Comparison of treatment effects between animal experiments and clinical trials: systematic reviewBMJ 2007; 334 doi: https://doi.org/10.1136/bmj.39048.407928.BE (Published 25 January 2007) Cite this as: BMJ 2007;334:197
- Pablo Perel, research fellow1,
- Ian Roberts, clinical coordinator CRASH 2 trial1,
- Emily Sena, PhD student2,
- Philipa Wheble, medical student2,
- Catherine Briscoe, medical student2,
- Peter Sandercock, professor of medical neurology2,
- Malcolm Macleod, senior lecturer2,
- Luciano E Mignini, researcher3,
- Pradeep Jayaram, senior house officer4,
- Khalid S Khan, professor of obstetrics-gynaecology4
- 1Crash Trials Coordinating Centre, London School of Hygiene and Tropical Medicine, London WC1E 7HT
- 2Clinical Neurosciences, University of Edinburgh
- 3Centro Rosarino de Estudios Perinatales, WHO Collaborative Centre in Maternal and Child Health, Rosario 2000, Argentina
- 4Division of Reproductive and Child Health, Birmingham Women's Hospital, University of Birmingham
- Correspondence to: P Perel
- Accepted 7 November 2006
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.
References w1-w228 are on bmj.com
We thank Sir Iain Chalmers for his constructive comments on the manuscript.
Contributors: IR, PS, MM, LEM, PJ developed the study protocol. All authors carried out the systematic reviews. PP and IR drafted the manuscript, which was revised on the basis of comments from all authors.
Funding: This work was funded by the National Health Service research and development health technology assessment programme. The views expressed in this publication are those of the authors and not necessarily those of the methodology programme, health technology assessment programme, or the Department of Health. Funding of this research by the NHS should not be taken as implicit support for any recommendations made by the authors.
Competing interests: IR was an investigator in the corticosteroid randomisation after significant head injury trial. The trial was funded by the UK Medical Research Council. Pharmacia and Upjohn (Pfizer from 2003) provided the Medical Research Council with the methylprednisolone (free of charge) needed for the trial, a grant in aid for preparation of the placebo, and support for collaborators' meetings. PS is co-chief investigator of the third international stroke trial, testing intravenous recombinant tissue plasminogen activator in acute ischaemic stroke; the start-up phase (completed in 2005) of this trial was supported by Boehringer Ingelheim, the manufacturers of tissue plasminogen activator, a donation of drug and placebo for the first 300 patients. The current phase of the trial is supported by the Medical Research Council and the Health Foundation. None of the authors have any relevant competing financial interests.
Ethical approval: Not required.
A table showing the quality of animal experiments included in the systematic reviews is available at www.crash2.lshtm.ac.uk.
- Accepted 7 November 2006