Select Committee on Animals In Scientific Procedures Report


APPENDIX 3

Committee Visits

This Appendix contains details of the visits undertaken by the Committee during the course of its Inquiry. The Committee is extremely grateful to all those who took considerable time and trouble to host visits and assist the Committee in its work.

2001
19 JulyHuntingdon Life Sciences, U.K.
24th JulyCambridge Institute for Medical Research, Wellcome Trust/MRC buildings, Addenbrooke's Hospital, Cambridge University
6th DecemberGlaxoSmithKline, Harlow
17th - 18th December Scottish Agricultural College; the Moredun Research Institute, and the Roslyn Institute
2002
25th February - 1st MarchUnited States of America
16th -17th MayFrance

* * * * *

Huntingdon Life Sciences, 19th July 2001

Visiting Party

Lord Smith of Clifton; Lord Brennan; Baroness Eccles of Moulton; Lord Lucas; Earl of Onslow; Baroness Richardson of Calow; Lord Soulsby of Swaffham Prior; Baroness Warnock; Professor Michael Reiss (Specialist Adviser) and the Clerk.

Programme of visit

The Committee was given a presentation of the work of contract research organisations, and of Huntingdon Life Sciences in particular. There was discussion of the regulatory requirements in the UK.

The Committee also received a presentation on the use and development of in vitro alternatives. The great majority of toxicological tests were required by regulators: where non-animal tests were validated they were always used, but money was needed to carry out the validation of new non-animal tests.

The Committee was given an extensive tour of the animal facilities.

* * * * *

Cambridge Institute for Medical Research, Wellcome Trust/MRC buildings, Addenbrooke's Hospital, Cambridge University, 24th July, 2001

Visiting Party

Lord Smith of Clifton; Baroness Eccles of Moulton; Lord Lucas; Baroness Nicol; Baroness Richardson of Calow; Lord Soulsby of Swaffham Prior; Professor Michael Reiss (Specialist Adviser); and the Clerk.

The Committee was given a presentation by the Certificate Holder on the use of animals in Cambridge University. It was said that the Act generally worked well, except that amendments to project licences took too long to process. This was important, as 68% of Cambridge University Home Office applications were for amendments to project licences. It was also said that institutional fast-track arrangements for Ethical Review Processes did not reduce the average time taken by the Home Office to approve amendments.

The Committee was given four further presentations on the purposes for which animal research was done.

"Mice and Men", which illustrated the similarity of mice to humans for research purposes, and noted in particular the usefulness of GM mice.

"Cardiovascular Disease" which illustrated the usefulness of mice for research into atherosclerosis, and emphasised that animal testing and testing in humans continued in tandem and informed research in the other species.

"Behavioural Neuroscience from Animal to Human Research" which discussed research linking brain mechanisms to behaviour.

"Translation of Laboratory Research into Patient Care" which gave examples of animal research leading to treatments for human conditions. It also noted that patients could be put at risk when research on animals was not done effectively.

The Committee was given a tour of the animal facilities, including the transgenic mouse facility and the surgical suite.

* * * * *

GlaxoSmithKline, Harlow, 6th December, 2001

Visiting party

Lord Smith of Clifton; Baroness Eccles of Moulton; Earl of Onslow; Lord Taverne; Baroness Warnock; and the Clerk.

Programme of visit

The Committee was welcomed by Tachi Yamada M.D., Chairman of Research and Development.

Dr Yamada gave a presentation on the process of drug discovery.

Dr Yamada and other GSK representatives also covered: an overview of the regulatory burden in the UK; comparison of UK, the US and other countries for R&D; and the recent developments concerning animal rights extremism in the UK.

Some of the issues Dr Yamada covered in his remarks included: (1) the true cost of developing a new medicine (approximately £500 million); (2) in vitro screening and in vivo imaging technology which would provide better focused R&D; (3) the importance of "blue skies" research, as useful outcomes could not always be predicted (GSK spent around £300 million each year on "blue skies" research out of a total research budget of £2.5 billion); and (4) the overall climate for research in the UK. Dr Yamada praised the excellent quality of universities and scientists although the burden of over regulation and the animal rights movement pose a long-term threat to the UK scientific base. Dr Yamada welcomed the Government's recent statements in support of animal experiments, and the fact that he considered the media to have become more balanced in its coverage of the issue.

The Committee was given a further presentation on regulation in the UK. Companies in the US had a competitive advantage, as bureaucracy was less and they could get projects up and running faster than companies in the UK. The problem with bureaucracy in the UK was not with the Inspectors themselves, but with a lack of IT and administrative support. GSK received accreditation from AAALAC, which they commended as it was not prescriptive but considered welfare outcomes.

The Committee was given a tour of the animal facilities.

* * * * *

Scotland, 18th-19th December, 2001

Visiting Party

Lord Smith of Clifton; Earl of Onslow; Baroness Warnock; Professor Michael Reiss (Specialist Adviser); and the Clerk. The party was augmented on the 19th December by Baroness Eccles of Moulton and Lord Hunt of Chesterton.

Tuesday 18th December

Scottish Agricultural College

The Committee was given a presentation on the work of the Scottish Agricultural College: about half their work was on animal and veterinary science, the rest was on farming systems, animal health and animal welfare.

