The 2010 Survey of Animal Use for Scientific Purposes in Canada has just been published by the Canadian Council on Animal Care for the fifteenth consecutive year (1996 to 2010). In 2010, 3,311,083 animals were used in research, teaching, testing and production of biological products for scientific purposes, a slight decrease from 2009 during which 3,375,027 animals were used. Fish were most commonly used, followed by mice, rats and birds.

An article just published in Personalized Medicine has questioned contemporary reliance on animal models for investigating human diseases and responses to pharmaceuticals. The authors note that humans and animals are complex systems, in which small changes in initial conditions - including genetic makeup - can dramatically alter outcomes. One result is that animal models are often poorly predictive for humans. The article explores at length the relevant characteristics of complex systems, and genetic differences between and within species.

On December 15th, the Institute of Medicine (IOM) released Chimpanzees in Biomedical and Behavioral Research: Assessing the Necessity. The report responded to a National Institutes of Health request for expert guidance on the scientific need to use chimpanzees within such research.

The IOM committee concluded that most current use of chimpanzees for biomedical research — including RSV vaccine, therapeutic hepatitis C (HCV) vaccine, and HCV antiviral drug development — is not warranted, with the possible exception of two very limited research uses: for the production of monoclonal antibodies (mAbs) and the development of prophylactic HCV vaccines. The committee stated, “it will be very difficult to defend the necessity of nearly all current biomedical research on chimpanzees.” Yet it stopped short of recommending an outright ban (Altevogt et al 2011).

Even this limited support of invasive chimpanzee research is questionable, however. The committee noted that, “Production of monoclonal antibodies after immunization in other species or through in vitro synthetic methods is equally powerful for the generation of such reagents.” They also noted four methods currently in use that lessen the need for safety tests of mAbs in chimpanzees. However, they still supported the use of chimpanzees for mAbs developed using older technologies, although they expected such use would cease within five years. Yet, it would seem far more ethical, and could also potentially yield safety, efficacy and financial benefits, if the most modern technologies were used without delay. As Bettauer (2011) noted with respect to chimpanzee use in mAb research and drug development, “Available alternatives, together with ethical and economic reasons, suggest that the use of the chimpanzee in this manner may not be necessary or appropriate.”

The committee noted that HCV antiviral drug and therapeutic vaccine development does not require the use of chimpanzees, but were uncertain about their necessity for the development of prophylactic vaccines. However, they also noted the existence of alternative research strategies: “studies in consenting individuals at high risk for natural HCV infection can be ethically done provided that these vaccines are first shown to be safe and immunogenic in experimental animals, such as mice and nonhuman primates”. After reviewing 109 chimpanzee HCV studies, Bettauer (2010) found considerable problems with statistical validity, repeatability, and the biological relevance of the chimpanzee model. Bailey (2010) similarly found that, “claims of the necessity of chimpanzees in historical and future hepatitis C research are exaggerated and unjustifiable, respectively.” He concluded that, “Unfounded claims of its necessity should not discourage changes in public policy regarding the use of chimpanzees in US laboratories.”

Although the committee failed to identify any current biomedical research field in which invasive chimpanzee studies are definitely necessary, it concluded that, “a new, emerging, or reemerging disease or disorder may present challenges to treatment, prevention, and/or control that defy nonchimpanzee models and technologies and thus may require their future use. Therefore, an outright ban on biomedical chimpanzee research would not be appropriate.”

In reaching this conclusion, however, the committee made very little mention of the profound animal welfare and ethical problems raised by invasive chimpanzee research. The advanced cognitive, sociological and related characteristics of chimpanzees render their use particularly ethically problematic. Such research is also particularly costly. Accordingly, the concrete benefits of such research — particularly in advancing human healthcare — must be particularly substantial, obvious and verifiable, in order for it to be ethically and fiscally justifiable. Yet the relevant systematic reviews published to date suggest that this is not the case. The contributions of invasive chimpanzee research to biomedical progress appear highly questionable, and it rarely, if ever, makes important contributions to clinical interventions efficacious in human patients (Bailey 2008, 2008 & 2010, Bettauer 2010 & 2011, Knight 2007 & 2008).

