The AA PP CC Animal Procedures Committee ANIMAL PROCEDURES COMMITTEE November 2013 REVIEW OF THE ASSESSMENT OF CUMULATIVE SEVERITY AND LIFETIME EXPERIENCE IN NON-HUMAN PRIMATES USED IN NEUROSCIENCE RESEARCH REPORT OF THE ANIMAL PROCEDURES COM0,77((·6 PRIMATE SUBCOMMITTEE WORKING GROUP CHAIRED BY PROFESSOR JOHN PICKARD FMedSci 1 Review of the assessment of cumulative severity and lifetime experience in non-human primates used in neuroscience research Contents 1. Executive summary and recommendations 5 1.1 Definitions 5 1.2 Findings of the review 6 1.3 Recommendations 9 2. Terms of reference 15 3. Background 3.1 Non-human primate research in the UK: Weatherall and Bateson reports 16 3.2 Ethics 18 3.3 General concept of cumulative severity 23 3.4 Concepts of cumulative suffering, severity and lifetime experience as applied to animal experimentation, including neuroscience research 24 3.5 Past and present systems of classification of severity of regulated procedures in the UK 34 3.6 National Centre for the Replacement, Refinement and Reduction of Animals in Research 37 4. Methodology 4.1 Consultation process 39 4.1.1 Stakeholders meeting (including overview of biomarkers) 39 4.1.2 Animal protection organizations and other interested parties, including written submissions 42 4.2 Pilot literature review 47 4.3 Design of questionnaire and Cloud-based database: Iterative refinement 4.3.1 Background: outline description of the experimental studies covered by the questionnaire and survey 48 4.3.2 Technical design and implementation 48 4.3.3 Questionnaire design and content 49 2 4.3.4 Analysis of the questionnaire 51 4.3.5 Submissions 51 5. Analysis of questionnaire 53 5.1 Weaning dates and return dates 52 5.2 Supply and condition on arrival 56 5.3 Housing, husbandry and care 57 5.4 Non-procedural life events 61 5.5 Anaesthesia and pain control 63 5.6 Surgery and maintenance of implants: generic procedural and intended effects, and complications 65 5.7 Restraint and handling 77 5.8 Food and fluid controls, training and motivators 79 5.9 Behaviour 81 5.10 Refinements in non-human primate neuroscience research: results from the user survey 86 5.11 Premature killing of non-human primates and post-mortem examination 88 5.12 Lifetime experience 90 5.13 Self-reported severity assessments 93 5.14 Cumulative severity and suffering 97 6. Visits to establishments 99 7. Discussion, future trends and conclusions 105 7.1 Qualitative assessment of cumulative experience 105 7.2 Quantitative assessment of cumulative experience 105 7.3 Considerations for establishing ongoing monitoring of cumulative experience 111 7.4 Thresholds for designation of severity 114 7.5 Vocabulary 117 8. Appendices 8.1 Membership of Working Group 118 8.2 Acknowledgements and list of contributors 120 3 8.3 Glossary and definitions 121 8.4 An example of the timelines for training of macaques on fluid control 123 8.5 Bibliography 127 8.6 The process of regulation of animal experiments in the UK 137 8.7 Directive 2010/63/EU: Severity categories and examples 142 8.8 Questionnaire 145 4 1. Executive summary and recommendations The Animals (Scientific Procedures) Act (ASPA) 1986 and now Directive 2010/63/EU provide the classification of severity to be adopted when applications for licences to undertake animal research are reviewed. This severity classification has referred mainly to single procedures and includes unambiguous examples. It is now recognized that the potential lifetime experience of an animal should also be considered. However, there has been difficulty in providing a coherent set of evidence-based guidelines with illustrative examples, particularly for nonhuman primate research. 7KLV 5HYLHZ E\ WKH $QLPDO 3URFHGXUHV &RPPLWWHH¶V 3Uimate Subcommittee Working Group considers how any cumulative suffering caused by multiple neuroscience research procedures over a prolonged period may be assessed in non-human primates ± macaque and marmoset monkeys. It is based on wide-ranging consultations, expert meetings, a questionnaire and visits to establishments. It provides the first detailed account in this sensitive area of animal research of the nature, incidence and severity of procedures and complications, including their cumulative impact. There was a diversity of opinion amongst contributors and members of the Working Group on the use of non-human primates in neuroscience research but, in the interest of promoting animal welfare, there was widespread engagement with the consultation process. Where possible we have reflected the range of opinions, many of which continue to be debated. 