Click for next page ( R2


The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page R1
ANIMAL MODELS FOR ASSESSING COUNTERMEASURES TO BIOTERRORISM AGENTS Committee on Animal Models for Assessing Countermeasures to Bioterrorism Agents Institute for Laboratory Animal Research Division on Earth and Life Studies THE NATIONAL ACADEMIES PRESS Washington, DC www.nap.edu

OCR for page R1
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 Institute of Medicine. The members of the Committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by the U.S. Department of Defense through Contract Number W911NF-09-C-0046. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for the project. The content of this publication does not necessarily reflect the views or policies of the Department of Defense, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. government. International Standard Book Number-13: 978-0-309-21909-9 International Standard Book Number-10: 0-309-21909-4 Additional copies of this report are available from The National Academies Press 500 Fifth Street, NW Box 285 Washington, DC 20055 800-624-6242 202-334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2011 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

OCR for page R1
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 responsibility 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 National 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

OCR for page R1

OCR for page R1
COMMITTEE ON ANIMAL MODELS FOR ASSESSING COUNTERMEASURES TO BIOTERRORISM AGENTS Members GEORGE W. KORCH, JR. (Co-Chair), Johns Hopkins University, Baltimore, MD STEVEN M. NIEMI (Co-Chair), Massachusetts General Hospital, Charlestown, MA NICHOLAS H. BERGMAN, Battelle National Biodefense Institute, Frederick, MD DANIEL J. CARUCCI, Global Health Consulting, Washington, DC SUSAN A. EHRLICH, Arizona Court of Appeals (retired), Phoenix, AZ GIGI KWIK GRONVALL, University of Pittsburgh Medical Center, Baltimore, MD THOMAS HARTUNG, Johns Hopkins University School of Public Health, Baltimore, MD ELIZABETH HEITMAN, Vanderbilt University Medical Center, Nashville, TN MALAK KOTB, University of Cincinnati College of Medicine, Cincinnati, OH JENS H. KUHN, National Institutes of Health, Frederick, MD C. RICK LYONS, Colorado State University, Fort Collins, CO STEPHEN S. MORSE, Columbia University School of Public Health, New York, NY FREDERICK A. MURPHY, University of Texas Medical Branch, Galveston, TX VIKRAM S. PATEL, Food and Drug Administration, Silver Spring, MD JAMES R. SWEARENGEN, Battelle National Biodefense Institute, Frederick, MD Staff LIDA ANESTIDOU, Study Director FRANCES SHARPLES, Acting Director, Institute for Laboratory Animal Research CARL-GUSTAV ANDERSON, Program Associate RUTH CROSSGROVE, Senior Editor INDIA HOOK-BARNARD, Program Officer MIRSADA KARALIC-LONCAREVIC, Manager, Technical Information Center RADIAH ROSE, Manager of Editorial Projects v

OCR for page R1
INSTITUTE FOR LABORATORY ANIMAL RESEARCH Council Members FLOYD BLOOM (IOM) (Chair), Molecular and Integrative Neuroscience Department (emeritus), Scripps Research Institute, La Jolla, CA KATHRYN A. BAYNE, Association for Assessment and Accreditation of Laboratory Animal Care International, Frederick, MD MYRTLE A. DAVIS, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, MD NELSON L. GARNETT, Laboratory Animal Care and Use Programs, Dickerson, MD JUDY A. MACARTHUR CLARK, Animals in Scientific Procedures Inspectorate, Home Office, London, United Kingdom DANIEL S. MARSMAN, Procter & Gamble, Mason, OH GARRY NEIL, Corporate Office of Science and Technology, Johnson & Johnson, New Brunswick, NJ TIMO OLAVI 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 Medicines, AstraZeneca, Alderley Park, United Kingdom BERNARD E. ROLLIN, Departments of Philosophy, Behavioral 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 SHARPLES, Acting Director LIDA ANESTIDOU, Senior Program Officer CAMERON H. FLETCHER, Managing Editor, ILAR Journal JASON WORTHY, Senior Program Assistant vi

