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.TRIALSRANDOMIZATIONALLOCATION UNTREATEDBLINDING ON SAMPLE SIZE CONCEALMENT CONTROL OUTCOMECALCULATION GROUP A B C D A. Corticosteroids on brain trauma; B. Antifibrinolytics agaisist hemorrhage C. Corticosteroids neonatal respiratory distress syndrome; D. Bisphosphonate and osteoporosis

META-ANALYSISMEDLINE RECORDS CLINICAL1 : ANIMAL 1 :

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 RATIOS METHODOLOGICAL QUALITY(95% CONFIDENCE INTERVAL) X 2 (DF)P Allocation concealment Adequate1.00 (referent)32.9 (1)<.001 Unclear0.70 ( ) Sequence generation Adequate1.00 (referent)0.31 (1)58 Inadequate0.95 ( ) Exclusions No1.00 (referent)0.99 (1)32 Yes1.07 ( ) Double-blinded Yes1.00 (referent)6.16 (1).01 No0.83 ( ) 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