The U.S. Food and Drug Administration released draft guidance formalizing the "plausible mechanism" framework to accelerate approvals for individualized cell and gene therapies targeting extremely rare genetic conditions. The agency’s draft clarifies evidentiary expectations for safety, manufacturing quality, and mechanistic rationale when randomized trials are infeasible. Regulators and sponsors now have a clearer roadmap for bespoke CRISPR edits and one‑off therapies, a move likely to increase submissions for ultra‑rare indications and to reshape trial design and regulatory planning across academic and small biotech developers.