1.1 Definitions Definitions of welfare, suffering, cumulative severity, cumulative experience and non-additive/additive potentiation effects used in this Review are as follows. Welfare: µAnimals experience both positive (for example, reward, satisfaction) and negative (for example, pain, stress) well-being. Welfare is the state of the individual animal as regards its attempts WRFRSHZLWKLWVHQYLURQPHQW+HQFHLWGHSHQGVRQWKHLQGLYLGXDO¶V needs in relation to physical, nutritional, social and other behavioural factors and, in the case of captive animals, on the people who carHIRUWKHDQLPDOVRUVXSHUYLVHVXFKZRUN¶ Sufferingµ$QHJDWLYHHPRWLRQDOVWDWHZKLFKGHULYHVIURPDGYHUVH SK\VLFDOSK\VLRORJLFDODQGSV\FKRORJLFDOFLUFXPVWDQFHV¶ Cumulative severity µ7KH VXP RI DOO WKH HYHQWV DQG HIIHFWV WKDW impact, adversely, positively and by way of amelioration, on the ZHOIDUHRIDQDQLPDORYHULWVOLIHWLPH¶ This definition of cumulative severity includes, unlike the term VXIIHULQJ ERWK DGYHUVH DQG µIDYRXUDEOH¶ FRPSRQHQWV +RZHYHU severity implies a net negative effect. 5 Cumulative experience is a less confusing term than cumulative VHYHULW\DQGKDVDVLPLODUGHILQLWLRQµ7KHVXPRIDOOWKHHYHQWVDQG effects, including their quantity, intensity, duration, recovery between and memory thereof, that impact, adversely, positively and E\ZD\RIDPHOLRUDWLRQRQWKHZHOIDUHRIDQDQLPDORYHULWVOLIHWLPH¶ It is important to consider how the effect of the first experience of a procedure impacts on the second experience of the same or a different procedure. A single procedure may have only a short- lasting impact on welfare. With sufficient time for recovery between procedures, there may be no influence on the impact of a second procedure (non-additive). The impact of repeated procedures may diminish (habituation). In contrast, if insufficient time is allowed for recovery, the residual effects of repeated procedures may add up (additive stacking up). Suffering from earlier events may actually increase the negative impact on welfare of subsequent events (additive potentiation). This framework of definitions and scenarios is intended to render cumulative severity and lifetime experience more susceptible to objective, quantitative measurement than has been achieved hitherto. 1.2 Findings of the Review 1.2.1 Centres of non-commercial neuroscience non-human primate research in the UK. The Review has established that non-commercial non-human primate neuroscience research in the UK is restricted to a small QXPEHU RI XQLYHUVLWLHV $OO RI WKHVH DFFHSW DQG DSSO\ WKH µ5V¶ (Replacement, Refinement and Reduction) principles of humane experimental technique. 1.2.2 National Centre for the Replacement, Refinement and Reduction of Animals in Research. The Review noted that the National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) has to date (May 2013) committed £1.4 million in grants for research to refine techniques used in primate neuroscience, and to assess objectively pain and distress. NC3Rs also leads an extensive programme of work designed to improve the welfare of laboratory primates. 1.2.3 The Questionnaire 7KH 5HYLHZ¶V TXHVWLRQQDLUH SURYLGHV D XVHIXO ILUVW VWHS LQ establishing a common methodological framework to document the various components of the lifetime experience of the animal and to facilitate systematic data collection across institutions. Following the initial completion of the survey, visits were made to the research establishments to gather further information and provide 6 clarification and discussion around the interpretation of the submitted data. These issues were debated at length amongst the members of the Review during the preparation of this report. In total 17 reports were received from users in 5 UK academic institutions and 10 reports from users in EU institutions. Data were supplied by researchers, named veterinary surgeons, animal technicians and named animal care and welfare officers. Data were based on observations made on 149 macaques and 82 marmosets housed in UK facilities and 3 macaques housed in 3 EU institutions over a 10-year period. Quantitative data were extracted from records and formed the main basis for the conclusions of this Report. In DGGLWLRQ WKH UHVSRQGHQWV¶ VXEMHFWLYH LPSUHVVLRQV RI HIIHFWV (favourable and adverse) and their severity are provided separately. The data included in the Review did not cover every animal used but are representative of the spectrum of animal experience, based on the data collected, the interviews/discussions with investigators, veterinarians and NACWOS and the further assessment of animal use made at some centres. The data are not overtly biased to either low or high severity procedures. This substantial database has provided the quantitative data required to address the terms of reference of the Review. 1.2.4 Adverse events and cumulative experience within individual events and procedures The Review found little evidence for adverse cumulative severity µDGGLWLYH