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Committee on Identifying and Prioritizing New Preventive Vaccines for Development Board on Population Health and Public Health Practice Board on Global Health Guruprasad Madhavan, Kinpritma Sangha, Charles Phelps, Dennis Fryback, Tracy Lieu, Rose Marie Martinez, and Lonnie King, Editors

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Gov- erning Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engi- neering, and the Institute of Medicine. The members of the committee respon- sible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract No. HHSP23337024T, TO #45 between the National Academy of Sciences and the National Vaccine Program Office of the Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-25525-7 International Standard Book Number-10: 0-309-25525-2 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; www.nap.edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2012 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. Suggested citation: IOM (Institute of Medicine). 2012. Ranking vaccines: A pri- oritization framework: Phase I: Demonstration of concept and a software blueprint. Washington, DC: The National Academies Press.

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“Knowing is not enough; we must apply. Willing is not enough; we must do.” — Goethe Advising the Nation. Improving Health.

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal govern- ment on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of out- standing engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in pro- viding services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Committee on Identifying and Prioritizing New Preventive Vaccines for Development LONNIE KING (Chair), Dean, College of Veterinary Medicine, and Executive Dean, Health Sciences College, Ohio State University PAUL CITRON, Retired Vice President, Technology Policy and Academic Relations, Medtronic, Inc. RITA COLWELL, Chair, Canon U.S. Life Sciences, Inc.; Distinguished Professor, University of Maryland, College Park and Johns Hopkins University Bloomberg School of Public Health; and Former Director, National Science Foundation KATHRYN EDWARDS, Sarah H. Sell Professor of Pediatrics, Vanderbilt University School of Medicine JOSHUA EPSTEIN, Professor of Emergency Medicine, Johns Hopkins University, and External Professor, Santa Fe Institute DENNIS FRYBACK, Professor Emeritus of Population Health Sciences and Industrial Engineering, University of Wisconsin–Madison PATRICIA GARCIA, Dean and Professor, School of Public Health, Cayetano Heredia University, Peru DEMISSIE HABTE, President, Ethiopian Academy of Sciences, Ethiopia VICTORIA HALE, Founder and Chief Executive Officer, Medicines 360 TRACY LIEU, Professor, Department of Population Medicine, Harvard Medical School WILLIAM PAUL, NIH Distinguished Investigator and Chief, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health CHARLES PHELPS, University Professor and Provost Emeritus, University of Rochester RINO RAPPUOLI, Global Head, Vaccines Research, Novartis Vaccines, Italy ARTHUR REINGOLD, Edward Penhoet Distinguished Professor of Global Health and Infectious Diseases, University of California, Berkeley VINOD SAHNEY, Senior Fellow, Institute for Health Care Improvement ROBERT STEINGLASS, Immunization Team Leader, Maternal and Child Health Integrated Program, John Snow, Inc. Staff GURUPRASAD MADHAVAN, Study Director KINPRITMA SANGHA, Research Associate MALCOLM BILES, Senior Program Assistant v

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HOPE HARE, Administrative Assistant DORIS ROMERO, Financial Associate ROSE MARIE MARTINEZ, Senior Director, Board on Population Health and Public Health Practice PATRICK KELLEY, Senior Director, Board on Global Health KATHLEEN STRATTON, Scholar (until September 2011) AMY PRYZBOCKI, Financial Associate (until December 2011) SAMANTHA ARNETT, Christine Mirzayan Science and Technology Policy Fellow (Winter 2011) Consultants, Modeling and Software Development SCOTT LEVIN, Assistant Professor of Emergency Medicine, Johns Hopkins University MATTHEW TOERPER, Senior Software Engineer, Johns Hopkins University PANAYIOTIS KARABETIS, Partner and Lead Information Designer, VIM Interactive MICHAEL KAPETANOVIC, Partner and Project Manager, Reef Light Interactive Consultants, Concept Evaluation JON ANDRUS, Deputy Director, Pan American Health Organization CLAIRE BROOME, Adjunct Professor, Department of Global Health, Rollins School of Public Health, Emory University JOACHIM HOMBACH, Acting Head, Initiative for Vaccine Research, World Health Organization PHILIP HOSBACH, Vice President of Immunization Policy and Government Relations, Sanofi Pasteur ROBERT LAWRENCE, Center for a Livable Future Professor, and Professor of Environmental Health Sciences, Health Policy, and International Health, John Hopkins Bloomberg School of Public Health ADEL MAHMOUD, Professor, Woodrow Wilson School of Public and International Affairs and Department of Molecular Biology, Princeton University; Former President, Merck Vaccines GREGORY POLAND, Mary Lowell Leary Professor of Medicine and Director, Mayo Vaccine Research Group, Mayo Clinic JAIME SEPULVEDA, Executive Director, Global Health Sciences, University of California, San Francisco EDWARD SHORTLIFFE, President and Chief Executive Officer, American Medical Informatics Association; Adjunct Professor, Department of Biomedical Informatics, Columbia University ALASTAIR WOOD, Partner, Symphony Capital, LLC vi

