Real-World Evidence: Amylyx’s Use Of External Controls To Frame Relyvrio’s Survival Benefit Rife With Problems
The post hoc comparison of an exploratory, long-term survival benefit in the CENTAUR trial to historical controls in two ALS patient databases lacked prespecification and a common treatment protocol, and potential differences in prognostic factors may have confounded the results.
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Agency discourages use of externally controlled trials in all but a very limited number of situations truly ripe for such an approach; new draft guidance discusses at length the various confounding factors that can introduce bias into a comparison between an investigational treatment and an external control using either real-world data or data from another clinical trial.
Amylyx’s Relyvrio survival data, drawn from a post hoc exploratory survival analysis of randomized patients, and the primary ALS functional endpoint ‘capture distinct concepts,’ FDA states. Use of long-term survival data from the same trial as confirmatory evidence was unusual, but not unique.
Despite broad interest, real-world evidence of efficacy in FDA decisions remains largely limited to orphan diseases and natural history, a Pink Sheet analysis shows.