The golden standard or fools gold Selective data, impact on safety Clinical trials on trial HAI...
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![Page 1: The golden standard or fools gold Selective data, impact on safety Clinical trials on trial HAI Europe Open Seminar 2008 Neues Stadthaus, Berlin, 21 November.](https://reader036.fdocuments.net/reader036/viewer/2022070305/5514b2d3550346ea6e8b6247/html5/thumbnails/1.jpg)
The golden standard or fool’s goldSelective data, impact on safety
Clinical trials on trialHAI Europe Open Seminar 2008
Neues Stadthaus, Berlin, 21 November 2008
Joan-Ramon Laporte
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RCTs – The golden standard or fool’s gold?
Internal validity
External validity - Efficacy vs Effectiveness
Publication bias
Fraud
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Internal validity
• Did the control group receive optimal treatment?
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Internal validity
• Did the control group receive optimal treatment?
• Was the dose of the control group adequate?
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Favoursatypical
Favourshaloperidol
Drop out rates by dose of comparator drug in trials of patientswith schizophrenia or related disorders (risk difference and95 % confidence intervals)
Geddes et al., 2000
≤ 12 mg haloperidol
> 12 mg haloperidol
-0.5 -0.4 -0.3 -0.2 -0.1 0 0.1
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Internal validity
• Did the control group receive optimal treatment?
• Was the sample size adequate to identify any relevant difference?
• Was the dose of the control group adequate?
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Internal validity
• Did the control group receive optimal treatment?
• Did the published results refer to the primary variable?
• Was the sample size adequate to identify any relevant difference?
• Was the dose of the control group adequate?
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Internal validity
• Did the control group receive optimal treatment?
• Have all the trial results been published?
• Did the published results refer to the primary variable?
• Was the sample size adequate to identify any relevant difference?
• Was the dose of the control group adequate?
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Internal validity
• Did the control group receive optimal treatment?
• Were the results presented as a relative risk reduction, or as an absolute risk reduction?
• Have all the trial results been published?
• Did the published results refer to the primary variable?
• Was the sample size adequate to identify any relevant difference?
• Was the dose of the control group adequate?
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RCTs – The golden standard or fool’s gold?
Internal validity
External validity - efficacy vs effectiveness
Publication bias
Fraud
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External validity of clinical trials
• Context
• Reference population
• Selection criteria
• Diagnostic criteria
• Follow up
• Treatments (doses, compliance)
• Duration
• Primary and other variables
• Adverse effects
Lancet 2005; 365: 82-93
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(Un)transferability to clinical practice
Patients in RCTs differ from those in real practice:– Age– Comorbidity– Other treatments– Doses taken, compliance– Diagnostic criteria
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Efficacy vs effectiveness
RCT UCP
Nº of patients 102-103 104-107
Duration Short Longer
Populations High risk groups Potentially the excluded whole
population Comorbidity Generally excluded Often present
Conditions Well defined Ill-defined
Nº of drugs One or limited Undetermined
Dose/dosage Generally constant Often variable
Pattern of use Continuous Intermittent
Follow up Careful Less careful
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RCTs – The golden standard or fool’s gold?
Internal validity
External validity - efficacy vs effectiveness
Publication bias
Fraud
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RCTs – The golden standard or fool’s gold?
Internal validity
External validity - efficacy vs effectiveness
Publication bias
Fraud
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Third Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol
in Adults (Adult Treatment Panel III) (ATP III)
Financial Disclosure: Dr Grundy has received honoraria from Merck, Pfizer, Sankyo, Bayer, and Bristol-Myers Squibb. Dr Hunninghake has current grants from Merck, Pfizer, Kos Pharmaceuticals, Schering Plough, Wyeth Ayerst, Sankyo, Bayer, AstraZeneca, Bristol-Myers Squibb, and G. D. Searle; he has also received consulting honoraria from Merck, Pfizer, Kos Pharmaceuticals, Sankyo, AstraZeneca, and Bayer. Dr McBride has received grants and/or research support from Pfizer, Merck, Parke-Davis, and AstraZeneca; has served as a consultant for Kos Pharmaceuticals, Abbott, and Merck; and has received honoraria from Abbott, Bristol-Myers Squibb, Novartis, Merck, Kos Pharmaceuticals, Parke-Davis, Pfizer, and DuPont. Dr Pasternak has served as a consultant for and received honoraria from Merck, Pfizer, and Kos Pharmaceuticals, and has received grants from Merck and Pfizer. Dr Stone has served as a consultant and/or received honoraria for lectures from Abbott, Bayer, Bristol-Myers Squibb, Kos Pharmaceuticals, Merck, Novartis, Parke-Davis/Pfizer, and Sankyo. Dr Schwartz has served as a consultant for and/or conducted research funded by Bristol-Myers Squibb, AstraZeneca, Merck, Johnson & Johnson-Merck, and Pfizer.
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Conclusions
• The RCT is the best epidemiological method for causal inference
• However, it is often performed in a way which favours the sponsor’s treatment:– In its design
– In data analysis and interpretation
– In the publication of results
• At best, RCTs are one of many pieces of evidence about therapeutic interventions
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Conclusions
• The appraisal of innovation should not only take into account the so-called EBM, but also other evidence:– Pharmacodynamics– Pharmacokinetics– Availability of therapeutic alternatives
• The medical literature is no longer reliable for valid information
• Research should be performed, analyzed and published in a way which should be independent from commercially interested parties