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SRFETY R ESR Kathleen Stratton, Alicia Gable, and Marie C. McCormick, Eclitors Immunization Safety Review Committee Boa rcl on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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NATIONAL ACADEMY PRESS 2101 Constitution Avenue, N.W. Washington, DC 20418 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 Insti- tute 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 the Centers for Disease Control and Preven- tion and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health as part of a National Institutes of Health Task Order No. 74. The views presented in this report are those of the Institute of Medicine Immunization Safety Review Committee and are not necessarily those of the funding agencies. International Standard Book Number 0-309-07636-6 Additional copies of this report are available for sale from the National Academy Press, 2101 Constitution Avenue, N.W., Box 285, Washington, DC 20055. Call 800-624- 6242 or (202) 334-3313 (in the Washington metropolitan area), or visit the NAP's home page at www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at www.iom.edu. For more information regarding this report and other reports to be issued by this committee, visit the IOM project web page at www.iom.edu/imsafety. Copyright 2001 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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1(nouJiny is not enough; we must apply. dribbing is not enough; we must do. Goethe INSTITUTE OF MEDICINE Shaping the Future for Health

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National Academy of Sciences National Academy of Engineering Institute of Mecl~cine FJationai Research Council 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 re- sponsibility 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. Kenneth I. Shine 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 Na- tional 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 chairman and vice chairman, respectively, of the National Research Council.

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IMMUNIZATION SAFETY REVIEW COMMITTEE MARIE C. McCORMICK, M.D., Sc.D., (Chair), Professor and Chair, De- partment of Maternal and Child Health, Harvard School of Public Health RONALD BAYER, Ph.D., Professor, Division of Sociomedical Sciences, School of Public Health, Columbia University ALFRED BERG, M.D., M.P.H., Professor and Chair, Department of Family Medicine, University of Washington School of Medicine ROSEMARY CASEY, M.D., Associate Professor of Pediatrics, Jefferson Medical College and Director, Lankenau Faculty Pediatrics, Wynnewood, Pennsylvania JOSHUA COHEN, Ph.D., Senior Research Associate, Harvard Center for Risk Analysis, Harvard School of Public Health CONSTANTINE GATSONIS, Ph.D., Professor of Medical Science and Ap- plied Math, and Director, Center for Statistical Sciences, Brown University MICHAEL KABACK, M.D., Professor, Pediatrics and Reproductive Medi- cine, University of California, San Diego GERALD MEDOFF, M.D., Professor, Department of Internal Medicine, Washington University School of Medicine, St. Louis REBECCA PARKIN, Ph.D., Associate Research Professor, Department of Occupational and Environmental Health, School of Public Health and Health Services, George Washington University BENNETT SHAYWITZ, M.D., Professor of Pediatrics and Neurology, Co- Director, Yale Center for the Study of Learning and Attention CHRISTOPHER WILSON, M.D., Professor and Chair, Department of Immu- nology, University of Washington The following individuals are members of the Immunization Safety Review Committee but were unable to attend the meeting on the topic of this report: VERNICE DAVIS-ANTHONY, M.P.H., Senior Vice President, Corporate Affairs and Community Health, St. John Health System, Detroit, Michigan BETSY FOXMAN, Ph.D., Professor, Department of Epidemiology, School of Public Health, University of Michigan STEVEN GOODMAN, M.D., M.H.S., Ph.D., Associate Professor, Depart- ment of Oncology, Division of Biostatistics, Johns Hopkins School of Medicine ELLEN HORAK, M.S.N., Chief of Local Services, Office of Local and Rural Health, Kansas Department of Health and Environment Health Promotion and Disease Prevention Board Liaison RICHARD B. JOHNSTON, Jr., M.D., Professor of Pediatrics, Department of Pediatrics, University of Colorado School of Medicine and National Jewish Medical and Research Center v

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Health Promotion and Disease Prevention Board Chair ROBERT WALLACE, M.D., Irene Ensminger Stecher Professor of Epide- miology and Internal Medicine, University of Iowa Colleges of Public Health and Medicine Study Staff KATHLEEN STRATTON, Ph.D., Study Director ALICIA GABLE, M.P.H., Program Officer PADMA SHETTY, M.D., Program Officer DONNA ALMARIO, M.P.H., Research Associate KYSA CHRISTIE, Research Assistant ANN ST. CLAIRE, Senior Project Assistant KATRINA LAWRENCE, M.S., Senior Project Assistant MARGARET GALLOGLY, Intern ROSE MARIE MARTINEZ, Sc.D., Director, Board on Health Promotion and Disease Prevention Contract Writer JANE S. DURCH, M.A., Freelance Writer and Editor, Arlington, Virginia Contract Editor STEVEN J. MARCUS, Ph.D., Freelance Editor, Brookline, Massachusetts V1

