Scientific Standards
FOR STUDIES ON
Modified Risk Tobacco Products

Committee on Scientific Standards for Studies on
Modified Risk Tobacco Products

Board on Population Health and Public Health Practice

INSTITUTE OF MEDICINE
OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

Washington, D.C.

www.nap.edu



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Scientific Standards FOR STUDIES ON Modified Risk Tobacco Products Committee on Scientific Standards for Studies on Modified Risk Tobacco Products Board on Population Health and Public Health Practice

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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 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. This study was supported by Contract No. HHSF22301011T, Task Order #17 between the National Academy of Sciences and the Food and Drug Administra - tion of the U.S. Department of Health and Human Services. Any opinions, find - ings, 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: 978-0-309-22398-0 International Standard Book Number-10: 0-309-22398-9 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; http://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. Scientific Standards for Studies on Modified Risk Tobacco Products. 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 outstanding engineers. It is autonomous in its administration and in the selection of its mem - bers, sharing with the National Academy of Sciences the responsibility for advis - ing 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 SCIENTIFIC STANDARDS FOR STUDIES ON MODIFIED RISK TOBACCO PRODUCTS Jane E. Henney (Chair), Professor of Medicine and Public Health Sciences, University of Cincinnati, Ohio Timothy B. Baker, Professor of Medicine and Associate Director, Center for Tobacco Research and Intervention, University of Wisconsin, Madison Rebecca Bascom, Professor of Medicine, Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey Shyam Biswal, Professor, Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland Daniel Carpenter, Professor of Government, Center for Government and International Studies, Harvard University, Boston, Massachusetts Constantine Gatsonis, Henry Ledyard Goddard University Professor and Chair, Department of Biostatistics, Brown University, Providence, Rhode Island Gary H. Gibbons,1 Professor of Medicine and Director, Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia Bonnie L. Halpern-Felsher, Professor, Department of Pediatrics, Division of Adolescent Medicine, University of California, San Francisco Stephen S. Hecht, Wallin Professor of Cancer Prevention, Department of Laboratory Medicine and Pathology, Masonic Cancer Center, University of Minnesota, Minneapolis Peter K. Honig, Head, Global Regulatory Affairs, AstraZeneca, Wilmington, Delaware Richard J. O’Connor, Associate Member, Department of Health Behavior, Division of Cancer Prevention and Population Sciences, Roswell Park Cancer Institute, Buffalo, New York Joel L. Schwartz, Professor, Oral Medicine and Pathology, Colleges of Dentistry and Medicine, University of Illinois at Chicago Donna-Bea Tillman, Director of Regulations and Policy, Microsoft Corporation, Health Solutions Group, Chevy Chase, Maryland Alastair J. J. Wood, Managing Director, Symphony Capitol LLC, New York, New York Anna H. Wu,2 Professor, Preventive Medicine, Division of Epidemiology, University of Southern California, Los Angeles 1 Committee member resigned October 2011. 2 Committee member resigned June 2011. v

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Study Staff Kathleen Stratton, Study Director (through September 2011) Joel Wu, Study Director (from September 2011) Michelle C. Catlin, Senior Program Officer (from September 2011) Erin Rusch, Research Associate (from September 2011) Hannan Braun, Research Assistant Malcolm Biles, Senior Program Assistant Rose Marie Martinez, Director, Board on Population Health and Public Health Practice Consultants Suchitra Krishnan-Sarin, Associate Professor of Psychiatry and Vice Chair, Human Investigations Committee, Yale University School of Medicine Holly E. R. Morrell, Assistant Professor, Department of Psychology, Loma Linda University Gary Stoner, Professor of Medicine, Department of Medicine, Medical College of Wisconsin Wendy Theobald, Researcher, Center for Tobacco Research and Intervention, University of Wisconsin Medical School Robert B. Wallace, Irene Ensminger Stecher Professor of Epidemiology and Internal Medicine, Department of Epidemiology, College of Public Health, The University of Iowa 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 procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its pub- lished 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: Linda S. Birnbaum, National Institute of Environmental Health Sciences Richard J. Bonnie, University of Virginia David B. Coultas, The University of Texas Health Science Center at Tyler Louis Anthony Cox, Jr., Cox Associates Sean P. David, Stanford University School of Medicine Jonathan Foulds, Penn State College of Medicine Mitchell H. Gail, National Cancer Institute John R. Hughes, University of Vermont College of Medicine Donald S. Kenkel, Cornell University Caryn Lerman, University of Pennsylvania Dean Lillard, Cornell University Ana Navas-Acien, Johns Hopkins Bloomberg School of Public Health vii

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viii REVIEWERS Dan Romer, The Annenberg Public Policy Center of the University of Pennsylvania Barry Sickels, AstraZeneca Brian L. Strom, Perelman School of Medicine at the University of Pennsylvania Clifford H. Watson, Centers for Disease Control and Prevention Although the reviewers listed above have provided many construc- tive 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 May R. Berenbaum, University of Illinois, and Robert S. Lawrence, Johns Hopkins Bloomberg School of 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 car- ried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final con - tent of this report rests entirely with the authoring committee and the institution.

