Multi-centre, multi-database studies with common protocols: lessons learnt from the IMI PROTECT project.

Purpose: To assess the impact of a variety of methodological parameters on the association between six drug classes and five key adverse events in multiple databases.

Methods: The selection of Drug-Adverse Event pairs was based on public health impact, regulatory relevance, and the possibility to study a broad range of methodological issues. Common protocols and data analytical specifications were jointly developed and independently and blindly executed in different databases in Europe with replications in the same and different databases.

Results: The association between antibiotics and acute liver injury, benzodiazepines and hip fracture, antidepressants and hip fracture, inhaled long-acting beta2-agonists and acute myocardial infarction was consistent in direction across multiple designs, databases and methods to control for confounding. Some variation in magnitude of the associations was observed depending on design, exposure and outcome definitions, but none of the differences were statistically significant. The association between anti-epileptics and suicidality was inconsistent across the UK CPRD, Danish National registries and the French PGRx system. Calcium channel blockers were not associated with the risk of cancer in the UK CPRD, and this was consistent across different classes of calcium channel blockers, cumulative durations of use up to >10 years and different types of cancer.

Conclusions: A network for observational drug effect studies allowing the execution of common protocols in multiple databases was created. Increased consistency of findings across multiple designs and databases in different countries will increase confidence in findings from observational drug research and benefit/risk assessment of medicines.