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ANIMAL RESEARCH IN A GLOBAL ENVIRONMENT MEETING THE CHALLENGES Proceedings of the November 2008 International Workshop Institute for Laboratory Animal Research Division on Earth and Life Studies

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Insti- tute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This workshop was supported by Contract No. N01-OD-4-2139, TO 205, between the National Academy of Sciences and the National Institutes of Health. Any opinions, find- ings, conclusions, or recommendations expressed in this publication are those of the au- thor(s) and do not necessarily reflect the views of the agency that provided support for the project. International Standard Book Number-13: 978-0-309-21502-2 International Standard Book Number-10: 0-309-21502-1 Additional copies of this report are available from the National Academies Press, 500 Fifth Street NW, Lockbox 285, Washington DC 20055; (800) 624-6242 or (202) 334- 3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the re- sponsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the Na- tional Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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STEERING COMMITTEE FOR THE INTERNATIONAL WORKSHOP ON ANIMAL RESEARCH IN A GLOBAL ENVIRONMENT: MEETING THE CHALLENGES Members Coenraad F.M. Hendriksen, Chair, Netherlands Vaccine Institute, Bilthoven, The Netherlands Stephen W. Barthold (IOM), Center for Comparative Medicine, University of California, Davis Kathryn A. Bayne, Association for Assessment and Accreditation of Laboratory Animal Care International, Frederick, Maryland Jeffrey Everitt, GlaxoSmithKline Research & Development, Research Triangle Park, North Carolina James G. Fox (IOM), Division of Comparative Medicine, Massachusetts Institute of Technology Joseph W. Kemnitz, Institute for Clinical and Translational Research, University of Wisconsin, Madison Hilton J. Klein (formerly with Merck Research Laboratories), Lansdale, Pennsylvania Judy A. MacArthur Clark (formerly with Pfizer), Animals Scientific Procedures Inspectorate, Home Office, London, United Kingdom Staff Joanne Zurlo, Director (until April 2010) Frances E. Sharples, Acting Director Lida Anestidou, Senior Program Officer Kathleen Beil, Administrative Coordinator (until April 2011) Cameron H. Fletcher, Senior Editor Rhonda Haycraft, Senior Project Assistant (until January 2011) Jason Worthy, Program Assistant v

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INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL: 2008 MEMBERSHIP Stephen W. Barthold (IOM), Chair, Center for Comparative Medicine, University of California, Davis Kathryn A. Bayne, Association for Assessment and Accreditation of Laboratory Animal Care International, Waikoloa, Hawaii Myrtle A. Davis, Toxicology, Drug Disposition, and Pharmacokinetics, Lilly Research Laboratories, Greenfield, Indiana Jeffrey Everitt, Comparative Medicine and Investigator Support, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina James G. Fox (IOM), Divisions of Comparative Medicine and of Biological Engineering, Massachusetts Institute of Technology, Cambridge Nelson L. Garnett, Consultant, Laboratory Animal Care and Use Programs, Dickerson, Maryland Estelle B. Gauda, Division of Neonatology, Johns Hopkins University School of Medicine, Baltimore, Maryland Joseph W. Kemnitz, National Primate Research Center, University of Wisconsin, Madison Judy A. MacArthur Clark, Animals Scientific Procedures Inspectorate, London, United Kingdom Martha K. McClintock (IOM), Institute for Mind and Biology, The University of Chicago Leticia V. Medina, Animal Welfare and Compliance, Abbott Laboratories, Abbott Park, Illinois Timo Olavi Nevalainen, National Laboratory Animal Center, University of Kuopio, Finland Bernard E. Rollin, Department of Animal Sciences, Colorado State University, Fort Collins Abigail Smith, School of Veterinary Medicine, University of Pennsylvania, Philadelphia Stephen A. Smith, Department of Biomedical Sciences and Pathobiology, VA-MD Regional College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg James E. Womack, Department of Veterinary Pathobiology, Texas A&M University, College Station vi

