Requiring Animal Research To Be More Evidence-based'

Main Category: Public Health
Also Included In: Biology / Biochemistry;  Clinical Trials / Drug Trials;  Regulatory Affairs / Drug Approvals
Article Date: 28 Jul 2008 - 1:00 PDT

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It is generally believed by the public that animal research is only carried out providing:

a) it leads to improvements in human health
b) non-animal models and technologies are unavailable
c) it is not duplicated unnecessarily
d) it is not done for trivial and non-medical reasons
e) it cannot be conducted ethically in humans
f) suffering of laboratory animals is minimised.

However, these conditions are not always met and while some animal experiments have been associated with important advances in medicine, researchers have uncovered uncertainties and flaws in the way animal research is designed and how it is approved and evaluated. In addition to this there are serious doubts about the predictive value of animal studies for human health.

While there is acceptance amongst the public that the use of animals as models of human disease for drug development and testing is mandatory, regulatory bodies and the research community should demonstrate a commitment to using the best available research methods in pre-clinical animal research. It has been found that this is not the standard practice and consequently the moral contract between animal research scientists and the public is not fulfilled and the health and safety of patients and research volunteers are put at risk.

SABRE Research UK is calling for evidence-based research methods and training to be implemented so that the public's expectations regarding animal research are met in a transparent and accountable manner. Furthermore, although pharmaceutical research and development is a highly prized industry, it should not be assumed that new drugs and medicines are always what patients want or need and consequently the way medical research funding is allocated needs closer examination and review.

REQUIREMENTS

'Systematic reviews and meta-analyses, such as those published by the Cochrane Library, are routinely used to assess clinical treatment trials but are currently underutilized in assessment of preclinical studies, despite urgent need for such assessment given limited understanding of how therapeutic testing in animals can be projected to humans. Standardization of methods for conducting and reporting experimental preclinical trials would facilitate formal statistical analysis of the data and an understanding of the significance of the results, in addition to informing the process of prediction between experimental models and from models to patients.'
Trevitt CR. Collinge J
"A systematic review of prion therapeutics in experimental models."
Brain. 2006 Sep;129(Pt 9):2241-65

1. Experimental design and statistical analysis of animal studies need improving. Project designs should include concealed random allocation, blinded outcome assessment and adequate sample size. Training in experimental design should be a requirement for animal research personnel before project licences are granted to conduct animal studies. It is essential that these requirements are implemented in order to demonstrate sincere commitment to the 3R's paradigm (refine, reduce, replace animal experiments), to avoid the waste of funding on unnecessary research and avoid the waste of laboratory animal lives. The NC3Rs and animal welfare groups have an interest in this requirement to ensure that the 3R's is put into practice more reliably and consistently. [i]

2. Systematic reviews [ii] and prospective registration of animal experiments8 are needed in order to i) identify and reduce potential sources of bias in animal research [iii], ii) determine the validity of animal studies, and iii) improve the way that animal experiments are evaluated for their predictive power and relevance to human health. Systematic reviews should be a requirement before all new animal research is carried out. [1] It is essential that researchers use the best available research methods if they are to avoid the risk of wasting charitable donations and research funding on unnecessary or scientifically flawed animal experiments, thereby increasing the potential for harm to patients and research volunteers and wasting funding on laboratory animal lives. The MRC, Wellcome Trust, ABPI, BBSRC and animal welfare organisations have an interest in funding this research. [iv]

3. Initial research is needed to discover the best methodological approaches for systematically reviewing animal studies. This research is needed to broaden and deepen the application and validity of systematic reviews and meta-analysis of animal studies.1, [2] [3] The NC3Rs and the MRC have a role to play in funding this research.iv, [v]

4. There should be more recognition by clinical triallists and translational researchers of the importance of carrying out systematic reviews of relevant animal and human studies where clinical trials are to be based on data from animal experiments. 2

5. There should be recognition by animal researchers and the regulatory bodies that basic animal research hypotheses can and should be systematically reviewed before proceeding to conduct further animal studies. 2, [4], [5]

6. There should be recognition by research ethics committees, medical research charities, patient groups and research volunteers that where clinical research is based on the results of animal studies there should be sound evidence from systematic reviews of relevant animal and human research to justify the research and to demonstrate the predictive value of the animal research. This requirement is essential before entering volunteers into Phase I clinical trials based on data from animal studies.

7. The current legislation governing animal research in the UK needs revision. Legislation contained in the Animals (Scientific Procedures) Act 1986 [6] does not include study quality in its remit.7 [vi] This is a failing of the Act which is outdated and should be brought in line with current thinking in research.

8. A core set of standards and the use of systematic reviews of animal studies should be widely adopted by animal researchers as best practice. It is argued that animal research in the UK is the most tightly regulated research in the world yet there is no requirement to use the best available research methods. There is a duty on scientists, researchers and regulatory bodies to ensure that patients and research volunteers are protected from flawed and/or inadequate research.

9. Research is needed to determine research priorities that are consistent with patients' preferences and needs above those of industry [7], [8]. This research will impact on how funding is allocated and the way it is divided between pre-clinical animal and clinical research.

References

[1] Perel P. et al, Comparison of treatment effects between animal experiments and clinical trials: systematic review. BMJ 2007; 334(7586):197
[2] CAMARADES website
[3] Personal communication Dr Malcolm Macleod, 01/03/2008
[4] Sandercock P, Roberts I. Systematic Reviews of animal experiments Lancet 2002; 360(9333):586
[5] 10 Downing Street E-petitions, Petition to improve methods to evaluate the validity and relevance of animal experiments
[6] Animals (Scientific Procedures) Act 1986
[7] Pound P, Britten N, Morgan M, Yardley L, Pope C, Daker-White G, Campbell R. Resisting medicines: a synthesis of qualitative studies of medicine taking. Soc Sci Med. 2005 Jul;61(1):133-55
[8] Schechter AN, Retting RA. Funding priorities for medical research. JAMA 2002;288:832

[i] The NC3Rs claim to be conducting a survey of the quality of experimental design and reporting of research using animals and have set up an Experimental Design Working Group. [i]
[ii] A fairly recent example of a rigorous systematic review of animal studies may be found in an SR of prion therapeutics - Trevitt CR. Collinge J, A systematic review of prion therapeutics in experimental models. Brain. 2006 Sep;129(Pt 9):2241-65
[iii] Potential sources of bias include - publication bias, study design and study validity, heterogeneity, genetics, variability in laboratory conditions, nuances in laboratory technique, timing and location, variability in the way disease or injury is induced in different animal models, disparate animal species and strains with a variety of metabolic pathways and drug metabolites leading to variation in efficacy and toxicity, variations in drug dosing schedules and regimen, variability in animal model selection, variation in choice of comparison therapy and reporting,
[iv]The Nuffield Council on Bioethics and the Weatherall committee have each published reports in which they acknowledge the importance of systematic reviews of animal studies. [iv], [iv]
[v] The NC3Rs claim to offer guidance and resources on conducting systematic reviews and meta-analysis.5
[vi] For more on study quality and how it relates to systematic reviews please visit www.cochrane-net.org/openlearning/html/mod0.htm