Relationship between uncontrolled trial designs and type of European marketing authorisation application

Abstract

Background: European marketing authorisations (MAs) differ based on the comprehensiveness of clinical trial data. When data are comprehensive at time of MA application (MAA), a standard marketing authorisation (SMA) is granted and when they are not (yet), authorisation under exceptional circumstances (AEC) or a conditional marketing authorisation (CMA) is granted. For all MAAs, randomised controlled trials are the gold standard to evaluate clinical efficacy. When uncontrolled trials are used, this must be justified. We aimed to get insight in the percentage of MAAs that accepted the use of uncontrolled trials and the relation between the different types of MAs and the arguments that were used to support approval based on uncontrolled trials.

Methods: We considered all MAAs approved by the EMA in 1995-2020 and included those that were based on full MAA dossiers (excluding e.g., generics and biosimilars) and uncontrolled pivotal trials. We divided this cohort in three groups of MAs: SMAs, AECs and CMAs. Thereafter, we extracted arguments for the acceptation of uncontrolled trials as the basis for initial MAA approval from European Public Assessment Reports. Data were analysed descriptively and visualised through UpSet plots.

Findings: Among 1454 MAAs, 752 were approved on the basis of a full dossier. Of these, 49/632 SMAs (8%) were based on uncontrolled trials, whereas this was 22/66 for AECs (33%) and 28/54 for CMAs (52%). The five most frequently used arguments to accept MAAs based on uncontrolled trials were lack of satisfactory treatment (n=28, 28%), rarity of disease (n=16, 16%), severity of disease and effect size of the efficacy endpoint (both n=15, 15%) and adherence to a disease-specific guideline (n=14, 14%). For AECs, the arguments often included rarity of disease (n=11, 50%). For CMAs, arguments often included lack of satisfactory treatment and effect size (both n=10, 36%) and severity of disease (n=6, 21%). For SMAs, arguments often included adherence to a disease-specific guideline (n=14, 28%), but for 15 SMAs (31%), arguments were not provided at all.

Conclusions: Uncontrolled trials were more often found in MAAs with non-comprehensive data (AECs and CMAs) than in MAAs with comprehensive data (SMAs). In SMAs, however, justification for acceptance was less clear. This should be improved to increase the understanding of stakeholders on type of MA and factors of comprehensiveness.