OCR for page R1
INSTITUTE FOR LABORATORY ANIMAL RESEARCH PUBLICATIONS Guidance for the Description of Animal Research in Scientific Publications (2011) Animal Research in a Global Environment – Meeting the Challenges (2011) Guide for the Care and Use of Laboratory Animals: Eighth Edition (2011) Recognition and Alleviation of Pain in Laboratory Animals (2009) Scientific and Humane Issues in the Use of Random Source Dogs and Cats for Research (2009) Recognition and Alleviation of Distress in Laboratory Animals (2008) Toxicity Testing in the 21st Century: A Vision and a Strategy (2007) Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents: Appropriate Use of Animal Models (2006) Guidelines for the Humane Transportation of Research Animals (2006) Science, Medicine, and Animals: Teacher’s Guide (2005) Animal Care and Management at the National Zoo: Final Report (2005) Science, Medicine, and Animals (2004) The Development of Science-based Guidelines for Laboratory Animal Care: Proceedings of the November 2003 International Workshop (2004) Animal Care and Management at the National Zoo: Interim Report (2004) National Need and Priorities for Veterinarians in Biomedical Research (2004) Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research (2003) International Perspectives: The Future of Nonhuman Primate Resources, Proceedings of the Workshop Held April 17-19, 2002 (2003) Occupational Health and Safety in the Care and Use of Nonhuman Primates (2003) Definition of Pain and Distress and Reporting Requirements for Laboratory Animals: Proceedings of the Workshop Held June 22, 2000 (2000) Strategies That Influence Cost Containment in Animal Research Facilities (2000) Microbial Status and Genetic Evaluation of Mice and Rats: Proceedings of the 1999 US/Japan Conference (2000) Microbial and Phenotypic Definition of Rats and Mice: Proceedings of the 1998 US/Japan Conference (1999) Monoclonal Antibody Production (1999) The Psychological Well-Being of Nonhuman Primates (1998) Biomedical Models and Resources: Current Needs and Future Opportunities (1998) Approaches to Cost Recovery for Animal Research: Implications for Science, Animals, Research Competitiveness and Regulatory Compliance (1998) Chimpanzees in Research: Strategies for Their Ethical Care, Management, and Use (1997) Occupational Health and Safety in the Care and Use of Research Animals (1997) Guide for the Care and Use of Laboratory Animals (1996) Rodents (1996) Nutrient Requirements of Laboratory Animals, Fourth Revised Edition (1995) Laboratory Animal Management: Dogs (1994) Recognition and Alleviation of Pain and Distress in Laboratory Animals (1992) Education and Training in the Care and Use of Laboratory Animals: A Guide for Developing Institutional Programs (1991) Companion Guide to Infectious Diseases of Mice and Rats (1991) Infectious Diseases of Mice and Rats (1991) Immunodeficient Rodents: A Guide to Their Immunobiology, Husbandry, and Use (1989) Use of Laboratory Animals in Biomedical and Behavioral Research (1988) vii

OCR for page R1
Animals for Research: A Directory of Sources, Tenth Edition and Supplement (1979) Amphibians: Guidelines for the Breeding, Care and Management of Laboratory Animals (1974) Copies of these reports may be ordered from the National Academies Press (800) 624-6242 or (202) 334-3313 www.nap.edu viii

OCR for page R1
Acknowledgments This report, Animal Models for Assessing Countermeasures to Bioterrorism Agents, has been reviewed in draft form by individuals chosen for their diverse perspectives and expertise in accordance with procedures approved by the Report Review Committee of the National Research Council (NRC). The purpose of this independent review is to provide candid and critical comments that will assist the Committee on Animal Models for Assessing Countermeasures to Bioterrorism Agents in making its published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberation process. The Committee thanks the following individuals for their review of the draft report: Joy Cavagnaro, Access BIO, LC Donald R. Drake, III, VaxDesign Corporation James Estep, Battelle Memorial Institute Thomas Geisbert, University of Texas Medical Branch Charles H. Hobbs, Lovelace Respiratory Research Institute Nancy King, Wake Forest University School of Medicine Terry McElwain, Washington State University Nathaniel Powell, Jr., Centers for Disease Control and Prevention Although the reviewers listed above have provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final draft of the report before its release. The review of this report was overseen by Leslie Z. Bennett, University of California-San Francisco and Ann Arvin, Stanford University School of Medicine. Appointed by the NRC, they were responsible for making certain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution. ix

