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The use of non-human primates in research The use of non-human primates in research A working group report chaired by Sir David Weatherall FRS FMedSci Report sponsored by: Academy of Medical Sciences Medical Research Council The Royal Society Wellcome Trust 10 Carlton House Terrace 20 Park Crescent 6-9 Carlton House Terrace 215 Euston Road London, SW1Y 5AH London, W1B 1AL London, SW1Y 5AG London, NW1 2BE December 2006 December Tel: +44(0)20 7969 5288 Tel: +44(0)20 7636 5422 Tel: +44(0)20 7451 2590 Tel: +44(0)20 7611 8888 Fax: +44(0)20 7969 5298 Fax: +44(0)20 7436 6179 Fax: +44(0)20 7451 2692 Fax: +44(0)20 7611 8545 Email: E-mail: E-mail: E-mail: [email protected] [email protected] [email protected] [email protected] Web: www.acmedsci.ac.uk Web: www.mrc.ac.uk Web: www.royalsoc.ac.uk Web: www.wellcome.ac.uk December 2006 The use of non-human primates in research A working group report chaired by Sir David Weatheall FRS FMedSci December 2006 Sponsors’ statement The use of non-human primates continues to be one the most contentious areas of biological and medical research. The publication of this independent report into the scientific basis for the past, current and future role of non-human primates in research is both a necessary and timely contribution to the debate. We emphasise that members of the working group have worked independently of the four sponsoring organisations. Our organisations did not provide input into the report’s content, conclusions or recommendations. The report is aimed at all those involved in non-human primate research, namely government, regulatory agencies, professional bodies, industry, research funders and the scientific community. For our part, we will consider and respond to its recommendations. We are grateful to the members of the working group for their considerable time and efforts in preparing this report. We especially thank Sir David Weatherall for leading on this important issue and producing a report that will be invaluable in taking forward this debate. Professor John Bell PMedSci Professor Colin Blakemore FRS FMedSci Academy of Medical Sciences Medical Research Council Lord Rees of Ludlow PRS Dr Mark Walport FMedSci The Royal Society Wellcome Trust Cover photograph reproduced with permission from the Wellcome Trust and the Medical Research Council CONTENTS Contents Abbreviations and acronyms 3 1 Summary 5 Recommendations 8 2 Introduction and methods of working 11 2. Background, objectives and timeliness 2.2 Scope and process of the report 4 3 Current position of non-human primate research 19 3. Introduction 9 3.2 A global overview 9 3.3 UK legal requirements 2 3.4 UK non-human primate use 24 3.5 Main fields of non-human primate research, excluding toxicology 3 3.6 Other uses of non-human primates 32 3.7 Discussion 32 4 Investigation into the scientific basis for current non-human primate research 35 4. Background 35 4.2 Why does the use of animals in biological and medical research vary so much between different fields? 35 4.3 Can research on humans replace work on non-human primates? 36 4.4 The distinction between basic and applied research 37 5 Infectious (communicable) disease 39 5. Introduction 39 5.2 HIV/AIDS 40 5.3 Malaria 47 5.4 Tuberculosis 50 5.5 Other infectious diseases 52 5.6 Discussion 56 6 Neuroscience 59 6. Introduction 59 6.2 Connectivity, neurons and circuits 60 6.3 Comparisons of vertebrate, non-human primate and human brains 62 6.4 Neuroscience research tools: direct and indirect techniques 64 6.5 Neuroscience research tools: observational and interventional techniques 67 6.6 The use of non-human primates in fundamental neuroscience research 68 6.7 The use of non-human primates in clinical neuroscience research 73 6.8 Brain-machine interfaces 8 6.9 Discussion 82 7 Other research areas 85 7. Introduction 85 7.2 Reproductive biology 85 The USE of Non-Human Primates in Research 7.3 Gender comparative studies relating to common human diseases 87 7.4 Fetal development and common disease in adult life 88 7.5 Ageing 89 7.6 Discussion 90 8 Drug discovery and development 91 8. Introduction 9 8.2 Regulations and regulatory agencies 9 8.3 Non-human primates and drug safety 9 8.4 Second species selection in regulatory toxicology 92 8.5 Non-human primates, regulatory toxicology and the 3Rs. 95 8.6 Discussion 97 9 Alternatives to the use of non-human primates for medical research and toxicology 99 9. Introduction 99 9.2 Molecular and cell biology approaches 99 9.3 Computer modelling and systems biology: in silico approaches 03 9.4 Human studies 04 9.5 Discussion 07 10 Welfare issues 109 0. Introduction 09 0.2 Breeding 0 0.3 Housing 2 0.4 Imported animals and transport 4 0.5 Welfare during the practice of research 5 0.6 Discussion 9 11 Ethics 123 . Introduction 23 .2 Moral status and legal personality 23 .3 Moral intuitions 24 .4 Costs and benefits 25 .5 Ethics and research involving non-human primates 26 .6 Discussion 