PROTECTING OUR FORCES

Improving Vaccine Acquisition and Availability in the U.S. Military

Stanley M. Lemon, Susan Thaul, Salem Fisseha, and Heather C. O’Maonaigh, Editors

Committee on a Strategy for Minimizing the Impact of Naturally Occurring Infectious Diseases of Military Importance: Vaccine Issues in the U.S. Military

Medical Follow-up Agency

INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military PROTECTING OUR FORCES Improving Vaccine Acquisition and Availability in the U.S. Military Stanley M. Lemon, Susan Thaul, Salem Fisseha, and Heather C. O’Maonaigh, Editors Committee on a Strategy for Minimizing the Impact of Naturally Occurring Infectious Diseases of Military Importance: Vaccine Issues in the U.S. Military Medical Follow-up Agency INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military 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 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. Support for this project was provided by U.S. Army Medical Research and Materiel Command (Contract No. DAMD17-00-C-0003). The views presented in this report are those of the Institute of Medicine Committee on a Strategy for Minimizing the Impact of Naturally Occurring Infectious Diseases of Military Importance: Vaccine Issues in the U.S. Military and are not necessarily those of the funding agency. International Standard Book Number 0-309-08499-7 Library of Congress Conrol Number 2002110509 Additional copies of this report are available for sale from the National Academies Press, 500 Fifth Street, N.W., Box 285, Washington, DC 20055. Call (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 2002 by the National Academy of Sciences. All rights reserved. Printed in the United States of America The serpent has been a symbol of long life, healing, and knowledge among almost all cultures and religions since the beginning of recorded history. The serpent adopted as a logotype by the Institute of Medicine is a relief carving from ancient Greece, now held by the Staatliche Museen in Berlin.

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military “Knowing is not enough; we must apply. Willing is not enough; we must do.” —Goethe INSTITUTE OF MEDICINE OF THE NATIONAL ACADEMIES Shaping the Future for Health

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military 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. 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 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. 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 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. 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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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military COMMITTEE ON A STRATEGY FOR MINIMIZING THE IMPACT OF NATURALLY OCCURRING INFECTIOUS DISEASES OF MILITARY IMPORTANCE: VACCINE ISSUES IN THE U.S. MILITARY STANLEY M. LEMON, M.D. (Chair), Dean of Medicine and Professor, University of Texas Medical Branch, Galveston CHARLES C. J. CARPENTER, M.D., Professor of Medicine, Brown University, and The Miriam Hospital, Providence, Rhode Island CIRO A. de QUADROS, M.D., M.P.H., Director, Division of Vaccines and Immunizations, Pan American Health Organization, Washington, D.C. R. GORDON DOUGLAS, Jr., M.D., Princeton, New Jersey LAWRENCE O. GOSTIN, J.D., LL.D. (Hon.), Codirector, Georgetown/ Johns Hopkins Joint Program in Public Health and Law, and Professor of Law, Georgetown University, Washington, D.C. M. CAROLYN HARDEGREE, M.D., Potomac, Maryland SAMUEL L. KATZ, M.D., Wilburt C. Davison Professor and Chairman Emeritus, Duke University Medical Center, Durham, North Carolina F. MARC LaFORCE, M.D., Director, Meningitis Vaccine Project, Program for Appropriate Technology in Health, Ferney-Voltaire, France STANLEY A. PLOTKIN, M.D., Doylestown, Pennsylvania GREGORY A. POLAND, M.D., Chief, Mayo Vaccine Research Group, Mayo Clinic and Foundation, Rochester, Minnesota N. REGINA RABINOVICH, M.D., M.P.H., Director, Malaria Vaccine Initiative, Program for Appropriate Technology in Health, Rockville, Maryland PHILIP K. RUSSELL, M.D., Special Advisor on Vaccine Development and Production, Office of Public Health Preparedness, Department of Health and Human Services, Washington, D.C. RONALD J. SALDARINI, Ph.D., Mahwah, New Jersey MARY E. WILSON, M.D., Chief of Infectious Diseases, Mount Auburn Hospital, and Associate Professor of Medicine, Harvard Medical School, Cambridge, Massachusetts Staff SUSAN THAUL, Ph.D., Study Director SALEM FISSEHA, Research Assistant RICHARD N. MILLER, M.D., M.P.H., Director, Medical Follow-up Agency HEATHER O’MAONAIGH, M.A., Program Officer PAMELA RAMEY-McCRAY, Administrative Assistant

