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Assessment of methodological quality and outcomes of clinical trials Chris tian Gluud

This study evaluates the methodological quality and outcomes of clinical trials, considering the patient's values and the best clinical research evidence. It discusses levels of evidence, systematic errors, random errors, and biases in clinical trials and meta-analyses. The study also examines the control of selection bias, allocation concealment, blinding, and industry sponsorship on research outcomes.

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Assessment of methodological quality and outcomes of clinical trials Chris tian Gluud

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  1. Assessment of methodological quality and outcomes of clinical trials Christian Gluud Copenhagen Trial Unit Centre for Clinical Intervention Research Rigshospitalet Copenhagen University Hospital

  2. Evidence-basedclinical practice • The patient’s values • (concerns, expectations, preferences) • The best clinical research evidence

  3. Levels of evidence

  4. Important aspects of clinical research- all levels of the hierachy Systematic errors (domains) Systematic errors (design) Random errors (play of chance)

  5. Levels of evidence Risk of systematic errors (domain) Risk of systematic errors (design) Risk of random errors

  6. Important aspects of randomised clinical trials and meta-analyses Systematic errors (domains) Systematic errors (design) Random errors (play of chance)

  7. Generation of the allocation sequence Allocation concealment Blinding Incomplete outcome data (intention-to-treat) Outcome reporting bias Industry bias Other components associated with bias Domains associated with bias risk

  8. Meta-analysis of several trials Low risk of bias High risk of bias Overall

  9. Ratio of odds ratios (ROR) Odds ratio of trials with unclear or inadequate component (high risk of bias) divided by odds ratio of trials with adequate component (low risk of bias)

  10. Control of selection bias • Generation of the allocation sequence • Low risk of bias • Computer system, • table of random numbers, or similar • High risk of bias • Not described or quasi-randomised • (excluded)

  11. BRANDOSequence generation 112 meta-analyses with 944 randomised clinical trials 696 (73.7%) with high risk of bias ROR 0.89 (95% CI 0.82 to 0.96)

  12. Control of selection bias • Allocation concealment • Low risk of bias • Central independent unit, • sealed envelopes (only if perfect placebo) • High risk of bias • Not described or open table of random • numbers

  13. BRANDOAllocation concealment 146 meta-analyses with 1292 randomised clinical trials 916 (70.9%) with high risk of bias ROR 0.93 (95% CI 0.87 to 0.99)

  14. Control of detection bias(reporting bias and observer bias) • Blinding • Low risk of bias • Identical placebo or comparator • High risk of bias • Not described or not blinded

  15. BRANDOBlinding 104 meta-analyses with 1057 randomised clinical trials 467 (44.2%) with high risk of bias ROR 0.87 (95% CI 0.79 to 0.96)

  16. Industry sponsorship and research outcome • Lundh et al, The Cochrane Library 2012 • Cross-sectional studies, cohort studies, systematic reviews and meta-analyses that quantitatively compared primary research studies of drugs or medical devices sponsored by industry with studies with other sources of sponsorship

  17. Favourable beneficial results

  18. Favourable harms results

  19. Favourable conclusions

  20. Important aspects of randomised clinical trials and meta-analyses Systematic errors (domains) Systematic errors (design) Random errors (play of chance)

  21. Design errors affecting external validity of randomised trials include ‘wrong’: • Centres • Participants • Experimental intervention • Control intervention • Goal - explanatory or pragmatic • Trial structure - parallel group, crossover, etc. • Objective - superiority, equivalence, non-inferiority • Outcome • Unit of analysis

  22. Important aspects of randomised clinical trials and meta-analyses Systematic errors (domains) Systematic errors (design) Random errors (play of chance)

  23. Mean number of patients per intervention arm (SEM) in 383 randomised trials published in Gastroenterology from 1964-2000 (Kjærgard et al. 2002)

  24. TA(C)E for hepatocellular carcinoma – trial sequential analysis

  25. The pernicious yin-yang interplay between random errors and systematic error PUBLICATION BIAS

  26. Number of patients with serum HBV DNA at end of treatment

  27. Trial sequential analysis of serum HBV DNA at end of treatment Trial sequential analysis of serum HBV DNA DARIS 4620 pts. Pc 54%, RRR 20%, alpha=5%, beta=20%, diversity=85%

  28. Number of pts without seroconversion from HBeAg to anti-HBe

  29. Trial sequential analysis of seroconversion from HBeAg to anti-HBe DARIS 891 pts. Pc 86%, RRR 20%, alpha=5%, beta=20%, diversity 79%

  30. Randomised clinical trials – most often false due to the people behind! Control intervention • Experimental intervention • systematic errors (domains) • systematic errors (design) • PUBLICATION bias “…why most research findings are false!” JP Ioannidis

  31. THANK YOU !

  32. The Cochrane Collaboration An international network of professionals, preparing , maintaining, and disseminating systematic reviews of the effects of health care

  33. Archie Cochrane (1979) ”It is surely a great criticism of our profession that we have not organised a critical summary, by speciality and subspeciality, adapted periodically, of all relevant randomised trials”

  34. The Cochrane Collaboration www.cochrane.org 670 000 randomised trials Now 5000 systematic reviews 500 new reviews per year 500 updated reviews per year JIF 6.2

  35. Answer to the question: When is it acceptable to make therapeutic decisions based on patient series, patient-control studies, and cohort studies?

  36. Answer to the question: When is it acceptable to make therapeutic decisions based on patient series, patient-control studies, and cohort studies? Only if you have exophtalmus producing intervention effects!

  37. Answer to the question: When is it acceptable to make therapeutic decisions based on patient series, patient-control studies, and cohort studies? As we do not know the intervention effect a priory – and medical research is a forward moving process – one should always test interventions in randomised clinical trials!

  38. Thomas C Chalmers More than 500 publications More than 25 000 citations H index above 77 Always randomize the first patient! The New England Journal of Medicine 1977;296(2):107

  39. Rare diseases and randomised trials With 7,000,000,000 (7 billion!) individuals in the world the disease has to be extremily rare – say less than 1/10,000,000 – before it becomes difficult to conduct randomised clinical trials! International patient registries Infrastructures like ECRIN

  40. James Lind 1747

  41. James Lind 1716-1794

  42. James Lind allocated Two oranges and lemons Two cider Two vinegar Two elixir vitriol Two spices and garlic Two sea water

  43. James Lind observed The two on oranges and lemons regained health in a few days and could care for the remainder, that stayed ill

  44. James Lind 1753

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