title: Drug-safety alerts issued by regulatory authorities: usefulness of meta-analysis in predicting risks earlier.
abstract: OBJECTIVE
  The purpose of this study was to evaluate how risk estimates generated from cumulative meta-analysis performs over time for drugs having their benefit/risk ratio re-evaluated due to safety issues and, additionally, assess whether results are consistent with regulatory authorities' conclusions.
  
  
  METHODS
  Four major regulatory authorities were searched for their issued safety alerts supported by longitudinal, comparative studies (experimentals and/or observationals). The random-effects model was used to pooled odds ratios (OR) over time by including studies according to the year they first became available.
  
  
  RESULTS
  Seventeen safety alerts were included in this study. In 2008, proton-pump inhibitors (PPIs) were associated with an increased risk for bone fractures [OR 1.25, 95 % confidence interval (CI) 1.00-1.55, P = 0.049); the US Food and Drug Association (FDA) issued a safety alert in 2010 and added warnings to the label. An increased risk for Clostridium-difficile-associated diarrhea was pooled for PPIs in 2004 (OR 1.89, 1.19-3.02, P = 0.007); US FDA issued a safety alert in 2012, adding warnings to the label. PPIs were associated with pneumonia in 2009 (OR 1.40, 1.06-1.85, P = 0.017); US FDA issued an alert in 2012 but concluded that the benefit/risk (B/R) ratio remains positive. Statins were associated with an increased risk for diabetes (OR 1.07, 1.01-1.15, P = 0.033) in 2008. The European Medicines Agency (EMA) issued an alert in 2012, including warnings to the label. The remaining cumulative meta-analyses did not estimate increased risks in advance of regulatory decisions.
  
  
  CONCLUSIONS
  This study demonstrates that meta-analysis may help predict iatrogenic risks. However, between-study heterogeneity can considerably affect the estimated results, and therefore, this technique should not replace further assessments during BR ratio re-evaluations.
authors.affiliation: Central Portugal Regional Pharmacovigilance Unit (UFC), Centre for Health Technology Assessment and Drug Research (CHAD), AIBILI - Association for Innovation and Biomedical Research on Light and Image Azinhaga de Santa Comba, Celas, 3000-548, Coimbra, Portugal, carlosmiguel.costaalves@gmail.com.
authors.forename: Carlos
authors.initials: C
authors.lastname: Alves
authors.forename: Francisco Batel
authors.initials: FB
authors.lastname: Marques
authors.forename: Ana Filipa
authors.initials: AF
authors.lastname: Macedo
mesh_terms: D002170:Canada; D003257:Consumer Product Safety / Q000331:legislation & jurisprudence*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000209:etiology / Q000517:prevention & control*; D005060:Europe; D035082:Federal Government; D033161:Government Regulation; D006801:Humans; D050316:Medical Order Entry Systems / Q000331:legislation & jurisprudence*; D015201:Meta-Analysis as Topic; D060735:Pharmacovigilance; D012306:Risk; D014481:United States