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REVIEWERS This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures ap- proved by the NRC's Report Review Committee. The purpose of this independ- ent review is to provide candid and critical comments that will assist the institu- tion 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: Thomas F. Anders, M.D., University of California at Davis Michael Aschner, Ph.D., Wake Forest University Ann Bostrom, Ph.D., Georgia Institute of Technology Thomas Clarkson, Ph.D., University of Rochester Samuel L. Katz, M.D., Duke University Marcel Kinsbourne, M.D., New School University Lynda P. Knobeloch, Ph.D., Wisconsin Division of Public Health Linda Linville, M.S., R.N., Texas Department of Health Edgar K. Marcuse, M.D., M.P.H., University of Washington Katherine Mathews, M.D., University of Iowa Craig J. Newschaffer, Ph.D., M.S., Johns Hopkins University Scott Ratzan, M.D., M.P.A., The George Washington University, Tufts University, Yale University Richard Rheingans, Ph.D., Emory University Patricia Rodier, Ph.D., University of Rochester Brian Ward, M.D., McGill University Paul M. Wax, M.D., Good Samaritan Hospital, Phoenix, Arizona Roberta F. White, Ph.D., A.B.P.P., Boston University Although the reviewers listed above have provided many constructive com- ments and suggestions, they were not asked to endorse the conclusions or rec- ommendations nor did they see the final draft of the report before its release. The review of this report was overseen by Robert Lawrence, Johns Hopkins Univer- sity and Charles Carpenter, Brown University. Appointed by the National Re- search Council and Institute of Medicine, they were responsible for making cer- tain that an independent examination of this report was carried out in accordance with institutional procedures and that all review comments were carefully consid- ered. Responsibility for the final content of this report rests entirely with the authoring committee and the institution. . . V11

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. . . V111 FOREWORD The rationale for imposing these stringent criteria was twofold. First, given growing public concern about vaccine safety and the public scrutiny surrounding this committee's work, it was important to es- tablish standards that would preclude any real or perceived conflict of interest or bias on part of the committee members. While the committee members all share a belief in the benefits of vaccines to the public health, none of them has any vested interest in any of the vaccine safety issues that will come be- fore them. Second, the IOM wanted to ensure consistency in the committee membership and avoid hav- ing members recuse themselves from the deliberations because they had participated in the development or evaluation of a vaccine under study. Thus, the IOM has convened a distinguished panel of ~ 5 members who possess significant breadth and depth of expertise in a number of fields, including pediatrics, neurology, immunology, internal medicine, infectious diseases, genetics, epidemiology, biostatistics, risk perception and communication, decision analysis, public health, nursing, and ethics. The committee members were chosen because they are leading authorities in their respective fields, are well-respected by their colleagues, and have no con- flicts of interest. This committee brought a fresh perspective to these critically important issues and ap- proached its charge with impartiality and scientific rigor. The IOM does not propose the use of the criteria it has laid out above in selecting members for federal vaccine advisory committees. The IOM committee was convened for a very different purpose from the usual federal vaccine advisory committees and, as such, required different standards. As with all reports from the IOM, the committee's work was reviewed by an independent panel of experts. The purpose of the review process is to enhance the clarity, cogency, and accuracy of the final report and to ensure that the authors and the IOM are creditably represented by the report published in their names. The report review process is overseen by the National Research Council's (NRC) Report Review Committee (RRC), comprised of approximately 30 members of the National Academy of Sci- ences, National Academy of Engineering, and IOM. The IOM, in conjunction with the RRC appoints a panel of reviewers with a diverse set of perspectives on key issues considered in the report. Unlike the selection criteria for committee membership (discussed above), many reviewers will have strong opin- ions and biases about the report topic. The composition of the review panel is not disclosed to the com- mittee until after the report is approved for release. While the committee must consider and evaluate all comments Tom reviewers, it is not obligated to change its report in response to the reviewers' com- ments. The committee must, however, justify its responses to the reviewers' comments to the satisfac- tion of the RRC's review monitor and the TOM's review coordinator. A report may not be released to the sponsors or the public, nor may its findings be disclosed, until after the review process has been satis- factorily completed and all authors have approved the revised draft. This report represents the unanimous conclusions and recommendations of that dedicated committee whose members deliberated a critical health issue. The report's conclusions and recommendations should be of value to all concerned about these important matters. Kenneth I. Shine President, [nstitute of Medicine

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Foreword Vaccines are among the greatest public health accomplishments of the past century. In recent years, however, a number of concerns have been raised about the safety of, and need for, certain immunizations. Indeed, immunization safety is a contentious area of public health policy, with discourse around it having become increasingly polarized and exceedingly difficult. The numerous controversies and allegations surrounding immunization safety signify an erosion of public trust in those responsible for vaccine research, development, licensure, schedules, and policymaking. Because vaccines are so widely used and because state laws re- quire that children be vaccinated to enter daycare and school, in part to protect others immunization safety concerns should be vigorously pursued in order to restore this trust. It is in this context that the Institute of Medicine (IOM) was approached more than a year ago by the Centers for Disease Control and Prevention and the National Institutes of Health to convene an independent committee that could provide timely and objective assistance to the Department of Health and Human Services in reviewing emerging immunization-safety concerns. The IOM was chartered by the National Academy of Sciences in 1970 to serve as an adviser to the federal government on issues affecting the public's health, as well as to act independently in identifying important issues of medical care, research, and education. The IOM thus brings to this mission three decades of experience in conducting independent analyses of significant public health policy issues. In particular, as described in more detail in this report, the IOM has a long history of involvement in vaccine safety. The IOM published its first 1X

