Abstract
Introduction
Several medicinal products have been withdrawn from the market because of drug-attributed deaths. However, there has been no investigation of whether such withdrawals were justified, and the extent to which confirmatory studies are used to investigate drug-adverse event relationships when deaths are reported is uncertain. We documented medicinal products withdrawn from the market because of drug-attributed deaths, identified confirmatory studies investigating the drug-adverse event relationships, examined whether withdrawals of medicinal products because of drug-attributed deaths after marketing were justified based on a mechanistic analysis, and examined the trends over time.
Methods
We searched electronic and non-electronic sources to identify medicinal products that were withdrawn because of drug-attributed deaths. We used a previously published algorithm to examine whether the withdrawals of products were justified. We then searched PubMed and Google Scholar to identify studies investigating the drug-adverse event relationships, used the Oxford Centre for Evidence-Based Medicine criteria to document the levels of evidence, and assessed whether the evidence of an association was confirmed.
Results
We included 83 medicinal products. The reasons for withdrawal appeared to have been justified in 80 cases (96%). The median interval between the first reported adverse reaction that was related to the cause of death and the first reported death was 1 year (interquartile range = 1–3); products were withdrawn sooner when the interval between the first reported relevant adverse reaction and the first death was shorter. Confirmatory studies were conducted in 57 instances (69%), and there was evidence of an association in 52 cases (63%). Four products (5%) were re-introduced after initial withdrawal.
Conclusion
Regulatory authorities have been justified in making withdrawal decisions when deaths have been attributed to medicinal products, using the precautionary principle when alternative decisions could have been made. Medicinal products are likely to be quickly withdrawn from the market when there is a short interval to the first reported deaths. The use of an algorithm such as we have used in this study could help to expedite the process of decision making.
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Funding
No sources of funding were used to assist in the preparation of this study. Igho Onakpoya receives scholarship funding from the Clarendon Fund for the DPhil Programme in Primary Care at the University of Oxford. Carl Heneghan is supported by the National Institute for Health Research School for Primary Care Research (NIHR-SPCR). He has received grant funding from the World Health Organization, the NIHR, and the NIHR-SPCR and occasionally receives expenses for teaching evidence-based medicine.
Conflict of interest
Igho Onakpoya, Carl Heneghan, and Jeffrey Aronson have no conflicts of interest that are directly relevant to the content of this study. Jeffrey Aronson has edited textbooks on adverse drug reactions, including some of the texts used for this systematic review; he is President Emeritus and an Honorary Fellow of the British Pharmacological Society, a member of a NICE technology appraisal committee, a member of the advisory board of the British National Formulary, an Honorary Fellow of the Faculty of Pharmaceutical Medicine, and chair of the British Pharmacopoeia Commission’s Expert Advisory Group on Nomenclature. However; the opinions expressed in this article are not necessarily shared by those organizations or their other members.
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Onakpoya, I.J., Heneghan, C.J. & Aronson, J.K. Post-Marketing Regulation of Medicines Withdrawn from the Market Because of Drug-Attributed Deaths: An Analysis of Justification. Drug Saf 40, 431–441 (2017). https://doi.org/10.1007/s40264-017-0515-4
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DOI: https://doi.org/10.1007/s40264-017-0515-4