Strategic Drivers Behind Early Withdrawal of Orphan Designations in the EU: A Retrospective Analysis (2000-2024)

The orphan legislation came into force in the European Union (EU) in 2000, providing incentives for the development of orphan medicines. To be eligible for incentives, the applicant needs to apply for an orphan designation (OD). However, at any time, the marketing authorisation holder (MAH) can request the removal of the OD. The possible motives underpinning premature removal of OD have been the subject of speculation. Our aim is to study every early OD removal for the orphan medicinal products (OMPs) approved in the EU between 2000 and 2024 and determine the main reasons behind this phenomenon.

We identified all the orphan medicines approved between 2000 and 2024. We considered approval date by the European Commission (EC), orphan designation (OD) status, company name, active substance name, trade name, ATC code and Therapeutic Area, and the date of the removal of the OD. Information on the OD withdrawal was cross-checked with the documents on the EMA website, and the legal status of the patent and supplementary protection certificates (SPC) was checked at the European Patent Register.

During the period 2000-2024, 285 OMPs were approved by the EC. Overall, 41 (11.8%) orphan designations were prematurely removed, corresponding to 23 different OMPs.

Three main motives for the early removal of the OD were identified: lack of clinical evidence supporting the significant benefit for the new indication proposed, the companies' preference towards SPC extensions for the paediatric indication (instead of the two additional years of marketing exclusivity), or the new therapeutic indication added is not rare. There is no evidence of commercial "pay to enter" agreements between pharmaceutical companies.