The FDA released draft guidance detailing the ‘plausible mechanism’ pathway to advance individualized cell and gene therapies for extremely rare genetic conditions. The framework outlines the evidence and manufacturing expectations sponsors must meet when randomized trials aren’t feasible, providing a regulatory roadmap for bespoke CRISPR, AAV, and other individualized approaches. The guidance builds on earlier agency signals and aims to standardize how developers demonstrate safety and efficacy for n‑of‑1 or ultra‑rare programs. It includes recommendations on mechanistic biology, confirmatory evidence, and quality controls for small‑batch manufacturing. Patient groups and academic developers hailed the guidance as a turning point for bespoke treatments, while industry participants noted practical challenges remain around scaling, post‑approval confirmatory obligations, and reimbursement for individualized products.