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Committee on Accelerating the Research, Development, and Acquisition of Medical Countermeasures Against Biological Warfare Agents Medical Follow-up Agency and Board on Life Sciences Lois M. Joellenbeck, Jane S. Durch, and Leslie Z. Benet, Editors

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. 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 Na- tional Academy of Sciences, the National Academy of Engineering, and the Institute of Medi- cine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. Support for this project was provided by Contract No. DAMD17-02-C-0099 between the National Academy of Sciences and the U.S. Army. The views presented in this report are those of the Institute of Medicine and National Research Council Committee on Accelerat- ing the Research, Development, and Acquisition of Medical Countermeasures Against Bio- logical Warfare Agents and are not necessarily those of the funding agencies. Library of Congress Cataloging-in-Publication Data Giving full measure to countermeasures : addressing problems in the DOD program to de- velop medical countermeasures against biological warfare agents / Committee on Acceler- ating the Research, Development, and Acquisition of Medical Countermeasures against Bio- logical Warfare Agents, Medical Follow-up Agency and Board on Life Sciences ; Lois M. Joellenbeck, Jane S. Durch, and Leslie Z. Benet, editors. p. ; cm. Includes bibliographical references. ISBN 0-309-09153-5 (pbk.) 1. Biological warfare--Health aspects--United States. 2. Biological warfare--United States--Safety measures. 3. Biological weapons--Health aspects--United States. 4. Biologi- cal weapons--United States--Safety measures. 5. Medicine, Preventive--United States. 6. Antitoxins--United States. 7. Vaccines--United States. [DNLM: 1. United States. Dept. of Defense. 2. Biological Warfare--prevention & control. 3. Drug Approval. 4. Antitoxins. 5. Military Personnel. 6. United States Govern- ment Agencies. 7. Vaccines. ] I. Joellenbeck, Lois M. (Lois Mary), 1963- II. Durch, Jane. III. Benet, Leslie Z. IV. Committee on Accelerating the Research, Development, and Acquisition of Medical Countermeasures against Biological Warfare Agents. UG447.8.G58 2004 358'.38--dc22 2004005890 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2004 by the National Academy of Sciences. All rights reserved. Printed in the United States of America. Cover credit: The upper cover photograph is from a U.S. Department of Defense news pho- tograph. [Online]. Available: http://www.defenselink.mil/photos/May1997/970422-F- 7719S-002.html.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating soci- ety of distinguished scholars engaged in scientific and engineering research, dedi- cated 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. Bruce M. Alberts 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 mem- bers, sharing with the National Academy of Sciences the responsibility for advis- ing 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. Wm. A. Wulf 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 Insti- tute 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 Sci- ences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal gov- ernment. Functioning in accordance with general policies determined by the Acad- emy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing ser- vices to the government, the public, and the scientific and engineering communi- ties. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce M. Alberts and Dr. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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COMMITTEE ON ACCELERATING THE RESEARCH, DEVELOPMENT, AND ACQUISITION OF MEDICAL COUNTERMEASURES AGAINST BIOLOGICAL WARFARE AGENTS LESLIE Z. BENET (Chair), Professor, Department of Biopharmaceutical Sciences, School of Pharmacy, University of California, San Francisco WALTER E. BRANDT, Senior Program Officer, Malaria Vaccine Initiative, Program for Appropriate Technology in Health BARRY S. COLLER, Vice President for Medical Affairs, David Rockefeller Professor of Medicine, and Head of the Laboratory of Blood and Vascular Biology, The Rockefeller University GLENNA M. CROOKS, President, Strategic Health Policy International, Inc. R. GORDON DOUGLAS, JR., Scientific Consultant JACQUES S. GANSLER, Professor and Roger C. Lipitz Chair, Center for Public Policy and Private Enterprise, School of Public Affairs, University of Maryland ANTHONY L. ITTEILAG, Independent Consultant DENNIS L. KASPER, Executive Dean for Academic Programs, William Ellery Channing Professor of Medicine, and Professor of Microbiology and Molecular Genetics, Harvard Medical School STEVEN J. KELMAN, Albert J. Weatherhead III and Richard W. Weatherhead Professor of Public Management, John F. Kennedy School of Government, Harvard University RICHARD F. KINGHAM, Partner, Covington and Burling PETER M. PALESE, Professor and Chair, Department of Microbiology, Mount Sinai School of Medicine PAUL D. PARKMAN, President, Parkman Associates RONALD J. SALDARINI, Scientific Consultant JANE E. SISK, Professor, Department of Health Policy, Mount Sinai School of Medicine ELAINE I. TUOMANEN, Professor and Chair, Department of Infectious Diseases, St. Jude Children's Research Hospital BENJAMIN J. WEIGLER, Director, Animal Health Resources, Division of Shared Resources, Fred Hutchinson Cancer Research Center JANET WESTPHELING, Associate Professor, Department of Genetics, University of Georgia v

