The FDA published a draft framework to expedite therapies tailored to ultra‑rare diseases, outlining a pathway for individualized genome‑editing and RNA‑based treatments when randomized trials are infeasible. Agencies signaled that submissions must still demonstrate a high evidentiary bar, including target engagement and mechanistic plausibility, while the guidance aims to streamline regulatory flexibility for conditions with tiny patient populations. At the same time, Commissioner Marty Makary publicly defended recent FDA rejections of several rare‑disease drug applications, stressing that internal reviewers and patient safety standards influenced decisions. Makary cited specific program concerns in interviews as the agency balances flexibility with evidentiary rigor under new leadership. Together these developments reflect a regulatory recalibration: the agency is signaling routes for accelerated access while reinforcing scrutiny on safety and data quality, which industry and advocates are watching closely for impacts on rare‑disease development timelines.