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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 proce- dures approved by the National Research Council’s Report Review Com- mittee. 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 confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this report: Yves Bergevin, United Nations Population Fund John Boslego, PATH Margaret Brandeau, Stanford University Michael Drummond, University of York, United Kingdom Maria Freire, The Albert and Mary Lasker Foundation Maryellen Giger, The University of Chicago Robert Greenes, Arizona State University Prasad Kulkarni, Serum Institute of India, Ltd. Shabir Madhi, University of Witwatersrand, South Africa Charles Manski, Northwestern University Osman Mansoor, United Nations Children’s Fund Regina Rabinovich, Bill & Melinda Gates Foundation John Robbins, National Institutes of Health Thomas Saaty, University of Pittsburgh Jeanne Stephenne, GlaxoSmithKline Biologicals, Belgium Detlof von Winterfeldt, University of Southern California 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 Stephen Fien- berg, Carnegie Mellon University, and Alfred Berg, University of Wash- ington School of Medicine. Appointed by the National Research Council and the Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accor- dance 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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Foreword Ranking Vaccines: A Prioritization Framework previews a product that is unique in the annals of the Institute of Medicine: an early-stage decision- support software for prioritizing new vaccines. Decision makers in the area of vaccine development—including developers, investors, practitioners, and policy makers—are constantly challenged by rapidly changing demographics, epidemiology, econom- ics, technologies, and health systems. Thus, a comprehensive yet adapt- able framework is needed to assist decision making. The Strategic Multi- Attribute Ranking Tool for Vaccines, or SMART Vaccines, described in this report, provides one such framework. SMART Vaccines was conceived with the appreciation that chang- ing circumstances, technological developments, and resource availability influence priorities for new vaccines. This tool should make it possible for decision makers in a variety of circumstances to weigh competing val- ues, test assumptions, and explore alternative scenarios to help guide the priority-setting process. Like all decision tools, SMART Vaccines is an aid for decision making, not a substitute for sound judgment. Beyond its potential applications in independent and collaborative decision making, SMART Vaccines can facilitate focused and informed dis- cussion among various stakeholders. In this role, it can provide a common platform for diverse constituents to arrive at mutually agreeable priorities and help foster collaborations among them. In addition, SMART Vaccines is being designed so that it can be adapted and configured to help set priori- ties related to health interventions other than vaccines. We intend the initial prototype to serve as a springboard to further development. With iterative enhancements, SMART Vaccines should become a dynamic, living guide that can be applied both domestically and internationally and reapplied according to changing health needs, scien- tific knowledge, and financial constraints. ix

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x Foreword I congratulate the members and staff of the Committee on Identify- ing and Prioritizing New Preventive Vaccines for Development for leading this exciting initiative and bringing the project to this promising stage of development. Harvey V. Fineberg, M.D., Ph.D. President, Institute of Medicine

