The FDA and authors including CBER director Vinay Prasad and Martin Makary published a ‘‘plausible mechanism’’ pathway in the New England Journal of Medicine proposing a streamlined route to clinic for bespoke and n‑of‑1 therapeutics for ultra‑rare diseases. The authors draw on high‑profile cases—including the in vivo CRISPR treatment for infant KJ—to argue regulators should accept mechanistic evidence where randomized trials are infeasible. Critics and proponents have weighed in: academic leaders such as Carl June supported calls for streamlined routes for autologous advanced therapies, while other experts urge clearer guardrails to preserve patient safety. The pathway targets therapies guided by specific molecular defects rather than broad diagnostic categories; a ‘‘plausible mechanism’’ here means biological rationale and supportive preclinical or biomarker data in lieu of large randomized evidence.