METHODOLOGICAL CHALLENGES IN BIOMEDICAL HIV PREVENTION TRIALS

Committee on the Methodological Challenges in HIV Prevention Trials

Board on Global Health

Stephen W. Lagakos and Alicia R. Gable, Editors

INSTITUTE OF THE MEDICINE OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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methodoloGical challenGes in Biomedical hiV preVention trials Committee on the Methodological Challenges in HIV Prevention Trials Board on Global Health Stephen W. Lagakos and Alicia R. Gable, Editors

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, N.W. Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Govern- ing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineer- ing, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropri- ate balance. This study was supported by Contract No. 43580 between the National Academy of Sciences and the Bill & Melinda Gates Foundation. Any opinions, findings, conclu- sions, 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: 978-0-309-11430-1 International Standard Book Number-10: 0-309-11430-6 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap. edu. For more information about the Institute of Medicine, visit the IOM home page at: www.iom.edu. Copyright 2008 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). 2008. Methodological challenges in biomedical HIV prevention trials. 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 wel- fare. 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. 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 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 engineer- ing programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is presi- dent of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Insti- tute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sci- ences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal 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. 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 THE METHODOLOGICAL CHALLENGES IN HIV PREVENTION TRIALS STEPHEN W. LAGAKOS (Chair), Professor of Biostatistics, Department of Biostatistics, Harvard School of Public Health, Boston HARVEY J. ALTER, Chief, Infectious Diseases Section, Department of Transfusion Medicine, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda RONALD BAYER, Professor, Department of Sociomedical Sciences, Mailman School of Public Health, Columbia University, New York SOLOMON R. BENATAR, Professor of Medicine; Director, Bioethics Centre, Department of Medicine, University of Cape Town, South Africa RONALD S. BROOKMEYER, Professor of Biostatistics, Department of Biostatistics; Chair of the Master of Public Health Program, Johns Hopkins Bloomberg School of Public Health, Baltimore CARLOS DEL RIO, Professor of Medicine (Infectious Diseases); Vice Chair for Grady Affairs, Department of Medicine; Director for Clinical Sciences and International Research, Center for AIDS Research; Director of AIDS International Training and Research Program, Emory University School of Medicine, Atlanta DAVID W. FEIGAL, Senior Vice President of Global Regulatory Affairs and Global Safety Surveillance, Élan Pharmaceuticals, San Francisco ELS GOETGHEBEUR, Associate Professor, Department of Applied Mathematics and Computer Science; Chair, Center for Statistics, Ghent University, Belgium LAURA A. GUAY, Associate Professor, Department of Pathology, Johns Hopkins School of Medicine, Balitimore SALLY L. HODDER, Director, HIV Program; Executive Vice Chair, Department of Medicine, University of Medicine and Dentistry of New Jersey, Newark SHABBAR JAFFAR, Reader in Epidemiology, London School of Hygiene and Tropical Medicine, London, UK EDWARD K. KIRUMIRA, Professor of Sociology; Dean, Faculty of Social Sciences, Makerere University, Kampala, Uganda GEORGE W. RUTHERFORD, Salvatore Pablo Lucia Professor and Vice Chair, Department of Epidemiology and Biostatistics; Director, Institute for Global Health, University of California, San Francisco OLIVE SHISANA, President and CEO, South African Human Sciences Research Council, Cape Town, South Africa GINA WINGOOD, Associate Professor, Emory University, Rollins School of Public Health, Atlanta v

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Staff ALICIA R. GABLE, Study Director SARAH SCHEENING, Senior Program Associate KIM LUNDBERG, Research Associate (through August 2007) RACHEL PASSMAN, Senior Program Assistant PATRICK KELLEY, Board Director Consultants SANDRA HACKMAN, Editor vi

