European Journal of Clinical Pharmacology

, Volume 70, Issue 6, pp 745–756 | Cite as

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

  • Carlos Alves
  • Francisco Batel Marques
  • Ana Filipa Macedo
Pharmacoepidemiology and Prescription



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.


Meta-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

Supplementary material

228_2014_1670_MOESM1_ESM.docx (48 kb)
ESM 1 (DOCX 47 kb)
228_2014_1670_MOESM2_ESM.docx (53 kb)
ESM 2 (DOCX 53 kb)


  1. 1.
    Madre LK, Califf RM, Reynolds RF et al (2006) Views from Academia, Industry, and Regulatory Agencies. In: Strom BL, Kimmel SE (eds) Textobook of pharmacoepidemiology. John Wiley & Sons, Chichester, England, pp 63–88Google Scholar
  2. 2.
    Moore TJ, Singh S, Furberg CD (2012) The FDA and new safety warnings. Arch Intern Med 172(1):78–80PubMedCrossRefGoogle Scholar
  3. 3.
    US Food and Drug Administration (2013) Drug Safety Communications. Available at: Accessed 24 September 2013
  4. 4.
    European Medicines Agency (2013) Safety monitoring of medicines. Available at: Accessed 24 September 2013
  5. 5.
    Wysowski DK, Swartz L (2005) Adverse drug event surveillance and drug withdrawals in the United States, 1969–2002: the importance of reported suspected reactions. Arch Intern Med 165(12):1363–1369PubMedCrossRefGoogle Scholar
  6. 6.
    Medicines and Healthcare products Regulatory Agency. Safety information. Drug safety update 2011;5(5). Citalopram and escitalopram: QT interval prolongation—new maximum daily dose restrictions (including in elderly patients), contraindications, and warnings. Available at: Accessed 24 September 2013
  7. 7.
    van Staa TP, Leufkens HG, Cooper C (2001) Use of inhaled corticosteroids and risk of fractures. J Bone Miner Res 16:581–588PubMedCrossRefGoogle Scholar
  8. 8.
    Papanikolaou PN, Christidi GD, Ioannidis JPA (2006) Comparison of evidence on harms of medical interventions in randomized and nonrandomized studies. CMAJ 174(5):635–641PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    US Food and Drug Administration (2012) Centre for Drug Evaluation and Research. Guidance drug safety information – FDA’s Communication to Public. Available at: Accessed 22 May, 2013
  10. 10.
    Kim CJ, Berlin JA (2006) The use of meta-analysis in pharmacoepidemiology. In: Strom BL, Kimmel SE (eds) Textobook of pharmacoepidemiology. John Wiley & Sons, Chichester, England, pp 353–365Google Scholar
  11. 11.
    Alves C, Batel-Marques F, Macedo AF (2012) Data sources on drug safety evaluation: a review of recent published meta-analyses. Pharmacoepidemiol Drug Saf 21:21–33PubMedCrossRefGoogle Scholar
  12. 12.
    Jüni P, Nartey L, Reichenbach S et al (2004) Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet 364:2021–2029PubMedCrossRefGoogle Scholar
  13. 13.
    Alves C, Macedo AF, Batel Marques F (2013) Sources of information used by regulatory agencies on the generation of drug safety alerts. Eur J Clin Pharmacol. doi:  10.1007/s00228-013-1564-y [Epub ahead of print]
  14. 14.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  15. 15.
    Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analysis. BMJ 327:557–560PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    Publication bias (2009) Borenstein M, hedges LV, Higgins JPT, Rothstein HR (eds). Introduction to meta-analysis. John Wiley & Sons, Chichester, England, pp 277–291Google Scholar
  17. 17.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCentralPubMedCrossRefGoogle Scholar
  18. 18.
    Bangalore S, Kumar S, Kjeldsen SE et al (2011) Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomized trials. Lancet Oncol 12(1):65–82PubMedCrossRefGoogle Scholar
  19. 19.
    Sattar N, Preiss D, Murray HM et al (2010) Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 375(9716):735–742PubMedCrossRefGoogle Scholar
  20. 20.
    Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC (2010) Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 11(7):627–636PubMedCrossRefGoogle Scholar
  21. 21.
    Vandenbroucke JP, Psaty BC (2008) Benefits and risks of drug treatments: how combine the best evidence on benefits with the best data about adverse effects. JAMA 300(20):2417–2419PubMedCrossRefGoogle Scholar
  22. 22.
    Alves C, Batel-Marques F, Macedo AF (2012) A meta-analysis of serious adverse events reported with exenatide and liraglutide: acute pancreatitis and cancer. Diabetes Res Clin Pract 98(2):271–84PubMedCrossRefGoogle Scholar
  23. 23.
    Eom CS, Jeon CY, Lim JW, Cho EG, Park SM, Lee KS (2011) Use of acidsuppressive drugs and risk of pneumonia: a systematic review and meta-analysis. Can Med Assoc J 183(3):310–319CrossRefGoogle Scholar
  24. 24.
    Giulianio C, Wilhelm SM, Kale-Pradhan PB (2012) Are proton pump inhibitors associated with the development of community-acquired pneumonia?: a meta-analysis. Expert Rev Clin Pharmacol 5(3):337–344CrossRefGoogle Scholar
  25. 25.
    Johnstone J, Nerenberg K, Loeb M (2010) Meta-analysis: proton pump inhibitor use and the risk of community-acquired pneumonia. Aliment Pharmacol Ther 31(11):1165–1177PubMedCrossRefGoogle Scholar
  26. 26.
    European Medicines Agency (2012). Working parties and other groups. Retired working parties. CHMP Pharmacovigilance Working Party. Monthly reports. Monthly report on safety concerns, guidelines and general matters - July 2012. Available at: Accessed 11 October 2013
  27. 27.
    Jick SS, Hernandez RK (2011) Risk of non-fatal venous thromboembolism in women using oral contraceptives containing drospirenone compared with women using oral contraceptives containing levonorgestrel: case–control study using United States claims data. BMJ. doi: 10.1136/bmj.d2151
  28. 28.
    Lester J, Neyarapaly GA, Lipowski E, Graham CF, Hall M, Dal Pan G (2013) Evaluation of FDA safety-related drug label changes in 2010. Pharmacoepidemiol Drug Saf 22(3):302–305PubMedCrossRefGoogle Scholar
  29. 29.
    Lasser KE, Allen PD, Woolhandler SJ, Himmelstein DU, Wolfe SM, Bor DH (2002) Timing for new black box warnings and withdrawals for prescription medications. JAMA 287(17):2215–2220PubMedCrossRefGoogle Scholar
  30. 30.
    Council for International Organizations of Medical Sciences. CIOMS Working Group X on “Considerations for applying good meta-analysis practices to clinical safety data within the biopharmaceutical regulatory process”. October 08-47-53/working-groups/working-group-x. Accessed 11 November 2013

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Carlos Alves
    • 1
    • 2
    • 3
  • Francisco Batel Marques
    • 1
    • 2
  • Ana Filipa Macedo
    • 3
  1. 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, CelasCoimbraPortugal
  2. 2.School of PharmacyUniversity of CoimbraCoimbraPortugal
  3. 3.Health Sciences Research CentreUniversity of Beira InteriorCovilhãPortugal

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