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Preface In April 2000, the Institute of Medicine (IOM) of the National Academies convened an expert committee to advise the U.S. Army Medical Research and Materiel Command on the management of its vaccine research programs for the protection of U.S. military personnel against naturally occurring infectious disease threats. The charge to the committee focused on the army’s Military Infectious Diseases Research Program and how it goes about its task of making available to the military new vaccines for the protection of warfighters against these constantly changing and emerging disease threats. That charge required the committee to examine broadly the process that the Department of Defense (DoD) uses to acquire and maintain the availability of vaccines. Doing so, the committee recognized that this process is too fragmented, too diffused, and too lacking in consolidation of its authority within a single responsible locus in DoD to operate efficiently and to be effective in meeting its critical mission. This report, the final product of the IOM Committee on a Strategy for Minimizing the Impact of Naturally Occurring Infectious Diseases of Military Importance: Vaccine Issues in the U.S. Military, details those findings as well as the information that was provided to the committee and that led it to reach these conclusions. At the time that this report is being prepared for publication, the world is very different from the way it was 2 years earlier when the committee first convened. The terrorist attacks of September 11, 2001, and the subsequent mailing of lethally weaponized anthrax spores to members of the media and the U.S. Congress in the weeks that followed have forever altered the nation’s sense of its vulnerability to terrorism in general and to the possibility of the intentional dissemination of potentially fatal infectious diseases in particular. These events have led to the proposal of enormous increases in the funding for infectious disease

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military research, focused on biodefense, but certain to have significant spillover into the area of naturally transmitted infections. These new funds may answer, in whole or in part, one of the recommendations of this committee: that DoD substantially increase its budgetary support for infectious disease research and vaccine acquisition if it is to provide the protections required for the nation’s warfighters in an increasingly complex and dangerous world. However, DoD’s interest in solving the problems with vaccine acquisition predated the events of September 11. Two important factors led to this growing concern over the functioning of vaccine acquisition efforts within DoD: (1) the awareness that the approach mandated by Congress for the development of countermeasures for biological warfare, the Joint Vaccine Acquisition Program, was failing to produce the vaccine products required and (2) the sudden loss from DoD’s armamentarium of the very successful vaccine that DoD had previously developed for the prevention of adenovirus serotype 4 and 7 disease in military recruits. These events led the Deputy Secretary for Defense to commission a separate study and report shortly after the creation of this IOM committee. That committee, chaired by Franklin Top, Jr., addressed many issues that overlapped the issues that this committee was charged to address. Although its contents were unknown to this committee for many months, the Report on Biological Warfare Defense Vaccine Research and Development Programs, through which DoD released the Top Report1 to the public, ultimately presented conclusions very similar to those arrived at by this committee. As explained in the pages that follow, this committee strongly believes that a full-fledged reorganization of DoD’s priority-setting and vaccine acquisition processes will be required if the department is to fulfill its pledge to protect U.S. warfighters against vaccine-preventable infectious diseases. It believes that this is an issue of national security, inasmuch as infectious diseases have well-proven abilities to significantly degrade and compromise the operations of military forces. The major limitations, it believes, in making available safe and efficacious vaccines for the protection of forces have not been scientific in nature but, rather, revolve around problems of organization, management, and budgetary support. Where possible, the committee has cited substantive data and evidence in support of these conclusions. In many instances, however, such hard data have simply not been available and the committee has had to draw on the past experiences and perceptions of its members, individuals who have spent their careers at the highest points of leadership in military research and development programs, 1   Vaccine Study Panel. Department of Defense Acquisition of Vaccines Program: A Report to the Deputy Secretary of Defense from the Independent Panel of Experts, December 2000). In DoD 2001d. Report on Biological Warfare Defense Vaccine Research and Development Programs. Washington, DC: Department of Defense. [Online]. Available: http://www.defenselink.mil/pubs/ReportonBiologicalWarfareDefenseVaccineRDPrgras-July2001.pdf [accessed September 7, 2001].

