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: What changes would you recommend clinical teams make now to future-proof trial protocols—especially when pursuing expedited programs—to avoid costly CRLs down the line?
Beckwith: It’s pretty obvious, just given the FDA’s comments here, but control groups where possible. Now, obviously, I do believe that a control group in Replimune’s case would have been unethical, and I think you’d struggle to get an IRB or an ethics committee to sign off on anything like a kind of a conventional RCT with a one-to-one randomization ratio. Now, there are constantly-improving kinds of options around match placebo controls often using AI to create synthetic data, or using a growing trove of real-world evidence to create that match control. I don’t believe Replimune included that. That is a relatively low-cost option to try and include, so that is something that sponsors could look into, but it’s very different in a space like cardio metabolic or type 2 diabetes, a more chronic condition, it would be very appropriate to include a control group. But again, there are also options which technology enables for us now, like adaptive trials, where you could have an adaptive randomization ratio and start with a one-to-one ratio, and as you notice an effect on the control group, reduce the number of participants who are randomized onto a placebo. Using technology now, you can do that without unblinding the study teams to the results, so those options do exist. Again, relatively low-cost ways of ensuring or preventing these CRL letters. If I were a clinops leader, I’d look into them. It’s something that we’ve been doing for some of our sponsors now. Certainly, we hope that in the near future, every clinical trial will be adaptive by default, and I think there’s really no reason not to.