FDA Review Changes and the Impact on Trial Design

In a recent video interview with Applied Clinical Trials, Meri Beckwith, Co-CEO, Lindus Health, discussed the evolving perception of breakthrough designation amid the FDA’s recent Complete Response Letters (CRLs) issued to Replimune and Capricor. He emphasized that breakthrough designation does not necessarily guarantee approval, but offers quicker decision access and investor signaling. Beckwith also stressed the importance of agility in trial design, advocating for adaptive trials and control groups where ethical. To mitigate regulatory unpredictability and avoid costly CRLs, he highlighted the need for future-proofing trial protocols with adaptive randomization and synthetic control groups.

ACT: With both Replimune and Capricor expressing surprise at receiving CRLs, what operational red flags should clinical teams be watching for earlier in the design or submission process?

Beckwith: Yeah, this is a tricky one. I think particularly in Replimune’s case, the FDA seemed to take issue with the fact that it was an uncontrolled study. I've got to say that that's pretty unfortunate, given, obviously the FDA were involved, and Replimune would have cleared that with them. I mean, it's also super common in this space, i.e., non-responders in oncology to run an uncontrolled study, because, arguably, having a control group would be, would be unethical because these people are going to die without treatment. I'm not really sure the clinical operations folks are really at fault here. I know a bit more about the Replimune case than I do Capricor, but in Replimune’s case, the study design had been approved by the FDA. Running a single-arm design is such a fundamental part of the study design, that there's no way that wouldn't have been carefully scrutinized by the FDA at the point at which they discussed the study design with them. I think they more just fell afoul of shifting internal politics at the FDA, and I'd say it's as simple as, with the change in administration, a lot of reviewers have changed. They went from a set of reviewers who were very comfortable with that approach to a different set of reviewers who are less comfortable. I think it's as simple as that. I don't think it's part of a grander shift in policy at the FDA. I think it's just a changing of the guard, and the new guard have a slightly different take on things, and unfortunately, Replimune has fallen foul of that.