Plausible mechanism pathway requirements make sense and are very encouraging for bespoke gene editing treatments in rare diseases. Companies with great relationships with FDA in this space will benefit greatly since requirements have lots of wiggle room baked in. One example of this is the flexibility around cell line, mice, or human data requirements necessary to get FDA approval. Plausible mechanism pathway (PMP): - RESERVED for cases where cause of disease and natural history is known. Conditions where genetics are known and determined to be causal and we know what the life course looks like for patients with the disease phenotype (**) - ONLY for therapies that target proven ROOT CAUSE - Needs evidence that target is drugged -- mice OK for first patient but direct tissue evidence from first patient / one of first few patients needed when clinically appropriate. - Needs improvement in clinical course for patients given therapy and pre-treatment patients can act as their own control. - POSTMARKETING surveillance for efficacy and no-off target edits. Feasibility of collecting information will be considered (i.e., brain biopsy may not be needed if its a brain-specific treatment but you may need to sequence bone marrow to show safety) -TOLERANCE of risk is contingent on risk-benefit balance. What else exists to treat? How can we mitigate toxicity? What is natural history of disease? These questions and how FDA regulators interpret them will guide approval requirements on a case-by-case basis. ** This more or less fits the ACMG guidelines for determining whether a genetic variant has enough evidence behind it to make treatment decisions. Prasad definitely knows ACMG guidelines, he's an oncologist and variant assessment for targeted therapies is huge.