Evidence supporting European Medicines Agency drug approvals (2020-2023): A cross-sectional study of trial design and...

The strength and transparency of clinical trial evidence supporting drug approvals have become increasingly scrutinized, particularly considering the increased use of regulatory flexibility and expedited pathways. While US Food and Drug Administration standards have been extensively analyzed, evidence standards at the European Medicines Agency remain less well-characterized. Thus, this study aims to systematically assess the design, quality, and outcomes of pivotal efficacy trials supporting European Medicines Agency drug approvals for new active substances between 2020 and 2023.

We conducted a cross-sectional analysis of drugs receiving positive opinions from the European Medicines Agency's Committee for Medicinal Products for Human Use and subsequent approval by the European Commission between January 2020 and December 2023. Data were extracted from European Public Assessment Reports and European Medicines Agency medicine databases. Key variables included trial design features, primary endpoint type and achievement status, and justification for approval in cases of failed efficacy endpoints.

Between 2020 and 2023, 227 new drugs were approved by the European Medicines Agency for 234 indications. Of these, 69 (30.4%) were granted orphan designation, and 53 (23.3%) were approved via an expedited pathway, most commonly conditional approval (29 drugs, 12.8%). Cancer was the leading therapeutic area, accounting for 59 approvals (26.0%). Approvals were supported by 404 pivotal clinical trials. Of the 227 drugs, 177 (78.0%) were supported by at least one randomized controlled trial, of which 138 (78.0%) were blinded. Out of those, 139 (78.5%) were supported exclusively by superiority trials. Regarding endpoint classification, 124/227 drugs (54.6%) relied exclusively on surrogate endpoints and 69 (30.4%) on clinical endpoints. Overall, 22 approvals (9.7%) were supported by at least one pivotal trial in which at least one primary endpoint was not met; in five of these cases (22.7%), the failed trial was the sole pivotal trial. The most common rationale for approval despite null primary results was reliance on the totality of evidence, secondary endpoints, or clinical judgment (nine products; 40.9%).

Our findings reveal substantial variability in the design and evidentiary strength of pivotal trials supporting European Medicines Agency approvals between 2020 and 2023. While the majority of studies were randomized controlled trials, reliance on surrogate endpoints was common. That 10% of approvals were based on pivotal trials with null primary endpoints highlights the nuanced role of regulatory judgment in therapeutic evaluation. These findings prompt reflection on evolving evidence standards in drug regulation and underscore the need for transparency and consistent justifications.