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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
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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 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.
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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 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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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