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Medical Follow-up Agency Board Liaison TIMOTHY R. GERRITY, Director, Bioengineering Institute, Worcester Polytechnic Institute Consultant JAMES D. MARKS, Professor, Anesthesia and Pharmaceutical Chemistry, University of California, San Francisco Project Staff LOIS JOELLENBECK, Senior Program Officer, Medical Follow-up Agency JANE DURCH, Senior Program Officer, Medical Follow-up Agency KAREN KAZMERZAK, Research Associate, Medical Follow-up Agency (through July 2003) PHILLIP BAILEY, Senior Project Assistant, Medical Follow-up Agency Auxiliary Staff RICHARD N. MILLER, Director, Medical Follow-up Agency (to November 2003) RICK ERDTMANN, Director, Medical Follow-up Agency (since November 2003) JENNIFER KUZMA, Senior Program Officer, Board on Life Sciences, Division on Earth and Life Studies (until January 2003) FRANCES SHARPLES, Director, Board on Life Sciences, Division on Earth and Life Studies REINE HOMAWOO, Senior Project Assistant, Medical Follow-up Agency PAMELA RAMEY-MCCRAY, Administrative Assistant, Medical Follow-up Agency ANDREA COHEN, Financial Associate, Institute of Medicine vi

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Reviewers T his report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council's Report Re- view Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution 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 confi- dential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: JAMES L. BLANCHARD, Tulane Regional Primate Center WILLIAM H. HABIG, Centocor, Inc. ROBERT HELMS, The American Enterprise Institute BRUCE KUHLIK, Pharmaceutical Research and Manufacturers of America MYRON M. LEVINE, University of Maryland at Baltimore JOHN S. PARKER, Science Applications International Corporation HOWARD R. SIX, Aventis Pasteur (retired) FRED THOMPSON, Willamette University JOHN P. WHITE, Harvard University GEORGE WHITESIDES, Harvard University Although the reviewers listed above have provided many construc- tive comments and suggestions, they were not asked to endorse the con- vii

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viii REVIEWERS clusions or recommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Alexander Flax, consultant, and Morton Swartz, Massachusetts General Hospital. Appointed by the National Research Council and the Institute of Medi- cine, they were responsible for making certain that an independent ex- amination of this report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Re- sponsibility for the final content of this report rests entirely with the authoring committee and the institution.

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Preface T he Gulf War of 19901991 renewed Cold War concerns that U.S. ser- vice members might be exposed to chemical or biological warfare agents on the battlefield. These concerns were reinforced after the war upon discovery of Iraqi stockpiles of weaponized biological and chemical agents.1 In 2001, the distribution of Bacillus anthracis spores through the U.S. postal system renewed public awareness of the threats posed by biological agents. At the time of the Gulf War, only one medical countermeasure ap- proved by the Food and Drug Administration (FDA)--the vaccine against anthrax--was available to the Department of Defense (DoD) to protect troops against possible biological warfare agents. In 2003, despite con- gressional attention and good-faith efforts on the part of DoD scientists, no new vaccines against biowarfare agents are available to service mem- bers.2 In the National Defense Authorization Act for Fiscal Year 2002 (P.L. 107-107), Congress directed the Secretary of Defense to accelerate the 1United Nations Special Commission. 1999. UNSCOM: Chronology of Main Events. New York: United Nations. [Online]. Available: http://www.un.org/Depts/unscom/Chronol- ogy/chronologyframe.htm. 2Since 2000, the FDA has renewed the product license for existing supplies of smallpox vaccine and has approved labeling ciprofloxacin (Cipro), tetracyclines (including doxycy- cline), and penicillins for treatment of anthrax. ix