In general, the scientific community was happy with the 1986 Act. The Act worked well as it obliged scientists to justify what they were doing. It was observed that it was not always clear which procedures fell within the Act. A study might not require a licence if carried out as part of normal animal husbandry, but the same study might require a licence if carried out in a research institute. All surgical interventions, including the taking of blood samples, required a licence. Accommodation for experimental animals was of a higher standard, and hence more expensive, than accommodation for farm animals.

It was argued that lay members on the ERP from within the institution had a better understanding of the organisation, and were often better placed to ask good questions than external lay members.

The Committee visited the SAC Howgate Welfare Centre and discussed behavioural studies on pigs. The Committee met licence-holders and Named Animal Care and Welfare Officers at the site, and saw the animal accommodation.

The Roslin Institute

The Committee was given a tour of the Roslin Institute. This included an explanation of how sheep were genetically modified, and the purposes for which this was done: sheep could be bred so that their milk contained alpha-1-antitrypsin, used in the treatment of cystic fibrosis, which would otherwise have to be extracted at great cost and difficulty from human blood. The Committee met Dolly, the first cloned sheep.

It was said that the Act worked well except for an overemphasis on technical breaches of regulations which had no adverse effect on animal welfare.

Wednesday 19th December

Moredun Research Institute

The Committee was given a presentation on the work of the Institute. The Committee was given a tour of the facility for large animals, and of the High Security Unit for research into ruminant infectious diseases. It was again said that accommodation standards for experimental animals differed from standards required for farm animals.

The Institute hosted a round table discussion involving Senior Project Licence holders, Certificate holders, and Named Veterinary Surgeons from the Scottish Agricultural College and the Moredun and Roslin Institutes.

It was said that the Act was necessary, and mostly good, but bureaucratically cumbersome. There was a problem recruiting technicians, particularly for working with farm animals as it was such a specialised field. What the Act covered was not always clear, and the views of Inspectors varied: some said that a particular nutritional study fell within the Act; another that it did not. Changes in protocols and accommodation were sometimes demanded, though they had no beneficial effect on animal welfare. To breed GM animals, four different committees had to be satisfied; the statistics on numbers of GM animals used were highly misleading, as many animals were never actually used in experiments, but were only used for breeding. The Statistics were also misleading, as although the total number of animals had increased, there had been great progress in developing refinements.

* * * * *

USA 24th February - 1st March 2002

Introduction

The Select Committee visited the United States of America between Sunday 24th February and Friday 1st March.

The purpose of the visit was to examine how animal experiments are licensed, monitored, and carried out in the USA, fulfilling the Committee's terms of reference which enjoin them to pay regard to 'EU and international law and practice.'

Visiting Party

Lord Smith of Clifton; Baroness Eccles of Moulton; Lord Hunt of Chesterton; Earl of Onslow; Lord Soulsby of Swaffham Prior; Baroness Warnock; Professor Michael Reiss (Specialist Adviser) and the Clerk.

The visit was arranged with the assistance of Dr Julie Moses from the British Embassy, Washington, who accompanied the Committee throughout its visit. Further assistance was given by Christopher Pook, British Embassy, Washington.

Principal points arising from the visit to the USA

Regulatory Oversight

There are three bodies which oversee the welfare of research animals. The United States Department of Agriculture (USDA), the Department of Health and Human Services (DHHS), and the voluntary accreditation body, AAALAC (the Association for the Assessment and Accreditation of Laboratory Animal Care).

    (i) The USDA covers all warm-blooded animals except rats, mice and birds. They are the only one of the three bodies to carry out unannounced inspections. There are 96 USDA Inspectors (in the Animals and Plant Health Inspection Service (APHIS)) to monitor c. 8,800 institutions. Each institution is visited every 6 months.

    (ii) The DHHS enforces regulations against all bodies in receipt of public funds. All vertebrates (including rats, mice and birds) are covered. The system was described as 'enforced self-regulation': institutions have to deposit an 'Animal Welfare Assurance' with OLAW (the Office for Laboratory Animal Welfare), but OLAW only carries out inspections where they have specific reason to believe that standards have been compromised.

    (iii) AAALAC is a private organisation which accredits animal research organisations. Accreditation is voluntary. Standards are high and cover all vertebrates. AAALAC visits laboratories, with advance warning, once every three years. Most large institutions, both public and private, obtain AAALAC accreditation to demonstrate publicly their commitment to high scientific standards and animal welfare.

The system of oversight is highly complex. The regulatory authorities emphasised that the various systems all worked together, but other witnesses said that there is duplication on the one hand, and omission on the other. Some institutions might be inspected by three bodies, others by none.

The US system is new, and still evolving. The reluctance to include rats, mice and birds under the Animal Welfare Act is based on practical difficulties, rather than on philosophical objections.

The US system is not explicitly founded on any ethical basis. There is no formal cost/benefit analysis, although there is an assessment of pain. It is also largely based on trust.

Institutions which are privately funded, use only use rats, mice and birds and choose not to be AAALAC accredited, have no legal oversight at all. This means that a number of rats, mice, and birds receive no legal protection. Estimates for how many rats, mice and birds are not covered ranged between 5% and 30%. No statistics are gathered on this. Several witnesses the Committee met, including Dr Peter Singer (at Princeton), and Dr Alan Goldberg (of the Johns Hopkins Center for Alternatives to Animal Testing), emphasised that they considered the US system to be unsatisfactory, and the UK system with respect to rats, mice and birds to be much better.

