The U.S. Food and Drug Administration unveiled the Rare Disease Evidence Principles (RDEP), a coordinated review program between its drug and biologics centers to facilitate expedited approval of drugs for ultra-rare conditions affecting fewer than 1,000 people in the U.S. The framework allows reliance on single-arm clinical trials supplemented by supportive evidence such as natural history studies and case reports for establishing efficacy. This initiative marks a significant regulatory shift towards flexibility and reduced burden on developers addressing critical unmet needs in rare diseases.