The FDA announced the Rare Disease Evidence Principles (RDEP) program, a new collaborative review process between drug and biologics centers for ultra-rare diseases affecting fewer than 1,000 U.S. patients. Under this program, single-arm clinical trials supplemented with supportive data such as natural history studies or case reports may suffice as pivotal evidence. This initiative aims to streamline the approval of therapies for genetically defined rare diseases with significant unmet needs, enhancing development efficiency and patient access.