The Food and Drug Administration introduced the Rare Disease Evidence Principles (RDEP) program to offer a more flexible and coordinated review process for drugs targeting ultra-rare genetic diseases affecting fewer than 1,000 patients in the U.S. The initiative allows reliance on single-arm clinical trials supplemented with supportive real-world evidence, such as natural history studies. This pathway aims to streamline development and facilitate approvals where traditional trial designs are infeasible due to small patient populations, addressing a critical unmet need in rare disease drug development.