AAALAC is expanding internationally and already monitors some breeding centres used by UK institutions.

IACUCs (Institutional Animal Care & Use Committees)

IACUCs are responsible for approving research protocols. They are required by law to contain a veterinarian and a lay member who has no affiliation with the institution.

IACUCs are based within the local institution; they can be extremely flexible and help to minimise bureaucracy. At least one person the Committee met expressed incredulity that all UK research protocols should have to go to a central body. The converse of this, however, is that standards vary between institutions — research forbidden by one IACUC might be approved by another.

The presence of a true lay member 'to represent the interests of the community' is beneficial, but lay members are not recruited openly. There is no statute of limitations — lay members can serve on Committees indefinitely.

Only one lay member per IACUC is required. The Committee was told that one IACUC had 24 members, therefore it could be difficult for the lay member to have much influence. While there could be a case for insisting on more than one lay member in large IACUCs, the difficulty in finding good lay members was mentioned a number of times.

The UK has an 'Ethical Review Process', while the US has an 'Animal Care and Use' committee. It was noted that Huntingdon Life Sciences was the only institution the Committee met in the US which incorporated ethics into its mission statement.

Development of Alternatives

The following points derive principally from the meeting with Dr Alan Goldberg, the Director of the Center for Alternatives to Animal Testing (CAAT) situated at Johns Hopkins University, and from the meeting with Dr Paul Silber of In Vitro Technologies, a company specialising in the development of research using animal and human cells instead of whole animals.

The development of alternatives should be a business opportunity, not an obligation. The UK should establish itself in this field early on for economic reasons as well as for animal welfare ones. The US has recently increased ten-fold the federal funds available for 'bioinformatics' (including mathematical and computer modelling).

The word "alternatives" is misleading, as it implies only replacement methodologies. Refinement and reduction should not be ignored.

There has been real progress in developing alternatives in recent years. However, relying on serendipity to develop alternatives is not enough. The scientific community is often conservative and reluctant to embrace new methods: a centre for excellence might help to overcome this resistance.

CAAT is a very small institution: it does not develop alternatives so much as promote them, through funding and by providing information.

If in vitro testing is to expand, the supply of human tissues also needs to increase.

Public Attitudes and Animal Rights

There is a growing trend towards animal rights in the US, encouraged by celebrity pressure groups (such as the Doris Day Animal League). The problem of illegal activism is not as severe as in the UK, but is more severe than the Committee had first thought.

As in the UK 10 years ago, scientists are reluctant to make the case for animal use. This was illustrated by the fact that the Committee did not visit any pharmaceutical company in the US: a number of pharmaceutical companies were approached but turned down a request to visit.

There is no publicity about the use of animals in scientific developments - when a new drug is announced, scientists do not habitually refer to the animal work which was required to develop it.

Science education no longer involves dissection; there might be opportunities to use in vitro experiments involving animal cells in schools.

Freedom of Information

Lack of information is a major cause for concern for animal rights and animal welfare organisations. Scientists should be encouraged to be braver and release more information. Releasing all information might be just as effective as withholding it, as industry and science would present a broad and united front to activists.

Conversely, in the US, scientists are lobbying the USDA to publish less information because activists are using 'triangulation' — cross-referring several pieces of anonymised, publicly available information — to work out the names and home addresses of researchers.

The potential for scaremongering is greatly increased if pieces of technical information are taken out of context (every substance is toxic if taken at sufficient dose).

In the US, companies have managed to obtain strict injunctions against activists which have effectively curtailed their activity. Similarly strict injunctions would not currently be granted in the UK.

Record of Meetings

Monday 25 February

Beltsville Agricultural Research Center (BARC)

Meeting with Dr Phyllis Johnson, Director of BARC

The operation of regulation of animal experiments in the USA was discussed. In particular, it was noted that there were different guidelines for the use of livestock as opposed to laboratory animals. Exhaustive details of protocols had to be submitted to the IACUC for experiments on farm animals, whereas no protocols had to be submitted for procedures carried out for animal husbandry.

Meeting with Dr Tom Saxton, Director, and David Granstrom, Associate Director, Animal & Natural Resources Institute, BARC

The research work undertaken at BARC was discussed. It was noted that 85% of funding came from federal sources, the remainder from individual grants or industry partnerships. All research was eventually published. BARC was not inspected by USDA Inspectors as it was part of the USDA. It was estimated that 90% of rats, mice and birds were covered by AAALAC (see below); objections to subjecting all rats, mice and birds to USDA inspection were based on practical difficulties. It was noted that the US had an Animal Welfare Information Centre, which gave advice on alternatives to animal experiments.

The Committee was given a bus tour of BARC.

Institute for Laboratory Animal Research (ILAR), National Academy of Sciences

Meeting with Dr Joanne Zurlo, Director, and Dr Ralph B Dell, Associate Director.

Institutions in receipt of federal funds are required to adhere to the standards of animal care laid out in the Guide for the Care and Use of Laboratory Animals produced by ILAR. They are also inspected by APHIS (see below).

