(173) Safety-Related Drug Label Changes After Large Cardiometabolic Trials. A Review of European Public Assessment Reports

Publication Number: 1218

Background: Cost-effectiveness and feasibility of large clinical trials may be improved by using simplified study protocols that collect only major clinical outcomes. Selective safety data collection, where non-serious adverse events are not captured in case report forms, may simplify trials without impacting overall safety knowledge.

Objectives: The aim of our study is to evaluate how much new safety information is added to the drug label for cardiometabolic agents following large trials reported after initial authorisation.

Methods: We evaluated changes made to the safety section (section 4.8 ‘undesirable effects’) of the Summary of Product Characteristics (SmPC) of cardiometabolic drugs approved between 2000 and 2020 following submission of the results of large (>1000 patients) clinical trials to the European Medicine Agency. We focused on three drug classes: blood glucose lowering, antithrombotic and lipid-modifying agents. The primary outcome was the number of changes in adverse drug reactions (ADRs) in the SmPC safety section.

Results: The EMA reviewed 55 large trials concerning 25 cardiometabolic agents after the initial marketing authorisation. These trials included 402,444 patients and were submitted a median of 4.7 years (interquartile range: 2.8; 8.3) after drug approval. Ultimately, 38 trials (69%) resulted in a safety section update of the SmPC, while 17 trials (31%) did not. Changes in ADRs were made following 19 (35%) trials for 12 agents: 77 new ADRs were added, 11 were deleted, and the frequencies of 43 were changed. Most changes in ADRs arose from trials with antithrombotic agents (88%) and trials performed in a new population (92%).

Conclusions: Large trials for cardiometabolic agents reported after authorisation add limited new safety information on ADRs, especially when performed in the population studied prior to approval. This suggests that limiting safety data collection does not reduce learnings from late-stage cardiometabolic trials in populations which had been comprehensively studied before. Adverse reactions may be collected further through spontaneous reporting systems.