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Considering adverse effects in prioritising reviews


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    • 1. Considering Adverse Effects in prioritising reviews Andrew Herxheimer Cochrane Adverse Effects Methods Group
    • 2. Why include harmful effects in reviews?
      • Considering only beneficial effects leads to bias
      • We must aim to assess benefit/ harm balance
      • Detailed evaluation needed esp. when:
        • narrow margin between benefit and harm
        • (e.g. aspirin/ CVD)
        • effective treatments differ in their harm profiles
        • AEs make patients stop treatment
    • 3. Reconsidering the review questions
      • What should the review questions be?
      • Depends on the aim of the review
        • All adverse effects relevant to clinical decisions?
        • A specific treatment or a class of treatments?
        • Specific AEs or specific populations ?
        • AEs across all conditions treated or
        • use in one specific condition
        • All dosages ?
        • All durations of use?
        • With an evolving method, what cut-off point to use?
    • 4. Gaps & weaknesses in data
      • poor or inaccessible data on human toxicology
      • patchy and unsatisfactory analysis of spontaneous reports of suspected ADRs
      • deficient monitoring of AEs in practice
      • no systematic study of mechanisms of AEs
      • little work on prevention or attenuation of AEs
      • no clear method to assess benefit/ harm balance
      • sparse knowledge of the social impact of medicines – on communities, development of dependence, quality of life …
    • 5. Searching and Sources
      • Need to search for studies of all designs, not just RCTs
      • AEs often treated as secondary outcomes
      • Poor reporting in titles, abstracts, so poor indexing
      • Inconsistent terminology and indexing
      • Many data sources: time and resource-intensive
      • Use industry, surveillance data, tertiary sources?
      • No consensus on best search strategy or sources
    • 6. Which study designs?
      • Most AE data come from studies other than RCTs -
      • Cohort studies, case-control studies, case series, case reports
      • So, new searches are needed
    • 7. Quality assessment & evidence synthesis 1
      • The evidence hierarchy differs from that for evaluative research: RCTs are not on top – other study designs must also be considered
      • Each study design contributes a different category of evidence
      • These categories of evidence are combined to summarise quantitatively: a. the relation between the cause of a disease and the risk of the disease; b. the extent to which the disease can be prevented
      • Such a teleoanalysis , unlike a meta-analysis, combines data from different classes of evidence rather than from one type of study
      • See Wald NJ, Morris JK. BMJ 2003;327:616-8
    • 8. Quality assessment & evidence synthesis 2
      • Do we know how AEs were detected ? Is reporting adequate ? Under-reporting is universal!
      • Data are ‘thinner’ & less reliable than those for effectiveness
      • Needs more tolerance of ambiguity
      • The precautionary principle applies
    • 9. Other difficulties
      • Takes time & resources
      • Frequencies often can’t be estimated
      • It’s tempting to exclude evidence with high risk of bias , but it’s better to explain that
      • Are definitions/ grouping of outcomes comparable across studies?
      • An intervention may have many potential AEs which cannot be analysed in detail but only 2 or 3 beneficial outcomes
    • 10. How all this influences priorities
      • Some of a CRG’s existing reviews & protocols may need urgent revision to include AEs
      • Important or widely used interventions with ill understood AEs deserve priority
      • AEs of doubtfully or marginally effective but widely used interventions need prompt review
      • Members of the AEMG will be glad to help by discussing your specific examples
    • 11. Working together
      • Cochrane Adverse Effects Methods Group
      • Website (
      • Advisory Team
      • Method Papers
      • Discussion List
      • Workshops
      • Enquiry Database ( FAQs )
      • Contact person for each Review Group
      • Collecting examples of review decisions and how they were made
      • Ongoing Research
    • 12. Guidelines so far
      • Cochrane Handbook
        • Higgins JPT, Green S (editors). Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.0 [updated February 2008]. The Cochrane Collaboration, 2008. Available from
      • BMC Paper
        • Loke  YK, Price D, Herxheimer A. Systematic reviews of adverse effects: framework for a structured approach    BMC Med Res Methodol 2007;7:32.
      • CRD Report 4
        • Forthcoming update/ intranet guidelines
    • 13.