It was said that animal testing was absolutely necessary for developing pharmaceuticals, but that good animal care was part of the conduct of good science. It was important to consider the overall welfare of animals, rather than try to specify details such as cage sizes. Pharmaceutical companies were putting money into alternatives. Research would follow money.

[Some members of the Committee had the opportunity to discuss matters further with Dr Dell when he visited the UK: see the minutes of that meeting in the volume of Oral Evidence.]

AAALAC: Association for Assessment and Accreditation of Laboratory Animal Care

Meeting with Dr John Miller, Director, and Dr Catherine Bayne Associate Director

The work of AAALAC and its relationship to the USDA and the Department of Health and Social Services was discussed. It was said that 90% of all animals were covered by regulation. All major producers of rodents, and all major drug companies were AAALAC accredited. Reports of inspections by the Office of Laboratory Animal Welfare (which inspected federally funded institutions) were made public, but inspection reports carried out by AAALAC remained confidential.

It was noted that cage sizes in the US and Europe were based on experience rather than on evidence-based science — the American College for Laboratory Medicine was starting to give grants for research into accommodation requirements for different species, and even different strains.

Dinner with representatives of animal welfare organisations

The Committee entertained to dinner representatives from: the Doris Day Animal League; the Humane Society of the US; the Animal Welfare Institute; the NIEHS (National Institute of Environmental Health Sciences); and researchers from the US Senate.

Tuesday 26 February

Animals and Plant Health Inspection Service (APHIS) USDA, & Office of Laboratory Animal Welfare (OLAW), National Institutes of Health

Meeting with Dr Chester Gibson and Richard Watkins (APHIS)
Dr Carol Wigglesworth, and Dr Stephen Potkay (OLAW)
Dr John Miller (AAALAC) was also present


A presentation was given by OLAW. The system in the US was described as "enforced self-regulation" - institutions had to deposit an "Animal Welfare Assurance" with OLAW. There was considerable local autonomy, but variation between local IACUCs. Each IACUC had to have one lay member. The percentage of experimental animals in the US monitored by OLAW was not known: estimates were 50% to 90%.

A presentation was given by APHIS. APHIS had 96 Inspectors and an annual budget of $12.5 million to monitor around 8,800 facilities, including 1265 registered research facilities, over 4,500 dealers and over 2,500 exhibitors (zoos and circuses). Inspectors made unannounced visits. Some states made the protocols of research publicly available.

All warm-blooded animals were covered by the Animal Welfare Act (fish and invertebrates were not covered, and rats, mice and birds were not actually inspected). Animals used in agricultural research for the betterment of the animal species were exempt from the Animal Welfare Act. Animals in defence research were not inspected by APHIS/USDA, but the Department of Defense stated that all animal defence research took place in AAALAC accredited institutions.

Lunch with representatives of industry and animal research

The Committee entertained to lunch representatives from: NABR (National Association for Biomedical Research); Americans for Medical Progress; PhRMA (Pharmaceutical Research and Manufacturers of America); BIO (Biotechnology Industry Organisation); and FASEB (Federation of American Societies for Experimental Biology).

National Institutes of Health (NIH)

Meeting withDr Michael Gottesman, NIH Deputy Director for Intramural Research
Dr Richard Wyatt, Executive Director, Office of Intramural Research
Dr James Taylor, Director, NIH Office of Animal Care & Use

The work of the NIH was discussed. OLAW was part of NIH, but also monitored the NIH research. NIH used around 700,000 rodents each year. NIH operated web-based training courses: training was compulsory, and a refresher course was required every 3 years.

Potential lay members for IACUCs were usually recommended by word of mouth, and their term of office was not time-limited. IACUCs often rejected protocols.

Animal use had reduced, but some animal work was still necessary: a reduction in animal tests had led to compounds being tested in humans too early — with fatal consequences. ICCVAM (the Interagency Coordinating Committee on the Validation of Alternative Methods) examined the methodology of toxicology tests, but this would have little impact on basic research. It was also said that it was necessary for surgeons to perfect their technical skills by using animals.

NIH protocols were made public after they had been approved. There was considerable effort in the US to take the "message of science" to the public: research led to improved quality of life.

The Committee was given a tour of the animal houses and surgery facility.

Meeting with Dr Yvonne Maddox, Acting Deputy Director, Intramural Research

Differences in public attitudes to animals in the US and the UK were discussed, and how these might relate to the greater availability of information in the US.

Wednesday 27 February

Johns Hopkins University, Baltimore

Meeting with Dr Theodore Poehler, Vice Provost for Research
Dr Nancy Ator, Chair, University Animal Care & Use Committee and
Professor, Department of Psychiatry - Behavioral Biology, School of Medicine
Dr Janice Clements, Vice Dean for Faculty Affairs, Professor & Acting Chair, Department of Comparative Medicine, School of Medicine
Dr Alan Goldberg, Director, Center for Alternative Testing, Professor, Department of Environmental Testing, Bloomberg School of Public Health

The animal research and the IACUC system at Johns Hopkins University was discussed. Johns Hopkins submitted 500 new animal research protocols each year, and 1,200 were in force at any one time. Johns Hopkins received AAALAC accreditation.

The Johns Hopkins IACUC reviewed 50 protocols each month. Most were slightly amended or deferred. None were absolutely prohibited. The time taken to approve protocols was, on average, one month, though some could take much longer, especially if they needed to be rewritten.