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Preface Vaccines have profoundly improved the practice and the quality of public health. New opportunities for developing or improving vaccines are prom- ising, even exciting, in this “decade of vaccines.” However, designing a national and global vaccine development strat- egy is a Herculean task. Such an effort would involve a concrete, crosscut- ting understanding of the health, demographic, economic, business, scien- tific, technological, policy, social, and operational dimensions of vaccines. The first step toward tackling this complex mission will be to pri- oritize which vaccines most need to be developed for both domestic and international use. This is a basic task but not an easy one, as the resulting decisions may have significant health, economic, and global consequences. Unfortunately, no universally accepted method or model exists to help guide these important decisions. To make progress in this area, the Institute of Medicine, at the request of the National Vaccine Program Office of the U.S. Department of Health and Human Services, created a 16-member Committee on Identifying and Prioritizing New Preventive Vaccines for Development. A central commit- ment of the committee was to ensure that stakeholders were significantly involved in informing the work and the deliberations of the committee. As part of fulfilling its charge, the committee developed and tested a model designed to assist in the prioritization of new vaccines. The commit- tee also prototyped the beta version of a software named Strategic Multi- Attribute Ranking Tool for Vaccines, or SMART Vaccines. This is a unique product within the National Academies and is expected to be an evolving tool. In this report we describe the committee’s thought process and mod- eling strategy, and introduce the software blueprint of SMART Vaccines Beta through illustrative screenshots. Since this is a work in progress and subject to additional improvements, we have chosen not to release SMART xi

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xii Preface Vaccines Beta along with this report. Further work in the next phase of this study is expected to result in SMART Vaccines 1.0, which would be made available for public use. Through this effort we hope to inspire a community of users who will improve, enhance, and potentially manage the capabilities of this product in an open-source environment and who will generate the required data for operating a multi-stakeholder vaccine prioritization software. On behalf of the committee, I would like to thank a number of indi- viduals and organizations who gave their time, advice, and expertise to our work. The committee is indebted to the Institute of Medicine study staff, whose diligence, creativity, and excellent organizational skills were criti- cal to our success. The committee gratefully acknowledges the outstanding work of Guru Madhavan, the study director; the invaluable contributions of Kinpritma Sangha, our research associate; and the able administrative assistance from Malcolm Biles. We recognize Rose Marie Martinez, director of the Board on Pop- ulation Health and Public Health Practice; Patrick Kelley, director of the Board on Global Health; and Kathleen Stratton, who skillfully led previous Institute of Medicine studies on vaccines, for their thoughtful insights. We deeply appreciate the wise counsel of Clyde Behney, deputy executive offi- cer of the Institute of Medicine, and Marc Gold, associate general counsel of the National Academy of Sciences, as well as the assistance of other staff members throughout this project. The committee is very appreciative of our modeling consultants, Scott Levin and Matthew Toerper from the Johns Hopkins University, and our software developers, Pete Karabetis of VIM Interactive and Michael Kapetanovic of Reef Light Interactive. The committee also thanks Robert Pool, Laura DeStefano, and Hannan Braun for their terrific editorial assis- tance and Samantha Arnett, the National Academies’ Christine Mirzayan Science and Technology Policy Fellow, for her research assistance. Our special thanks go to Jon Andrus, Claire Broome, Joachim Hom- bach, Philip Hosbach, Robert Lawrence, Adel Mahmoud, Gregory Poland, Jaime Sepulveda, Edward Shortliffe, and Alastair Wood whose thoughtful comments and critical feedback during our concept evaluation sessions have helped us improve SMART Vaccines Beta. Finally, we would like to thank the National Vaccine Program Office of the Department of Health and Human Services for its sponsorship, sup- port, and encouragement. Lonnie King, Chair July 2012

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Contents DISCLAIMER xvii SUMMARY 1 1 INTRODUCTION: FROM SMALLPOX TO SMART VACCINES 11 Study Scope and Process, 14 Vaccine Market Dynamics, 16 Prioritization Efforts in the Vaccine Enterprise, 17 Capturing the Value of Vaccination, 21 Previous IOM Efforts in Vaccine Prioritization, 22 Previous WHO Efforts in Vaccine-Related Prioritization, 23 New Technologies and Development Strategies, 24 Stakeholder Priorities, 26 2 MODELING STRATEGY: FROM SINGLE ATTRIBUTE TO MULTIPLE ATTRIBUTES 27 New Vaccine Development (1985–1986) and Vaccines for the 21st Century (2000), 27 Modeling Beyond Cost-Effectiveness, 29 Values and Objectives in Priority Setting, 29 Multi-Criteria Decision-Making Methods, 30 Axiomatic Foundation, 31 Priority Scaling, 31 Sensitivity Analysis, 32 Transparency, 32 Mathematical Programming or Optimization, 33 Analytic Hierarchy Process, 34 Multi-Attribute Utility Theory, 35 xiii