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x FOREWORD major vaccine-safety report in 1977, followed by a subsequent report in 1988, both focused on the safety of polio vaccines. Two subsequent major reports, published in 1991 and 1994, examined the adverse events of childhood vaccines. Since then, the IOM has conducted several smaller studies and workshops fo- cused on various vaccine-safety topics. These studies were all well received by both the public and policy makers, and previous IOM committees on vaccine safety issues have been viewed as objective and credible. Given the sensitive nature of the present immunization safety review study, the IOM felt it was especially critical to establish strict criteria for committee membership. These criteria prevented participation by anyone with financial ties to vaccine manufacturers or their parent companies, previous service on major vaccine-advisory committees, or prior expert testimony or publications on issues of vaccine safety. The rationale for imposing these stringent criteria was twofold. First, given growing public concern about vaccine safety and the public scrutiny surrounding this committee's work, it was important to establish standards that would pre- clude any real or perceived conflict of interest or bias on the part of the com- mittee members. While the committee members all share a belief in the benefits of vaccines to the public health, none of them has any vested interest in any of the vaccine safety issues that will come before them. Second, the IOM wanted to ensure consistency in the committee membership and avoid having members recuse themselves from the deliberations because they had participated in the development or evaluation of a vaccine under study. Thus, the IOM has convened a distinguished panel of 15 members who pos- sess significant breadth and depth of expertise in a number of fields, including pediatrics, neurology, immunology, internal medicine, infectious diseases, ge- netics, epidemiology, biostatistics, risk perception and communication, decision analysis, public health, nursing, and ethics. The committee members were cho- sen because they are leading authorities in their respective fields, are well re- spected by their colleagues, and have no conflicts of interest. This committee brought a fresh perspective to these critically important issues and approached its charge with impartiality and scientific rigor. The IOM does not propose the use of the criteria it has laid out above in se- lecting members for federal vaccine advisory committees. The IOM committee was convened for a very different purpose from the usual federal vaccine advisory committees and, as such, required different standards. As with all reports from the IOM, the committee's work was reviewed by an independent panel of experts. The purpose of the review process is to en- hance the clarity, cogency, and accuracy of the final report and to ensure that the authors and the IOM are creditably represented by the report published in their names. The report review process is overseen by the National Research Coun- cil's (NRC) Report Review Committee (RRC), comprised of approximately 30 members of the National Academy of Sciences, National Academy of Engi-

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FOREWORD X1 peering, and IOM. The IOM, in conjunction with the RRC, appoints a panel of reviewers with a diverse set of perspectives on key issues considered in the re- port. Unlike the selection criteria for committee membership (discussed above), many reviewers will have strong opinions and biases about the report topic. The composition of the review panel is not disclosed to the committee until after the report is approved for release. While the committee must consider and evaluate all comments from reviewers, it is not obligated to change its report in response to the reviewers' comments. The committee must, however, justify its responses to the reviewers' comments to the satisfaction of the RRC's review monitor and the IOM's review coordinator. A report may not be released to the sponsors or the public, nor may its findings be disclosed, until after the review process has been satisfactorily completed and all authors have approved the revised draft. This report represents the unanimous conclusions and recommendations of that dedicated committee whose members deliberated a critical health issue. The report's conclusions and recommendations should be of value to all concerned about these important matters. Kenneth I. Shine President, Institute of Medicine

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Acknowledgments The committee would like to acknowledge the many speakers and attendees at its open meeting held on July 16 in Boston. The discussions were informative and helpful. The committee would also like to thank those people who have submitted information to the committee through the mail or e-mail. Finally, the committee would like to thank the IOM staff for their dedication to this project. Without their commitment, attention to detail, creativity, sensitivity, and hard work, this project would be unworkable. x~

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Contents Executive Summary 1 Immunization Safety Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders Origins of the Immunization Safety Review Project ......................... The Charge to the Committee The Study Process ............ The Framework for Assessing Causality .. Under Review: Thimerosal-Containing Vaccines and Neurodevelopmental Disorders Plausibility Assessment Causality Argument .... Significance Assessment ..... Recommendations Regarding the Public Health Response ................. Summary . . . References Appendix A Appendix B Appendix C Appendix D .19 20 . 22 23 .23 27 38 65 66 75 . 82 ........ 86 95 107 111 117 . . . X111

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