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IMMUNIZATION SAFETY REVIEW

MEASLES-MUMPS-RUBELLA VACCINE AND AUTISM

Kathleen Stratton, Alicia Gable, Padma Shetty, and Marie McCormick, Editors

Immunization Safety Review Committee

Board on Health Promotion and Disease Prevention

INSTITUTE OF MEDICINE

NATIONAL ACADEMY PRESS
Washington, D.C.



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Page i IMMUNIZATION SAFETY REVIEW MEASLES-MUMPS-RUBELLA VACCINE AND AUTISM Kathleen Stratton, Alicia Gable, Padma Shetty, and Marie McCormick, Editors Immunization Safety Review Committee Board on Health Promotion and Disease Prevention INSTITUTE OF MEDICINE NATIONAL ACADEMY PRESS Washington, D.C.

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Page ii 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 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 the Centers for Disease Control and Prevention and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health as part of a National Institute 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 0-309-07447-9 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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Page iii “Knowing is not enough; we must apply. Willing is not enough; we must do. —Goethe ~ enlarge ~ INSTITUTE OF MEDICINE Shaping the Future for Health

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Page iv THE NATIONAL ACADEMIES National Academy of Sciences National Academy of Engineering Institute of Medicine National 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. William 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. 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 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. William A. Wulf are chairman and vice chairman, respectively, of the National Research Council.

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Page v IMMUNIZATION SAFETY REVIEW COMMITTEE MARIE MCCORMICK, M.D., Sc.D., (Chair), Professor and Chair, Department 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 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 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 CONSTANTINE GATSONIS, Ph.D., Professor of Medical Science and Applied Math, and Director, Center for Statistical Sciences, Brown University STEVEN GOODMAN, M.D., M.H.S., Ph.D., Associate Professor, Department 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 MICHAEL KABACK, M.D., Professor, Pediatrics and Reproductive Medicine, 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 & 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 Immunology, University of Washington ALFRED BERG, M.D., M.P.H., Professor and Chair, Department of Family Medicine, University of Washington School of Medicine is a member of the Immunization Safety Review Committee but was unable to attend the meeting on the topic of this report. Health Promotionand 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 & Research Center

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Page vi Study Staff KATHLEEN STRATTON, Ph.D., Study Director ALICIA GABLE, M.P.H., Program Officer PADMA SHETTY, M.D., Program Officer DONNA ALMARIO, Research Associate KYSA CHRISTIE, Research Assistant ANN ST. CLAIRE, Senior Project Assistant ROSE MARIE MARTINEZ, Sc.D., Director, Board on Health Promotion and Disease Prevention Contract Writer JANE S. DURCH, M.A., Assistant Research Professor, Department of Epidemiology and Biostatistics, George Washington University Contract Editor STEVEN J. MARCUS, Ph.D., Freelance Editor, Brookline, Massachusetts

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Page vii REVIEWERS The report was reviewed by individuals chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council's Report Review Committee. The purpose of this independent review is to provide candid and critical comments to assist the authors and the Institute of Medicine in making the 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 content of the review comments and the draft manuscript remain confidential to protect the integrity of the deliberative process. The committee wishes to thank the following individuals for their participation in the report review process: Linda Cowan, Ph.D., University of Oklahoma Eric Fombonne, M.D., FRCPsych, Institute of Psychiatry, King's College London Neal Halsey, M.D., Johns Hopkins University Samuel Katz, M.D., Duke University Medical Center Ronald Kennedy, Ph.D., University of Oklahoma Linda Linville, M.S., R.N., Texas Department of Health Catherine Lord, Ph.D., University of Chicago Gerald Mandell, M.D., University of Virginia Health Sciences Center Edgar Marcuse, M.D., M.P.H., University of Washington John Menkes, M.D., University of California, Los Angeles Peter Meyers, J.D., George Washington University Law School Elizabeth Miller, B.Sc., M.B.B.S., Public Health Laboratory Service, United Kingdom Richard Rheingans, Ph.D., Emory University Fred Volkmar, M.D., Yale University Brian Ward, M.D., McGill University 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 Floyd Bloom, The Scripps Research Institute, and Robert Lawrence, Johns Hopkins University School of Hygiene and Public Health. Appointed by the National Research Council and Institute of Medicine, 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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Page viii

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Page ix 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 policy-making. Because vaccines are so widely used—and because state laws require that children be vaccinated to enter day-care 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 hypotheses. 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 fast major vaccine-safety report in 1977, followed by a subsequent report in 1988,

