Cochrane Adverse Effects Methods Group. Systematic reviews of adverse effects: framework for a structured approach

School of Medicine, Health Policy and Practice, University of East Anglia, Norwich, UK. <>
BMC Medical Research Methodology (Impact Factor: 2.27). 02/2007; 7(1):32. DOI: 10.1186/1471-2288-7-32
Source: PubMed


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.
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.
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.
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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    • "Despite the 243 patients included in the systematic review, which may correspond roughly to the affected population of a big European city or a little region with less than 1 million inhabitants, the authors concluded that the evidence for any effect was insufficient . Moreover, despite the efforts over the years to improve the reporting of adverse effects[Loke et al., 2007], systematic reviews still tend to underreport them[Zorzela et al., 2014]; so, not only insufficient evidence exists for positive effects of the treatment with betahistine, but also its harmful effects may be underestimated. In fact, different studies have shown that betahistine can cause bronchospasms [Jeck-Thole andWagner, 2006;White et al., 1987]and, according to Food and Drug Administration , betahistine dihydrochloride 'has caused asthma, drowsiness, lethargy, nausea, headache. "
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    ABSTRACT: Ménière's disease is a disorder of the inner ear affecting hearing and balance to a varying degree. It is characterized by episodes of vertigo, low-pitched tinnitus, and hearing loss. There is currently no gold standard treatment for Ménière's disease. We conducted a systematic search of the Cochrane Database, as a high-quality source of evidence-based therapies, for reviews on the efficacy of etiological therapy or on Ménière's disease or its symptoms. Following recent positive experiences reported by other research teams, we decided to involve a patients' representative in the assessment and analysis of the evidence retrieved in the literature in order to achieve a more patient-centered evaluation of the therapies. Evidence confirms that an effective treatment of Ménière's disease is still missing, but recent discoveries on the microvascular etiology of Ménière's disease may be assimilated by new evidence-based therapeutic approaches. © 2015 S. Karger AG, Basel.
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    • "Based on the above and observations of other authors [30-34], we decided to include a wide assortment of study designs: randomized controlled trials (RCTs); non-randomized trials with concurrent control (n-RCTs); controlled trials; uncontrolled or non-concurrent controlled trials; cohort studies; cross-sectional studies and other observational designs. "
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    • "However, there is no consensus regarding the detail of how such reports should be elicited, in particular how participants should be questioned about ill health and their use of medications other than the study drug(s). Heterogeneity in elicitation methods provides potential for measurement error if questioning methods are sub-optimal, and undermines meta-analyses of adverse effects [1,2]. Staff may use general enquiries to identify AEs, such as 'How have you been feeling?’, "
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