A challenge to the Home Office

Open letter to Dr John Richmond, head ASP Division [Sent by recorded delivery]

[email protected]

Cc: Dr Judy MacArthur-Clark chief home office inspectorate
APC chair Ms Sara Nathan
Rt Hon Meg Hillier

19 June 2008.

Dear Dr Richmond,

INVASIVE EXPERIMENTS INVOLVING NON HUMAN PRIMATES

Further to disclosure under the Freedom of Information Act (attached) and my subsequent correspondence to you dated 3 August 2007 (attached) concerning a Home Office Application project licence, I would like to bring the following additional information to your attention, which relates to section 5(5) of the Animals (Scientific Procedures) Act of 1986, which states: "The Secretary of State shall not grant a project licence unless he is satisfied - that the purpose of the programme to be specified in the licence cannot be achieved satisfactorily by any other reasonably practicable method not entailing the use of protected animals".

Further to the FOIA disclosure, it is my understanding that Professor Tipu Aziz obtained a Home Office project licence in 2004, under which he was authorised to conduct invasive brain research in non human primates at Oxford University. It is also my understanding that the current project licence is due to expire in 2009 and that a new project licence will need to be issued by the Home Office if the programme of research is to continue.

I am therefore writing to you now, to allow your department and the APC sufficient time to consider the information provided herewith, in the event that you should receive an application to renew the current licence.

The information I am sending you consists of six sections:

1. Introduction
2. Weight of evidence
3. Cost-benefit assessment
4. Expert statements
5. Relevant published scientific articles
6. Conclusion

1. Introduction

In an era of evidence based medicine, it is increasingly considered unethical to conduct more animal or human research while existing studies have not been systematically evaluated. In the words of Sir Iain Chalmers, Scottish Wellcome Trust Clinical Research Facility, (Edinburgh, 30 June 2005):

"New research should not be designed or implemented without first assessing systematically what is known from existing research. The failure to conduct that assessment represents a lack of scientific self-discipline which results in an inexcusable waste of public resources. In applied fields like health care, failure to prepare scientifically defensible reviews of relevant animal and human data results not only in wasted resources but also in unnecessary suffering and premature death. All new research - whether basic or applied - should be designed in the light of scientifically defensible syntheses of existing research evidence, and reported setting the new research in the light of the totality of the available evidence, thus making clearer to readers what contribution - if any - new studies have made to knowledge"(1).

2. Weight of evidence

There is a growing swell of public opinion as well as political support for a ban on the use of non human primates, as seen in the signing by 433 MEPs of Written Declaration 40/2007 and the signing by 166 MPs of EDM 1704, calling for such a prohibition. These figures reflect a desire by civil society to recognise pain and suffering in our closest evolutionary relatives, especially at a time when animal research does not appear to stand up to scientific scrutiny. In March 2004, Caroline Flint MP, responding to a parliamentary question on behalf of the Home Secretary, stated that 'The Home Office has not commissioned or evaluated any formal research on the efficacy of animal experiments', and had 'no plans to do so'.

Pursuant to this admission by the Home Office, there is no escaping the imperative of evidence based medicine and the pivotal role of systematic reviews in rigorously assessing the value of any particular set of scientific studies. There are a good number of published articles that illustrate the discordance between treatment outcomes in human patients and laboratory animals, e.g. Perel P et al. "Comparison of treatment effects between animal experiments and clinical trials: systematic review" (2,3,4,5,6).

By the same token, we should be able to subject the research conducted on non human primates by Professor Tipu Aziz, to the same rigorous assessment. A good deal of his research has centred around the intervention known as 'Deep Brain Stimulation' (DBS). The technique has been applied to various centres of the brain of macaque monkeys, including the subthalamic nucleus (STN) and the pedunculopontine nucleus (PPN). Although DBS is currently used in human medicine, it would appear not to have undergone formal systematic review to objectively assess its efficacy. Since the 'jury is still out' regarding the value, or efficacy, of DBS in human subjects, evidence based medicine warrants the placing of a moratorium on all DBS research involving non human primates.

There is already good evidence to support such a move:

Human studies in the UK

In an article published in 2007 and entitled "Deep brain stimulation for chronic pain investigated with magnetoencephalography [MEG]", researchers demonstrated the feasibility of using non invasive MEG to map whole-brain changes in neural activity induced by DBS in human patients (7). Similarly, in a study in 2008, entitled "Pre-operative DTI and probabilistic tractography in four patients with deep brain stimulation for chronic pain", diffusion tensor imaging (DTI) and MRI scan were used prior to electrode placement in human subjects (8). Interestingly, Professor Aziz was among the authors of both of these studies.

