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THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
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.
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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
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
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
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 pharmaceuticals, 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 associated with international outsourcing.
In addition, pressures on both the health care industry—which relies heavily on animal models for biomedical research and preclinical trials—and science in general continue to build. A variety of sources provide data showing that demands 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 population 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, adjusted 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).
Animal research will play an essential role in efforts to meet these increasing 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 animal 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 societies, 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 Development 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 harmonization of animal care standards, specifically its merits and challenges. While scientific 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 related 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
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 regulatory 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 services from certain regions of the world. Calls for improvement in laboratory animal welfare and data quality became more prominent and the need for globally accepted approaches to the responsible and ethical conduct of animal research 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 conduct 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 nutritious food and potable water) for animals, both during transport and at the institution; ethical review of the proposed work and ongoing oversight of the animal program; suitable facilities and equipment in which to conduct the work; appropriate 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 pharmaceutical industry, contract research organizations (CROs), and academia describing their experiences; and the training and educational challenges of working 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 international rodent resources, for example by facilitating transportation, enhancing databases, and addressing repository issues. The afternoon presentations
were devoted to nonhuman primate resources, reviewing the scope of the need for primates in research, the concept of an International Primate Plan to investigate 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 presentations conveyed in these proceedings. It has been a vital bridge for diverse colleagues 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 involvement 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 Laboratory 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 Science (AFLAS) Associations in Taipei. More than 100 individuals representing 27 countries participated in the three meetings, the results of which will be published 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, California, to determine the outline and approach to the plan. The participants represented key stakeholders such as researchers, veterinarians, and suppliers. Focused meetings were held in association with the 2010 AFLAS congress, and the IPP has been discussed with the National Institutes of Health (NIH), EUPRIMNET (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 biomedical 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—
requiring additional attention and resources—to address many of the issues described 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 outcome 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 Professional 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 Workshop. Washington: National Academies Press.
OIE [World Organization for Animal Health]. 2010. Use of Animals in Research: Terrestrial 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. Available 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.
CONTENTS
Science & Technology and US Foreign Policy
Norman Neureiter
Building Momentum: Lessons Learned from the 2003 ILAR International Conference
Hilton Klein
CHALLENGES AND OPPORTUNITIES FOR HARMONIZATION
Perspectives from International Organizations
International Council for Laboratory Animal Science (ICLAS)
Cecilia Carbone
World Organization for Animal Health (OIE)
David Bayvel
Judy MacArthur Clark
Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) International
Kathryn Bayne
International Air Transport Association (IATA)
Carl Kole
Institute for Laboratory Animal Research (ILAR)
Joanne Zurlo
Malachy Hargadon
Global Issues: Working Across Different Standards
Operational Challenges—Pharmaceutical Industry
Margaret Landi
Overcoming Challenges—Contract Research Organizations (CROs): Setting Up a CRO in a Foreign Country
Bryan Ogden
Global Issues: Operational Challenges to Working across Different Standards in Academia
Steven M. Niemi
Overcoming Challenges—Academia in Europe
Harry van Steeg
Charles River: A Model of International Training
Marilyn Brown
Patri Vergara
Animal Research in a Global Environment: Meeting the Challenges
John Baldoni
VETERINARY CARE FOR LABORATORY ANIMALS
Standards of Veterinary Care for Laboratory Animals
Kathryn Bayne
State of Laboratory Animal Medicine Around the World
Hans Hedrich
Rafael Hernandez
James G. Fox
David Bayvel
Marguerite Pappaioanou
Michael Chaddock
Online Training and Distance Learning
Patricia V. Turner
International Approaches and Principles for Distress, Pain, and Euthanasia
David Morton
Pain: International Differences Across Guidelines and Approaches
Matt Leach
Gilly Griffin
International Approaches and Principles for Humane Endpoints
Humane Endpoints in Cancer Research
Fraser Darling
Humane Endpoints in Infectious Disease
Carol Eisenhauer
Humane Endpoints and Genetically Modified Animal Models: Opportunities and Challenges
Margaret Rose
Cross-Cultural Ethical Perceptions and Ways to Resolve Challenges
Bernard Rollin
COORDINATION OF INTERNATIONAL RODENT RESOURCES
Mice Traveling the World: Issues in Sharing and Transferring Mice
Lili M. Portilla
Knockout Mouse Databases: The Knockout Mouse Project and Repository
Franziska Grieder
NorCOMM, the North American Conditional Mouse Mutagenesis Project
Colin McKerlie
EUCOMM, the European Conditional Mouse Mutagenesis Program
Martin Hrabé de Angelis
Yuichi Obata
Repository Issues—Lessons Learned
James Womack
Transportation and the “Mouse Passport,”
William White
INTERNATIONAL COORDINATION OF NONHUMAN PRIMATES
Joseph Kemnitz
Supply and Use of NHP Around the World
William Morton
C.K. Hsu
New World Primates in Research
Chris Abee
Challenges in Outsourcing Studies
James Macy
Alex Zhang
Transportation Issues with Nonhuman Primates
Saverio Capuano
The Future of the Use of Nonhuman Primates in the UK
Judy MacArthur Clark
Proposed International NHP Plan
Joseph Kemnitz