This is why almost all nations that have considered invasive chimpanzee experimentation have implemented policy or legislative bans on such research, with the exception of noninvasive observational or behavioural research, or research conducted at ensuring the survival of the individual in question, or of the species. Only the US, and possibly Gabon — whose status is unclear — are known to persist with invasive chimpanzee research.

The US should utilize the opportunity afforded by the Great Ape Protection and Cost Savings Act of 2011 to similarly ban invasive chimpanzee experimentation. This would not require the banning of all chimpanzee research, however. Clear-cut examples include non-invasive observational or behavioural studies of free-living or sanctuary chimpanzees; the education of veterinary students and veterinary medical technicians via participation in beneficial clinical or surgical procedures on genuine animal patients; and experimental treatment of chimpanzees genuinely suffering from severe, naturally occurring disease or injury, when conventional treatment is ineffective. Rigorous implementation of policies such as these would restore to chimpanzee research the balance between human and animal interests expected by society, and demanded by detailed ethical review.

Instead however, the committee concluded that invasive chimpanzee research would be acceptable if it met certain criteria: the knowledge gained must be necessary to advance public health; the research cannot ethically be done on a human being, and is impossible using other species or inanimate research tools; and the chimpanzees used in the research must be given appropriate living conditions. Additionally, forgoing the use of chimpanzees for the research in question must significantly slow or prevent important advancements to prevent, control, and/or treat life-threatening or debilitating conditions. For studies of comparative genomics and behavioural research, the criteria were that studies must provide otherwise unobtainable insight into comparative genomics, normal and abnormal behaviour, mental health, emotion, or cognition; and that all experiments must be performed on acquiescent animals (who participate voluntarily, without coercion), using techniques that are at most minimally invasive, painful or distressing.

NIH Director Francis Collins reportedly accepted the committee's recommendations. The NIH will not award any new grants for such research until an assessment process is in place, and a project-by-project review will be conducted to determine if ongoing research fits the criteria. Dr Collins estimated that about 37 research projects might be affected, of which perhaps half could be discontinued (Anon. 2011).

See the Washington Post for further information. Further information about the IOM report is available here.


References (most available here)

• Altevogt BM, Pankevich DE, Pope AM, and Kahn JP. Guiding limited use of chimpanzees in research. Science epublication ahead of print 15 Dec. 2011. DOI: 10.1126/science.1217521.
• Anon. NIH to adopt strict new limits on using chimpanzees in medical research, saying most unneeded. The Washington Post 15 Dec, 2011. http://www.washingtonpost.com/national/health-science/major-science-group-says-chimpanzees-should-hardly-ever-be-used-for-medical-research-anymore/2011/12/15/gIQAEcf5vO_story_1.html, accessed 15 Dec. 2011.
• Bailey J. An assessment of the role of chimpanzees in AIDS vaccine research. Altern Lab Anim 2008; 36: 381–428.
• Bailey J. An examination of chimpanzee use in human cancer research. Altern Lab Anim 2009; 37: 399-416.
• Bailey J. An assessment of the use of chimpanzees in hepatitis C research past, present and future: 1. validity of the chimpanzee model. Altern Lab Anim 2010; 38: 387-418.
• Bettauer RH. Chimpanzees in hepatitis C virus research: 1998–2007. J Med Primatol 2010; 39: 9-23.
• Bettauer RH. Systematic review of chimpanzee use in monoclonal antibody research and drug development: 1981-2010. ALTEX 2011; 28(2): 103-16.
• Knight A. The poor contribution of chimpanzee experiments to biomedical progress. J Appl Anim Welf Sci 2007; 10(4): 281-308.
• Knight A. The beginning of the end for chimpanzee experiments? Philos Ethics Humanit Med 2008; 3:16 (2 June 2008). http://www.peh-med.com/content/3/1/16.

Public surveys have consistently shown the general public to be uneasy about the use of non human primates in scientific research. For example, 80 per cent of respondents to the European Commission’s public consultation on the revision of Directive 86/609/EEC, which directs laboratory animal use in EU member states, responded that the use of primates in laboratories was “not acceptable”.

Now, a team of scientists, including a professor of neuroscience based at the University of California in San Diego, has published an analysis that questions not just the ethics of using these animals in research, but also the science that underpins their use as ‘models’ of human diseases. The article, published December 6th, 2011 in the online peer-reviewed journal Medicolegal and Bioethics, represents a rare challenge to the use of non human primates in science. It was published in response to the 2011 Review of Research Using Non-Human Primates by Bateson and colleagues, which concluded that 91% of 67 primate studies conducted from 1997 – 2006 were ethically justifiable.

