The U.S. Food and Drug Administration published draft guidance laying out a new 'plausible mechanism' pathway to speed individualized and ultra‑rare therapies, including bespoke gene‑editing approaches. The guidance describes evidence expectations for approvals when randomized controlled trials are impractical and provides a regulatory framework for patient‑specific interventions. Regulatory leaders framed the policy as a modernization of approval standards—allowing a single well‑controlled trial plus complementary evidence or mechanistic rationale to support approvals in certain settings. The agency also released parallel material on testing and evidentiary standards for personalized cell and gene therapies. Biotech developers and rare‑disease advocates hailed the guidance as a potential accelerant for small‑n programs and individualized CRISPR or AAV treatments, while payer and manufacturing stakeholders will need to adapt to new commercialization and quality expectations. The draft status invites stakeholder comments that could define implementation timelines.