The approval pathway for CAR T-cell therapies is entering a new phase as regulators signal a shift toward more rigorous clinical evidence. Leaders from the Center for Biologics Evaluation and Research (CBER) outlined an updated regulatory approach in a recent JAMA publication, indicating that randomized controlled trials (RCTs) will become the preferred standard for most future CAR T approvals.
This marks a significant change from the early years of CAR T development, when several products were approved based on single-arm studies in heavily pretreated, relapsed or refractory populations.
A Move Toward Stronger Clinical Endpoints
According to CBER officials, future CAR T submissions should be supported by well-controlled studies that allow a clear comparison between investigational products and appropriate standard treatments. This includes approved CAR T therapies when relevant.
Regulators emphasized that the choice of control group is critical. Trials should reliably distinguish outcomes driven by the investigational therapy from those influenced by disease progression, patient expectations, or other treatments. Evidence demonstrating superiority over the control group will generally be expected.
Although overall survival is considered the most meaningful endpoint for patients, other clinical outcomes may be acceptable depending on the disease setting. These include durable remission, quality-of-life improvements, or delays in the need for additional therapy. For slower-progressing cancers where survival data may take years to collect, surrogate endpoints may be considered.
When Single-Arm Trials Are Still Acceptable
Regulators acknowledged that in rare cancers or settings where patients have undergone multiple relapses, conducting an RCT may not be feasible or ethical. In these cases, single-arm studies could still support accelerated approval, provided the therapy demonstrates a high and durable response rate.
However, traditional approval would require confirmation of clinical benefit, usually through an RCT.
Expectations for Accelerated Approval
For accelerated approval, sponsors must show that the therapy addresses a serious condition with an unmet medical need. Regulators noted that unmet need can be justified either by the absence of available therapies or by meaningfully improved benefit or safety compared with existing options.
If an accelerated approval is granted based on nonrandomized evidence, sponsors should plan to conduct a confirmatory RCT to verify the therapy’s clinical benefit.
Greater Clarity for Development Programs
CBER officials recommended that sponsors engage early with regulators to discuss trial design, selection of endpoints, use of biomarkers such as minimal residual disease, and plans for confirmatory evidence. These discussions should occur before pivotal trials begin to ensure alignment with regulatory expectations.
The article emphasized that while innovation in CAR T therapies continues at a rapid pace, stronger and more consistent evidence standards will help ensure that treatments entering the market provide clear, meaningful benefit to patients.
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Reference:
Prasad, V., et al. (2025). FDA regulation of CAR T-cell therapies. JAMA.
Regulatory Affairs Professionals Society. (2025). FDA to tighten approval requirements for CAR T-cell therapies.
