FDA set to raise bar for clinical trials of CAR-T therapies

The FDA looks set to make it harder for developers of CAR-T therapies to bring their products to market by making full randomised, controlled trials (RCTs) the new standard it will accept for regulatory filings.

At the moment, it has been possible to develop CAR-Ts based on single-arm trials, i.e. without a control, although some have used an active comparator. Now, with the number of CAR-Ts on the market now in double figures, the FDA is minded to require RCTs with a control group as well as "a survival or acceptable time-to-event endpoint."

Selection of the control group "must take into account the available standard treatments, including approved CAR-T cell therapies, ethical considerations, and most importantly the ability to reliably distinguish the outcome caused by an investigational product from the outcomes caused by other factors."

Those could include the natural history of the disease, the expectations of patients or clinicians, or other treatments, writes Vinay Prasad, director of the FDA's Center for Biologics Evaluation and Research (CBER), with three colleagues in the Journal of the American Medical Association (JAMA).

The move towards a higher threshold for showing efficacy for new CAR-Ts comes after the FDA loosened the requirements for safety monitoring by eliminating the risk evaluation and mitigation strategies (REMS) formerly required for already-marketed therapies targeting CD19 and BCMA, which the agency said would make them more accessible.

According to the JAMA paper, single-arm trials may continue to be acceptable in rare cancers, as well as in patients whose disease has relapsed despite multiple prior therapies. Meanwhile, response rate data will continue to be a suitable endpoint for getting accelerated approval, but converting that to a full license will need a stronger endpoint like overall survival generated in an RCT.

The regulator's perspective on CAR-Ts has evolved, but will still be based on high evidentiary standards for approval, according to the authors, whilst retaining regulatory flexibility "when necessary, to advance the development of these products."

The move comes as the FDA is steadily rewriting the regulations surrounding drug development in the US, albeit as yet more by proclamation than guidance document, and follows earlier pronouncements such as requiring only one RCT rather than two, the rapid review of "personalised" products with a "plausible mechanism," and a new, stricter approval process for new vaccines.