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INSTITUTE FOR LABORATORY ANIMAL RESEARCH COUNCIL: 2011 MEMBERSHIP Members Floyd E. Bloom (IOM), Chair, Molecular and Integrative Neuroscience Department (emeritus), Scripps Research Institute, La Jolla, California Kathryn A. Bayne, Association for Assessment and Accreditation of Laboratory Animal Care International, Frederick, Maryland Myrtle A. Davis, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland Nelson L. Garnett, Consultant, Laboratory Animal Care and Use Programs, Dickerson, Maryland Judy A. MacArthur Clark, Animals Scientific Procedures Inspectorate, London, United Kingdom Daniel S. Marsman, Personal Health/Feminine Care Safety, Procter & Gamble, Mason, Ohio Garry Neil, Corporate Office of Science and Technology, Johnson & Johnson, New Brunswick, New Jersey Timo O. Nevalainen, Professor Emeritus, University of Eastern Finland, Kuopio Steven M. Niemi, Center for Comparative Medicine, Massachusetts General Hospital, Charlestown Melinda A. Novak, Department of Psychology, University of Massachusetts, Amherst Menelas Pangalos, Innovative Medicine Units, AstraZeneca, Alderley Park, United Kingdom Bernard E. Rollin, Departments of Philosophy, Behavorial Sciences, and Animal Sciences, Colorado State University, Fort Collins James A. Roth, Center for Food Security and Public Health, College of Veterinary Medicine, Iowa State University, Ames Staff Frances E. Sharples, Acting Director Lida Anestidou, Senior Program Officer Cameron H. Fletcher, Managing Editor, ILAR Journal Jason Worthy, Program Assistant vii

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Preface THE GLOBALIZATION OF ANIMAL RESEARCH: SCIENCE AND ETHICS AS A FOUNDATION FOR STANDARDS Impacts of Globalization International economist Jagdish Bhagwati has called globalization the “most powerful force for social good in the world today” (Bhagwati 2004, ix). Yet, in the wake of highly publicized news stories about counterfeit pharmaceu- ticals, the 2007 pet food recall, and tainted heparin supplies, other voices loudly criticize the loss of jobs in America and of quality assurance for products asso- ciated with international outsourcing. In addition, pressures on both the health care industry—which relies heav- ily on animal models for biomedical research and preclinical trials—and science in general continue to build. A variety of sources provide data showing that de- mands for new and better medications and for research on health and quality of life will grow, in large part due to the expanding global population.  In 2006 the United Nations noted that in just 12 years the world popu- lation was expected to climb from 6.7 billion to 7.6 billion (UN 2006b).  The American Veterinary Medical Association has described the health risks to this increasing population: “The convergence of people, animals, and our environment has created a new dynamic in which the health of each group is inextricably interconnected. The challenges associated with this dynamic are demanding, profound, and unprecedented” (AVMA 2008, 3).  The World Health Report states that “the global health economy is growing faster than gross domestic product (GDP)…. In absolute terms, ad- justed for inflation, this represents a 35% growth in the world’s expenditure on health over a five-year period” (WHO 2008, xii).  And three of the UN Millennium Development Goals (www.un.org/ millenniumgoals) specifically address health: child health (Goal 4), maternal health (Goal 5), and the prevention and treatment of HIV/AIDS, malaria, and other diseases (Goal 6). ix