Genetic engineering technologies would lead to an increase in the use of animals. The university currently had 50,000 mice; 10 years ago there had been only 5,000. The university had NIH funding for many new projects, and a new animal facility was being built to house 140,000 mice.

Dr Goldberg discussed the Center for Alternatives to Animal Testing (CAAT), which was founded 20 years ago. It had a role to educate the public, educate scientists about alternatives, and provide funding for small projects on alternatives. He said that he still considered himself to be an animal scientist.

[Dr Goldberg was subsequently invited to present formal, oral evidence to the Committee: see the transcript of the meeting on 23 April printed in the volume of Oral Evidence]

The Committee was given a tour of the animal facilities, and met several research scientists and technicians who worked with animals.

In Vitro Technologies, Baltimore

Meeting with Dr Paul Silber, CEO, In Vitro Technologies

Dr Silber had been a toxicologist working with animals. He had moved into in vitro studies, not for ethical reasons, but because it was better science. He still used animal tissue. He also used human tissue, and discussed the logistical difficulties in obtaining it. He said that in the US there was not a particular concern with using human tissue, but there were cultural difficulties with using human tissue in other societies, such as Japan.

The number of animals used to develop each drug were decreasing, as pharmaceutical companies used more in vitro research to identify toxic compounds early, before they were tested on animals. This was driven by cost: a chronic bioassay (using 200 rats over 2 years) could cost between one and one and a half million dollars. An in vitro study, which might identify toxicity at an earlier stage, cost between $10,000-$50,000. Drug development costs increased exponentially once animal research was required.

Animals may be used less, but there would still be a need for animal testing in toxicology for at least another 20 years.


Thursday 28 February

Huntingdon Life Sciences (HLS), New Jersey

The Committee was given a presentation about the type of work undertaken by HLS, and the US regulatory compliance framework. The campaign against HLS was also discussed, and the costs to the company which this had incurred. HLS had been successful in obtaining injunctions against activists.

The differences between the regulatory system in the US and the UK were discussed. There were also discussions about the public acceptance of animal work in the US and how this differed from the UK.

The Committee was given an extensive tour of the animal facilities.

Centre for Human Values, Princeton

Meeting with Professor Peter Singer, Professor of Bioethics

The moral and ethical arguments surrounding animal experimentation were discussed. Professor Singer said that human beings should not consider that they had a privileged moral status simply by virtue of belonging to a particular species. Privileged status should be based on identifiable characteristics, such as intelligence or self-awareness.

Professor Singer considered that 50% of science students in Princeton did not want to work with animals. The other 50% were prepared to use animals, but were concerned not to inflict pain.

Professor Singer said that the UK regulatory system for animal experiments was good as it allowed for ethical input in the cost/benefit analysis. By contrast, in the US, IACUCs were not asked to make ethical judgements. IACUCs were also greatly variable as there were no clear guidelines.

Friday 1 March

The Committee held a private meeting to discuss the visit.

* * * * *

France, 16th - 17th May, 2002

The Select Committee visited the Paris region in France between Thursday 16th and Friday 17th May.

The purpose of the visit was to examine how animal experiments are licensed, monitored, and carried out in France, fulfilling the Committee's terms of reference which enjoin them to pay regard to 'EU and international law and practice'.

In the course of receiving evidence, the Committee had already received evidence from the British Science Attaché in the Paris Embassy, and from the French Science Attachée in the London Embassy.

Visiting Party

Lord Smith of Clifton; Baroness Eccles of Moulton; Lord Lucas; Earl of Onslow; Lady Richardson of Calow; Professor Michael Reiss (Specialist Adviser) and the Clerk.

The visit was arranged with the assistance of Mr Andrew Holt, Foreign and Commonwealth Office, British Embassy, Paris, who accompanied the Committee throughout its visit.

Meeting with Dr Sylvain Posière, Chef du Service de Protection et Santé Animales, and Dr Daniel Faibra Djok, Veterinary Inspector, Direction des Services Vétérinaires de Paris

Licensing and inspection

Dr Posière said that the Ministry of Agriculture made law which the decentralised Veterinary Service enforced. EU legislation required two licences. An Institutional Licence would be granted following an inspection of the premises and lasted for 5 years. A Personal Licence would be granted following the receipt of the relevant application form — there was no formal interview or visit by the Veterinary Service.

Under this system, protocols themselves were not approved. Each researcher was given responsibility to ensure the suitability of protocols. This made it difficult for the inspectorate to tell whether alternatives were seriously considered. Recently, however, non-compulsory ethics committees had begun to be introduced which did consider the 3Rs. Most recently of all, a National Commission on Animal Experiments had been set up which had the power to oversee protocols and monitor standards of training.

Inspections were usually pre-arranged, although unannounced visits were sometimes made. If laws were contravened, sanctions were available and usually consisted of fines. Dr Posière knew of no institution in the Paris region that had lost its licence, although this sanction was possible. He noted that the Veterinary Service had been trying to encourage numerous small animal houses to merge into fewer larger ones, to make them easier to monitor.

Personal Licence applicants had to possess scientific qualifications and also undergo 15 days of initial training. No further training was then required. The inspectors could ensure that laboratories kept up-to-date with new techniques, but did not oblige individual scientists to do so. Those involved in breeding animals were also required to undergo basic scientific training.

