Analysis of Real-World Data Utilization in the Orphan Drug Approval Process: Focusing on New Drug Marketing Applications Submitted to the FDA

Abstract

In the field of rare diseases-where traditional clinical trials are often impractical-real-world data (RWD) have emerged as a scientifically valid alternative to support regulatory decision making. This study systematically evaluates the utilization of RWD in orphan drug approvals by the FDA Center for Drug Evaluation and Research (CDER) over the past 5 years (2020-2024). We reviewed marketing applications for orphan drugs approved during this period, identifying those that included RWD. Each case was categorized based on the type and purpose of RWD use, sample size, FDA's evaluation, and label inclusion. A total of 129 orphan drugs were approved during this 5-year period, representing approximately 53% of all new drug approvals. Among these, 25 applications (19%) incorporated RWD, and 8 of them (32%) included RWD-derived findings in the product labeling. Among the 26 types of RWD usage, natural history studies were the most frequently employed (n = 14, 53.8%), followed by observational studies and Phase 3 trials utilizing external comparators. The primary purpose of RWD use was comparative evaluation (n = 19, 76%), and nearly half of the RWD data sets (n = 12, 48%) involved fewer than 100 patients. This study offers strategic insights into how RWD can be effectively leveraged in the development and regulatory approval of orphan drugs. The study offers practical guidance on designing regulatory-grade RWD studies and underscores key considerations for future submissions that aim to meet evidentiary standards in support of rare disease drug approvals.