Building on previous rare disease guidance, the FDA unveiled the Rare Disease Evidence Principles (RDEP), facilitating streamlined approval for therapies treating ultra-rare conditions affecting fewer than 1,000 people. The agency plans to accept evidence from single-arm clinical trials with supporting real-world data such as case reports and natural history studies to meet efficacy thresholds. This approach aims to foster the development of treatments where conventional trials are impractical, reflecting a significant regulatory evolution in rare disease drug development.