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The FDA is looking to raise the bar for clinical trials of CAR-T cell therapies for cancer. Vinay Prasad, director of the agency's Center for Biologics Evaluation and Research (CBER), penned a piece for the Journal of the American Medical Association (JAMA) on Monday outlining how randomised controlled trials (RCTs) will be the standard moving forward.The more stringent clinical guidance comes after the FDA made the treatments more accessible to patients. In June, the US regulator updated the risk evaluation and mitigation strategies (REMS) for currently approved CAR-Ts to eliminate a requirement that healthcare facilities be specially certified to administer the therapies. That decision was indicative of the FDA's "commitment to patient-centered drug regulation, removing burdensome regulation, and enthusiasm for this class of product," Prasad and his co-authors wrote in the JAMA piece, explaining that the updated clinical framework "expands that thinking."Of the seven CAR-Ts marketed in the US today, all received initial approval based on "high and durable response" data from single-arm trials in patients with relapsed or refractory disease. And biopharmas are continuing to innovate on the modality, with many exploring therapies that target multiple antigens, utilise rapid manufacturing technologies, can be given off-the-shelf, or are capable of inserting CAR genes in vivo (see – Spotlight On: Pharma buys into in vivo cell therapies)."Although the FDA shares enthusiasm for all these avenues of investigation, the statutory evidentiary requirement for these biological products is not distinct from existing standards: demonstration of safety and substantial evidence of effectiveness is required for marketing authorisation," Prasad wrote. He proposed a regulatory framework that will see RCTs with a survival or time-to-event primary endpoint become "the preferred approach" for drugmakers seeking the first approval of a new CAR-T. The control group should take into account standard-of-care treatments, including already-approved CAR-Ts, and the experimental arm should establish superiority over the control. While durable response rate data from a single-arm trial can inform an accelerated approval, a RCT will be required to confirm the clinical benefit. "Traditional approval will generally require evidence of effectiveness on a direct clinical endpoint such as overall survival from an RCT," Prasad wrote. He highlighted the "1-trial approach," in which an RCT that can be analysed early for response rate results to support accelerated approval, followed by a time-to-event endpoint to support full approval.Exceptions to the rulePrasad also laid out a couple of exceptions. For slow-growing cancers where it takes years for overall survival data to mature, the FDA will consider "on a case-by-case basis" whether biomarkers like minimal residual disease can be used as a surrogate endpoint to support either accelerated or traditional approval. Single-arm studies may also be the best approach in rare cancers, or for patients with late-line relapsed or refractory disease for whom "conducting an RCT may not be feasible or ethical."The FDA leader said the agency will also employ "maximum regulatory flexibility" to accelerate products intended to treat children with cancer. However, Prasad did not address how the new framework will affect CAR-Ts already in mid- to late-stage development. Both AstraZeneca and Gilead Sciences shared data from their CAR-T programmes at the American Society of Hematology (ASH) meeting this month. In the pivotal Phase II iMMagine-1 trial, Gilead's BCMA-directed CAR-T cell therapy anitocabtagene autoleucel avoided delayed neurotoxicities in patients with relapsed or refractory multiple myeloma (RRMM). Early findings from the Phase Ib portion of the Phase Ib/II DURGA-1 trial of AZD0120, AstraZeneca's dual BCMA and CD19-targeting CAR-T, showed a 100% ORR in 15 patients with RRMM.