Sponsors should make every effort to enroll older adults in their pivotal randomized trials, the U.S. Food and Drug Administration (FDA) says in a new draft guidance. “To encourage and facilitate the enrollment of older adults in cancer trials, FDA is available to discuss flexible approaches to trial design and analysis,” the agency says.
For example, the FDA said it may be acceptable to design a trial with stratification based on age, so that analyses can focus on benefits and risks among older adults. Alternatively, an open-label safety study can enroll and analyze an older adult population separately in a parallel arm of a trial, the FDA suggests in the guidance. In some cases, the older adult arm(s) can be actively accruing at the time of a New Drug Application or Biologics License Application submission.
For example, clinical trial practitioners could consider a trial design approach with a randomized controlled trial that enrolls younger and older adults and stratifies by age. In this scenario, the intent-to-treat (ITT) population consists of all enrolled patients and a modified ITT (MITT) consists only of the patients under 75 years of age. The trial would use hierarchical testing, and the primary analysis would be conducted in the MITT population, with subsequent analyses in the ITT population to provide safety and efficacy information about all patients. If the size of the older patient population is adequate and hypothesis driven, results in the older population can also be analyzed separately.
Distinctive benefit-risk considerations should be considered during drug development for older adults. FDA recommends that sponsors consider perspectives of older adults, including those of patients and patient and caregiver partners, clinicians, and advocacy groups, during the design of the clinical trial protocol. This is intended to ensure patient preferences are incorporated in clinical trial activities, when possible, to facilitate enrollment of older adults, and to improve identification of meaningful endpoints and overall trial design.
FDA notes that, in general, most cancer trials do not have an upper age limit for exclusion. However, older adults, particularly adults 75 years and older, continue to be “underrepresented in these trials.” FDA encourages sponsors and clinical trial cooperative groups to develop strategies to recruit patients who are reflective of the intended population. Possible challenges with recruiting older adults that could be mitigated, particularly among patients over 75 years, include: location of clinical trial sites (e.g., sites in community-based settings may be more accessible to older adults than sites located in urban academic centers), format and content of informational material for the trial, caregiver support, accommodations needed for impairment (e.g., visual, mobility, cognitive, etc.), and travel and other logistics.
“Sponsors should discuss specific goals for enrollment of older adults with clinical investigators and keep the clinical trial sites updated on the progress of enrolling older adults in the trial,” FDA says. Sponsors should discuss the importance of enrolling older adults during study training provided to the clinical sites. In addition, sponsors should consider recruitment of geriatric oncologists and oncologists with expertise in treating older adults.
Comments on the draft guidance are due by May 5, 2020.
Author: Michael Causey