German study

"Multicenter Study on Deep Brain Stimulation in Parkinson's Disease: An Independent Assessment of Reported Adverse Events at 4 Years".

"This analysis of reported adverse effects in this subset of a multicenter study shows that they [adverse events] were not rare, especially in the STN DBS group, despite broadly similar motor improvement in both STN and GPi [internal globus pallidus] groups. It demonstrates the importance of considering adverse effects in functional surgery for a disease such as Parkinson's, where a potential motor benefit may be offset by adverse effects that may mitigate the results, and may negatively affect the patient's quality of life. Also, it is important to be able to properly distinguish between adverse effects that may be induced by chronic DBS and those that are due to changes in medication or disease progression. To that end, a randomized study of patients allocated to surgery or to medical management, such as the recently published multicenter German study, or the Medical Research Council (MRC) sponsored "PD SURG" trial currently in progress in the UK, may help to settle this issue"(9).

Prospective UK study

The Parkinson's Disease Research Group at the University of Birmingham and City Hospital have currently undertaken the largest medical and surgical trials ever mounted in Parkinson's disease worldwide, The PD MED and PD SURG studies will randomize thousands of patients over the next five years and will provide invaluable data on the effects of interventions on quality of life and health economics (10). Expert comment

The Oxford Student paper in 2007 published a misdirected email written by independent analyst and neurologist Dr Malcolm Macleod. In the email, MacLeod revealed that he thought DBS was an "area of weakness often trumpeted as a success, but which in reality is probably a failure". Macleod said that he believed Aziz's research not to be the miracle cure it has been described as, stating, "My own experience shows that, except in a small minority of cases, there is uncertainty in the evidence for the clinical efficacy of DBS"(11).

3. Cost-benefit assessment

"It is a legal requirement that in determining whether and on what terms to grant a project licence to carry out scientific procedures on animals the Secretary of State is required to weigh the likely adverse effects on the animals concerned against the benefit likely to accrue as a result of the programme to be specified in the licence" (Section 5(4) of the Act).

Speaking at the public launch of the Animal Procedures Committee (APC) reports in 2003, Professor Michael Banner, the APC chairman said:

"We have concluded that the overall severity banding process could be improved, both for purposes of cost-benefit assessment and for providing public information about the level of severity of individual scientific projects. We invite the Home Office to revise the process in order to improve information available to the public" (12).

Notwithstanding the Government response to the APC's Cost-Benefit report in Appendix G of the 2005 APC report, significant progress has yet to be made on this crucial issue. As a veterinary surgeon, I am appalled at the level of animal suffering allowed, under the "protection" afforded by the Animals (Scientific Procedures) Act 1986. Perhaps my colleague, Dr MacArthur Clark, would agree with me that permitting animals to experience these levels of pain and suffering from a clinical perspective, would constitute disgraceful misconduct, based on the RCVS code of ethics, which requires a veterinary surgeon to treat all patients of whatever species, humanely, with respect, and with welfare as the primary consideration and to take steps to provide 24-hour emergency cover for the care of animals, including immediate first aid and pain relief.

You will know that, in the recent judicial review brought by the British Union for the Abolition of Vivisection (BUAV) arising out of its investigation of primate neuroscience research at Cambridge, the High Court judge thought that some of the protocols clearly involved a 'major departure from the animals' usual state of health or well-being'. The Court of Appeal ruled that he was wrong to second-guess the chief inspector in this way, without, as I understand the position, ruling that he was correct to describe them as 'moderate'. However, leaving aside the legal technicalities, I have to say that any reasonably competent veterinary surgeon would regard the symptoms which were foreseen and actually experienced by the animals, as involving a very high degree of suffering.

The underestimation of suffering in this way seems to be endemic. By appearing to downplay animal suffering, the Home Office inescapably distorts operation of the cost-benefit test and also misleads the public.

In previous correspondence to you in 2006, with regard to invasive dog experiments conducted at the University of Leeds I asked the following questions:

"In conducting the cost/benefit analysis prior to granting the licence(s):

(i) what were the costs that were identified?
(ii) what were the benefits that were identified?
(iii) how did the Animals in Scientific Procedures inspectorate
decide what weighting to attribute to the various costs/benefits; and
(iv) in order to determine whether the benefits outweighed the costs,
was any particular calculation formula used?

In Annex A of your reply dated 18th September 2006, you stated that "The 1986 Act does not require that benefit outweighs cost". Does this statement not render the legal requirement contained in Section 5(4) of the Act irrelevant and therefore meaningless?