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x Preface Animal research will play an essential role in efforts to meet these increas- ing demands for global health care. Yet the animal research community faces the challenge of overcoming negative impressions that industry and academia engage in international collaborations in order to conduct work in parts of the world where animal welfare standards are less stringent. Thus the importance of ensuring the international harmonization of the principles and standards of ani- mal care and use cannot be overstated. A number of national and international groups are actively working toward this goal. The Role of the Institute for Laboratory Animal Research The Institute for Laboratory Animal Research (ILAR), a program unit of the US National Research Council, is committed to promoting both the welfare of animals used in research and the quality of the resulting science. To that end, it convenes those involved in such research and related activities—investigators, attending veterinarians and animal care technicians, policymakers and oversight committee members, and educators, from academia, industry, professional so- cieties, and government—to participate in workshops that address both broad and particular challenges in the increasing globalization of animal research. In 2003 ILAR hosted an international workshop to examine the Develop- ment of Science-Based Guidelines for Laboratory Animal Care (NRC 2004). Participants discussed the available knowledge that could positively influence a framework of standards of laboratory animal care and identified gaps in critical information. A common thread in the discussions was the subject of harmoniza- tion of animal care standards, specifically its merits and challenges. While scien- tific evidence was certainly identified as critical to decisions regarding animal care, participants also recognized cultural context as an intrinsic factor in such decisions. Many speakers and participants observed that, despite much progress in the establishment of standards for the objective evaluation of animal care and housing practices, a great deal of work remained to be done. In 2007 ILAR convened an international meeting of laboratory animal medicine specialists to review the regulatory and guidance documents of several countries; the group analyzed descriptions in these documents of the role of the veterinarian in this type of work and also determined whether training in areas specific to laboratory animal species is required or recommended. This review (Zurlo et al. 2009) revealed both commonalities (e.g., in the provision of clinical care) and significant differences (e.g., in the designation of who at the institution has decision-making authority regarding euthanasia). In 2008, to follow up on the 2003 event, ILAR convened a workshop to define more precisely the types of information still needed and to identify the data necessary to enable prioritization of research and funding support for re- lated initiatives. This workshop, on Animal Research in a Global Environment: Meeting the Challenges, brought together 200 participants from 17 countries with a diversity of perspectives. The speakers and participants noted that the

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Preface xi landscape of animal-based research had changed in some significant ways since the 2003 workshop. Globalization of biomedical research was well under way. Outsourcing of research, sometimes to countries with widely divergent regula- tory systems of oversight, had become an important element of the biomedical research enterprise, and academic collaborations across country borders were commonplace. Yet air transportation of animals was becoming more restricted. And there was increasing public concern about the quality of products and ser- vices from certain regions of the world. Calls for improvement in laboratory animal welfare and data quality became more prominent and the need for glob- ally accepted approaches to the responsible and ethical conduct of animal re- search more pressing. Organization and Content of the Workshop Fully cognizant of the demands and cautions related to the globalization of animal research, ILAR appointed a Workshop Steering Committee, composed of US and foreign individuals from academia, industry, and the nonprofit sector, to design the program for the 2008 workshop such that session speakers might identify and promote better understanding of important challenges in the con- duct of animal research across country boundaries. These challenges appear in the sourcing of animals; the quality of veterinary care; appropriately qualified and competent staff; the provision of a suitable environment (including nutri- tious food and potable water) for animals, both during transport and at the insti- tution; ethical review of the proposed work and ongoing oversight of the animal program; suitable facilities and equipment in which to conduct the work; appro- priate policies and procedures; and protection of the personnel involved in the animal program. General topics that framed the first day of discussions were challenges and opportunities for harmonization, with representatives from seven organizations providing a variety of international perspectives; operational challenges of working across differing global standards, with representatives from the phar- maceutical industry, contract research organizations (CROs), and academia de- scribing their experiences; and the training and educational challenges of work- ing across different global standards, with colleagues from various regions of the world illustrating how training programs can overcome those challenges. On the second day speakers examined in more detail specific issues that require attention. They discussed the varying standards and state of veterinary care for research animals around the world as well as potential steps toward harmonizing veterinary education in laboratory animal medicine and standards for laboratory animal care. Presenters also described international principles and approaches to pain, distress, euthanasia, and humane endpoints. The third day opened with a session concerning efforts to coordinate in- ternational rodent resources, for example by facilitating transportation, enhanc- ing databases, and addressing repository issues. The afternoon presentations

