The U.S. Food and Drug Administration released draft guidance formalizing a 'plausible mechanism' pathway to accelerate individualized and ultrarare therapies that cannot rely on traditional randomized trials. The draft, published by the agency, provides a framework for developers of bespoke gene‑editing and personalized cell therapies to generate safety and effectiveness evidence using mechanistic and external data. FDA leadership framed the guidance as the first step toward regulatory predictability for one‑off and small‑n therapeutics; the agency emphasized manufacturing controls, safety monitoring, and the need for clear mechanistic rationale. The final guidance will be shaped by public comments and stakeholder input. Regulators, academic researchers, and patient groups hailed the clarity while noting remaining operational challenges—manufacturing scale, clinical follow‑up, and evidentiary standards for broad acceptance. The draft formalizes elements previously previewed by agency officials and could unlock more applications for CRISPR and individualized vectorized therapies.