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military the commercial vaccine industry, regulatory agencies, and academic infectious disease-related research and development communities. The committee perceives with particular concern that the technology base and basic research activities of DoD are much narrower and limited in scope than they were in past decades, reflecting reductions in the numbers of military professional personnel, reductions in underlying budget support, and changes in program priorities. Although these trends are very difficult to document across the tens of years and the different military organizational structures that have evolved over time, none of the evidence that the committee reviewed refutes this belief. The committee believes that the technology base resides at the core of DoD’s capacity to meet its mission in protecting U.S. warfighters against infectious disease threats. Its erosion should be a matter of national concern, and one that must be reversed through a sustained commitment of budget and personnel as the nation enters the twenty-first century. To accomplish the task for which it convened this committee, IOM recognized that committee membership must include individuals with considerable expertise and experience in pharmaceutical research, development, and manufacturing. IOM found it impossible to recruit individuals with such backgrounds who do not also hold significant amounts of equity in the industry. IOM chose retired industry experts to minimize the potential conflict of interest. Committee members R. Gordon Douglas, Jr., Stanley A. Plotkin, and Ronald J. Saldarini each own significant stock and stock option holdings in pharmaceutical companies that are involved in vaccine development and manufacture. Their biographical summaries (included in Appendix C) illustrate the invaluable experience that they brought to this committee’s work. At the first committee meeting, the Deputy Executive Officer of IOM conducted the required bias and conflict-of-interest discussion. All committee members were apprised of the points-of-view, experiences, and current activities of these committee members, as of all committee members, and were alerted to potential conflicts of interests. The vaccine manufacture section of Chapter 4 boldly presents a pharmaceutical industry view of the issues and labels it as such. The whole committee—aware of the source of advice—uniformly agreed with the analysis. It is my firm opinion that this judicious use of committee members whose potential conflicts of interest would ordinarily preclude their serving on IOM committees has been outstandingly successful and has served this committee and its sponsor well. The committee gained substantively from the experiences of those who have been close to commercial vaccine manufacture in the past, while it maintained its integrity by placing known biases and conflicts of interest on the table during discussions and also drawing heavily on the past experiences of other committee members in the regulation of vaccines and in both public and private vaccine development efforts. Stanley M. Lemon, M.D. Committee Chair

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Acknowledgments This project had a scope that included laboratory procedures and personnel; protection of human subjects in research; federal regulation; organizational design and management; financing; history; military operational readiness; political, military, and public health intelligence; vaccinology; and the study, prevention, and treatment of infectious diseases worldwide. Individual committee members are recognized experts in many of these fields, but all of them—and the study staff—needed education to introduce, review, or update areas in which they were less involved. For this education, we turned to people in DoD, FDA, CDC, NIH, and the vaccine industry, along with other colleagues. Appendix B contains the agenda listings from committee meeting open sessions; the invited presenters listed there shared a lot of information and perspective with the committee and staff. We thank them. Some information required staff pursuit by telephone, e-mail, and fax. Thanks are due to Dr. Kathryn Zoon and her colleagues Bette Goldman, Dr. Karen Midthun, and Loni Warren at FDA; Drs. Ellen Boudreau, Mark Kortepeter, and Phillip Pittman at USAMRIID; COL John Frazier Glenn and William Howell at USAMRMC; Dr. John Brundage, WRAIR; Dr. Francis E. Cole, Jr., JVAP; and Michael A. Paysan, Jr., Requirements and Acquisition Division, Joint Staff, Pentagon. The recipient of the bulk of our requests for information was our sponsor representative COL Charles H. Hoke, Jr., director of the Military Infectious Diseases Research Program at USAMRMC through the core of the IOM project. He and his colleagues Drs. Lawrence Lightner and Rodney Michael fielded our questions through hundreds of e-mails, telephone calls and voice-mail messages, and perhaps a dozen in-person meetings. COL Hoke’s task was large and his efforts to convey the scope of his concern for the direction of DoD in infectious

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military mendations nor did they see the final draft of the report before its release. The review of this report was overseen by Robert M. Chanock, M.D., National Institute of Allergy and Infectious Diseases, National Institutes of Health, and Enriqueta C. Bond, Ph.D., Burroughs Wellcome Fund. Appointed by the Institute of Medicine and the National Research Council, 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.

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Contents     EXECUTIVE SUMMARY   1     Project Rationale and Organization,   1     Historical Overview,   3     Vaccine Mission and Procedures of USAMRMC,   4     Discussion,   5     Recommendations,   6     Conclusion,   8 1   INTRODUCTION AND HISTORY   9     Naturally Occurring Infectious Diseases in the U.S. Military,   9     Setting Priorities for Military Medical Research Through the Twentieth Century,   15     About This Report,   18 2   RESOURCES, RESPONSIBILITIES, AND DYNAMICS IN THE MILITARY’S VACCINE MISSION   20     Vaccine Mission of the U.S. Army Medical Research and Materiel Command,   20     Research, Development, and Acquisition in Context,   29     Procurement, Storage, and Distribution in Context,   34     External Interactions,   35

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military 3   CURRENT STATUS OF VACCINES FOR MILITARY PERSONNEL   39     Current Status of Vaccines for Military Use,   39     Current Status of Select Military Vaccine-Related Research Programs,   45     Regulatory Status of Special-Use Vaccines,   50 4   RECOMMENDATIONS WITH ACCOMPANYING ANALYSIS OF LIMITATIONS IMPOSED BY CURRENT DEPARTMENT OF DEFENSE STRUCTURE FOR MANAGING ACQUISITION OF VACCINES AGAINST INFECTIOUS DISEASES   55     Organization, Authority, and Responsibility,   59     Funds and Program Management,   67     Manufacturing,   80     Regulatory Status of Special-Use Vaccines,   90     Conclusion,   93     REFERENCES   95     APPENDIXES         A Reprint of the Committee’s November 2000 Interim Report, Urgent Attention Needed to Restore Lapsed Adenovirus Vaccine Availability: A Letter Report,   107     B Open Meeting Agendas,   119     C Committee and Staff Biographies,   127

