systematic review

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Systematic Reviews of Animal Experiments Demonstrate Poor Human Clinical and Toxicological Utility

Andrew Knight

The assumption that animal models are reasonably predictive of human outcomes provides the basis for their widespread use in toxicity testing and in biomedical research aimed at developing cures for human diseases. To investigate the validity of this assumption, the comprehensive Scopus biomedical bibliographic databases were searched for published systematic reviews of the human clinical or toxicological utility of animal experiments. In 20 reviews in which clinical utility was examined, the authors concluded that animal models were either significantly useful in contributing to the development of clinical interventions, or were substantially consistent with clinical outcomes, in only two cases, one of which was contentious. These included reviews of the clinical utility of experiments expected by ethics committees to lead to medical advances, of highly-cited experiments published in major journals, and of chimpanzee experiments — those involving the species considered most likely to be predictive of human outcomes. Seven additional reviews failed to clearly demonstrate utility in predicting human toxicological outcomes, such as carcinogenicity and teratogenicity. Consequently, animal data may not generally be assumed to be substantially useful for these purposes. Possible causes include interspecies differences, the distortion of outcomes arising from experimental environments and protocols, and the poor methodological quality of many animal experiments, which was evident in at least 11 reviews. No reviews existed in which the majority of animal experiments were of good methodological quality. Whilst the effects of some of these problems might be minimised with concerted effort (given their widespread prevalence), the limitations resulting from interspecies differences are likely to be technically and theoretically impossible to overcome. Non-animal models are generally required to pass formal scientific validation prior to their regulatory acceptance. In contrast, animal models are simply assumed to be predictive of human outcomes. These results demonstrate the invalidity of such assumptions. The consistent application of formal validation studies to all test models is clearly warranted, regardless of their animal, non-animal, historical, contemporary or possible future status. Likely benefits would include, the greater selection of models truly predictive of human outcomes, increased safety of people exposed to chemicals that have passed toxicity tests, increased efficiency during the development of human pharmaceuticals and other therapeutic interventions, and decreased wastage of animal, personnel and financial resources. The poor human clinical and toxicological utility of most animal models for which data exists, in conjunction with their generally substantial animal welfare and economic costs, justify a ban on animal models lacking scientific data clearly establishing their human predictivity or utility.
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Reviewing Existing Knowledge Prior to Conducting Animal Studies

Andrew Knight

Highly polarised viewpoints about animal experimentation have often prevented agreement. However, important common ground between advocates and opponents was demonstrated within a discussion forum hosted at www.research-methodology.org.uk in July–August 2008, by the independent charity, SABRE Research UK. Agreement existed that many animal studies have methodological flaws — such as inappropriate sample sizes, lack of randomised treatments, and unblinded outcome assessments — that may introduce bias and limit statistical validity. There was also agreement that systematic reviews of the human utility of animal models yield the highest quality of evidence, as their reliance on methodical and impartial methods to select significant numbers of animal studies for review, serves to minimise bias. Unfortunately, disagreement remained that animal experimental licence applications should reference systematic reviews of existing studies, before approval. The UK Medical Research Council requires that researchers planning human clinical trials must reference such reviews of related previous work. Existing knowledge is thereby fully and appropriately utilised, and redundant experimentation is avoided. However, objections were raised that a similar requirement would interfere with animal experimental licensing, because, to date, there have been very few systematic reviews of animal studies. In fact, the relative dearth of such reviews is a matter of considerable concern, and may partially explain the very poor human success rates of drugs that appear safe and/or efficacious in animal trials. Nevertheless, the disturbing number of human trials which have proceeded concurrently with, or prior to, animal studies, or have continued despite equivocal evidence of efficacy in animals, clearly demonstrate that many researchers fail to conduct adequate prior reviews of existing evidence. Where neither sufficient primary studies, nor systematic reviews of such studies, exist, for citation within a licence application, researchers should be able to provide evidence of this shortcoming, and, concurrently, demonstrate that the available literature and evidence have been adequately reviewed. This should also enable them to clearly demonstrate the need and scientific appropriateness of their proposed study, the validity of its design, and — importantly — that the benefits are reasonably likely to exceed the animal welfare, bioethical and financial costs. Invasive animal studies should never be permitted solely on the basis of less probable,speculative or intangible human benefits, or the mere satisfaction of scientific curiosity.
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A Gold Standard Publication Checklist to Improve the Quality of Animal Studies, to Fully Integrate the Three Rs, and to Make Systematic Reviews More Feasible

Carlijn R. Hooijmans, Marlies Leenaars and Merel Ritskes-Hoitinga

Systematic reviews are generally regarded by professionals in the field of evidence-based medicine as the highest level of medical evidence, and they are already standard practice for clinical studies. However, they are not yet widely used nor undertaken in the field of animal experimentation, even though there is a lot to be gained from the process. Therefore, a gold standard publication checklist (GSPC) for animal studies is presented in this paper. The items on the checklist have been selected on the basis of a literature analysis and the resulting scientific evidence that these factors are decisive in determining the outcome of animal studies. In order to make future systematic reviews and meta-analyses of animal studies possible, to allow others to replicate and build on work previously published, diminish the number of animals needed in animal experimentation (reduction), improve animal welfare (refinement) and, above all, improve the quality of scientific papers on animal experimentation, this publication checklist needs to be used and followed. We have discussed and optimised this GSPC through feedback from interviews with experts in the field of animal experimentation. From these interviews, it became clear that scientists will adopt this GSPC when journals demand it. The GSPC was compared with the current instructions for authors from nine different journals, selected on the basis that they featured a high number of publications on animal studies. In general, the journals’ demands for the description of the animal studies are so limited that it is not possible to repeat the studies, let alone carry out a systematic review. By using the GSPC for animal studies, the quality of scientific papers will be improved. The use of the GSPC and the concomitant improvement in the quality of scientific papers will also contribute to decreased variation and increased standardisation and, as a consequence, a reduction in the numbers of animals used and a more reliable outcome of animal studies. It is of major importance that journal editors become convinced of and adopt these recommendations, because only then will scientists follow these guidelines to the full extent.
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