The U.S. Food and Drug Administration proposed a draft ‘plausible mechanism’ framework to accelerate development of individualized and ultra‑rare therapies when randomized controlled trials are impractical. The guidance targets genome‑based, RNA and gene‑editing approaches for conditions with extremely small patient populations and outlines evidentiary expectations focused on mechanistic proof and rigorous molecular validation. The draft invites industry and stakeholder input on when and how single‑patient or n‑of‑1 evidence can underpin approvals, while emphasizing high evidentiary standards for target biology, on‑target activity and safety. Regulators signaled a willingness to exercise flexibility but stressed the need for robust preclinical data and post‑marketing evidence collection. Sponsors developing bespoke medicines for ultrarare diseases will need to align early with regulators, document precise mechanisms of action, and plan for comprehensive safety monitoring to leverage the pathway effectively.