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x PREFACE department's efforts to develop FDA-licensed medical countermeasures against biological warfare agents. In addition, the Secretary was directed to contract with the Institute of Medicine (IOM) and the National Research Council (NRC) for a study of the review and approval process for new medical countermeasures in order to identify new approaches to acceler- ate that process and to identify methods for ensuring that new counter- measures will be safe and effective. To carry out the study, IOM and NRC convened the Committee on Accelerating the Research, Development, and Acquisition of Medical Countermeasures Against Biological Warfare Agents. The members of the committee bring to the study expertise in drug and vaccine acquisition in DoD; vaccine and drug research, development, testing, and evaluation in academia and the pharmaceutical and biotech- nology industries; laboratory animal science; federal drug and vaccine regulatory policy; legal and economic issues in drug and vaccine devel- opment; and management processes in government and industry. The committee has the following charge: The committee will examine DoD's biowarfare countermeasure drug and vaccine acquisition process. The acquisition process includes the early science and technology development (research and development pro- gram elements 6.1, 6.2, 6.3) and advanced development (program ele- ments 6.4, 6.5) through the approval and licensure of products. The study will not examine production and procurement processes. The committee will identify factors that are impeding or slowing the acquisition pro- cesses and will recommend strategies or options for accelerating these processes. Guided by discussion with DoD representatives and congressional staff at its first meeting, the committee interpreted this charge as calling for its work to focus on the manner in which DoD organizes and manages research, development, and acquisition of medical countermeasures, rather than on the details of specific scientific approaches. The medical products covered by the study include vaccines, antitoxins, chemopro- phylactics, and chemotherapeutics. In keeping with its charge, the com- mittee did not examine the acquisition of diagnostic products or other biodefense products, such as protective suits, decontamination equip- ment, or sensors for detection of biological agents, that are also being de- veloped as essential components of DoD's Chemical and Biological De- fense Program. The military services and combatant commands have an important role in these broader aspects of biodefense that were not a fo- cus of this study. Previous independent advisory committees requested by DoD re-

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PREFACE xi leased reports in 2000 and 20023 addressing aspects of the development and production of vaccines for military needs and providing important context for the present study. Because those and other reports have dealt in detail with some of the topics covered here, the committee chose in this report to focus attention on the opportunities it identified for improve- ment, rather than on extensive historical and background information. To that end, the report begins with the committee's major recommendations in Chapters 1 and 2, with additional, second-order recommendations in Chapter 3. Brief background material on the current DoD program to de- velop medical biowarfare countermeasures and the current status of biowarfare countermeasures is provided in Appendix A. The committee met six times between December 2002 and July 2003. At five of those meetings, the committee met in public session for presen- tations from and discussions with invited speakers (see Appendix B for the agendas of the public sessions). Small subgroups of committee mem- bers also participated in a series of informal meetings with officials from the several DoD organizations with a role in the current Chemical and Biological Defense Program (see Figure 2-1 for an organizational chart), with congressional staff, and with representatives from DynPort Vaccine Company, the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health, the FDA, and the Depart- ment of Homeland Security. An interim report was submitted to the sponsor in March 2003. As chair, I am very grateful to my fellow committee members for the dedication and industry that they exhibited in addressing a very complex and difficult problem. They willingly and enthusiastically participated in the six formal meetings of the committee, and many were available for the 20 informal meetings with various governmental and other relevant con- tacts as described above. Finally, the entire committee participated in four conference calls as this report evolved. The committee was frequently pre- sented with very contradictory opinions and recommendations, while the landscape continually changed as the administration's response to per- ceived bioterrorism threats and the progress of the war in Iraq brought different perspectives to our charge. 3 Institute of Medicine. 2002. Protecting Our Forces: Improving Vaccine Acquisition and Avail- ability in the U.S. Military. Lemon SM, Thaul S, Fisseha S, O'Maonaigh HC, eds. Washington, DC: National Academies Press. Top FH Jr., Dingerdissen JJ, Habig WH, Quinnan GV Jr., Wells RL. 2000. DoD Acquisition of Vaccine Production: Report to the Deputy Secretary of Defense by the Independent Panel of Experts. In DoD. 2001. Report on Biological Warfare Defense Vaccine Research and Development Programs. Washington, DC: Department of Defense. [Online]. Available: http://www.acq.osd.mil/cp/bwdvrdp-july01.pdf.

