title: Multi-centre, multi-database studies with common protocols: lessons learnt from the IMI PROTECT project.
abstract: OBJECTIVE
  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.
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands.
authors.forename: Olaf H
authors.initials: OH
authors.lastname: Klungel
authors.affiliation: European Medicines Agency (EMA), London, United Kingdom.
authors.forename: Xavier
authors.initials: X
authors.lastname: Kurz
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.|Department of Clinical Chemistry and Haematology, Division of Laboratory and Pharmacy, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Mark C H
authors.initials: MC
authors.lastname: de Groot
authors.affiliation: Quantitative Safety and Epidemiology, Novartis Pharma AG, Basel, Switzerland.
authors.forename: Raymond G
authors.initials: RG
authors.lastname: Schlienger
authors.affiliation: Global Pharmacovigilance and Epidemiology, Sanofi, Chilly-Mazarin, France.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Tcherny-Lessenot
authors.affiliation: LA-SER and Pasteur Institute (Pharmacoepidemiology and Infectious Diseases Unit), Paris, France.
authors.forename: Lamiae
authors.initials: L
authors.lastname: Grimaldi
authors.affiliation: Fundació Institut Català de Farmacologia (FICF), Barcelona, Spain.
authors.forename: Luisa
authors.initials: L
authors.lastname: Ibáñez
authors.affiliation: Utrecht Institute for Pharmaceutical Sciences (UIPS), Division of Pharmacoepidemiology and Clinical Pharmacology, Utrecht University, Utrecht, the Netherlands.|Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht (UMCU), Utrecht, the Netherlands.
authors.forename: Rolf H H
authors.initials: RH
authors.lastname: Groenwold
authors.affiliation: Epidemiology, Pfizer, New York, NY, USA.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Reynolds
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects; D000928:Antidepressive Agents / Q000009:adverse effects; D001569:Benzodiazepines / Q000009:adverse effects; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology; D016208:Databases, Factual; D064420:Drug-Related Side Effects and Adverse Reactions; D005060:Europe; D005260:Female; D006620:Hip Fractures / Q000209:etiology; D006801:Humans; D008297:Male; D015337:Multicenter Studies as Topic; D012042:Registries
chemical_list: D000900:Anti-Bacterial Agents; D000928:Antidepressive Agents; D001569:Benzodiazepines
keywords: European Medicines Agency; Innovative Medicines Initiative; PROTECT; electronic healthcare databases; methodology; observational studies; pharmacoepidemiology; pharmacoepidemiology (PE)