The Australian code of practice for the care and use of animals for scientific purposes provides an ethical framework and governing principles for the use of animals for scientific or educational purposes. All Australian States and Territories have variously incorporated the Code into their animal welfare legislation. The current 7th edition of the Code was published in 2004. It is now being reviewed, and public comments sought. The Deadline is 5pm AEST, Friday 2 December 2011.

Relevant documents, including the draft of the next edition of the Code, are available here, from which people can reach the online submission page (preferred option). But submissions can also be emailed to the address given there.

The Code is perhaps the most advanced and progressive policy of its kind, internationally. Nevertheless, several features give rise to major concern, including: the possibility that invasive animal surgery may be conducted by those who have not undergone veterinary surgical and anaesthesia training, the broadening of animal ethics committees to include additional employees of the research facility, thereby potentially biasing ethical decision-making, the allowance of procedures resulting in long-lasting pain, suffering or distress, those deliberately inflicting neurological impairment (e.g. spinal cord damage), those resulting in death as an end point, those deliberately exposing prey animals to predators, the production of monoclonal antibodies by the ascites or other in vivo methods (given the availability of non-animal bioreactors for this purpose), and a clause that makes it likely that educational institutions will misrepresent their opinions about the necessity of certain animal use to students as facts, thereby decreasing legitimate student requests for humane teaching methods. Several of these are discouraged, but unfortunately they remain permissible under the Code. However, such procedures and clauses may no longer reasonably be considered ethically acceptable.

Interested parties are encouraged to provide submissions addressing these and other points. A more detailed analysis designed to assist such people is available on request.

Andrew Knight


SEE ALSO the August 15th Veterinary Times article


In 2010, British scientists conducted scientific procedures on more than 2,600 monkeys, many of whom were used more than once (1). Invasive research on non-human primates (NHPs) is rendered particularly ethically problematic by their advanced cognitive, social and related abilities. It is also particularly expensive. Accordingly, in 2006 a UK working group recommended that the major organisations funding such research should undertake a systematic review of its outcomes.

In July 2011, the subsequent Review of Research Using Non-Human Primates was publicly released (2). It was commissioned by major funders of such NHP research in the UK, namely the Biotechnology and Biological Sciences Research Council, the Medical Research Council and the Wellcome Trust. It examined all such all NHP research funded by these organisations from 1997 to 2006 inclusive.

The Review Panel considered the scientific importance of each research project, the probability of medical and public benefit, and the likelihood of animal suffering. They asserted that in many cases the use of NHPs was justifiable, but were concerned about approximately 9% of research programmes from which no clear scientific, medical or social benefit had emerged. However, for three important reasons the proportion of cases that were ethically justifiable was probably far lower than 91%.

1. Animal welfare impacts
Firstly, the review Panel appears to have systematically underestimated the animal welfare impacts of the research it assessed. Of 31 neuroscience studies examined for example, half were assessed as having imposed a high welfare impact on the animals used. Disturbingly high though this is, unfortunately it appears to have been an underestimate. Studies involving the surgical creation of experimental lesions (that is, tissue or organ damage) were not assessed as having a high welfare impact, unless ‘significant and lasting impairments to the monkeys’ welfare’ resulted. Therefore, surgery causing significant damage that was not long-lasting would probably have received a moderate impact rating, even such procedures may still severely impact animal welfare.

Additionally, studies conducted under terminal anaesthesia received a low welfare impact rating. This may have been technically correct from a strict welfare perspective, if minimal suffering resulted. However, if makes no allowance at all for the serious moral issues raised by killing. Laboratory animals are not simply expendable. Their deaths should not have been so lightly dismissed simply because they were killed under anaesthesia. The intrinsic value of their lives should have been included in the moral calculus.

2. Importance of experimental outcomes
Secondly, the review Panel appears to have considered animal experiments that contribute to scientific advancements in general to be of similar importance to those providing medical benefits. However, nearly all experiments contribute to the advancement of science. Therefore, they would all be ethically justifiable, if they were cost-free. But of course they are not. The very substantial costs incurred by invasive primate experimentation include animal welfare costs, the consumption of considerable financial and scientific resources, and adverse impacts on human patients and consumers affected by any misleading results. Therefore, experiments that simply contribute to the advancement of science, without providing any credible medical benefit — which comprise a substantial proportion of the 91% condoned by the Review Panel — should not have been assessed as ethically justifiable.

