The FDA published draft guidance outlining a 'Plausible Mechanism' framework and a complementary ultra‑rare therapies pathway to accelerate development of highly personalized genomic and genome‑editing treatments. The documents aim to tailor regulatory expectations for conditions with extremely small patient populations where randomized controlled trials are infeasible. Both drafts emphasize mechanistic rationale, genotypic targeting, and rigorous evidence proportional to patient numbers while leaving stakeholders seeking clarification on evidentiary standards and operational details. The moves reflect regulatory pressure to balance rapid access for patients with the evidentiary rigor needed for safe approvals.