Comparison of treatment effects between animal experiments and clinical trials: systematic review

Abstract

Objective: To examine concordance between treatment effects in animal experiments and clinical trials. Study design Systematic review.

Data sources: Medline, Embase, SIGLE, NTIS, Science Citation Index, CAB, BIOSIS.

Study selection: Animal studies for interventions with unambiguous evidence of a treatment effect (benefit or harm) in clinical trials: head injury, antifibrinolytics in haemorrhage, thrombolysis in acute ischaemic stroke, tirilazad in acute ischaemic stroke, antenatal corticosteroids to prevent neonatal respiratory distress syndrome, and bisphosphonates to treat osteoporosis. Review methods Data were extracted on study design, allocation concealment, number of randomised animals, type of model, intervention, and outcome.

Results: Corticosteroids did not show any benefit in clinical trials of treatment for head injury but did show a benefit in animal models (pooled odds ratio for adverse functional outcome 0.58, 95% confidence interval 0.41 to 0.83). Antifibrinolytics reduced bleeding in clinical trials but the data were inconclusive in animal models. Thrombolysis improved outcome in patients with ischaemic stroke. In animal models, tissue plasminogen activator reduced infarct volume by 24% (95% confidence interval 20% to 28%) and improved neurobehavioural scores by 23% (17% to 29%). Tirilazad was associated with a worse outcome in patients with ischaemic stroke. In animal models, tirilazad reduced infarct volume by 29% (21% to 37%) and improved neurobehavioural scores by 48% (29% to 67%). Antenatal corticosteroids reduced respiratory distress and mortality in neonates whereas in animal models respiratory distress was reduced but the effect on mortality was inconclusive (odds ratio 4.2, 95% confidence interval 0.85 to 20.9). Bisphosphonates increased bone mineral density in patients with osteoporosis. In animal models the bisphosphonate alendronate increased bone mineral density compared with placebo by 11.0% (95% confidence interval 9.2% to 12.9%) in the combined results for the hip region. The corresponding treatment effect in the lumbar spine was 8.5% (5.8% to 11.2%) and in the combined results for the forearms (baboons only) was 1.7% (-1.4% to 4.7%).

Conclusions: Discordance between animal and human studies may be due to bias or to the failure of animal models to mimic clinical disease adequately.

Fig 1 Meta-analysis showing effects of corticosteroids on ability of mice to remain on a taut string (grip test)

Fig 2 Funnel plot showing effects of thrombolysis using recombinant tissue plasminogen activator or related agents in animal models of acute ischaemic stroke

Fig 3 Effects of thrombolysis using recombinant tissue plasminogen activator or related agents in animal models of acute ischaemic stroke. Comparisons are ranked according to effect on infarct volume, neurobehavioural scores, and odds of haemorrhage. Grey bars are 95% confidence limits of global estimate of efficacy. Vertical error bars are 95% confidence limits for individual estimates

Fig 4 Effect of tirilazad in animal models of acute ischaemic stroke. Comparisons ranked according to effect on infarct volume or neurobehavioural scores. Grey bars are 95% confidence limits of global estimates of efficacy. Vertical error bars are 95% confidence limits for individual estimates

Fig 5 Point estimates and 95% confidence intervals for change in bone mineral density after alendronate administration in baboons, rats, and all animals combined compared with results from clinical trials