title: Post-Marketing Regulation of Medicines Withdrawn from the Market Because of Drug-Attributed Deaths: An Analysis of Justification.
abstract: Several medicinal products have been withdrawn from the market because of drug-attributed deaths.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 We documented medicinal products withdrawn from the market because of drug-attributed deaths, identified confirmatory studies investigating the drug-adverse event relationships, examined whether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.
  
  
  
  We searched electronic and non-electronic sources to identify medicinal products that were withdrawn because of drug-attributed deaths.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.
  
  
  
  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was related to the cause of death and the first reported death was 1 year (interquartile range = 1-3); products were withdrawn sooner when the interval between the first reported relevant adverse reaction and the first death was shorter.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.
  
  
  
  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 Medicinal products are likely to be quickly withdrawn from the market when there is a short interval to the first reported deaths.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.
authors.affiliation: Nuffield Department of Primary Care Health Sciences, Centre for Evidence-Based Medicine, University of Oxford, Gibson Building, Radcliffe Observatory Quarter, Oxford, OX2 6GG, UK. igho.onakpoya@kellogg.ox.ac.uk.
authors.forename: Igho J
authors.initials: IJ
authors.lastname: Onakpoya
authors.affiliation: Nuffield Department of Primary Care Health Sciences, Centre for Evidence-Based Medicine, University of Oxford, Gibson Building, Radcliffe Observatory Quarter, Oxford, OX2 6GG, UK.
authors.forename: Carl J
authors.initials: CJ
authors.lastname: Heneghan
authors.affiliation: Nuffield Department of Primary Care Health Sciences, Centre for Evidence-Based Medicine, University of Oxford, Gibson Building, Radcliffe Observatory Quarter, Oxford, OX2 6GG, UK.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Aronson
mesh_terms: D000465:Algorithms; D002423:Cause of Death; D003657:Decision Making; D064420:Drug-Related Side Effects and Adverse Reactions / Q000453:epidemiology / Q000401:mortality*; D019317:Evidence-Based Medicine; D006801:Humans; D011358:Product Surveillance, Postmarketing; D056737:Safety-Based Drug Withdrawals / Q000706:statistics & numerical data*