The Panel stated that, ‘In most cases… little direct evidence was available of actual medical benefit in the form of changes in clinical practice or new treatments.’ And, ‘This contrasts with the emphatic public statements about the medical benefits of NHP research made by some of the funding bodies and by grant applicants’.

They recommended that: ‘In their public engagement, the funders and researchers should avoid overstating and generalising the medical benefit of NHP research, since this cannot be substantiated in many cases.’ And, ‘It is important that the justifications offered for research projects are soundly based and demonstrable. Health benefits should only be claimed when their potential is real.’

3. Withholding of information
Thirdly, among 72 questionnaires, three researchers did not respond or declined to participate. Five more could not be contacted. Hence, fully 11% were not included in this survey. As the Panel noted, ‘It is reasonable to expect the recipients of public or charitable funding to be held accountable on issues of public interest and therefore this attitude was regarded as unacceptable’. One can only speculate as to why some researchers chose not to provide information about the animal welfare impacts and scientific benefits arising from their work.

While providing important insights into NHP research, this review cannot be considered conclusive. For several reasons noted in their report, this review could not be considered a systematic review in the formal sense. It has also not yet been published in a peer-reviewed scientific journal.

Formal systematic reviews
In The Costs and Benefits of Animal Experiments (3), I reviewed 30 systematic reviews assessing the contributions to human healthcare of animal experiments. All of these have been successfully published in the peer-reviewed scientific literature. The evidence provided by these reviews is remarkably consistent. When considering costs and benefits overall one cannot reasonably conclude that the benefits accruing to human patients or consumers, or to those motivated by scientific curiosity or profit, exceed the costs incurred by animals subjected to scientific procedures. On the contrary, the evidence indicates that actual human benefit is rarely — if ever — sufficient to justify such costs. Those costs are greatest when NHPs are used.

Recommendations
The Panel did, however, provide several commendable recommendations, which animal researchers working with all species would do well to comply with. For example, it recommended that ‘where grants were awarded on the promise of human health benefits, the grant-holders should provide evidence of interest in and use by the medical and biopharmaceutical sectors,’ to ensure their claims can be verified.

It also noted the disproportionate failure to published negative results, and asserted that researchers have a moral obligation to publish results — even if negative — in order to prevent work being repeated unnecessarily.

The full report can be found here.


References
1. Home Office (2011). Statistics of Scientific Procedures on Living Animals: Great Britain 2010. London, UK: The Stationery Office.
2. Bateson P et al. (2011). Review of Research Using Non-Human Primates. Biotechnology and Biological Sciences Research Council, Medical Research Council and Wellcome Trust, London. http://www.bbsrc.ac.uk/web/FILES/Reviews/review-research-using-nhps.pdf, accessed 29 Jul. 2011.
3. Knight A (2011). The Costs and Benefits of Animal Experiments. Basingstoke, England: Palgrave Macmillan.

Andrew Knight

In July the 2010 laboratory animal use statistics for Great Britain were released by the Home Office. Just over 3.7 million scientific procedures using animals were commenced in 2010, an increase of 3% (105,000) compared with the previous year. 3.6 million animals were used for the first time in procedures started in 2010, an increase of 3% (101,000). The number of procedures is always slightly higher than animal numbers, due to re-use of some animals.

Laboratory animal numbers have steadily risen over the last decade. There were 1.0 million more procedures than in 2000 (37%), mostly accounted for by the use of an additional 921,000 animals in breeding procedures to produce genetically altered animals. Such animals include those whose genomes have been artificially modified during the initial stages (GM animals), rather than through natural breeding or mutation, as well as animals with harmful genetic mutations. The maintenance and expansion of all genetically altered strains requires further breeding, however. Excluding such breeding procedures, there were still 4% (89,000) more procedures than in 2000.

Consistent with these trends, the 2010 increases when compared to 2009 were largely due to greater use of genetically altered animals. The increase in procedures using GM animals was 6% (88,000), and the increase in procedures using animals with harmful genetic mutations was 4% (17,000). Most of these increases were attributable to an 8% (73,000) increase in the use of GM mice in breeding procedures.

