Presentation (CTI)

OBJECTIVES: It is expected that the magnitude and type of uncertainty in the clinical evidence will be inversely associated with the probability of a positive outcome being granted by a regulatory authority (e.g. marketing authorisation, MA). One type of potentially impactful uncertainty is failing to meet primary endpoints in pivotal clinical trials. However, the extent to which this type of uncertainty occurs and its association with the regulatory outcome remain unclear.
METHODS: A database was created using publicly available information from the European Medicines Agency (EMA) on MA procedures applied between 2021 and 2025. The study dataset included all medicines authorised under conditional marketing authorisation (CMA) or exceptional circumstances (EC), as well as non-authorised products (e.g. MA that were refused or applications that were withdrawn before the final decision). The percentage of products with unmet primary endpoints was determined for each group following a review of the European Public Assessment Reports (EPARs) of these products.
RESULTS: The study dataset included 45 products authorised under CMA/EC and 50 non-authorised products [MA applications that were refused (n=13) or withdrawn before the final decision (n=37)]. The highest percentage of unmet primary endpoints was found in the refused applications group (69.2%), followed by withdrawn applications group (40.5.9%), and products authorised under CMA/EC (11.1%; P<0.001 for the difference).
CONCLUSIONS: Our results confirm that the MA granted by the EMA is strongly evidence-based. Failure to meet primary endpoints in a pivotal clinical trial is a relatively common occurrence when medicines are MA application is withdrawn or MA is refused. However, this type of uncertainty has also been observed in a subset of products authorised under the CMA or EC. These results suggest that, in certain circumstances, failure to meet the primary endpoint could be offset by other factors favouring an MA issued by the EMA.