New FDA guidance signals a major shift for CAR-T development, calling for randomized trials with standard-of-care control groups and clear evidence of superiority over existing therapies, while simultaneously easing REMS requirements to reduce logistical burdens for treatment centers and patients.
FDA Biologics Chief Vinay Prasad, MD, MPH, has outlined new plans for how the agency will be approving chimeric antigen receptor (CAR) T-cell therapies in oncology.
In a new commentary published in JAMA, Prasad, along with other top FDA officials, described how the agency will be requiring potential CAR-T therapies to demonstrate superiority over existing CAR-Ts through a control group in randomized controlled clinical trials (RCTs).
“As the field of cell therapy matures, the FDA’s perspective continues to evolve to (1) maintain the high evidentiary standards for approval, and (2) exercise regulatory flexibilities, when necessary, to advance the development of these products,” the authors wrote.1
There are currently seven CAR-Ts approved, all of which were brought to market on the heels of data from single-arm trials without a control group.
The FDA officials emphasized the choice of control group, calling for sponsors to evaluate both standard of care and ethical components when deciding on treatments. The new goal for sponsors in RCTs evaluating CAR-Ts should be to ensure that outcomes from an investigational therapy are reliably distinguished from factors such as natural disease history and other treatments.
“Evidence should generally demonstrate superiority of the investigational CAR T-cell therapy compared with control,” Prasad and his colleagues wrote in the article. "Any plan to establish effectiveness of a new CAR T-cell product compared with an approved CAR T-cell therapy based on demonstration of equivalence or noninferiority must be adequately justified and discussed with the FDA.”
In June, Gilead and Arcellx unveiled results from a pivotal, single-arm trial evaluating their anti-BCMA CAR-T therapy for multiple myeloma. Data showed that it had potentially better safety than Legend Biotech and Johnson & Johnson’s CAR-T Carvykti.2 While Gilead and Arcellx plan to seek approval, it is unclear how this new FDA perspective will impact the potential therapy.
Meanwhile, pharmas including Bristol Myers Squibb, Gilead, and Lyell Immunopharma are currently running Phase III trials that compare CAR-Ts to standard of care, meeting the FDA’s new outline. However, challenges could unfold as more details from the FDA on trial design emerge.
This new perspective from the FDA follows significant developments in the CAR-T space that occurred earlier this year.
The agency announced in June that the—at the time—six approved CAR-Ts (Abecma, idecabtagene vicleucel; Breyanzi, lisocabtagene maraleucel; Carvykti, ciltacabtagene autoleucel; Kymriah, tisagenlecleucel; Tecartus, brexucabtagene autoleucel; and Yescarta, axicabtagene ciloleucel) were no longer required to adhere with risk evaluation and mitigation strategies (REMS) reporting requirements.3
Under the REMS elimination:
The FDA stated that REMS was deemed unnecessary due to the medical community’s understanding in managing risks associated with cytokine release syndrome (CRS) and neurological toxicities related to autologous CAR-Ts, citing the consistency of adverse event reporting.
“Given the established management guidelines and extensive experience of the medical hematology/oncology community in diagnosing and managing the risks of CRS and neurologic toxicities across products in the class of BCMA- and CD19-directed autologous CAR-T cell immunotherapies, FDA has determined that the safe and effective use of CAR T cell immunotherapies for the indicated population can be assured without a REMS,” the agency wrote in a statement. “Adverse event reporting for CRS and neurological toxicity have remained stable.”
1. Mahat U, Das A, Kumar V, Prasad V. Advancing CAR T-Cell Therapy: Evidence-Based Trial Design for Chimeric Antigen Receptor T-Cell Therapy in Oncology. JAMA. Published online December 08, 2025. doi:10.1001/jama.2025.21721
2. Investor Relations Event at the 30th EHA Congress. Acrellx. June 13, 2025. Accessed December 9, 2025.
3. FDA Eliminates Risk Evaluation and Mitigation Strategies (REMS) for Autologous Chimeric Antigen Receptor (CAR) T cell Immunotherapies. FDA. June 26, 2025. Accessed December 9, 2025.