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Page x 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 focused 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 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 have 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 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 conflicts of interest. This committee brought a fresh perspective to these critically important issues and approached its charge with impartiality and scientific rigor. As with all reports from the IOM, the committee's work was reviewed by an independent panel of experts. 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. 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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Page xi Preface With growing concerns about vaccine safety, the Centers for Disease Control and Prevention and the National Institutes of Health recognized the need for an independent group to address these concerns in a timely and objective manner. The establishment of the Immunization Safety Review committee in the Institute of Medicine (IOM) represents both an extension of the IOM's prior work and an experiment. The committee is charged with examining three vaccine safety hypotheses each year during the 3-year study period of 2001–2003. This pace represents a significant departure from previous reports and will require substantial staff and committee-member commitment, as well as a streamlining of the review process to assure timely reports of the traditional IOM caliber. We expect that, as the committee gains experience with the process, we will refine our procedures and approaches. In doing its work, the committee proposes to be as open as possible. For each of the hypotheses examined, a session open to the public will be held. These meetings will take place in different parts of the country to facilitate public access. Audio broadcasts of the open meetings and handouts from those sessions will be posted on the committee's web page ( www.iom.edu/imsafety). A listing of other materials reviewed by the committee will be available through the National Academies Public Access and Records Office (202-334-3543). Comments can be sent to imsafety@nas.edu. Previous IOM vaccine-safety studies limited their conclusions to causality assessments and recommendations on future research directions. By contrast, the Immunization Safety Review Committee has been asked to consider not only the scientific plausibility of the hypothesized association but also the significance of

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Page xii the issue in a broader societal context. This significance assessment addresses such considerations as the burden of the adverse health event in question, the burden of disease that vaccine use prevents, and the level and potential consequences of public concern about the safety of vaccine use. The findings of both the plausibility and significance assessments provide the basis for the committee's recommendations regarding public health policy, current and future research, surveillance, and effective communication strategies for the specific immunization-safety questions. While this report contains some specific recommendations with regard to the hypothesized linkage between MMR vaccine and autism, the committee members already recognize that a number of recurring issues will stimulate further recommendations. Among these will surely be more systematic approaches to the investigation of the adverse events; ready access to needed information about vaccines, including the role of the Internet in disseminating information; and the development of future vaccine policy. Thus, the fact that these issues are not addressed in this fast report of the committee does not indicate a lack of attention, but rather a recognition of the need to gather more information and develop a process to address them. We thank those who have taken the time and effort to help us in this important project, and we look forward to the same thoughtful and concerned participation in the remainder of the study. Perhaps the most noteworthy observation to date is that all participants share a commitment to assuring the safest possible vaccine policy and program for the United States. Marie McCormick Committee Chair

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Page xiii Acknowledgments The Committee wishes to acknowledge the valuable contributions that were made to this study by the many individuals who shared their experiences and their expertise. We are especially grateful for the insight provided by many parents and advocacy groups who spoke with the committee and submitted written testimony. The committee particularly thanks Elizabeth Birt, Peter and Elizabeth Bell, Barbara Loe Fisher, Kathi Williams, and Sallie Bernard. Many other comments were submitted to the committee by researchers, public health officials, and members of vaccine safety and autism interest groups. Those comments were of great value to the committee members and proved to be instrumental in developing the thought process and deliberations of the committee. The committee also appreciates the efforts of the staff of the National Immunization Program of the Centers for Disease Control and Prevention and the National Institute for Allergies and Infectious Diseases of the National Institutes of Health for providing materials and background documents to the committee. Special thanks go to the two project officers, Gina Mootrey and Sarah Landry. In addition, the committee greatly benefited from the scientific expertise provided by workshop speakers and colleagues consulted in the course of this effort. The list of speakers' presentations at the committee's meetings can be found in Appendix A and Appendix B . Of particular note, the committee would like to thank Michael Stoto, Sean Cleary, and Virginia Foster for their background paper, “Epidemiologic Studies of MMR Vaccine and Autism.” Their paper and Michael Stoto's presentation contributed greatly to the discussions of the epidemiology studies of the Mea-

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Page xiv sles-Mumps-Rubella vaccine and autism. Special thanks also go to Jane Durch as contract writer and Steven Marcus as contract editor. In addition, the committee would like to thank Health Promotion Disease Prevention Board liaison Richard Johnston for his assistance in the production of this report. The committee has benefited from his insight and experience with previous Institute of Medicine vaccine reports. Finally, we are indebted to the dedication and energy provided by the Institute of Medicine staff in coordinating and steering the committee through this process. In particular, Kathleen Stratton, Alicia Gable, and Padma Shetty provided direction, insight, and clarity of purpose. The committee is indebted to Rose Marie Martinez for her assistance in providing valuable advice and perspective. The committee appreciates the efforts of Donna Almario, Kysa Christie, and Ann St. Claire in conducting thorough research required for our review and deliberations, creating data tables and illustrations for the report, and otherwise maintaining the committee coordination and study process.

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Page xv Contents Executive Summary 1 Immunization Safety Review: Measles-Mumps-Rubella Vaccine and Autism 13     Origins of the Immunization Safety Review Project 14     The Charge to the Committee 15     The Study Process 16     The Framework for Assessing Causality 17     Under Review: The MMR–Autism Hypothesis 18     Plausibility Assessment 21     Causality Argument 44     Significance Assessment 46     Recommendations 55     Summary 60     References 60 Appendix A 71 Appendix B 75 Appendix C 79 Appendix D 85

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