Every year around 5 million people are affected by stroke, and the cellular and molecular pathophysiology of ischaemic brain injury is - at least in animal models of the disease - well understood. Where it has been possible to observe pathophysiological processes in human stroke these same pathophysiological processes appear to operate. However, results from preclinical testing of candidate neuroprotective drugs in experimental stroke models have not translated to positive results in human studies. Over 350 interventions have published efficacy in animal stroke models, of which around 100 have been tested, and been found to be ineffective, in human stroke studies. The number of animals used varies considerably from drug to drug, but a highly conservative estimate would be that over the last 20 years at least 250,000 animals have been sacrificed in the pursuit of treatments for acute stroke.

If animal models of cerebral ischaemia faithfully represent human pathophysiology (and what evidence there is suggests that this is, for the most part, the case) there are a number of potential explanations for the systematic failure of animal experiments to identify effective human neuroprotectants:

• The interpretation of results from the animal experiments may be biased or imprecise.
• Systematic flaws in experimental design or conduct might exaggerate efficacy (that is to say such flaws may introduce a study quality bias or a study design bias), or a disproportionate publication of positive studies may introduce a publication bias.
• The animal models used might not faithfully reflect human pathophysiology, and so the results might not be generalisable to patient populations.
• The population characteristics of the animals used might be different - in terms of age, sex, co-morbidity - from those of the patient population in whom the disease usually occurs.
• Clinical trials may have failed to detect a treatment effect where one exists.

It is our contention that there is significant scope for improvements in the design, conduct, analysis and reporting of animal experiments. By minimising bias, such improvements would improve the amount of valid information gained from those animals used. By providing (using systematic review and meta-analysis) 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. The proposed research is therefore crucial to the development of "reduction"strategies.

This has been reflected in the recent report from the Nuffield Council on Bioethics, "The Ethics of Research Involving Animals", which recommends...

• "At present, there is a relatively limited number of useful systematic reviews and meta-reviews that address the question of the scientific validity of animal experiments and tests.

  In principle, it would therefore be desirable to undertake further systematic reviews and meta-analyses to evaluate more fully the predictability and transferability of animal models (paragraph 10.39). We recommend that the Home Office in collaboration with major funders of research such as the Wellcome Trust, the MRC, the Biotechnology and Biological Sciences Research Council (BBSRC), animal protection groups and industry associations such as the Association of the British Pharmaceutical Industry (ABPI) should consider ways of funding and carrying out these reviews."

CAMARADES began as the "Collaborrative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies", refelecting the interests of the investigators in translational failure in Stroke.

However, through the work of others (Bebarta et al, Bednar et al) it was apparent that some of the issues of internal and external validity which we have identified on the stroke field might also be relevant in animal modelling of other diseases.

We were interested to take our approach to thre modelling of other neurological diseases where we perceived there to be translational failure, partly to ascertain whether the apparent shortcomings in the stroke field were more generally prevalent.

As a result we have now looked systematically across the modelling of a range of conditions including spinal cord injury, multiple sclerosis, cerebral glioma, Parkinson's disease, Huntington's disease and Alzheimers disease; many of these are either published or in press. Broadley speaking, our hypothesis that findings in these domains might similarly be confounded by poor study quality has been confirmed.

It seems likely that similar issues might confound animal modelling of non-neurological disease, or indeed more fundamental research in the life sciences. This is an increasing focus of our current work, and to reflect this we have decided to change the S of CAMARADES from "Stroke" to "Studies". Although we will also be looking at non-animal studies, for the time being we leave the third A as it stands!

The Edinburgh group acknowledge the support of the MRC Trials Methodology Hub, the MS Society, the Scottish Chief Scientist Office and the NC3Rs