OCR for page R1
The Committee expresses its appreciation to Karen Goldenthal who served on this panel until July 2011. The Committee also extends its appreciation to Judith Hewitt for the white paper Developing Animal Models for Use in Animal Rule Licensure: The NIAID Approach. Finally, the Committee thanks the speakers who addressed the Committee in the public meetings of September and November 2009, and February 2010. Lastly, and certainly most importantly, the Committee wishes to thank the diligent efforts of the ILAR leadership and staff who provided many levels of support to this endeavor. We are especially thankful to Dr. Lida Anestidou for her tireless work in guiding and helping craft this report while concomitantly assuming unanticipated extra duties for ILAR. The Committee very much appreciated the technical input and teamwork provided by Dr. India Hook-Barnard from the Board on Life Sciences. We also want to posthumously recognize the great support the Committee received from Ms. Kathy Beil, who made sure we got to the right places at the right time during the active period of the committee’s meetings in Washington D.C. George W. Korch, Jr., Co-Chair Steven M. Niemi, Co-Chair Committee on Animal Models for Assessing Countermeasures to Bioterrorism Agents x

OCR for page R1
Contents SUMMARY .................................................................................................................................... 1 1 INTRODUCTION.............................................................................................................. 7 The Nature of Threat, 7 Addressing the Unknown Threat through the Transformational Medical Technologies Initiative, 8 Statement of Task, 11 Approach by the Committee, 12 References, 12 EVALUATION OF CURRENT AND FUTURE TMT-USED ANIMAL MODELS. ..... 15 2 Animal Models Are Analogous, Not Homologous Systems, 17 Considerations for Animal Models for Countermeasure Development, 18 Filoviruses, 19 Tularemia, 28 Anthrax, 29 Lessons Learned from Developing Animal Models for Therapeutic Purposes against Biothreat Agents, 30 References, 32 3 ETHICAL AND REGULATORY CHALLENGES IN THE DEVELOPMENT OF COUNTERMEASURES ................................................................................................... 39 History of the Animal Rule and Ethical Considerations, 39 The Low Approval Rate to Date under the Animal Rule, 44 Regulation of Drug Development, 46 References, 48 xi

OCR for page R1
4 DEVELOPING NEW ANIMAL MODELS FOR BIODEFENSE RESEARCH. ............. 51 Use of Human Data to Improve the Value of Animal Models, 52 Interactions with the Food and Drug Administration, 54 “Validation” of Animal Models for Biodefense Research, 55 Comparative Biology and Compartmentalization in Animal Model Development, 56 Optimizing Current Animal Models, 57 References, 58 5 ALTERNATIVE APPROACHES TO ANIMAL TESTING FOR BIODEFENSE COUNTERMEASURES ................................................................................................... 61 General Principles of Alternative Approaches, 62 Animal Efficacy Studies Are Clinical Trials, 64 In Vitro Tools and Replacement Strategies, 66 Promises and Challenges for the Future, 70 References, 72 APPENDICES THE ANIMAL RULE ....................................................................................................... 77 A DRAFT GUIDANCE TO INDUSTRY: ANIMAL MODELS – ESSENTIAL B ELEMENTS TO ADDRESS EFFICACY UNDER THE ANIMAL RULE ...................... 89 DEVELOPING ANIMAL MODELS FOR USE IN ANIMAL RULE LICENSURE: THE C NIAID APPROACH ...................................................................................................... 109 PRESENTATIONS TO THE COMMITTEE ................................................................. 123 D STATEMENT OF TASK ................................................................................................ 127 E ABOUT THE AUTHORS .............................................................................................. 131 F BOXES, FIGURES, AND TABLES Boxes 1-1 Transformational Medical Technologies Initiative, 9 4-1 Formal Meetings with the FDA, 54 Figures 1-1 TMT concepts for broad capability against general categories or clusters of pathogens, 10 4-1 Definition of validation, 55 xii

OCR for page R1
5-1 Regulatory science proceeds as a function of regulatory stringency and technological advancement, 72 Tables 2-1 Current State of Animal Model Development for Selected Pathogens in the Context of the Animal Rule, 19 2-2 Transformational Medical Technologies Viral Pathogen Focus Group: Filoviruses, 20 2-3 Symptoms of Marburg Virus-Infected Humans, 22 2-4 Symptoms of Ebola Virus-Infected Humans, 23 2-5 Symptoms of Bundibugyo Virus-Infected Humans, 24 2-6 Animals Used for the Development of Animal Models for Filovirus Disease, 25 2-7 Animal-Specific Hematological Differences in Nonhuman Primate Models of Ebola Virus Disease, Infected with 1-10 LD50, 26 2-8 Comparison of Data from Ebola Virus Animal Models with Data from Humans, 27 2-9 Common Causes of Reduced External Validity of Animal Studies, 32 xiii

OCR for page R1