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xii Preface were devoted to nonhuman primate resources, reviewing the scope of the need for primates in research, the concept of an International Primate Plan to investi- gate and report on supply and demand, the need for harmonized care standards, and transportation concerns. Impacts of the Workshop The impact of this 2008 workshop has extended beyond the oral presenta- tions conveyed in these proceedings. It has been a vital bridge for diverse col- leagues and organizations around the world to advance initiatives designed to fill gaps in standards, professional qualifications, and coordination of animal use. The World Organization for Animal Health (the OIE), with the involve- ment of speakers from the 2008 ILAR workshop, has published standards on the use of animals in research as part of its Terrestrial Animal Code, which includes a specific chapter regarding the care and use of research animals. Thanks to the OIE’s status as a reference organization for the World Trade Organization (WTO), the Code serves as a standards template for the 178 member countries and territories of the OIE and thus applies to numerous economies and cultures. In addition, ILAR, the OIE, and the International Association of Colleges of Laboratory Animal Medicine (IACLAM) convened focus groups to assess the laboratory animal veterinary community’s perspective on harmonizing global veterinary qualifications and training in laboratory animal medicine. These groups met in 2010 at three pivotal laboratory animal science meetings held in Europe, the United States, and Asia: the June meeting of the Federation of Labo- ratory Animal Science Associations (FELASA) in Helsinki; the September meeting of the Association for Laboratory Animal Science (AALAS) in Atlanta; and the November meeting of the Asian Federation of Laboratory Animal Sci- ence (AFLAS) Associations in Taipei. More than 100 individuals representing 27 countries participated in the three meetings, the results of which will be pub- lished in the online ILAR Journal. Finally, development of an International Primate Plan (IPP) continues to gain momentum. In 2009 ILAR hosted an international meeting in Irvine, Cali- fornia, to determine the outline and approach to the plan. The participants repre- sented key stakeholders such as researchers, veterinarians, and suppliers. Fo- cused meetings were held in association with the 2010 AFLAS congress, and the IPP has been discussed with the National Institutes of Health (NIH), EUPRIM- NET (the European Primate Network), and the Interagency Research Advisory Committee (IRAC) of the US federal government. Substantial progress has been made toward the launch of the plan. The papers in these proceedings describe important topics facing the bio- medical research enterprise. Time has not stood still since the workshop and there has been progress in some areas, yet much work remains to be done—

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Preface xiii requiring additional attention and resources—to address many of the issues de- scribed in the following papers. A Note about the Transcripts The transcripts in these proceedings are those approved by the speakers; presentations shown on the agenda but without a corresponding transcript are those for which the speaker did not provide permission for publication. The transcripts have been only lightly edited, largely for clarity, the addition of sources, and, when appropriate and possible, updating to incorporate the out- come of reports issued or events held since 2008. The report and speakers’ slides are posted on the ILAR website. Acknowledgments ILAR thanks the US National Institutes of Health, which sponsored this workshop, and the members of the Workshop Steering Committee. Kathryn A. Bayne Global Director, AAALAC International References AVMA [American Veterinary Medical Association]. 2008. One Health: A New Profes- sional Initiative. Available online (www.avma.org/onehealth/onehealth_final.pdf), accessed on April 14, 2011. Bhagwati J. 2004. In Defense of Globalization. New York: Oxford University Press. NRC [National Research Council]. 2004. Development of Science-Based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Work- shop. Washington: National Academies Press. OIE [World Organization for Animal Health]. 2010. Use of Animals in Research: Terres- trial Animal Health Code. Available online (www.oie.int/index.php?id=169&L= 0&htmfile=chapitre_1.7.8.htm), accessed on April 14, 2011. UN [United Nations]. 2006a. The Millennium Development Goals Report 2006. Avail- able online (http://mdgs.un.org/unsd/mdg/Resources/Static/Products/Progress2006/ MDGReport2006.pdf), accessed on April 14, 2011. UN. 2006b. World Population Prospects: The 2006 Revision. Available online (www. un.org/esa/population/publications/wpp2006/WPP2006_Highlights_rev.pdf), accessed on April 14, 2011. WHO [World Health Organization]. 2008. The World Health Report 2008: Primary Health Care Now More Than Ever. Available online (www.who.int/whr/2008/ whr08_en.pdf), accessed on April 14, 2011. Zurlo J, Bayne K, MacArthur Clark J. 2009. Adequate veterinary care for animals in research: A comparison of guidelines from around the world. ILAR J 50:85-88.

