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Database WITHDRAWN lists 578 drugs that were pulled out of global markets due to safety reasons. Most importantly, the database contains information about therapeutic targets, off-targets, underlying mechanisms of toxicity involved, and biological pathways. In addition, the database maps single nucleotide polymorphism (SNPs), genetic variations that are associated with toxicity in some people [1].

Post-market safety withdrawals occur for a variety of reasons, from lack of efficacy to manufacturing and business reasons. Yet, for approximately half of the drugs in the database, safety concerns were the main reason for withdrawal. Siramshetty et al. argue that this toxicological knowledge could be used to examine the propensity of drugs to cause adverse drug effects in vitro, using appropriate panels. Idiosyncratic adverse drug reactions (IADRs) such as drug-induced liver injury (DILI) serve as an example of a rare event that is currently very difficult to predict [2].

In 2016, Onakpoya, I., Heneghan, C. and Aronson, J. published a study of patterns of 462 safety withdrawals of medicinal products they identified in the period from 1953 to 2013 and examined the evidence that led to those withdrawals. The authors also investigated the geographical patterns of withdrawals and the interval between first approval and withdrawal dates. In 72% of cases of medicinal products withdrawn due to adverse drug reactions, the evidence supporting the decision to withdraw the drugs consisted of anecdotal reports. The authors rated the level of evidence that led to product withdrawal based on the Oxford Centre for Evidence-based Medicine (OCEBM) criteria and documented the highest level of evidence available to support the decision.

List based on the number of withdrawn drugs and the highest level of evidence available

  • Level 4, case-series or case-control studies 330 (all marketed drugs) / 189 (drugs launched since 1950)
  • Level 5, mechanism-based reasoning (lowest): 56 (all) /36 (since 1950)
  • Level 3, non-randomized, cohort, or follow-up studies: 43 (all) / 30 (since 1950)
  • Level 2, randomized clinical trials: 27 (all) / 25 (since 1950)
  • Level 1, systematic reviews (highest): 6 (all) / 6 (since 1950)

The median interval between launch and the year the adverse drug reaction was first reported was 8 years (ranging from 2 to 20 years) for all drugs and 4 years for drugs launched after 1960. The interval between the first launch and date of first publication has been gradually shortening. The time lag between first launch and withdrawal is significantly longer, however: 18 years for all drugs (ranging from 6 to 34 years) and 10 years for drugs launched after 1960 (ranging from 3 to 19 years). The median interval between the first reported adverse drug reaction and the year the drug was withdrawn was 6 years for all drugs and 3 years for drugs launched after 1960. Worryingly, there is no consistently observable trend of shortening the time lag between the first report of a safety concern and eventual withdrawal decision [3]. The current pharmacovigilance system does not seem to be able to detect safety concerns faster and more reliably than a half a century ago.

According to Grand View Research, Inc. (2019), the pharmacovigilance market will be worth $11.64 Billion by 2026. The key growth drivers are the increasing incidence of adverse drug reactions due to increasing drug consumption and demographic developments and increasingly stringent regulatory requirements. Phase IV (post-market surveillance) held a dominant market share compared to adverse drug reactions from clinical trials. The trend to outsource pharmacovigilance services to Asia to reduce operational costs continues [4].

European Federation of Pharmaceutical Industry and Associations (EFPIA) in their presentation on “Looking forward. Pharmacovigilance in the next 5 years: The Industry Vision” emphasizes the need to reverse the current trend of exponentially growing costs and limited value of pharmacovigilance outputs through automation, cognitive computing and the incorporation of other data sources such as real-world and OMICS data [5].

Long time lag between the first discovery of a safety concern and appropriate action, low quality of evidence produced by the system, and an exponentially increasing cost of pharmacovigilance operations are not characteristics of a sustainable, responsive system. Optimized pharmacovigilance system shall produce timely, high-quality, robust and reliable evidence that can support decision-making and serves all stakeholders, whose operations depend on such system.


[1] Siramshetty V.B., Nickel-Seeber J., Omieczynski C., Gohlke B.-O., Drwal M.N., Preissner R.: WITHDRAWN-a resource for withdrawn and discontinued drugs Nucleic Acids Res (Database issue 2015). http://cheminfo.charite.de/withdrawn/ [Accessed 4 May 2019].

[2] Siramshetty, V., Nickel, J., Omieczynski, C., Gohlke, B., Drwal, M. and Preissner, R. (2015). WITHDRAWN—a resource for withdrawn and discontinued drugs. Nucleic Acids Research, [online] 44(D1), pp.D1080-D1086. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702851/ [Accessed 4 May 2019].

[3] Onakpoya, I., Heneghan, C. and Aronson, J. (2016). Post-marketing withdrawal of 462 medicinal products because of adverse drug reactions: a systematic review of the world literature. BMC Medicine, [online] 14(1). Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4740994/ [Accessed 4 May 2019].

[4] Grand View Research (2019). Pharmacovigilance Market Worth $11.64 Billion By 2026 | CAGR: 13.3%. [online] Grand View Research. Available at: https://www.grandviewresearch.com/press-release/global-pharmacovigilance-market [Accessed 4 May 2019].

[5] Edwards, V. (2018). Looking forward. Pharmacovigilance in the next 5 years: The Industry Vision. https://www.ema.europa.eu/en/documents/presentation/presentation-pharmacovigilance-next-5-years-industry-vision-v-edwards_en.pdf [Accessed 4 May 2019].

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