Age-Based Disparities in Clinical Trials Supporting FDA Approval of Therapies for Hematologic Malignancies

Abstract

Introduction: Older adults comprise the largest proportion of patients diagnosed with hematologic malignancies, with most new cases occurring in adults age 65 years and older. The under-representation of older adults in oncology clinical trials has been previously described, however data specific to hematologic malignancy trials is sparse. We conducted an analysis of the trials supporting Food and Drug Administration approval of new hematologic malignancy therapies over a 5-year period to evaluate the median age of participants and compared it to the real-world age distribution for the respective malignancy. Methods: Prescribing information for novel new hematologic malignancy therapies that were first approved for an indication in adult patients between 2015 and 2019 was reviewed for the median age in the evaluable population of the supporting clinical trials. Pediatric indications were excluded. Median age estimates among adults for each indication were obtained from the Surveillance, Epidemiology and End Results database. The difference in median age (DMA) was calculated for each trial by subtracting the median age in the disease population from the median age in the trial (Ludmir et al, JAMA Onc 2019). Additional details on trial protocols were obtained from approval packages accessed in the Drugs@FDA database and FDA's Office of Tissues and Advanced Therapies approvals website. Data are presented using descriptive statistics. Results: A total of 22 hematological malignancy therapies were approved based on 26 trials, with 6033 patients in the evaluable populations. Less than half of the trials were phase 3 (10; 38%) or were randomized with a control group (11; 42%). The median age of the trial participants was a mean of 3.8 years younger than the median age of the disease populations (95% CI: −6.0 to −1.6 years; p<0.01). By indication (Table), acute myeloid leukemia trials most often enrolled younger participants (mean DMA -7.8 years), followed by large B-cell lymphoma trials (mean DMA -7.0 years). The protocols for the majority of the trials (24; 92%) did not specify upper age limits, however most required an ECOG performance status ≤2, with only 2 trials (8%) permitting ECOG status 0-3. All trials had eligibility restrictions related to comorbidities, organ function, or hematopoietic function. Conclusions: The median age of hematologic malignancy clinical trial participants was nearly 4 years younger than their respective disease populations, despite few trial protocols having upper age limits. Poor performance status, the presence of comorbidities, or organ/hematopoietic impairment may have contributed to older patients' ineligibility to participate in the trials. Adequate representation in clinical trials is critical to evaluate the safety and efficacy of new therapies in the patient population who will eventually receive them. Given the inherent limitations of clinical trial design and accrual on older patient inclusion, post-approval real-world research is needed to understand the effect of these therapies on older adults. Disclosures Gajra: Cardinal Health: Current Employment. Zettler:Cardinal Health: Current Employment. Phillips Jr.:Cardinal Health: Current Employment. Feinberg:Cardinal Health: Current Employment.