The U.S. Food and Drug Administration published draft guidance formalizing a ‘plausible mechanism’ framework to accelerate approvals for individualized therapies targeting extremely rare genetic conditions. The agency’s draft guidance lays out evidentiary expectations when randomized controlled trials are infeasible, specifying how mechanistic, preclinical, and limited clinical data can support approvals under tailored pathways. The documents come with complementary CBER/CDER considerations intended to help sponsors generate safety and efficacy data for single‑patient or ultra‑rare programs. The plausible‑mechanism framework lets developers rely on a biologic rationale plus confirmatory evidence; in one sentence: it enables tailored regulatory approaches when traditional trial designs are impossible.