Contribution of Real-World Evidence for the Orphan Medicines Approvals in the European Union Between 2000 and 2025

We aimed to assess the role of real-world data (RWD)/real-world evidence (RWE) for regulatory decision-making of the marketing authorisation approvals of orphan medicinal products (OMPs) in the European Union (EU) between 2000 and 2025.

All European public assessment reports (EPAR) of the OMPs approved in the EU between 1 January 2000 and 31 December 2025 were screened for RWD/RWE submitted by the applicant in the initial application (pre-authorisation phase) and classified as 'main', 'supportive' or 'not known'. Post-authorisation measures foreseen, described in Annex II conditions or additional pharmacovigilance activities required to address specific safety concerns were checked and were included if RWD/RWE was present.

RWD/RWE were present in about 80% of the marketing authorisation applications analysed. RWD had a supportive role in the benefit-risk assessment in 68% of cases and contributed to the main evidence in 21% of the cases. The RWE in the pre-authorisation phase comes from data from early access programs (36%), case reports and natural history studies used as historical controls (24%), clinical data from electronic health records (17%), and safety data from post-marketing experience in other geographic regions (11%). RWD sources in the post-authorisation phase were most commonly registries (67%), followed by electronic health records (19%).

Our findings confirm that RWD/RWE have become an essential component of the regulatory evaluation of orphan medicinal products. In the period studied, more than 80% of the marketing authorisation approvals of OMPs contained RWD/RWE. The prevalence of RWD/RWE was higher in the post-authorisation phase (72%) than in the pre-authorisation phase (66%). In the pre-authorisation phase, the role of RWD was mainly (68%) supportive. The RWE studies in the post-authorisation phase intended to investigate specific safety concerns, including collecting long-term safety data, and evaluate effectiveness in real-world conditions.