overall response rates increased from 62% following bortezomib-based induction to 80% following in-class transition to IRd (Kaplan-Meier estimated 2-year progression-free survival of 71%; 2-year overall survival of 86%). Results from this trial have been submitted for publication (Rifkin et al, unpublished data, May 2023).
Up to 72% of real-world patients with MM are considered ineligible for randomized controlled trials (RCTs).19 Analysis showed that approximately 40% of patients enrolled in US MM-6 would likely not have been eligible for an RCT. The US MM-6 trial was able to enroll patients representative of the real world; 18% were African American compared with 5% enrolled in pharmaceutical-sponsored clinical trials8 and 20% of patients with newly diagnosed MM in the United States.20 Although more than half of patients with newly diagnosed MM have comorbidities and ≥30% are considered frail, in US MM-6, 94% of patients had at least 1 comorbidity at the start of IRd therapy and 55% were considered frail.21 Figure 1 further demonstrates the advantage of trial proximity to community oncology centers in relation to the ability to continue enrollment during COVID-19.
Enrollment on US MM-6, 2017–2021. Enrollment was uninterrupted, nationwide, during the COVID-19 pandemic. US MM-6 provided an oral, accessible, continuous treatment option for patients during the height of transmission.
Citation: Journal of the National Comprehensive Cancer Network 21, 8; 10.6004/jnccn.2023.7058
US MM-6 demonstrated the feasibility of conducting prospective clinical trials in the community. Because the trial sites in US MM-6 were limited to community oncology centers, demographics were expected to represent real-world patients with MM. However, to ensure adequate representation of racial and ethnic minorities, site selection was based, in part, on geographic distribution and their predicted enrollment of these individuals. Several Veterans’ Affairs research centers were included to adequately represent that population. Inclusion and exclusion criteria were broad, yielding a high number of patients included in US MM-6 who would have been ineligible for RCTs.
Accurately characterizing the efficacy and safety of pharmaceuticals is necessary to optimize patient outcomes, particularly in the age of personalized medicine. The FDA’s guidance on diversity and inclusion is a catalyst for the healthcare industry to rethink clinical development. Reaching underrepresented populations can be challenging, but this report demonstrates the feasibility of leveraging US community oncology centers in prospective interventional clinical studies to reach real-world populations.
References
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JOSHUA RICHTER, MD
Joshua Richter, MD, is an Associate Professor of Medicine, Hematology and Oncology in the Myeloma Division at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, and the Director of Myeloma at the Blavatnik Family Chelsea Medical Center at Mount Sinai. Dr. Richter completed his hematology/oncology fellowship at the Yale Cancer Center. In 2018, he joined the Myeloma Division at Mount Sinai Hospital. He has an interest in immunotherapy, multifunctional antibodies, and precision medicine.
STEPHEN J. NOGA, MD, PhD
Stephen J. Noga, MD, PhD, is the US Medical Lead for Multiple Myeloma and Immuno Oncology for Takeda Oncology and previously served as Clinical Professor of Medicine at the University of Maryland, Baltimore.
ROBERT RIFKIN, MD
Robert Rifkin, MD, is a board-certified medical oncologist and hematologist specializing in malignant and benign hematology, treating blood cancers and disorders. He has an advanced sub-specialty expertise in coagulation disorders, multiple myeloma, and biosimilars.