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xiv Contents The Rank Order Centroid Approximation, 36 Data Demands, 37 The Modeling Framework for SMART Vaccines Beta, 37 Foundation for the Computational Submodel, 39 Foundation for the Value Submodel, 53 User Entries and Prioritization Categories, 56 Demographic Inputs, 56 Disease Epidemiology and Clinical Inputs, 57 Economic Inputs, 58 Vaccine Inputs, 58 Disease Burden Summary Measures, 59 Other Attributes, 60 Ranking Method, 60 The Meaning and Interpretation of Weights, 62 The Risk of Double Counting, 63 Discounting and Inflation, 65 Time Horizon and Uncertainty, 66 3 DATA EVALUATION AND SOFTWARE DEVELOPMENT 67 Selection of Vaccine Candidates, 67 Data Sourcing and Analysis, 68 SMART Vaccines Submodels, 73 Development of the Computational Submodel, 74 Evaluation of the Computational Submodel, 76 Simulation of the Value Submodel, 78 The Value Experiment and Scenarios, 84 Software Development: Operational Features of SMART Vaccines Beta, 88 Step 0: Terms of Agreement, 88 Step 1: Values, 88 Step 2: Demographics, 90 Step 3: Disease Burden, 92 Step 4: Vaccines, 97 Step 5: Value Assessment, 102 Step 6: Value Assessment and Score, 103 Consideration of Uncertainty, 103 Uncertainty About the Likelihood of Successful Licensure, 103 Other Uncertainties, 105 Current Capability for Sensitivity Analysis, 107 Beta Concept Evaluation, 108

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xv Contents 4 OBSERVATIONS AND LOOKING FORWARD 109 Data Requirements, 109 Looking Ahead, 111 Model Attributes, 111 Model Evaluation, 112 Trade-Off Considerations, 112 Enhancing the Software Capabilities, 113 REFERENCES 115 APPENDIXES A Mathematical Functions 121 B Candidate Disease Profiles and Data 127 C Stakeholder Speakers 153 D Biographical Information 155

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Disclaimer This report presents SMART Vaccines, a prioritization model and blueprint of associated software in development. This work is being developed by the Institute of Medicine Committee on Identifying and Prioritizing New Preventive Vaccines for Development with the assistance of consultants from Johns Hopkins University and VIM Interactive. This report does not intend to actually provide a ranking of vaccine priorities. It describes the committee’s modeling strategy and assumptions in order to demonstrate a proof of concept. This consensus study is being conducted in two phases. The Phase I statement of task asked for a model to be developed that prioritizes the development of new preventive vaccines, tested with two or three vaccine candidates. In Phase II the committee will ob- tain feedback from the stakeholders on the Phase I model and use it to enhance SMART Vaccines in addition to adding three test vaccine candidates. Thus this report describes a product that is purposefully midstream in development. The committee has chosen to employ a modeling approach based on multi-attribute utility theory, supported by a computa- tional engine and a user-friendly interface. SMART Vaccines Beta processes available or expert-informed data for three conditions (influenza, tuberculosis, and group B streptococcus) in two nations (the United States and South Africa). Thus the examples that appear in this report are limited to comparing hypothetical vaccines only. SMART Vaccines is intended to serve only as a decision-support tool for vaccine prioritization and not to be used as a decision mak- er. Final decisions should not be made based on the scores provided by SMART Vaccines. The Institute of Medicine does not warrant the completeness of the model, the accuracy of the software in devel- opment, or the reliability of any data presented in this report. July 2012 xvii

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