Inspectors attempted to enforce animal welfare standards (such as cage sizes) but were understaffed. This was partly because they had a responsibility for a whole range of animal welfare issues.

The Paris area was the largest animal research area in France with 150 institutions and 1,500 personal licence holders. To monitor this activity there were only three part-time inspectors in the Paris area. This situation was better than in most other départements.

The Chairman suggested that the principal difference between France and the UK was that the UK validated each protocol, while France enforced training standards and then trusted the scientists.

Dr Posière agreed that the lack of inspectors meant that the French system was based on trust. Nonetheless, from 7 years experience in the veterinary service, he considered that fewer and fewer researchers now operated outside the regulations. Particularly in the large laboratories animal welfare standards were good.

Veterinary Services inspectors

Local inspectors were all trained to the same standards on the same courses but preserved their autonomy. Dr Posière said that he was employed by the Ministry of Agriculture, but that his colleagues were employed by the département. The posts were fairly well paid, were well respected, and provided interesting work. They were becoming increasingly sought after.

Expertise varied between départements depending on local need; some inspectors specialised in cattle farms. Not all inspectors were trained in laboratory animal science, and those that were had only taken the same 15 day course as potential personal licence holders.

Public opinion and animal activism

Dr Posière said that there were a few animal extremists with whom rational dialogue was not possible. About 50% of the population, however, were in some way concerned about the use of animals. Scientists were not so concerned for their safety as they were in the UK, which meant that they viewed animal rights campaigners as a necessary evil. Dialogue happened more easily and regularly and institutions were more ready to open their doors to campaigners.

Animal activists played an important role in maintaining standards. They often gave information to inspectors with whom they were on good terms.

Ethical Review Process

There had been some debate as to whether the Ministry of Agriculture should make ethical panels compulsory. No research had yet been done to establish the effect of ethical review on animal welfare. Most large companies had now set up ethical panels which usually incorporated an external lay member.

National institutions were also encouraging the adoption of ethical review. Scientists acknowledged the need to consider the 3Rs, and realised that ethical review could improve the quality of the science. Many international journals also required evidence of ethical review of animal experiments. Dr Posière hoped that ethical panels would play an increasing role in monitoring animal procedures.

Miscellany

Dr Posière said that:

Animal use would never disappear. There would be more use of rodents and GM animals, and fewer dogs, cats and primates. Statistical matters were the responsibility of the Ministry of Research;

Surgeons were permitted to practise surgical techniques on animals;

Some cosmetics testing still occurred, though many tests were now banned by the EU;

Animals were not usually allowed to recover from severe procedures, although they were in certain circumstances — it was a question of the level of pain. Those animals which were allowed to recover could not be re-used in another experiment;

He did not know of any instances of UK scientists moving their research to France to take advantage of the different regulatory system;

Scientists visiting from abroad would have to undergo full training to acquire a licence;

Students did not need licences, but trained under the direction of a licensed Professor. Laboratory assistants similarly were required to undergo some general training, but did not need licences. The head of the research team would be held responsible for any breaches of standards;

Matters relating specifically to GM animals (such as regulations to prevent the release of animals into the general population) were regulated by the Ministry of the Environment.

Meeting with Mr Herman Koeter, Organisation for Economic Co-operation and Development.

Held in the British Embassy, Paris

Mr Herman Koeter is the Principal Administrator in the Environment Health and Safety Division of the Environment Directorate of the OECD. The OECD produces test guidelines for assessing the toxicity of chemical compounds. As the OECD is a consensus organisation, these guidelines cannot be implemented until accepted by all member states.

The OECD is not responsible for the harmonisation of tests relating to new medicinal products. They are negotiated through the International Conference on Harmonisation (ICH).

Discussion

Role of the OECD

Mr Koeter said that his division of the OECD was primarily concerned with the regulatory assessment of new chemical compounds in order to protect human health and the environment.

International toxicology agreements did not insist on animal use, but insisted on safety standards. Animal experiments were just one aspect of any toxicological assessment. The OECD had begun to take account of the 3Rs, but alternatives to animal experiments were not considered a priority. The development of in vitro tests had been driven by economic concerns and had been enabled by improvements in basic science — researchers had recently acquired a much better understanding of events at the cellular level.

The OECD had not yet sought to harmonise regulations governing animal procedures. Each country still had its own regulations and OECD guidelines were incorporated into national law.

OECD test guidelines were developed in the mid 1990s to harmonise the different requirements of national regulators, and hence reduce the amount of testing required to establish the safety of new compounds. Following harmonisation, one set of tests would be accepted by regulators in all OECD member states. This would obviously reduce the duplication of animal tests. In addition, statisticians had been involved in drawing up the guidelines to ensure that the optimal number of animals was used.

A few replacement tests had also been developed and were in the process of being adopted. The number of animals replaced by such alternatives was very few (one hundredth of 1% of the total), but those few had been involved in tests of the most substantial severity. Better welfare guidelines had also been developed.

Mr Koeter acknowledged that the consensual nature of the OECD was a difficulty in implementing alternatives. The greater difficulty, however, was the nature of toxicology.