Within the 3.7 million total procedures in 2010, 1.6 million procedures (43%) used GM animals and 400,000 procedures (11%) used animals with harmful genetic mutations. Procedures using such genetically altered animals exceeded those using normal animals for the second year in a row. Genetically normal animals accounted for the remaining 1.7 million procedures (virtually the same level as in 2010), slightly less than half (46%) of the 3.7 million total.

The welfare implications of such heavy reliance on GM animals are disturbing. Particularly in the initial stages, the production of GM strains involves surgical procedures and significant physiological challenges. It is also an inherently inefficient process, frequently resulting in a high proportion of discarded animals, with the welfare of the survivors more likely to be adversely affected than for non-GM strains.

The use of non-human primates rose by 10% (425, to a total of 4,688) when compared to 2009. The advanced emotional, psychological and social capacities of primates markedly increase their risks of suffering within laboratory environments and procedures. They have advanced capacities to understand and remember that certain people, tools or procedures are likely to cause pain and distress, and their ability to anticipate future aversive experiences is likely to compound the distress such events may cause.

Sixty nine per cent of all procedures (2.6 million) did not utilise any form of anaesthesia. This was an increase of 6% (154,000) compared to 2009, and represented the greatest number of procedures conducted without anaesthesia since records commenced in 1988. From 1988 to 2010, the proportion of procedures conducted without anaesthesia fluctuated from approximately 59 to 69%. Analgesic use was not reported.

Whilst anaesthetic and analgesic use undoubtedly alters normal physiology, claims that such alterations are sufficiently important to hypotheses under investigation to warrant their exclusion, require careful scrutiny. Despite increasing recognition that pain relief improves both animal welfare and research quality – via minimisation of pain-related physiological, psychological and behavioural distortions – pain monitoring and analgesic provision remains less than optimal within many research protocols.

The steady increases in the use of GM animals and those with harmful mutations, of non-human primates, and of procedures conducted without any form of anaesthesia, several of which are now at record highs, demonstrate that neither the British government nor its research community are serious about reducing the use of animals, or of procedures that pose the greatest threats to animal welfare.

PRESS RELEASE 27 MAY 2011

Are animal experiments justified? A book published today by Palgrave Macmillan sheds new light on one of the greatest controversies in animal ethics.

This comprehensive review of recent scientific evidence examines the contributions of animal experimentation to human healthcare, and the extent to which animals suffer as a result. It asks whether students really need to dissect or experiment on animals, and examines the effects on their attitudes towards them.

Bioethicist and veterinarian Andrew Knight presents more than a decade of ground- breaking scientific research, analysis and experience to provide evidence-based answers to a key question: is animal experimentation ethically justifiable?

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On the 8th of September 2010, the European Parliament adopted Directive 2010/63/EU on the protection of animals used for scientific purposes. This replaces Directive 86/609/EEC on the protection of animals used for scientific purposes, which had governed European laboratory animal use for more than two decades.

Although weakened considerably in comparison to earlier drafts, in most respects and for many European countries the new Directive nevertheless strengthens the protection of animals used for scientific purposes. It explicitly requires systematic, compulsory ethical evaluation and authorisation of scientific protocols. Likely harms to animals must be balanced against the scientific or educational validity, usefulness and relevance of the expected result, and 3Rs strategies must be utilised wherever ‘possible’ — a concept that is notoriously open to interpretation, and that remains widely abused.

The scope of the Directive is also broadened. Protection is extended from living vertebrates to include mammalian foetuses in their last trimester of gestation, independently feeding larval forms, cephalopods, and animals bred for organ-harvesting. The use of non-human primates is restricted — particularly in the case of great apes — although not prohibited. However, the latter may be used only in the case of an unexpected outbreak of a life-threatening or debilitating human disease, or when the survival of the species itself is at stake.

Notably, the new Directive specifies an upper limit of pain, suffering and distress, above which animal use is not normally permissible. Procedures resulting in severe pain, suffering or distress, which is likely to be long-lasting and unable to be ameliorated, are largely — although not entirely — prohibited.

The new Directive has now entered into force. It will become effective on the 1st of January, 2013, and European Member States will have 24 months (until autumn 2012) to adopt and publish national legislation which will transpose its provisions. Further information.