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