The FDA released a draft framework to expedite therapies for ultra‑rare diseases, focusing on individualized, mechanism‑targeting treatments including genome editing and RNA modalities. The guidance emphasizes requiring high‑quality evidence of target engagement and disease causation while allowing flexibility where randomized trials are infeasible. Agency leaders framed the proposal as removing barriers for patients with extremely small populations while maintaining evidentiary rigor. The draft targets therapies that directly correct or modulate a known genetic, cellular, or molecular abnormality. Stakeholders should prepare for tight analytical and mechanistic datasets and ongoing agency expectations for post‑approval evidence generation for bespoke treatments.