The nature of uncertainties on the benefit-risk balance of anticancer medicines at initial marketing authorisation in the European Union

Background: Uncertainties regarding treatment outcomes remain after a medicine is authorised due to the inherent limitations of (pre)clinical research. We aimed to evaluate uncertainties on the benefit-risk balance of oncology medicines assessed by the European Medicines Agency (EMA) for initial marketing authorisation.

Objectives: To evaluate the nature of uncertainties on the benefit-risk balance of oncology medicines identified by the Committee for Medicines for Human Use (CHMP) of the European Medicines Agency (EMA) at initial marketing authorisation.

Methods: We included all medicines containing a new active substance that were assessed by the EMA and granted an initial marketing authorisation by the European Commission in 2011-2022 for an oncology indication. We extracted characteristics of these oncology medicines and uncertainties on their benefit-risk balance from the European Public Assessment Reports. The uncertainties were categorised and their frequencies stratified according to time of marketing authorisation, and medicine and regulatory characteristics.

Results: In total, 121 oncology medicines were included for which 800 (median 6, range 0-23) uncertainties were identified. Uncertainties pertained to five main categories: safety (n=404, 51%), efficacy (n=322, 40%), pharmacology (n=58, 7%), use in clinical practice (n=10, 1%) and quality (n=6, 1%). Among 27 subcategories, most uncertainties were related to specific adverse events (n=156, 20%), effect size (n=155, 20%), safety in subpopulations (n=124, 16%), or efficacy in subpopulations (n=88, 11%). The number of uncertainties seemed driven by the type of medicine (p=0.012), the regulatory pathway (p=0.001), and the year of marketing authorisation (p=0.007), with the highest number of uncertainties observed for cell and gene therapies (8 [3-23]), medicines granted conditional marketing authorisation (7 [3-23]), and medicines authorised in 2019-2022 (7 [2-23]). Medicines with more than one of these characteristics were associated with even higher numbers of uncertainties.

Conclusions: At the initial authorisation of oncology medicines, uncertainties on their benefit-risk balance most often concerned safety aspects, followed by efficacy. The number of uncertainties was highest for cell and gene therapies, conditionally authorised medicines and medicines authorised in recent years.