Explosion of knowledge since the 1970 s Textbooks outdated before publication 1
Scientific chaos Meta - analyses Systematic reviews Implementation of evidence into practice 2
KNOWLEDGE TRANSFER IN MEDICINE EVIDENCED-BASED CLINICAL PRACTICE The patient s values (concerns, expectations, preferences) The best clinical research evidence 3
LEVELS OF EVIDENCE DEFINITIONS Cochrane systematic review a review based on a peer reviewed, published protocol of primary research on a particular question that tries to identify, select, synthesize, and appraise all high quality research evidence relevant to that question in order to answer it Systematic review as above, but most often without a protocol (CAVE!!!)! Meta-analysis - a statistical analysis of a collection of results in order to integrate the results (but also used as a publication term - most often without a protocol (CAVE!!!)! 4
NUMBER OF PUBLICATIONS 50000 Meta-analyses 40000 Systematic reviews Number of publications 30000 20000 Cochrane systematic reviews 10000 0 1970-74 1975-79 1980-84 1985-89 1990-94 1995-99 2000-04 2005-09 2010- Year The best clinical research evidence coupled with the patient s values and the clinician s experience 5
HISTORIC DEVELOPMENT OF EVIDENCE-BASED MEDICINE Avicenna (980-1037) Stop doing experiments in horses and lions! Such experiments prove nothing about the effect in humans Medicine ought to be evaluated in two comparable cases The reproducibility ought to be evaluated JAMES LIND 1716 1794 6
JAMES LIND 1716 1794 JAMES LIND ALLOCATED 2 - oranges and lemons 2 - spices and garlic 2 - vinegar 2 - elixir vitriol 2 - cider 2 - sea water 7
JAMES LIND OBSERVED The two on oranges and lemons regained health in a few days and could care for the remainder, that stayed ill JAMES LIND 1753 8
GEORGE LÖHNER AND...1835 GEORGE LÖHNER AND HIS TEAM OF TRUTH LOVING MEN Clear protocol, published before launch Large number of participants (n = 50) Perfect randomisation Placebo controlled (melted ice) Blinded for all parties Account for drop outs Statistical comparison 9
WITHOUT RANDOMISATION INTERVENTION 1 INTERVENTION 2 10
WITH RANDOMISATION INTERVENTION 1 INTERVENTION 2 DANGERS IN NON-RANDOMISED TRIALS Biological mechanisms - Limited time of diseases - Cyclical progression of diseases - When do we see patients? Psychological mechanisms -The Rosenthal effect, we see what we want to see (BIAS)! -The Barnum effect, we believe what we want to believe (astrology)! 11
PERIODIC GROWTH OF PUBLICATIONS ON RANDOM AND CONTROLLED CLINICAL TRIALS 140000 131223 120000 121584 100000 99373 80000 67522 60000 45020 40000 26322 20000 16155 0 1900 to 1946 75 498 979 1647 3118 1947 to 1951 1952 to 1956 1957 to 1961 1962 to 1966 8823 1967 to 1971 1972 to 1976 1977 to 1981 Year period 1982 to 1986 1987 to 1991 1992 to 1996 1997 to 2001 2002 to 2007 NUMBER OF PUBLICATIONS ON RANDOMISED AND CONTROLLED CLINICAL TRIALS PUBLISHED PER MILLION INHABITANTS 1200 1000 1127 1014 945 881 800 600 400 200 713 666 632 594 587 559 438 430 426 355 349 254 250 199 188 175 0 12
IMPORTANT ASPECTS OF CLINICAL RESEARCH Systematic errors (bias) Random errors (play of chance) Design errors Low risk of systematic error High risk of systematic error Low risk of random error X High risk of random error X design errors may also lead to bias! 13
Mean number of patients per intervention arm (SEM) in 383 randomised trials published in Gastroenterology from 1964-2000 (Kjærgard et al. 2002) RANDOM ERROR IN SMALL TRIALS False positive results (type I error) False negative results (type II error) 14
DESIGN ERRORS AFFECTING EXTERNAL VALIDITY OF RANDOMISED TRIALS INCLUDE Centres Participants Experimental intervention Control intervention Goal - explanatory or pragmatic Trial structure - parallel group, crossover, ect. Objective - superiority, equivalence, non-inferiority Outcome Unit of analysis 15
An international network of professionals, preparing, maintaining, and disseminating systematic reviews of the effects of health care 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 Archie Cochrane (1979) 16
RANDOMISED CLINICAL TRIALS 670.000 in The Cochrane Library 1,5 million trials have been conducted, however, a large number has never been published. (10 years after the publication of a trial as an abstract, only about 60% are published as an article!) still only 19 years old needs at least another 10-15 years to cover major parts of medicine with support from researchers and fundholders the misssion can be accomplished. 17
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FROM TITLE TO SYSTEMATIC REVIEW Request for title registration 19
FROM TITLE TO SYSTEMATIC REVIEW Information Management System (IMS) specialised software Cochrane Collaboration s electronic infrastructure RevMan (Review Manager) Archie FROM TITLE TO SYSTEMATIC REVIEW RevMan 5 (Review Manager 5) Software for preparing and maintaining Cochrane Reviews text preparation, building tables, graphical presentation of results Archie Central server titles, protocols and reviews storage Managing documents and contact details 20
Abstract Systematic review Background Objectives Search methods Selection criteria Data collection and analysis (risk of bias, measures of treatment effect,missing data,assessment of heterogeneity,assesment of reported biases, data synthesis, subgroup analysis, sensitivity analysis) Results Conclusions 21
1605 references found 1555 excluded references 50 references 18 RCTs included (4811 patients) Šimin et al., Aliment Pharm et Ther 2007 22
Revision of meta-analisys: Comparison of pegylated interferon monotherapy with standard interferon Comparison of different dosage and therapy duration of pegylated interferon Comparison of administration of pegylated interferon in combination with different therapeutic possibilities other than ribavirin 23
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CURRENT ACTIVITIES OF OUR GROUP Collaboration with London Cochrane Centre- Pancreatic diseases V.Giljača Systematic reviews and update of systematic reviews EBM course Rijeka (March 2012) The Cochrane systematic review as PhD thesis FURTHER PLANS Establishment of a cooperative satellite Cochrane center of the Hepatobiliary Group in Rijeka Collaboration with Copenhagen Trial Unit HPB Cochrane Centre and London Cochrane Centre- Pancreatic diseases FP7 and FP8Program Participation Education of last years students and young doctors Application of EBM in clinical practice 25
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 26