The FDA is raising the bar for approval of CAR T-cell therapies in oncology. Under plans outlined by the FDA’s biologics chief Vinay Prasad, M.D., the agency will require developers of many CAR-Ts to show superiority over existing treatments.
Single-arm trials have been common in the CAR-T field to date. The labels of the seven CAR-Ts approved to date describe multiple single-arm studies, although, in many cases, there is also at least one trial versus an active control. Under new leadership, the FDA has assessed whether the approach it has taken since approving Novartis’ Kymriah in 2017 remains the best model for CAR-T regulation.
Writing in the medical journal JAMA, Prasad and three colleagues said the goal was to maintain high evidentiary standards for approval and exercise regulatory flexibilities, when necessary, to advance CAR-T development.
The leaders said randomized control trials (RCTs) with a survival or acceptable time-to-event endpoint should be the preferred approach for initial approval of new CAR-Ts. Prasad and his colleagues expect a new CAR-T to beat the comparator.
“Evidence should generally demonstrate superiority of the investigational CAR T-cell therapy compared with control,” the FDA leaders said in the JAMA 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.”
The choice of control group is critical, the article's authors article also said. The FDA officials want sponsors to assess the standard of care and ethical considerations when choosing control treatments. The goal is to ensure the trial can reliably distinguish the outcome caused by an investigational product from outcomes caused by other factors such as natural history of disease, observer or patient expectations or other treatments.
Single-group trials may be appropriate in rare cancers and in multiple relapsed or refractory populations in which RCTs may not be feasible or ethical. While noting that high, durable response rates previously supported traditional approval of CAR-T cell therapies in aggressive, relapsed or refractory hematologic malignancies, the FDA officials said they are resetting the bar.
“The response rate supported by durability from a single-group trial will generally be considered for an accelerated approval,” Prasad and his colleagues said. “Traditional approval will generally require evidence of effectiveness on a direct clinical end point such as overall survival from an RCT.”
The impact on drug developers is unclear and could be uneven, given the various study designs adopted for CAR-T trials. Gilead Sciences and Arcellx said Sunday that they plan to seek approval for their BCMA CAR-T in the U.S. based on a single-arm trial. While analysts have seen signs the therapy could have an edge over Johnson & Johnson’s Carvykti, the FDA policy could prevent full approval with the current data.
Companies including Bristol Myers Squibb, Gilead and Lyell Immunopharma are running phase 3 studies that compare CAR-Ts to standard-of-care treatments. While the designs meet the high-level request for a control, details of the FDA’s policy such as its approach to comparator selection could still create hurdles.
Allogene Therapeutics has included an observation control arm, which it says is the standard of care in the setting, in a registrational trial of its CD19 CAR-T. While that trial has a control group, Allogene CEO David Chang, M.D., Ph.D., told investors last month that all the indications from the FDA suggested the single-arm route to market was “still wide open.” Weeks later, the route looks to have narrowed.