The FDA unveiled the Rare Disease Evidence Principles (RDEP) program to expedite review of therapies for ultrarare genetic conditions affecting fewer than 1,000 patients in the U.S. The program facilitates collaboration between the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research, allowing acceptance of data from single-arm trials supplemented by real-world and natural history evidence. This framework promises a more flexible yet rigorous path to approval, addressing critical unmet medical needs.