Trends in orphan medicinal products approvals in the European Union between 2010–2022

**Background:** The orphan drug regulation in the European Union (EU) has evolved over the past two decades, with increasing complexity in regulatory pathways and tools to facilitate innovation and accelerate approvals for rare diseases. Rare diseases affect an estimated 6,000 to 9,000 conditions and over 30 million people in Europe, yet about 95% lack approved treatments. The study aims to characterize orphan medicinal products (OMPs) authorized by the European Commission between 2010 and 2022, analyzing 18 variables to inform the ongoing discussion on the proposed new Pharmaceutical Legislation.

**Methods:** Data were extracted from European Public Assessment Reports (EPARs) for all OMPs approved via the centralized procedure between January 2010 and December 2022, including withdrawn products. Variables included year of approval, legal basis, applicant, protocol assistance, type of authorization, registration status, molecule type, ATC code, therapeutic area, target age, disease prevalence, number of pivotal clinical trials, trial designs, efficacy endpoints, and patient numbers. Descriptive statistical analysis was applied.

**Key Results:** A total of 192 OMPs were identified. Key findings include: 89% had a legal basis of "full application" (Article 8.3); 86% received protocol assistance; 64.6% benefited from accelerated assessment; 52.6% were small molecules, 34.9% biologics, 7.8% ATMPs, and 3.1% oligonucleotides; 17.2% were repurposed; 39.6% had ATC code L (antineoplastic and immunomodulating agents); 55.7% were intended for adults only; 71% were approved based on a single pivotal trial; 48.5% of pivotal trials were randomized, double-blind, controlled; 51% of oncological OMPs used surrogate primary endpoints; the median number of patients enrolled in pivotal trials was 166 (mean 245). Non-standard marketing authorizations (conditional or exceptional circumstances) accounted for 32.9% of approvals, with an increasing trend over the period. The number of OMPs approved per year rose from 5 in 2010 to 26 in 2022.

**Clinical Implications:** The study reveals a shift in rare disease drug development, with increasing approvals of non-small molecules, accelerated assessments, and non-standard marketing authorizations. The high proportion of approvals based on a single pivotal trial and surrogate endpoints underscores the challenges of generating robust evidence in small patient populations. The findings highlight the need for clear guidelines on unmet medical need and significant benefit in the proposed new Pharmaceutical Legislation, as well as the potential role of real-world evidence and innovative trial designs. The high competition in oncological indications and the early removal of orphan drug designations raise questions about market dynamics and transparency. The study provides valuable insights for regulators, drug developers, and policymakers involved in the implementation of the new legislation.