The above correspondence about Leeds University referred to a series of terminal dog experiments, in which the animals were anaesthetised for the duration of the experiments and killed immediately thereafter, without regaining consciousness. Your reply in Annex A to question (i) above, was that the "main cost to the animals was the deemed to be minor discomfort of inducing anaesthesia". I must conclude, therefore, based on the Home Office assessment, that the 'cost' to the dog of the 'minor discomfort' of anaesthesia carries more weight than the 'cost' to the dog of its own life. This is indeed a very sad state of affairs.

4. Expert statements

Expert 1

Letter to Dr D Zumsteg, and reply received 4 May 2008:

Dear Dr Zumsteg,

I refer to your published paper "Cortical activation with deep brain stimulation of the anterior thalamus for epilepsy"(Clin Neurophysiol. 2006 Jan;117(1):192-207. Epub 2005 Dec 20).

Based on your human studies and your clinical work with epilepsy patients, I would be interested to know your opinion on whether there is still a genuine need in Deep Brain Stimulation research for studies involving non human primates.

I look forward to receiving your thoughts and comments.

Reply:

"Dear Mr Menache

Thank you for your email. I don't think that non-human primate research is of great value re DBS in epilepsy. Hence, the answer to your question is no".

http://lib.bioinfo.pl/auth:Zumsteg,D

Expert 2

Presentation by Professor Paul Furlong at the European Parliament (Bruxelles, 13 February 2008 conference entitled: "Progress without pain - alternatives to animal experiments").

Title: Functional neuroimaging to replace primate research in behavioural neuroscience

Current neuroimaging techniques such as Magnetoencephalography (MEG) and functional Magnetic Resonance Imaging (fMRI), offer significant opportunities to replace non-human primate experimentation in behavioural neuroscience.

Paul Furlong is professor of Clinical Neuroimaging at Aston University Birmingham U.K. Head of the Neuroimaging Research group, and also Director of the Clinical Neurophysiology Unit , the Wellcome Trust Laboratory for Magnetoencephalographic Studies and the Wellcome Trust Laboratory for Gastrointestinal Physiology. Professor Furlong worked for 10 years in the National Health Service (U.K.) in the field of Clinical Neurophysiology before becoming an academic to pursue his clinical research interests. These include the study of pain and epilepsy , together with the development of novel neurophysiological measures and humane research techniques.

5. Relevant scientific publications

Following is a list of scientific publications involving DBS.

Section (i) details clinical studies involving human subjects (see attachment).
Section (ii) details some non animal methodologies (see attachment).

Unlike animal experiments, the above research is species specific - the observations are directly relevant to humans; and the intention of the researchers is to benefit the individual(s) concerned.

6. Conclusion

The ethical as well as scientific and economic imperatives described above provide a compelling reason to halt all DBS research involving non human primates. As documented above, DBS is currently undergoing a systematic evaluation (PD SURG) and the results will be known in 5 years' time. There is thus no scientific defence or justification for currently pursuing this research in non human primates.

In addition to the individuals copied on this open letter, I should like to inform you that I am also sending this letter to the National Audit Office and the House of Commons public accounts committee.

Yours faithfully,

Andre Menache MRCVS

Address supplied

References

1. www.sabre.org.uk
2. Perel P et al. BMJ, doi:10.1136/bmj.39048.407928.BE (published 15 December 2006) "Comparison of treatment effects between animal experiments and clinical trials: systematic review".
3. Horn J et al. Stroke. 38(2):388-394, February 2007. "Systematic Review and Meta-Analysis of the Efficacy of Tirilazad in Experimental Stroke"
4. Pound P et al. BMJ 2004;328:514-517 (28 February), doi:10.1136/bmj.328.7438.514 "Where is the evidence that animal research benefits humans"?
5. Roberts I et al. BMJ 2002;324:474-476 ( 23 February). "Does animal experimentation inform human healthcare? Observations from a systematic review of international animal experiments on fluid resuscitation"?
6. Knight A. ATLA: Alternatives to Laboratory Animals 2007; 35(6): 641-659. "Systematic reviews of animal experiments demonstrate poor human clinical and toxicological utility".
7. Kringelbach M et al. Neuro Report vol 18 (3), 12 February 2007. "Deep brain stimulation for chronic pain investigated with magnetoencephalography".
8. Owen S et al. J Clin Neurosci. 2008 15 (7):801-5. "Pre-operative DTI and probabilisitic tractography in four patients with deep brain stimulation for chronic pain".
9. Hariz M et al. Movement Disorders Vol. 23, No. 3, 2008, pp. 416-421. "Multicenter study on deep brain stimulation in Parkinson's disease: an independent assessment of reported adverse events at 4 years".
10. http://www.neuroscience.bham.ac.uk/research/pdrg.htm
11. The Oxford Student 2007. Article written by reporter Rachel Bennett
12. APC review of cost-benefit assessment in the use of animals in research (June, 2003)