In the field of rare diseases—where conducting traditional clinical trials is often impractical—real-world data (RWD) has emerged as a scientifically valid alternative to support regulatory evaluation. This study systematically examines how RWD has been utilized in the approval of orphan drugs by the FDA’s Center for Drug Evaluation and Research (CDER) over the past five years (2020–2024). We reviewed new drug marketing applications for orphan drugs approved during this period, identifying those that included RWD. Each case was categorized based on the purpose of RWD use, the type of RWD employed, the FDA’s assessment, and whether the RWD was incorporated into the product label. A total of 129 orphan drugs were approved during the study period, accounting for approximately 53% of all new drug approvals. Of these, 25 cases (19%) included RWD in their applications. Notably, Phase 3 clinical trials using RWD as external comparators and natural history studies were among the most commonly accepted forms of high-quality evidence. In some instances, RWD was directly reflected in product labeling. Despite limitations such as potential biases and the lack of direct comparability with internal control arms, several RWD sources were recognized by the FDA as providing substantial or supportive evidence due to the soundness of study design and the credibility of analytical results. These findings demonstrate the FDA’s willingness to adopt a flexible, scientifically grounded regulatory approach, particularly in light of the unique challenges associated with rare disease drug development. (This research was supported by a grant 24202MFDS172 from Ministry of Food and Drug Safety in 2025)