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      Delays in the post-marketing withdrawal of drugs to which deaths have been attributed: a systematic investigation and analysis

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      BMC Medicine

      BioMed Central

      Death, Drug withdrawal, Review, Voluntary recall

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          Abstract

          Background

          Post-marketing withdrawal of medicinal products because of deaths can be occasioned by evidence obtained from case reports, observational studies, randomized trials, or systematic reviews. There have been no studies of the pattern of withdrawals of medicinal products to which deaths have been specifically attributed and the evidence that affects such decisions. Our objectives were to identify medicinal products that were withdrawn after marketing in association with deaths, to search for the evidence on which withdrawal decisions were based, and to analyse the delays involved and the worldwide patterns of withdrawal.

          Methods

          We searched the World Health Organization’s Consolidated List of [Medicinal] Products, drug regulatory authorities’ websites, PubMed, Google Scholar, and textbooks on adverse drug reactions. We included medicinal products for which death was specifically mentioned as a reason for withdrawal from the market. Non-human medicines, herbal products, and non-prescription medicines were excluded. One reviewer extracted the data and a second reviewer verified them independently.

          Results

          We found 95 drugs for which death was documented as a reason for withdrawal between 1950 and 2013. All were withdrawn in at least one country, but at least 16 remained on the market in some countries. Withdrawals were more common in European countries; few were recorded in Africa (5.3%). The more recent the launch date, the sooner deaths were reported. However, in 47% of cases more than 2 years elapsed between the first report of a death and withdrawal of the drug, and the interval between the first report of a death attributed to a medicinal product and eventual withdrawal of the product has not improved over the last 60 years.

          Conclusions

          These results suggest that some deaths associated with these products could have been avoided. Manufacturers and regulatory authorities should expedite investigations when deaths are reported as suspected adverse drug reactions and consider early suspensions. Increased transparency in the publication of clinical trials data and improved international co-ordination could shorten the delays in withdrawing dangerous medicinal products after reports of deaths and obviate discrepancies in drug withdrawals in different countries.

          Please see related article: http://dx.doi.org/10.1186/s12916-015-0270-2.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12916-014-0262-7) contains supplementary material, which is available to authorized users.

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          Most cited references 58

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          Systematic reviews of adverse effects: framework for a structured approach

          Background As every healthcare intervention carries some risk of harm, clinical decision making needs to be supported by a systematic assessment of the balance of benefit to harm. A systematic review that considers only the favourable outcomes of an intervention, without also assessing the adverse effects, can mislead by introducing a bias favouring the intervention. Much of the current guidance on systematic reviews is directed towards the evaluation of effectiveness; but this differs in important ways from the methods used in assessing the safety and tolerability of an intervention. A detailed discussion of why, how and when to include adverse effects in a systematic review, is required. Methods This discussion paper, which presupposes a basic knowledge of systematic review methodology, was developed by consensus among experienced reviewers, members of the Adverse Effects Subgroup of The Cochrane Collaboration, and supplemented by a consultation of content experts in reviews methodology, as well as those working in drug safety. Results A logical framework for making decisions in reviews that incorporate adverse effects is provided. We explore situations where a comprehensive investigation of adverse effects is warranted and suggest strategies to identify practicable and clinically useful outcomes. The advantages and disadvantages of including observational and experimental study designs are reviewed. The consequences of including separate studies for intended and unintended effects are explained. Detailed advice is given on designing electronic searches for studies with adverse effects data. Reviewers of adverse effects are given general guidance on the assessment of study bias, data collection, analysis, presentation and the interpretation of harms in a systematic review. Conclusion Readers need to be able to recognize how strategic choices made in the review process determine what harms are found, and how the findings may affect clinical decisions. Researchers undertaking a systematic review that incorporates adverse effect data should understand the rationale for the suggested methods and be able to implement them in their review.
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            Methods for causality assessment of adverse drug reactions: a systematic review.

            Numerous methods for causality assessment of adverse drug reactions (ADRs) have been published. The aim of this review is to provide an overview of these methods and discuss their strengths and weaknesses. We conducted electronic searches in MEDLINE (via PubMed), EMBASE and the Cochrane databases to find all assessment methods. Thirty-four different methods were found, falling into three broad categories: expert judgement/global introspection, algorithms and probabilistic methods (Bayesian approaches). Expert judgements are individual assessments based on previous knowledge and experience in the field using no standardized tool to arrive at conclusions regarding causality. Algorithms are sets of specific questions with associated scores for calculating the likelihood of a cause-effect relationship. Bayesian approaches use specific findings in a case to transform the prior estimate of probability into a posterior estimate of probability of drug causation. The prior probability is calculated from epidemiological information and the posterior probability combines this background information with the evidence in the individual case to come up with an estimate of causation. As a result of problems of reproducibility and validity, no single method is universally accepted. Different causality categories are adopted in each method, and the categories are assessed using different criteria. Because assessment methods are also not entirely devoid of individual judgements, inter-rater reliability can be low. In conclusion, there is still no method universally accepted for causality assessment of ADRs.
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              Anecdotes that provide definitive evidence.

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                Author and article information

                Contributors
                igho.onakpoya@phc.ox.ac.uk
                carl.heneghan@phc.ox.ac.uk
                jeffrey.aronson@phc.ox.ac.uk
                Journal
                BMC Med
                BMC Med
                BMC Medicine
                BioMed Central (London )
                1741-7015
                5 February 2015
                5 February 2015
                2015
                : 13
                Affiliations
                Nuffield Department of Primary Care Health Sciences, Centre for Evidence-based Medicine, University of Oxford, New Radcliffe House, Radcliffe Observatory Quarter, Oxford, OX2 6GG UK
                Article
                262
                10.1186/s12916-014-0262-7
                4318389
                © Onakpoya et al.; licensee BioMed Central. 2015

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                Categories
                Research Article
                Custom metadata
                © The Author(s) 2015

                Medicine

                voluntary recall, review, drug withdrawal, death

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