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Reviewers T his report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s (NRC’s) Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in mak- ing 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: Zvavahera Michael Chirenje, Department of Obstetrics and Gynaecology, University of Zimbabwe Thomas J. Coates, UCLA AIDS Institute and Division of Infectious Diseases at the David Geffen School of Medicine, University of California, Los Angeles Myron Cohen, Division of Infectious Diseases, University of North Carolina François Dabis, Université Victor Segalen, Bordeaux, France Susan Ellenberg, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania School of Medicine David Holtgrave, Department of Health, Behavior and Society, Johns Hopkins Bloomberg School of Public Health Jeffrey Kahn, Center for Bioethics, University of Minnesota vii

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viii REVIEWERS Veronica Miller, Forum for Collaborative HIV Research, Department of Prevention & Community Health, George Washington University Steve Morin, Center for AIDS Prevention Studies, Division of Prevention Science, Department of Medicine, University of California, San Francisco James D. Neaton, Division of Biostatistics, School of Public Health, University of Minnesota Suniti Solomon, Voluntary Health Services, Y.R. Gaitonde Centre for AIDS Research and Education, Chennai, India Steffanie A. Strathdee, Division of International Health & Cross-Cultural Medicine, School of Medicine, University of California, San Diego Jeremy Sugarman, Berman Institute of Bioethics and Department of Medicine, Johns Hopkins University Scott Zeger, Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health 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 Dr. Kristine M. Gebbie, Columbia University School of Nursing, and Dr. Paul A. Volberding, San Francisco VA Medical Center and Department of Medicine, University of California, San Francisco. Appointed by the NRC and the Institute of Medicine, they were responsible for making certain that an independent examination of this report was carried out in accordance with institu- tional 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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Contents Summary 1 Introduction 27 Charge to the Committee, 28 Scope of Work, 29 Study Process, 32 Study Considerations, 32 Report Structure, 33 1 The Status and Challenges of Biomedical HIV Prevention Trials 37 Recent Late-Stage Trials of Non-Vaccine Biomedical Preventions, 47 Methodological Challenges in Biomedical HIV Prevention Trials, 55 Behavioral and Sociocultral Influences on Biomedical Trials, 58 2 Basic Design Features: Size, Duration, and Type of Trials, and Choice of Control Group 69 Trial Sample Size and Duration, 69 Efficacy vs. Effectiveness Trials, 75 Choice of Control Group, 82 3 Design Considerations: Risk-Reduction Counseling 88 Ethical Reasons for Risk-Reduction Counseling, 89 Effectiveness of Behavioral Risk-Reduction Interventions, 90 ix

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x CONTENTS Adapting Efficacious Behavioral Risk-Reduction Interventions, 96 Evaluating Behavioral Risk-Reduction Interventions in the Context of a Biomedical Intervention Trial, 97 Summary, 99 4 Design Considerations: Pregnancy 104 When Pregnancy Occurs During Trials, 105 Statistical Implications of Pregnancies Occurring During Trials, 106 Collecting Information on Benefits and Risks, 107 5 Design Considerations: Adherence 119 Defining Adherence, 120 Measuring Adherence, Sexual Behavior, and Condom Use, 123 Strategies to Improve Adherence, 131 Analyzing Adherence, 135 6 Design Considerations: Recruitment and Retention 148 Recruitment Strategies, 148 Retention Strategies, 151 7 Site Preparedness 160 Developing Capacity and Infrastructure, 161 Protocol Development, 168 Pretrial Research, 169 Ensuring Sustainability, 170 8 Estimating HIV Incidence 175 Direct Longitudinal Follow-Up: Cohort Studies, 176 Biomarkers of Recent Infection, 177 Mathematical Models, 181 9 Interim Monitoring and Analysis of Results 186 Ensuring Effective Interim Monitoring, 186 Analyzing Trial Results, 196 10 Alternative Designs 204 Factorial and Other Multiarm Designs, 205 Discordant Couple Designs, 211 Noninferiority Designs, 214 Cluster Randomization, 215 Dynamic Designs, 219

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xi CONTENTS APPENDIXES A Public Committee Meeting Agendas 225 B Acronyms 234 C Supporting Materials for Chapter 2 236 D Methods for Analyzing Adherence 245 E Committee Biographies 250

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