Drug-safety alerts issued by regulatory authorities: usefulness of meta-analysis in predicting risks earlier
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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.
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.
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.
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.
KeywordsMeta-analysis Safety alerts Data sources Regulatory agencies
Conflict of interest
Carlos Alves is supported by a research grant from the Foundation for Science and Technology, Portugal; reference: SFRH/BD/64957/2009.
Ana Filipa Macedo declares that she has no conflict of interest.
Francisco Batel Marques declares that she has no conflict of interest.
Details of ethical approval
No ethics approval was required for this study
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