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