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Drug-safety alerts issued by regulatory authorities: usefulness of meta-analysis in predicting risks earlier

  • Pharmacoepidemiology and Prescription
  • Published:
European Journal of Clinical Pharmacology Aims and scope Submit manuscript

Abstract

Purpose

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.

Conclusion

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.

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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

Author information

Authors and Affiliations

  1. 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

    Carlos Alves & Francisco Batel Marques

  2. School of Pharmacy, University of Coimbra, Coimbra, Portugal

    Carlos Alves & Francisco Batel Marques

  3. Health Sciences Research Centre, University of Beira Interior, Covilhã, Portugal

    Carlos Alves & Ana Filipa Macedo

Authors
  1. Carlos Alves
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  2. Francisco Batel Marques
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  3. Ana Filipa Macedo
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Corresponding author

Correspondence to Carlos Alves.

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Contributions of authors

Carlos Alves conceived the study, collected and analyzed data, and wrote the paper. Ana Filipa Macedo and Francisco Batel Marques conceived the study, analyzed data, and reviewed the paper. In case of disagreement between Carlos Alves and Ana Filipa Macedo, the opinion of Francisco Batel Marques was sought.

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Alves, C., Marques, F.B. & Macedo, A.F. Drug-safety alerts issued by regulatory authorities: usefulness of meta-analysis in predicting risks earlier. Eur J Clin Pharmacol 70, 745–756 (2014). https://doi.org/10.1007/s00228-014-1670-5

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  • DOI: https://doi.org/10.1007/s00228-014-1670-5

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