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CONTENTS PLENARY LECTURE ................................................................................................ 1 Science & Technology and US Foreign Policy, 3 Norman Neureiter INTRODUCTORY LECTURE .............................................................................. 13 Building Momentum: Lessons Learned from the 2003 ILAR International Conference, 15 Hilton Klein CHALLENGES AND OPPORTUNITIES FOR HARMONIZATION Perspectives from International Organizations .......................................... 23 International Council for Laboratory Animal Science (ICLAS), 25 Cecilia Carbone World Organization for Animal Health (OIE), 27 David Bayvel Adequate Veterinary Care and the International Association of Colleges of Laboratory Animal Medicine (IACLAM), 29 Judy MacArthur Clark Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International, 32 Kathryn Bayne International Air Transport Association (IATA), 34 Carl Kole Institute for Laboratory Animal Research (ILAR), 36 Joanne Zurlo The European Union, 38 Malachy Hargadon xv

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xvi Contents Global Issues: Working Across Different Standards ................................. 41 Operational Challenges—Pharmaceutical Industry, 41 Margaret Landi Overcoming Challenges—Contract Research Organizations (CROs): Setting Up a CRO in a Foreign Country, 46 Bryan Ogden Global Issues: Operational Challenges to Working across Different Standards in Academia, 54 Steven M. Niemi Overcoming Challenges—Academia in Europe, 62 Harry van Steeg Training and Education .................................................................................... 67 Charles River: A Model of International Training, 67 Marilyn Brown The FELASA Training Program, 73 Patri Vergara PLENARY LECTURE .............................................................................................. 79 Animal Research in a Global Environment: Meeting the Challenges, 81 John Baldoni VETERINARY CARE FOR LABORATORY ANIMALS .............................. 93 Standards of Veterinary Care for Laboratory Animals, 95 Kathryn Bayne State of Laboratory Animal Medicine Around the World ..................... 102 Europe, 102 Hans Hedrich Latin America, 106 Rafael Hernandez North America, 109 James G. Fox A Path Forward ................................................................................................. 113 Role of the OIE, 113 David Bayvel Introduction to AAVMC, 117 Marguerite Pappaioanou AAVMC Strategic Plan, 119 Michael Chaddock Online Training and Distance Learning, 122 Patricia V. Turner

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xvii Contents International Approaches and Principles for Distress, Pain, and Euthanasia ...................................................................... 128 Distress, 128 David Morton Pain: International Differences Across Guidelines and Approaches, 135 Matt Leach Euthanasia, 141 Gilly Griffin International Approaches and Principles for Humane Endpoints ........................................................................................... 153 Humane Endpoints in Cancer Research, 153 Fraser Darling Humane Endpoints in Infectious Disease, 156 Carol Eisenhauer Humane Endpoints and Genetically Modified Animal Models: Opportunities and Challenges, 160 Margaret Rose Cross-Cultural Ethical Perceptions and Ways to Resolve Challenges, 173 Bernard Rollin COORDINATION OF INTERNATIONAL RODENT RESOURCES ......................................................................................... 185 Mice Traveling the World: Issues in Sharing and Transferring Mice, 187 Lili M. Portilla Knockout Mouse Databases: The Knockout Mouse Project and Repository, 191 Franziska Grieder NorCOMM, the North American Conditional Mouse Mutagenesis Project, 194 Colin McKerlie EUCOMM, the European Conditional Mouse Mutagenesis Program, 199 Martin Hrabé de Angelis The RIKEN BioResource Center, 202 Yuichi Obata Repository Issues—Lessons Learned, 205 James Womack Transportation and the “Mouse Passport,” 209 William White

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xviii Contents INTERNATIONAL COORDINATION OF NONHUMAN PRIMATES .................................................................................... 215 Framing the Issues, 217 Joseph Kemnitz Supply and Use of NHP Around the World ............................................... 219 The United States, 219 William Morton China as a Resource for NHP, 224 C.K. Hsu New World Primates in Research, 228 Chris Abee Challenges in Outsourcing Studies ............................................................... 232 An Academic Perspective, 232 James Macy Perspective from China, 236 Alex Zhang Transportation Issues with Nonhuman Primates, 239 Saverio Capuano The Future of the Use of Nonhuman Primates in the UK, 241 Judy MacArthur Clark Proposed International NHP Plan, 246 Joseph Kemnitz ABBREVIATIONS................................................................................................... 249 APPENDIX A: WORKSHOP AGENDA ........................................................... 252 APPENDIX B: STEERING COMMITTEE BIOS........................................... 258 APPENDIX C: WORKSHOP SPEAKERS ....................................................... 261

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ANIMAL RESEARCH IN A GLOBAL ENVIRONMENT MEETING THE CHALLENGES Proceedings of the November 2008 International Workshop

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