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Boxes, Figures, and Tables BOXES ES-1   Committee Recommendations,   7 4-1   Committee Recommendations,   58 FIGURES 1-1   U.S. Army hospital admissions during war,   10 2-1   Military infectious disease-related research, development, and acquisition activities: USAMRMC interfaces with army and Office of the Secretary of Defense organizations,   22 2-2   U.S. Army Medical Department organizational chart,   24 2-3   U.S. Army Medical Research and Materiel Command organizational chart,   25 2-4   Research and development path for vaccines,   32 4-1   Military infectious disease-related research, development, and acquisition activities: USAMRMC interfaces with army and Office of the Secretary of Defense organizations,   60

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military TABLES 1-1   Historical Highlights in the Control of U.S. Military Infectious Diseases by Vaccines,   12 1-2   Major Infectious Disease Threats for Which There Were No Licensed Vaccines at the Time of Deployments and Overseas Exercises,   14 2-1   USAMRMC Infectious Disease-Related Research Funding, FY 2002,   27 2-2   Selected Current Vaccine-Related Agreements,   36 3-1   Status of Vaccines for Specific Infectious Disease Threats to the U.S. Military,   40 3-2   FDA-Licensed Vaccines and Related Biologics Available to U.S. Military Personnel,   43 3-3   Selected Vaccines Previously Licensed by FDA but Not Available,   44 3-4   Vaccines Available to U.S. Military Personnel as IND Products,   44 3-5   Vaccines Administered as INDs That Are No Longer Being Produced and That Are of Limited Availability,   45 3-6   USAMRMC Fiscal Year 2001 Program Priorities, in Decreasing JTCG-2– Assigned Rank, and FY 2000 Investment in Exploratory Research,   46 3-7   FDA-Licensed Vaccines Used by SIP as of March 2002,   50 3-8   Vaccines with IND Status Used by SIP as of March 2002,   51 3-9   Vaccines with CDC-Sponsored IND Status Administered by SIP,   51 4-1   History of Funding for Science and Technology Base Through the USAMRMC Research Area Directorate for Infectious Diseases, FYs 1994 to 2002,   70

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military Abbreviations and Acronyms ACAT acquisition category AFEB Armed Forces Epidemiological Board AMEDD Army Medical Department ASA(ALT) Assistant Secretary of the Army for Acquisition, Logistics, and Technology ASBREM Armed Services Biomedical Research, Evaluation and Management (Committee) ASD(HA) Assistant Secretary of Defense for Health Affairs BSL Biological Safety Level CDC Centers for Disease Control and Prevention CRADA Cooperative Research and Development Agreement DHHS Department of Health and Human Services DoD Department of Defense DNA deoxyribonucleic acid DSCP Defense Supply Center, Philadelphia DTO Defense Technology Objective DUST Dual-Use Science and Technology ETEC enterotoxigenic Escherichia coli FDA Food and Drug Administration FHP Force Health Protection

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military FOC Future Operational Capability FY fiscal year GAO General Accounting Office GOCO government-owned, contractor-operated (manufacturing facility) GSK GlaxoSmithKline HEV hepatitis E virus HIV human immunodeficiency virus IND investigational new drug IOM Institute of Medicine JTCG-2 Joint Technology Coordinating Group-2 JVAP Joint Vaccine Acquisition Program JWG Joint Working Group MEDCOM U.S. Army Medical Command MIDRP Military Infectious Diseases Research Program NAMRU-2 Navy Medical Research Unit 2 NIC National Intelligence Council NIH National Institutes of Health ORD Operational Requirements Document OSD Office of the Secretary of Defense RAD Research Area Directorate RDA research, development, and acquisition SIP Special Immunizations Program STEP Science and Technology Evaluation Program STO Science and Technology Objective TBE tick-borne encephalitis TRADOC U.S. Army Training and Doctrine Command TSI-GSD The Salk Institute, Government Services Division USAMMA U.S. Army Medical Materiel Agency USAMMDA U.S. Army Medical Materiel Development Activity USAMRAA U.S. Army Medical Research Acquisition Activity USAMRIID U.S. Army Medical Research Institute of Infectious Diseases USAMRMC U.S. Army Medical Research and Materiel Command

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military USD(AT&L) Under Secretary of Defense for Acquisition, Technology, and Logistics WRAIR Walter Reed Army Institute of Research

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Protecting Our Forces: Improving Vaccine Acquisition and Availability in the U.S. Military PROTECTING OUR FORCES

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