Translation of preclinical data - Critical Care Canada Forum · Preclinical Phase 1 Phase 2 Phase 3...
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Translation of preclinical research to clinical research or clinical practice
Transcript of Translation of preclinical data - Critical Care Canada Forum · Preclinical Phase 1 Phase 2 Phase 3...
Translation of preclinical research
to clinical research or clinical practice
Continuum of research
Preclinical Phase 1 Phase 2 Phase 3
Initial testing in the lab, with animals
First studies in humans
Testing efficacy using information from phase 1
Large studies
Looking for evidence of a beneficial effect
Emphasis on safety Surrogate outcomes Patient-importantoutcomes
Limited exposure to treatment
Dose escalation
« …the goal of the majority of animal studies is to gain knowledge and insights that are useful for understanding human biology, the response of humans to treatments or other interventions, or both. »
Ioannidis, Sci Trans Med 2012
Unfortunate surprises
Why ?
• Incomplete reporting, publication bias• Biased experiments• Irrelevant experiments
Preclinical studies often do not predict the outcome of clinical trials
What can clinicians / clinical researchers do?
Cook Annals of Internal Medicine 1997
Systematic reviews are tools for more accurate inferences
Are systematic reviews already prevalent?
Lamontagne Crit Care Med 2010
Is the review comprehensive and objective?
Are the primary studies clinically relevant?
Are the primary studies valid?
Macleod Stroke 2004
Is comprehensiveness important?
Certain misalignments are explained by incomplete reviews and/or publication bias
→ Reviewing 14 preclinical studies of nicotinamide for acute ischemic stroke
→ “Comparisons published in abstract only gave a significantly lower estimate of effect size than those subjected to peer review and published in full”
Is comprehensiveness important?
Sena Plos Biol 2010
Certain misalignments are explained by incomplete reviews and/or publication bias
→ Reviewing 16 systematic reviews of 525 unique publications
→ Only 6 studies (1.2%) reported no significant result
→ Using funnel plots, Egger regression and imputation techniques, publication bias may account for 1/3 of reported efficacy
Is appraisal of the risk of bias important?
Is appraisal of the risk of bias important?
Certain misalignments are explained by invalid animal results
Bebarta Acad Emerg Med 2003 → Reviewing 290 animal studies, positive results were more likely in studies that were NOT blinded (OR 3.2) and NOT randomized (OR 3.4) or neither randomized nor blinded (OR 5.2)
Macleod Stroke 2008 → Reviewing 11 animal studies testing an intervention proven to be inefficacious (NXY-059, a free radical scavenger)
→ Studies that were NOT blinded or NOT randomized obtained the most favorable results
Is appraisal of the clinical relevance important?
Certain misalignments are explained by irrelevant animal results?
Crossley Stroke 2008 → Reviewing 10 meta-analyses, and comparing studies of animals with and without comorbidities, those without overestimated ES by 11.5%
Systematic reviews of preclinical evidence could…
It is possible to reduce the risk of making spurious inferences from animal experiments by
1. Conducting comprehensive and objective reviews of available evidence
2. Identifying risk of random error and bias in preclinical studies
3. Identifying studies whose results are unlikely to apply to patients
Continuum of research
Preclinical Phase 1 Phase 2 Phase 3
Initial testing in the lab, with animals
First studies in humans
Testing efficacy using information from phase 1
Large studies
Looking for evidence of a beneficial effect
Emphasis on safety Surrogate outcomes Patient-importantoutcomes
Limited exposure to treatment
Dose escalation
« …the goal of the majority of animal studies is to gain knowledge and insights that are useful for understanding human biology, the response of humans to treatments or other interventions, or both. »
Ioannidis, Sci Trans Med 2012
systematic reviewssystematic reviews
What does the future hold?
“Using Reporting Guidelines Measurably Improves the Quality of Reporting”“Good Reporting Is Essential for Peer Review and to Inform Future Research”
“By providing a precise and robust overview of existing data, the need for further experiments, and the precise areas in which those experiments should focus, this approach would ensure that unnecessary replication did not occur”
“To determine how well animal studies implement practices that reduce threats to valid causal inference, and whether application of these practices predicts successful clinical translation”
Is appraisal of the clinical relevance important?
Clinical relevance may mean different things in different areas ?
Lamontagne Crit Care Med 2010
Unfortunate surprises
