OBJECTIVES: Since the implementation of orphan drugs (ODs) legislation in the European Union (EU) in 2000, the number of medicines granted orphan drug designation and market authorization (MA) has substantially increased. The aim of this study was to analyse the reasons why the orphan designated drugs (ODDs) failed to get MA from European Medicinal Agency (EMA).

METHODS: The ODDs that have applied for centralized MA until 30/05/2018 were identified from the EMA’s official website. The MA status of these drugs, as well as relevant reasons for rejection of MA were extracted.

RESULTS: Around 87% of ODDs (103 out of 119 applications) have successfully been granted a centralized MA in EU, among which 15 were given conditional approval and 16 were approved under exceptional circumstances. Four ODDs’ MA were withdrawn by their MA holder due to lack of market demands (Glybera® and Rilonacept Regeneron®), the failure to provide additional post-market data (Onsenal®), and due to supply shortage (Unituxin®). The 12 remaining ODD applications were rejected due to one or more of the following reasons: insufficient effectiveness evidence resulting from no or inappropriate comparator (N=4), insignificant improvement in patients outcome (N=2), inadequate data submitted (N=2), improper surrogate endpoint (N=2), questionable study design (N=2) and/or non-compliance with trial protocol (N=1). Among the rejected ODDs, Elelyso® was the only one assessed with positive benefit-risk balance, however it was rejected due to similarity with another approved orphan drug which had 10-year market exclusivity. Ten ODDs were rejected, 5 due to safety issuesand 5 due to concerns with a quality control problem during their manufacturing procedure.

CONCLUSIONS: Sixteen lost opportunities for patients were identified. Insufficient effectiveness evidence from poorly designed clinical trials was a major challenge. Early EMA scientific consultation may become compulsory for ODDs to ensure a higher success rate wider and access to patients.