FDA Leaders Outline New Regulatory Framework for Oncologic CAR T-Cell Therapy Approvals

Leaders from the Food and Drug Administration outlined a shift toward randomized clinical trials (RCTs) as the preferred evidentiary standard for initial approval of new chimeric antigen receptor (CAR) T-cell therapies in oncology in a viewpoint published Dec. 8 in JAMA.

In the article, Marty Makary, MD, MPH, commissioner of food and drugs; and Vinay Prasad, MD, MPH, director of the Center for Biologics Evaluation and Research, noted that earlier CAR T-cell therapy approvals were largely based on single-group trials in relapsed or refractory settings, with response rate as the primary endpoint. More recent supplemental approvals have relied on randomized trials, demonstrating improvements in event-free survival, progression-free survival and, in some cases, overall survival compared with standard-of-care therapies.

Under the agency’s planned pathway, RCTs with overall survival or other acceptable time-to-event endpoints should generally form the basis of initial approval for new CAR T-cell therapies when feasible and ethical. Trial designs should account for available standard treatments, including approved CAR T-cell therapies, and should generally demonstrate superiority over control therapies. Sponsors should also discuss confirmatory evidence with FDA.

Makary and Prasad emphasized that while overall survival is the most direct measure of clinical benefit, FDA may also consider patient-centered end points such as quality of life, durable remission, delays in subsequent toxic therapies and cure. In indolent cancers, where survival data may take years to mature, biomarkers such as minimal residual disease may be evaluated as surrogate end points on a case-by-case basis.

They also affirmed that single-group trials may remain appropriate in rare cancers or heavily pretreated populations where RCTs are not feasible or ethical, but durable responses from such studies will generally support accelerated rather than traditional approval. When accelerated approval is granted based on a single-group trial, the agency expects sponsors to provide confirmatory evidence, which may include additional randomized studies, longer-term follow-up or real-world evidence. They also noted that accelerated approval is intended to expedite access for patients with serious or life-threatening cancers and requires sponsors to justify the unmet medical need their product addresses.

The officials also highlighted the importance of long-term safety monitoring, noting that the FDA currently recommends follow-up for 15 years for patients treated with CAR T-cell products manufactured using integrating viral vectors, though the agency may reconsider this requirement in the future.