The FDA announced a novel Rare Disease Evidence Principles (RDEP) pathway aimed at expediting the development and review of drugs targeting ultra-rare genetic conditions affecting fewer than 1,000 patients in the U.S. This program allows acceptance of evidence from single-arm clinical trials, supplemented by case reports and natural history studies, as sufficient for demonstrating substantial effectiveness. The pathway mandates that eligible diseases lead to rapid deterioration with serious disability or death and lack alternative treatments. The initiative reflects an evolution in regulatory flexibility to address unmet needs in rare diseases, promising a clearer and more efficient approval route for sponsors.