The nature of toxicology

Toxicological assessments involved numerous different tests which fitted together like pieces in a jigsaw puzzle. Trying to devise an alternative to one particular test was like trying to replace one piece of the jigsaw puzzle: each alternative would need to be an exact replica of the test it replaced. This process was therefore difficult and saved few animals. What was needed was a new jigsaw, a whole new system of toxicological assessment.

Developing a whole new toxicological system however would be particularly difficult as so many different countries were involved. Austria and Sweden, for a combination of cultural and historical reasons, were opposed to the use of human tissue. Testing on humans would be ideal but would usually be unacceptable: there was also a danger that tests on humans would be carried out in unregulated environments such as Africa and South America to the potentially severe detriment of the health of volunteers.

In order to develop such a new toxicological system, short-term thinking related to specific projects was not enough. Alternatives research needed a long-term perspective which would require government funding. Currently, around ?40-50 million was spent on alternatives each year in Germany and the Netherlands. This contrasted with the Home Office's current alternatives budget of £280,000.

Moreover, Mr Koeter said that the alternatives centre at Johns Hopkins in the USA had been criticised for being too closely linked to and funded by industry. Alternatives Centres needed to be funded by government as well as industry.

Mr Koeter argued that a Government funded UK alternatives centre would be "a big step forward".

A Centre for Alternatives

Mr Koeter considered that the science community was starting to take alternatives more seriously, and scientists specialising in alternatives were now accepted and respected. This was illustrated by the forthcoming '4th World Conference on Animal Welfare' which had expanded enormously since its inception 12 years ago. Nonetheless, there was still an important role for integrated alternatives centres.

Independent alternatives centres had no future. ECVAM's research laboratories were now practically empty, although ECVAM still had a function in co-ordinating and promoting alternatives. Similarly, the 'stand alone' laboratories at FRAME had done some very good work, but had had little effect on the regulatory use of animals.

By contrast, the Johns Hopkins Centre for Alternatives to Animal Testing (CAAT) was integrated with animal research. The most successful centre was ZEBET, in Germany, which was embedded in traditional science and involved experts in numerous fields. Most of the alternatives claimed by ECVAM were actually developed at ZEBET.

Embedded centres for alternatives could also take account of local idiosyncrasies. For example, there was enthusiasm for alternatives in the UK, Germany, the Netherlands and Sweden. There was little enthusiasm in France, Spain, Portugal or Italy. Scientists in Spain, however, were sensitive to the welfare of fish — the result of local, cultural differences.

Successful centres were always integrated into traditional science. Conferences and seminars alone were not effective. Alternatives scientists must be kept up-to-date with developments in animal science and vice versa — this would lead to overall better science. Moreover, having the alternatives centre as part of an integrated animal and non-animal laboratory would lead to a greater acceptance of alternatives by animal scientists.

A nucleus of 'alternatives science', possibly consisting of just one scientist, needed to be situated within the principal life-sciences research centres. Obvious places to site such nuclei would be in the Medical Research Council research centres and in universities.

Environmental Enrichment

Mr Koeter indicated various difficulties with enriching the environment of laboratory animals. Woodchips, for example, could not be used as a nesting material as they contained too many chemicals which could interfere with toxicological tests. There could also be difficulties with allowing animals to express natural behaviour patterns too freely. Currently, domesticated laboratory rats liked to be picked up; undomesticated rats, however, would become so stressed if they were picked up that changes in their physiology would interfere with the experiment.

Nonetheless, some forms of environmental enrichment, such as substituting solid-bottomed cages for wire-bottomed ones, could easily be investigated. As yet, however, no-one had suggested to the OECD that the necessary research, to discover how solid-bottomed cages affected test results, should be carried out.

Validation of Animal Tests

Mr Koeter said that the issue of the effectiveness of animal tests had been extensively discussed at the OECD conference in Stockholm in March 2002. The validity of a test was composed of its relevance and its reliability.

In vitro tests could indicate whether a chemical had adverse effects, but could not explain why. He gave the example that, if a new chemical kills a plant, scientists would not immediately discard the chemical, as humans shared few mechanisms for toxicity with plants. Scientists would first try to understand the underlying mechanism in order to know whether the chemical would have a similar effect on humans.

Animals, however, shared many physiological characteristics with humans, and many of the mechanisms for toxicity were similar. Even so, a new chemical which caused an adverse reaction in animals would not be automatically discarded; scientists still needed to assess whether the underlying mechanisms of a particular adverse reaction were relevant to humans.

Experience and use was vital in assessing which animal species should be used to provide relevant data. In general, scientists used the rat, as more was known about the rat than about any other species, including humans. It was also known where different reactions between the rat and humans were likely to occur.

Mr Koeter was against a systematic, retrospective assessment of all animal tests. Many tests had proven themselves with use — teratogenicity tests, for example, had prevented any reoccurrence of the thalidomide episode. A new validation of all animal tests would be impractical, expensive, and involve enormous numbers of animals in new experiments.

Good Laboratory Practice

Mr Koeter was not especially concerned that animal procedures would be carried out in countries with little regulation. For results of animal experiments to be acceptable to the OECD, laboratories needed to comply with Good Laboratory Practice (GLP). Laboratories needed to be accredited by an approved government authority. Results from animal tests in Brazil, for example, would be rejected as there was no government oversight of GLP.

