Overall and subgroup analysis • If the OVERALL results show highly significant evidence of a worthwhile effect of treatment, but a few subgroups of the overview unexpectedly indicate no benefit (which could well happen by chance), then the appropriate question is whether there is good evidence that this life-saving treatment should be denied to these patients. • REVERSAL of the usual demand that there should be proof of worthwhile benefit. Courtesy of Dr. K. Wheatl
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Overall and subgroup analysis• If the OVERALL results show highly significant
evidence of a worthwhile effect of treatment, but a few subgroups of the overview unexpectedly indicate no benefit (which could well happen by chance), then the appropriate question is whether there is good evidence that this life-saving treatment should be denied to these patients.
• REVERSAL of the usual demand that there should be proof of worthwhile benefit.
Courtesy of Dr. K. Wheatley
Meta-analysis vs. randomized controlled trials: internal validity vs. generalizibility
• Have complimentary roles– RCT, large adequately powered
• If our desire is to assess the efficacy of treatment (i.e. understand a measure of benefit of the treatment under ideal conditions of a clinical trial using narrow defined eligibility criteria)
– Meta-analysis (of totality of evidence)• If our goal is to obtain reliable estimate about the
treatment effectiveness (i.e. understand the extent to which a given treatment can produce a beneficial effect under variety of circumstances and eligibility criteria)
Meta-analysis vs. randomized controlled trials
Small CTs To study mechanisms
Meta-analyses of small RCTs
To generate hypotheses for more reliable RCTs
Large RCts
Meta-analyses of large RCTs
To obtain reliable overall answers under specificconditions of a trial
To obtain a typical and unbiased and generalizible estimate of treatment effect and to explore interactionsamong subgroups
Literature-based vs. individual patient data meta-analysis?
• IPD MA gold-standard
• LMA may be misleading– Data extraction, patient exclusion,
length of follow-up, method analysis may be less accurate in LMA
Lancet 1993;341:418-22; Stat Med 1998;14:2057-2079
IV Ethical obligations to account of what’s already known
• To avoid unnecessary trials if reliable knowledge already exists
• Conversely, to determine if there is true uncertainty about relative values of competing treatment alternatives – A new trial should be conducted if there is a substantial
uncertainty which of the trial treatments would benefit the patient better
• Requirement that equipoise (uncertainty principle) is met
Ethical obligation of building systematically on what is already known
• Clinical trials should be preceded by a systematic review and should be reported with a discussion of assessing the trial’s results in the context what is already known– Ethical requirement for updating systematic
reviews
• UK, Denmark, Holland now mandates search or conduct of SR before a new clinical trial is done
JAMA 1998;280:280-282;Lancet 2001:358:1648
V Knowledge resources
“It is surely a great criticism of our profession that we have not organised a critical summary, by specialty or subspecialty, adapted periodically, of all relevant randomised controlled trials.”
Archie Cochrane
Cochrane Database of Systematic Reviews -
The Cochrane Collaboration - an international network of individuals and institutions committed to preparing, maintaining, and promoting the accessibility of systematic reviews of the effects of health care interventions.
Meta-analyses in radiation oncology: an example of reliable review with long-term
(20 years) follow-up
• Favourable and unfavourable effects on long-term survival of radiotherapy for early breast cancer: an overview of the randomised trials
Early Breast Cancer Trialists' Collaborative Group*
Lancet 2000; 355: 1757 70 (20 May 2000 )
Proportional effects on all-cause mortality
in 40 trials of radiotherapy
Lancet 2000; 355: 1757 70 (20 May 2000 )
Absolute effects of radiotherapy
on cause-specific survival
Absolute benefits and hazards
Part VIEvidence and decision-making
Clinical Decision Making
Evidence from research
Patient circumstances
Preferences,values andrights
Courtesy of Dr. G. Lyman
Reporting data on benefits and harms
• If evidence on benefits and harms are not reported or is of poor quality, one has to wonder how physicians make decisions and recommendations for their patients
Eddy D. JAMA 1990;264:1737-39
Reporting data on benefits and harms: RCTs in myeloma