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xii PREFACE The committee is also in debt to numerous officials from DoD, con- gressional staff, senior leadership staff from DynPort Vaccine Company, NIAID, FDA, and the Department of Homeland Security who assisted the committee in its fact finding, and in particular our study contact with DoD, Dr. Carol Linden. These individuals, as noted in Appendix C, gra- ciously appeared before the committee at our formal meetings, sometimes two or three times, to make presentations. In addition many of them often attended the committee meetings when they were not making a formal presentation, and they were always willing to be available to meet infor- mally with subsets of the committee and to respond to questions from the staff. We could not have completed our work in a timely manner without the cooperation of these officials. The committee and I are extremely grateful to the outstanding IOM staff that tirelessly and with unselfish dedication helped to prepare this report in a timely manner. We are particularly appreciative of our two Senior Program Officers Lois Joellenbeck and Jane Durch, and the com- mittee certifies that they are jewels, whose brilliance and worth shone brightly in enlightening and assisting committee members in evaluating the many controversial and technical issues related to the study. The com- mittee also acknowledges and appreciated the work of Research Associ- ate Karen Kazmerzak, and Senior Project Assistants Phillip Bailey and Reine Homawoo, who were unflagging in their effective responses to com- mittee needs. This level of commendation speaks well of Richard N. Miller, the director of the Medical Follow-up Agency, who has assembled such a responsive staff, and the committee thanks him for his support and frequent inobtrusive input into its deliberations. We are grateful as well to Bronwyn Schrecker, Clyde Behney, Janice Mehler, Jennifer Bitticks, Jen- nifer Otten, and Andrea Cohen, the IOM and NRC staff who participated in the report review, preproduction, dissemination, and financial man- agement for the report. Leslie Z. Benet, Ph.D. Chair

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Contents ABBREVIATIONS AND ACRONYMS xvii EXECUTIVE SUMMARY 1 1 ENDING HALF-MEASURES FOR COUNTERMEASURES: THE CHALLENGE AND MAJOR RECOMMENDATIONS 19 The Current Context for the Development of Medical Countermeasures, 20 Problems Hindering the DoD Effort, 25 Are Medical Countermeasures a Priority?, 31 Recommendations for Change, 35 References, 40 2 ORGANIZING RESEARCH AND DEVELOPMENT FOR MEDICAL COUNTERMEASURES TO ACCOMPLISH ESSENTIAL FUNCTIONS 44 A DoD Agency for Acquisition of Medical Countermeasures for Biological Defense, 45 Consideration of Alternative Approaches, 64 References, 71 xiii

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xiv CONTENTS 3 CHALLENGES IN THE RESEARCH AND DEVELOPMENT OF MEDICAL COUNTERMEASURES AGAINST BIOLOGICAL WARFARE AGENTS 73 Engaging Academia and Industry, 74 Supporting the Regulatory Process, 82 Overcoming Current and Potential Resource Bottlenecks, 89 Ensuring the Availability of a Well-Trained Workforce, 94 References, 97 APPENDIXES A Background: The Current DoD Medical Biowarfare Countermeasures Program 103 B Agendas for Information-Gathering Meetings 117 C Acknowledgments 127 D Biographical Sketches 131

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Figures, Tables, and Boxes FIGURES 1-1 Budget authority for the medical biodefense component of the Chemical and Biological Defense Program and other selected DoD research, development, testing, and evaluation programs, FY 1996 2004, 34 2-1 Simplified representation of current offices and organizations with a role in the DoD research, development, and acquisition program for medical biological defense, 46 2-2 Placement of the proposed Medical Biodefense Agency within DoD, 52 TABLES 1-1 Budget Authority for the Medical Biodefense Component of the Chemical and Biological Defense Program (CBDP) and Other Se- lected DoD Research, Development, Testing, and Evaluation Pro- grams, FY 19962004, 32 2-1 Advantages and Disadvantages of Alternative Approaches to the Or- ganization and Management of Research and Development of Medi- cal Biodefense Countermeasures to Meet DoD Needs, 66 xv