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Preface Tobacco use remains the leading cause of preventable morbidity and mortality in the United States. While the adverse health effects of tobacco use are well established in the scientific literature, an understanding of the science is not required to appreciate the human cost; every day, people see close friends and family suffer with the consequences of tobacco use. Every day, cigarette smokers try to quit, and yet, the vast majority of them will fail. An estimated 70 percent of smokers want to quit completely, and while 45 percent attempt to quit each year, only 6 percent of smokers are able to successfully quit. Instead of quitting, many cigarette smokers have sought a product with less risk, and for decades, the tobacco industry has purposefully misled the public into believing that there have been safer alternatives. The most prominent example is the “light” cigarette—a product implied to be safer, which in fact, when used, was as hazardous as “regular” ciga - rettes. The prospect of a less hazardous tobacco product is not in and of itself problematic. The fundamental issue is that if a product is going to be marketed as being “safer,” then the claim must be true. Section 911 of the Family Smoking Prevention and Tobacco Control Act of 2009 directly addresses the problem of false and unfounded claims for modified risk tobacco products (MRTPs). The law remains open to the possibility that less hazardous products that reduce harm to public health may enter the market, but it gives the government the authority and the power to assure that they are actually reducing risk and harm. The law also directed the U.S. Food and Drug Administration (FDA) to develop, in ix

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x PREFACE consultation with the Institute of Medicine (IOM), regulations and guid - ance on the design and conduct of scientific studies of MRTPs, which was the task of the committee. Regulating tobacco products creates unique challenges. Unlike most products regulated by the FDA, tobacco is inherently hazardous and offers primarily risks rather than any significant physiological benefit to the user’s health. Recognizing this, the law provides a public health standard and additional requirements of these products that must be considered as the FDA regulates these products. First, the law creates a public health standard that requires the FDA to evaluate the effect of the MRTP on not only users of the product, but also nonusers and the entire population as a whole. Second, the law requires postmarket observational studies of the MRTPs as a condition of approval, and also requires the annual submission of data about the MRTPs to the FDA. Finally, the law sets expiration dates on the orders to market the MRTPs. In addition, the FDA can revoke an order for any failure to comply with regulatory requirements or if there is evidence that the product is in fact harmful to public health. The evaluation of the effect of MRTPs on public health will require a wide range of evidence and therefore will require many different types of study designs, including studies of the composition of MRTPs and studies of human exposure, human health effects, the likelihood of addiction and abuse, and the perception and understanding of the product by the public. Furthermore, the evidence must be able to reliably support predictions about the effect of marketing the product on public health, and therefore these studies must be properly designed and rigorously conducted. Study designs will need to include all relevant populations including popula - tions at a high risk for tobacco use. Study designs must be able to support not only inferences about the mechanisms of the products effects, but also predictions about the products’ effects in the real world. Also, relevant to the committee’s deliberations as it considered the conduct of studies is the history of the tobacco industry’s past behav - ior. The tobacco industry has a long and well-documented history of illegal and improper conduct, and its practices have only recently been regulated. Because of the health impact of its products and the opaque practices that have been engaged by the tobacco industry, many academic institutions and their faculty that would normally be involved in a prod - uct’s evaluation have been separated from conducting research related to tobacco products for many years. Thus, the committee concluded that the tobacco industry currently lacks not only the trustworthiness, but also the expertise, infrastructure, and other resources needed to independently produce the scientific evidence necessary to meet the public health stan- dards set by the law. In the report, the committee explores the possibility