29 12 Discussion 131 2. A polarised debate 3 2.2 The pace and unpredictability of biomedical research 3 2.3 A lack of integration in non-human primate research 3 2.4 The anecdotal nature of some of the issues in this report 32 2.5 The need for wider public debate 32 2.6 The future of UK non-human primate research 33 2.7 Future action based on this report 34 13 Conclusions and recommendations 135 Appendix I Report preparation 143 Appendix II List of consultees and respondents to the call for evidence 145 2 Abbreviations Abbreviations and acronyms 3Rs Replacement, Refinement and Reduction Ab Amyloid b protein ABPI Association of the British Pharmaceutical Industry AD Alzheimer’s disease ADME Absorption, Distribution, Metabolism and Excretion AIDS Acquired Immune Deficiency Syndrome AMS Accelerator Mass Spectrometry APC Animal Procedures Committee APP Amyloid Precursor Protein A(SP)A Animals (Scientific Procedures) Act 986 BBSRC Biotechnology and Biological Sciences Research Council BMI Brain-Machine Interface BOLD Blood Oxygen Level Dependent Activity BSE Bovine Spongiform Encephalopathy BUAV British Union for the Abolition of Vivisection CAT Computer Assisted Tomography CFM Centre for Macaques CITES Convention on International Trade in Endangered Species of Wild Fauna and Flora CNS Central Nervous System CSP Circumsporozoite protein CTL Cytotoxic T Lymphocyte DBS Deep Brain Stimulation Defra Department for Environment Food and Rural Affairs DNA Deoxyribonucleic Acid Dstl Defence Science and Technology Laboratory DTI Diffusion Tensor Imaging DWA Dangerous Wild Animals ECVAM European Centre for the Validation of Alternative Methods EEG Electroencephalogram EFPIA European Federation of Pharmaceutical Industries and Associations EMEA European Medicines Agency EPAA European Partnership on Alternative Approaches to Animal Testing ERP Ethical Review Process ES cells Embryonic Stem cells ESG Expert Scientific Group EU European Union EUMAPP European Union Microdose AMS Partnership Programme FDA US Food and Drug Administration fMRI Functional Magnetic Resonance Imaging GDNF Glial Cell Derived Neurotrophic Factor GM Genetically Modified HAART Highly Active Anti-Retroviral Therapy HBV Hepatitis B Virus HCV Hepatitis C Virus HIV Human Immunodeficiency Virus HO Home Office IAT Institute of Animal Technology 3 Non-HUman PriMATes in Medical Research IPS International Primate Society JALAS Japanese Association for Laboratory Animal Science LASA Laboratory Animals Science Association LGN Lateral Geniculate Nucleus MAbs Monoclonal Antibodies MCI Mild Cognitive Impairment MDR Multi-Drug Resistant MEG Magnetoencephalography MHC Major Histocompatibility Complex MHRA Medicines and Healthcare products Regulatory Agency MoD Ministry of Defence MPTP 1-methyl 4-phenyl ,2,3,6-tetrahydropyridine MRI Magnetic Resonance Imaging MS Multiple Sclerosis MTD Maximum Tolerated Dose MVA Modified vaccinia virus ankara NC3Rs National Centre for the Replacement, Refinement and Reduction of Animals in Research NFT Neurofibrillary Tangle NHP Non-human Primate OECD Organisation for Economic Co-operation and Development OHSS Ovarian Hyperstimulation Syndrome OPV Oral live poliovirus vaccine PCOS Polycystic ovarian syndrome PD Parkinson’s disease PET Positron Emission Tomography PPN Pedunculopontine Nucleus R&D Research and Development RNA Ribonucleic acid SARS Severe Acute Respiratory Syndrome SHIV Simian Human Immunodeficiency Virus SIV Simian Immunodeficiency Virus STAIR Stroke Therapy Academic Industry Roundtable STN Subthalamic Nucleus TB Tuberculosis TMS Transcranial Magnetic Brain Stimulation VEGF Vascular Endothelial Growth Factor WHO World Health Organization 4 SummarY Summary The central goal of this study was to examine ethical issues were considered. The members the scientific case for the use of non-human of the working group accepted a moral case primates for research into the prevention for careful, well monitored and meticulously or treatment of disease, or for fundamental regulated non-human primate research, research that has the long-term potential provided it is of a high quality and has the of achieving the same end. The material potential to benefit mankind, and if it is the presented in this report is primarily targeted only way of solving important scientific or at policy-makers in government, research medical questions. This does not preclude the funders, universities, scientific societies and need for consideration of ethics, together with relevant professional and regulatory bodies, scientific and welfare issues, in the cost-benefit as well as all other interested parties. It assessment of each research proposal. should be emphasised that its conclusions and recommendations reflect the views of the The total number of non-human primates members of the working group; the sponsors used for scientific or medical purposes in the played no part in determining its contents or in UK has remained fairly constant over the shaping its conclusions.