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xvi FIGURES, TABLES, AND BOXES A-1 Medical Countermeasures Available Against Biological Threat Agents, 110 A-2 DoD-Related Research and Development Activities for Medical Bio- logical Warfare Countermeasures, 112 BOXES ES-1 Recommendations, 13 1-1 Events Related to the Development of Medical Biodefense Counter- measures, 22 1-2 Factors in the Pace of Countermeasure Development and Licensure, 26 2-1 Essential Functions of the DoD Research and Development Program for Medical Countermeasures Against Biological Warfare Agents, 48 2-2 Intramural Expertise Needed for a DoD Research and Development Program for Vaccines and Other Medical Countermeasures, 51 3-1 Mechanisms for Engaging Academic Institutions, Industry, and Oth- ers in the Private Sector in Federally Funded Research and Develop- ment, 76 A-1 Key Features of DoD Policy and Requirements Concerning Acquisi- tion and Use of Medical Countermeasures to Protect the Health of Military Forces Against Biological Warfare Threat Agents, 106 A-2 Potential Biological Threats as Presented by DoD Medical Biological Defense Research and Development Program, 108 A-3 Diseases and Biological Agents Identified by the CDC as Posing a Threat to National Security, 109

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Abbreviations and Acronyms AAE Army Acquisition Executive (Secretary of the Army) ASD(HA) Assistant Secretary of Defense for Health Affairs ATSD(NCB) Assistant to the Secretary of Defense for Nuclear and Chemical and Biological Defense Programs BoT botulinum toxoid vaccine BSL biosafety level CBD Chemical and Biological Defense Directorate CBDP Chemical and Biological Defense Program CBMS Chemical Biological Medical Systems CDC Centers for Disease Control and Prevention C.F.R. Code of Federal Regulations cGMP current Good Manufacturing Practice CJCS Chairman of the Joint Chiefs of Staff CRADA Cooperative Research and Development Agreement DARPA Defense Advanced Research Projects Agency DATSD(CBD) Deputy Assistant to the Secretary of Defense for Chemical and Biological Defense DHHS Department of Health and Human Services DHS Department of Homeland Security DoD Department of Defense DTRA Defense Threat Reduction Agency DUS&T Dual-Use Science and Technology xvii

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xviii ABBREVIATIONS AND ACRONYMS DVC DynPort Vaccine Company FDA Food and Drug Administration FY fiscal year GAO General Accounting Office GMP Good Manufacturing Practice IND Investigational New Drug IOM Institute of Medicine JPEO Joint Program Executive Office JPEO-CBD Joint Program Executive Office for Chemical and Biological Defense JRO Joint Requirements Office JRO-CBRN Joint Requirements Office for Chemical, Biological, Radiological, and Nuclear Defense JVAP Joint Vaccine Acquisition Program MBDRP Medical Biological Defense Research Program MCBDRP Medical Chemical and Biological Defense Research Program MCDRP Medical Chemical Defense Research Program MIDRP Military Infectious Diseases Research Program MITS Medical Identification and Treatment Systems MRMC Medical Research and Materiel Command NDA New Drug Application NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NRC National Research Council OTA Office of Technology Assessment PDUFA Prescription Drug User Fee Act P.L. Public Law SAFETY Act Support of Anti-terrorism by Fostering Effective Technologies Act of 2002 SBIR Small Business Innovation Research SECDEF Secretary of Defense STTR Small Business Technology Transfer

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ABBREVIATIONS AND ACRONYMS xix USAMMDA U.S. Army Medical Materiel Development Activity USAMRIID U.S. Army Medical Research Institute of Infectious Diseases USAMRMC U.S. Army Medical Research and Materiel Command U.S.C. United States Code USD Under Secretary of Defense USD(AT&L) Under Secretary of Defense for Acquisition, Technology, and Logistics USD(P&R) Under Secretary of Defense for Personnel and Readiness WRAIR Walter Reed Army Institute of Research

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