Evaluation of orphan maintained biological medicinal products in the European Union between 2018 to 2023: a regulatory perspective

Objectives: Orphan medicinal products (OMPs) authorized by the European Union (EU) benefit from market exclusivity, fee waivers, and national incentives. Maintaining orphan status during a marketing authorization application requires meeting eligibility criteria, especially demonstrating significant benefit (SB), which is challenging. This study identifies key features linked to successful orphan status maintenance for biological OMPs approved in the EU between 2018 and 2023. Methods: Data from European public assessment reports and orphan maintenance assessment reports were analyzed. Results: Among the 50 biological OMP maintained orphan designations, 68.0% had to demonstrate SB over existing treatments, with 91.2% leveraging the clinically relevant advantage area, utilizing better clinical efficacy (83.9%) and efficacy in subpopulations (38.7%) subdomains. However, 32.0% did not need to demonstrate SB due to a lack of alternative treatments, most of which were ultra-orphan drugs. Advanced therapy medicinal products and monoclonal antibodies were the most numerous OMP categories, whereas oncology and immunomodulation were the preferred therapeutic areas. Conclusion: The Orphan Regulation is essential in advancing treatments for rare diseases, fostering innovation while addressing unmet medical needs. Nonetheless, the insufficient return on investment criterion remains underused, whereas refining major contribution to patient care guidelines and incorporating real-world evidence may enhance regulatory evaluations.