Comments on Draft Guidance, “Considerations for the Use of the Plausible Mechanism Framework to Develop Individualized Therapies that Target Specific Genetic Conditions with Known Biological Cause”

FDA should limit the proposed plausible mechanism framework to ultra-rare diseases so that its flexible evidentiary standards do not extend to conditions for which established approval pathways already exist, and should direct qualifying products to accelerated approval rather than traditional approval. For therapies approved using this framework, FDA should also require robust post-marketing safety follow-up, provide greater transparency on the predictive validity of surrogate endpoints used, and ensure that the drug’s label clearly discloses the limitations of the supporting evidence.