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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Available from: Deirdre Price, Oct 09, 2015
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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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    ABSTRACT: The objective was to find evidence to substantiate assertions that electronic applications for medication management in ambulatory care (electronic prescribing, clinical decision support (CDSS), electronic health record, and computer generated paper prescriptions), while intended to reduce prescribing errors, can themselves result in errors that might harm patients or increase risks to patient safety. Because a scoping search for adverse events in randomized controlled trials (RCTs) yielded few relevant results, we systematically searched nine databases, including MEDLINE, EMBASE, and The Cochrane Database of Systematic Reviews for systematic reviews and studies of a wide variety of designs that reported on implementation of the interventions. Studies that had safety and adverse events as outcomes, monitored for them, reported anecdotally adverse events or other events that might indicate a threat to patient safety were included. We found no systematic reviews that examined adverse events or patient harm caused by organizational interventions. Of the 4056 titles and abstracts screened, 176 full-text articles were assessed for inclusion. Sixty-one studies with appropriate interventions, settings and participants but without patient safety, adverse event outcomes or monitoring for risks were excluded, along with 77 other non-eligible studies. Eighteen randomised controlled trials (RCTs), 5 non-randomised controlled trials (non-R, CTs) and 15 observational studies were included. The most common electronic intervention studied was CDSS and the most frequent clinical area was cardio-vascular, including anti-coagulants. No RCTS or non-R,CTS reported adverse event. Adverse events reported in observational studies occurred less frequently after implementation of CDSS. One RCT and one observational study reported an increase in problematic prescriptions with electronic prescribing CONCLUSIONS: The safety implications of electronic medication management in ambulatory care have not been established with results from studies found in this systematic review. Only a minority of studies that investigated these interventions included threats to patients' safety as outcomes or monitored for adverse events. It is therefore not surprising that we found little evidence to substantiate fears of new risks to patient safety with their implementation. More research is needed to focus on the draw-backs and negative outcomes that implementation of these interventions might introduce.
    BMC Medical Informatics and Decision Making 12/2013; 13(1):133. DOI:10.1186/1472-6947-13-133 · 1.83 Impact Factor
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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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    ABSTRACT: Accurately characterizing a drug's safety profile is essential. Trial harm and tolerability assessments rely, in part, on participants' reports of medical histories, adverse events (AEs), and concomitant medications. Optimal methods for questioning participants are unclear, but different methods giving different results can undermine meta-analyses. This study compared methods for eliciting such data and explored reasons for dissimilar participant responses. Participants from open-label antimalarial and antiretroviral interaction trials in two distinct sites (South Africa, n = 18 [all HIV positive]; Tanzania, n = 80 [86% HIV positive]) were asked about ill health and treatment use by sequential use of (1) general enquiries without reference to particular conditions, body systems or treatments, (2) checklists of potential health issues and treatments, (3) in-depth interviews. Participants' experiences of illness and treatment and their reporting behaviour were explored qualitatively, as were trial clinicians' experiences with obtaining participant reports. Outcomes were the number and nature of data by questioning method, themes from qualitative analyses and a theoretical interpretation of participants' experiences. There was an overall cumulative increase in the number of reports from general enquiry through checklists to in-depth interview; in South Africa, an additional 12 medical histories, 21 AEs and 27 medications; in Tanzania an additional 260 medical histories, 1 AE and 11 medications. Checklists and interviews facilitated recognition of health issues and treatments, and consideration of what to report. Information was sometimes not reported because participants forgot, it was considered irrelevant or insignificant, or they feared reporting. Some medicine names were not known and answers to questions were considered inferior to blood tests for detecting ill health. South African inpatient volunteers exhibited a "trial citizenship", working to achieve researchers' goals, while Tanzanian outpatients sometimes deferred responsibility for identifying items to report to trial clinicians. Questioning methods and trial contexts influence the detection of adverse events, medical histories and concomitant medications. There should be further methodological work to investigate these influences and find appropriate questioning methods.
    BMC Medical Research Methodology 11/2013; 13(1):140. DOI:10.1186/1471-2288-13-140 · 2.27 Impact Factor
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    • "The scope of our review was focussed enough to enable us to concentrate on one specific indication of midazolam and clonidine, but broad enough for us to feel that we have included as much information about the side effects of these drugs when given in this situation as possible. Our review was conducted according to a predefined protocol, which was designed according to the guidelines suggested by the Cochrane Adverse Effects Methods Group [53]. In doing so we feel we have not only systematically identified all the relevant literature, but also rigorously appraised it. "
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    ABSTRACT: Background Adequate sedation is crucial to the management of children requiring assisted ventilation on Paediatric Intensive Care Units (PICU). The evidence-base of randomised controlled trials (RCTs) in this area is small and a trial was planned to compare midazolam and clonidine, two sedatives widely used within PICUs neither of which being licensed for that use. The application to obtain a Clinical Trials Authorisation from the Medicines and Healthcare products Regulatory Agency (MHRA) required a dossier summarising the safety profiles of each drug and the pharmacovigilance plan for the trial needed to be determined by this information. A systematic review was undertaken to identify reports relating to the safety of each drug. Methodology/Principal Findings The Summary of Product Characteristics (SmPC) were obtained for each sedative. The MHRA were requested to provide reports relating to the use of each drug as a sedative in children under the age of 16. Medline was searched to identify RCTs, controlled clinical trials, observational studies, case reports and series. 288 abstracts were identified for midazolam and 16 for clonidine with full texts obtained for 80 and 6 articles respectively. Thirty-three studies provided data for midazolam and two for clonidine. The majority of data has come from observational studies and case reports. The MHRA provided details of 10 and 3 reports of suspected adverse drug reactions. Conclusions/Significance No adverse reactions were identified in addition to those specified within the SmPC for the licensed use of the drugs. Based on this information and the wide spread use of both sedatives in routine practice the pharmacovigilance plan was restricted to adverse reactions. The Clinical Trials Authorisation was granted based on the data presented in the SmPC and the pharmacovigilance plan within the clinical trial protocol restricting collection and reporting to adverse reactions.
    PLoS ONE 03/2013; 8(3):e51787. DOI:10.1371/journal.pone.0051787 · 3.23 Impact Factor
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