Role of the ICH

The ICH (International Conference on Harmonisation) had been set up to harmonise the testing guidelines for the development of pharmaceuticals. The OECD was only responsible for issuing guidelines on chemicals.

Only the US, the EU and Japan were members of the ICH. The intention was that the ICH, comprising only three members, would operate more efficiently than the OECD. In practice, however, the same scientists in the same laboratories were used by both organisations to validate tests. Mr Koeter therefore considered that the ICH was not significantly more efficient.

The secretariat of the two bodies worked closely together to prevent any duplication of effort.

Visit to a pharmaceutical company

The Committee was given a short introduction to the pharmaceutical company.

It was emphasised that work on animals formed one part of the many processes involved in drug development. Similarly, work on genomics was just one research activity among many. Pharmaceutical companies all conducted considerable in vitro work.

Working under French Legislation

French law took account of EU Directive 86/609/EEC and required site licences and personal licences. It was argued that there was little significant difference in animal welfare between France and the UK. Good animal health was necessary for good science. The following issues were discussed.

Site licences

Site licences were, on average, 4 pages long (and numerous appendices depending on the size and activity of the site). They needed to state the maximum number of animals of each species which could be housed on the site, and they needed to justify the use of animals. Such justification, however, could be very general, "To prove the safety and efficacy of new drugs". If no reply had been received from the local inspector 3 months after submitting the dossier, the site would be most probably approved with the official notification sent later. The local veterinary service inspected the site once each year, for one day. The authorities have to be informed of any major subsequent modifications to the site.

Personal licences

The licence holder was the scientist in charge of the project, and was held legally responsible for the welfare of the animals used. Personal licences, which included details of the proposed protocols (akin to the 'Project Licence' in the UK) were a maximum of 10 pages long. The holder of the licence must have a university level qualification and undergo 80 hours of training. (Animal technicians were also obliged to attend a 40 hour training course approved by the Ministry of Agriculture.)

To obtain a licence, the researcher had to submit a dossier stating what would be done and why. The researcher had also to state that there were no available alternatives. Since May 2001, the researcher had also to assess expected levels of pain. No single system of pain assessment had been universally adopted, although it was said that the Swiss Scale was both practical and informative.

Only a very general indication of the work of the researcher needed to be given. Individual protocols would be discussed in ethical review committees, but would not be specified on the licence. Personal licences were usually processed within a month, and often within 2 weeks. The authorities have to be informed of any significant modifications, but no active decision was usually taken by the Préfecture — the veterinary inspectors were simply notified.

GM animals

Under French and European legislation, GM animals solely used for breeding were not covered by animal experimentation legislation. The actual number of animals used in experiments was decreasing, as many experiments required either a few, targeted GM animals, or many more ordinary animals. Moreover, genetic modification had led to the use of more mice, but fewer dogs and rabbits.

It was further observed that in France, but not necessarily in the rest of Europe, animals killed to obtain tissues for in vitro work were also included in the numbers of experimental animals.

Alternatives

Research scientists were at the forefront of the development of alternatives — an example was the introduction of radio-telemetry which benefited both the animal and the researcher. By contrast, ECVAM, which only considered regulating testing, including toxicology, was said to have little effect on animal welfare but had been set up as a matter of good PR.

Public opinion: dogs and micropigs

The French public were much more tolerant of animal research than the public in the UK, and there was a much healthier relationship between scientists and animal welfare associations. European trade associations had been talking to the ABPI in the UK to try to learn from the experience of Huntingdon Life Sciences. European pharmaceutical companies were beginning to realise that they needed to be more transparent and more proactive in explaining what they did.

In France, however, there was a strong aversion to the use of dogs. Any proposed laboratory or breeding centre which could house more than 50 dogs was automatically subject to a public inquiry. There was thus strong pressure to reduce the use of dogs, but the usual alternative was to use primates, which many scientists considered unacceptable. Researchers had begun therefore to use micropigs: these had the additional advantage of being better scientific models for some types of cardiovascular research.

Ethical Review

Ethical review committees were not required by law, but were becoming increasingly common in France. Ethical review committees had begun in pharmaceutical companies around 15 years ago, and only now was a French National Committee being set up. All large and medium sized pharmaceutical companies in France now used ethical review. Committees usually consisted of scientists but also involved non-scientific members. These lay persons, however, were frequently employed by the pharmaceutical companies in non-scientific capacities.

The implementation of ethical review processes was driven by many factors. Ethical review could improve the science. Leading academic journals required evidence of ethical review before they would publish articles. Major investors, such as US pension funds, had started to require evidence of ethical review as part of their assessment of pharmaceutical companies. Researchers were becoming increasingly aware of the need for transparency and good ethical standards to maintain public confidence in animal research.

Visit to animal facilities

The Committee was given a tour of the animal holding facilities and laboratories, including explanations of various refinements in housing standards.

Visit to the Pharmacy Faculty, Université René Descartes, Paris V

The Committee was welcomed by Jean-Pierre Clot, Professor of Endocrinology, and Chantal Martin.

The Committee was given a tour of the animal holding facilities and saw rats, mice and rabbits. The Committee also viewed experimentation rooms and saw a procedure on a rat taking place.

The Dean and Vice President of the University, Professeur Dominique Durand, showed the Committee around the University.

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