DALLA CLINICA AL LABORATORIO: TRASLAZIONE INVERSA Milano 3 Febbraio 2009 SILVIO GARATTINI.
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Transcript of DALLA CLINICA AL LABORATORIO: TRASLAZIONE INVERSA Milano 3 Febbraio 2009 SILVIO GARATTINI.
DALLA CLINICA AL LABORATORIO: TRASLAZIONE INVERSA
Milano 3 Febbraio 2009
SILVIO GARATTINI
ANIMAL EXPERIMENTS
ARE MODELS OF
CLINICAL TRIALS
ANIMAL EXPERIMENTS CANNOT BE AT PRESENT SUBSTITUTED BY OTHER APPROACHES.
PRACTICAL AIMS ARE TO ESTABLISH
EFFICACY TOXICITY
MECHANISM OF ACTION PHARMACOKINETICS
PHARMACODYNAMICS CANCEROGENESIS
REPRODUCTION ADVERSE REACTIONS
NEED TO EVALUATE AGREEMENT
BETWEEN ANIMAL AND CLINICAL OUTCOMES
DISCORDANCE MAY BE RELATED TO
• EFFECT ESTIMATES BY CLINICAL TRIALS MAY BE BIASED OR IMPRECISE
• ANIMAL MODELS MAY BE INADEQUATE TO REPLICATE HUMAN PATHOLOGY
• RESULTS FROM ANIMAL EXPERIMENTS MAY BE BIASED OR IMPRECISE
NEED OF HOMOGENUOUS METHODOLOGY
• RANDOMIZATION
• BLINDING
• INCLUSION AND EXCLUSION CRITERIA
• APPROPRIATE CONTROLS
• SIGNIFICANT END-POINTS
• EXPECTED DIFFERENCE
• CALCULATION OF SAMPLE SIZE
• STATISTICAL ANALYSIS
N.TRIALS RANDOMIZATION ALLOCATION UNTREATED BLINDING ON SAMPLE SIZECONCEALMENT CONTROL OUTCOME CALCULATION
GROUP
A 19 2 4 7 14 -
B 08 2 0 3 04 -
C 31 6 0 - 2 0
D 16 5 0 - 16 0
A. Corticosteroids on brain trauma; B. Antifibrinolytics agaisist hemorrhageC. Corticosteroids neonatal respiratory distress syndrome; D. Bisphosphonate and osteoporosis
META-ANALYSIS MEDLINE RECORDS
CLINICAL 1 : 1.000
ANIMAL 1 : 10.000
ASSOCIATION BETWEEN FOUR DIMENSIONS OF METHODOLOGICAL QUALITY AND ESTIMATES
OF TREATMENT EFFECT IN THE 229 ADEQUATELY AND UNCLEARLY CONCEALED TRIALS
MEASURE OF RATIO OF ODDS RATIOSMETHODOLOGICAL QUALITY (95% CONFIDENCE INTERVAL) X2(DF) P
Allocation concealment
Adequate 1.00 (referent) 32.9 (1) < .001
Unclear 0.70 (0.62 - 0.79)
Sequence generation
Adequate 1.00 (referent) 0.31 (1) 58
Inadequate 0.95 (0.81 - 1.12)
Exclusions
No 1.00 (referent) 0.99 (1) 32
Yes 1.07 (0.94 -1.21)
Double-blinded
Yes 1.00 (referent) 6.16 (1) .01
No 0.83 (0.71 - 0.96)
Schulz et al., 1996
SYSTEMATIC REVIEW HAS ALLOWED THE ANALYSIS OF SAMPLE SIZE
IN STUDIES OF FK506 IN ANIMAL MODELS OF STROKE; THE OBSERVED
VARIANCE SUGGESTS THAT 65 ANIMALS PER GROUP WOULD BE
NEEDED TO GIVE AN 80% CHANCE OF DETECTING AN IMPROVEMENT
IN OUTCOME OF 20%. IN FACT, THE LARGEST STUDY REPORTED
16 ANIMALS PER GROUP AND THE AVERAGE WAS EIGHT ANIMALS PER
GROUP. PERFORMING UNDERPOWERED STUDIES IS AS UNETHICAL
IN ANIMAL STUDIES AS IT IS IN HUMAN STUDIES.
Macleod et al., 2005
Bebarta et al., 2003
ANIMAL META-ANALYSIS OR SYSTEMATIC REWIEVS
• SHOULD BE DONE BEFORE PERFORMING NEW EXPERIMENTS
• ARE USEFUL TO FIND OUT OPTIMAL CONDITIONS OF TESTING
• CAN SPARE FUTILE CLINICAL TRIALS
• POOR METHODOLOGICAL QUALITY