The contribution of animal studies to clinical medicine requires urgent formal evaluation. Systematic reviews and meta-analyses of the existing animal experiments would represent an important step forward in this process. Systematic reviews (particularly cumulative meta-analyses of ongoing experiments22
) could more efficiently determine when a valid conclusion has been reached from the animal studies. The UK Medical Research Council requires researchers who are planning clinical trials to reference systematic reviews of previous related work.23
A requirement to reference, or where necessary conduct, systematic reviews of relevant animal studies before clinical trials would make it difficult to disregard or selectively cite the evidence from animal studies, or for animal and human trials to proceed simultaneously.
Methodological problems of animal experiments
- Disparate animal species and strains, with a variety of metabolic pathways and drug metabolites, leading to variation in efficacy and toxicity
- Different models for inducing illness or injury with varying similarity to the human condition
- Variations in drug dosing schedules and regimen that are of uncertain relevance to the human condition
- Variability in the way animals are selected for study, methods of randomisation, choice of comparison therapy (none, placebo, vehicle), and reporting of loss to follow up
- Small experimental groups with inadequate power, simplistic statistical analysis that does not account for potential confounding, and failure to follow intention to treat principles
- Nuances in laboratory technique that may influence results may be neither recognised nor reported—eg methods for blinding investigators
- Selection of a variety of outcome measures, which may be disease surrogates or precursors and which are of uncertain relevance to the human clinical condition
- Length of follow up before determination of disease outcome varies and may not correspond to disease latency in humans
By ensuring that animal experiments do not set out to answer questions that have already been answered, systematic reviews support the principle of reduction. This principle, outlined in the “three Rs,” (reduction and replacement of animals and refinement of procedures), is held to be a cornerstone of animal research.24
Systematic reviews would also be relevant in veterinary medicine to evaluate the efficacy of treatments for sick animals.
Systematic reviews of animal research would increase the precision of estimated treatment effects used in calculating the power of proposed human trials, reducing risk of false negative results. They are able to throw light on the process of translation (or its lack) between animal and clinical research as well offering the opportunity to review the appropriateness of the animal models used. Finally, the results of the animal and human research need to be compared to see how well one predicts the other.
In the 1970s Comroe and Dripps conducted an ambitious study to determine the relative contributions of basic and clinical research to important medical advances.25
They concluded that 62% of key articles that led to advances were the result of basic research. In the 1980s Smith highlighted many of the methodological shortcomings of Comroe and Dripps' study.26
He concluded that the study was unscientific but that the main lesson to be gained is that research itself needs to be researched so that scarce funds can be allotted more intelligently rather than on the basis of anecdotal evidence. More recently, Grant et al noted that Research Council expenditure on basic research increased in the United Kingdom from 42% of the total civil research and development in 1991-2 to 61% in 1998-9.5
While recognising that it would be difficult to attribute this increase to the work of Comroe and Dripps, they observe that their study is often quoted in support of increased funding for basic biomedical research. Grant et al attempted to replicate the Comroe and Dripps study and found that it was “not repeatable, reliable, or valid and thus is an insufficient evidence base for increased expenditure on basic biomedical research.”5
The value of animal research into potential human treatments needs urgent rigorous evaluation
Systematic reviews can provide important insights into the validity of animal research
The few existing reviews have highlighted deficiencies such as animal and clinical trials being conducted simultaneously
Many animal studies were of poor methodological quality
Systematic reviews should become routine to ensure the best use of existing animal data as well as improve the estimates of effect from animal experiments
The Cochrane and Campbell Collaborations for systematically reviewing evidence in health care and social science offer models for how the literature on animal experiments might be systematically organised and examined.27,28
Several sources of potential bias exist in systematic reviews—for example, pharmaceutical industry animal trials are likely to be excluded from the public domain for commercial reasons, resulting in publication bias in systematic reviews—but space precludes considering them here. Ideally, new animal studies should not be conducted until the best use has been made of existing animal studies and until their validity and generalisability to clinical medicine has been assessed.