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xi PREFACE of new governance mechanisms to address this problem, including the potential creation of a third-party governance entity. The committee does recognize that there are MRTPs that may not be developed by the tobacco industry and thus believes the need for third-party governance may not be applicable in all cases. Overall, the committee’s goal was to develop enduring guidelines and considerations for the production of credible and comprehensive evidence of the effects of MRTPs. The committee emphasized that the principle of public disclosure, which adds the sunshine of openness and transparency, must be applied to the entire process of product develop - ment. It is hoped that this report will provide guidance not only to the FDA but also to all stakeholders (the tobacco industry, academic research- ers, and journal editors, etc.) on how the important work of evaluating these products can move ahead. This committee has volunteered a great deal of time and energy into completing a remarkably complex task, and for that I am very appre- ciative. I thank its members for their collective and individual efforts. I would also like to extend my own and the committee’s gratitude to Suchitra Krishnan-Sarin, Holly E. Morrell, Gary Stoner, Wendy Theobald, and Robert B. Wallace for their assistance and expertise as external con - sultants. On behalf of the committee, appreciation is also extended to each who provided information, data, or even an informed opinion during open sessions or by mail. Finally, the committee and I would like to thank the IOM staff for their hard work and diligence: Kathleen Stratton, Joel Wu, Michelle C. Catlin, Erin Rusch, Hannan Braun, Malcolm Biles, and Rose Marie Martinez. Jane E. Henney, Chair Committee on Scientific Standards for Studies on Modified Risk Tobacco Products

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Contents SUMMARY 1 1 INTRODUCTION 21 Tobacco Harm in the United States, 21 Harm Reduction, 24 History of Tobacco Regulation in the United States, 26 FSPTCA Overview, 34 Section 911, 34 Comparison of Regulatory Frameworks, 38 Burden of Proof, 39 Committee Charge and Statement of Task, 40 Committee Process, 41 Overview of the Report, 42 References, 42 2 GOVERNANCE AND CONDUCT OF STUDIES 45 History of Scientific Research Funded or Conducted by the Tobacco Industry, 46 Relevance of Third-Party Governance, 54 Toward a Tobacco Research Governance Entity, 61 Conclusions, 66 References, 67 xiii

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xiv CONTENTS 3 EVIDENCE BASE AND METHODS FOR STUDYING HEALTH EFFECTS 73 Product Composition, 74 Biomarkers, 80 Preclinical Studies, 96 Clinical Studies, 115 The Use of Modeling in Estimating Health Effects of MRTPs, 131 References, 132 4 METHODS FOR INVESTIGATING ADDICTIVE POTENTIAL 149 Evaluation of Reinforcement and Addictive Potential, 149 Evaluation of Public Health Risk Using Randomized Clinical Trial Methods, 165 References, 184 5 METHODS FOR STUDYING RISK PERCEPTION AND RISK COMMUNICATION 191 Background and Rationale: Importance of Risk Perceptions, 192 Perceptions of Epidemiologic Data for Tobacco Use, 192 Perceptions of Tobacco-Related Risks and Benefits to the Individual, 193 Scientific Standards for Studies on Risk Perception and Risk Communication, 199 References, 213 6 DECISION MAKING AND OVERSIGHT OF MRTP STUDIES: FINDINGS AND RECOMMENDATIONS 221 Issues with Evidence, 222 Integration of Evidence and Decision Making, 229 Findings and Recommendations, 238 References, 244 APPENDIXES A Section 911 of the Family Smoking Prevention and Tobacco Control Act of 2009 247 B Chapters 1 and 2 from Evaluation of Biomarkers and Surrogate 257 Endpoints in Chronic Disease C Committee Biographies 339 D Meeting Agendas 347

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xv CONTENTS BOXES S-1 Statement of Task, 3 1-1 Advertising, Promotion, and Marketing Restrictions Resulting from the Master Settlement Agreement, 33 1-2 Definitions and Historical Comparisons, 36 1-3 Statement of Task, 40 3-1 Definitions Related to Biomarkers, Clinical Endpoints, and Surrogate Endpoints, 81 3-2 Some Examples of Short-Term Health Outcomes for Which MRTPs Might Be Evaluated, 117 5-1 Sample Items to Assess Tobacco Use, 204 5-2 Sequence of Questions to Assess Prior Smoking Cessation Attempts, 205 5-3 Sample Questions for Measuring Intentions to Use an MRTP, 210 FIGURE 5-1 Sample advertisement rating questions, 212 TABLES S-1 Evidence Domains Relevant to an MRTP Application and Examples of Types of Findings, 9 1-1 Diseases and Conditions Caused by Active Cigarette Smoking, 22 1-2 Summary of Milestones in Decreasing Indoor Tobacco Smoke in the United States, 28 3-1 Representative Exposure Biomarkers Related to Tobacco Carcinogens and Toxicants, 84 3-2 Summary of Preclinical Studies for the Evaluation of Harms from Smokeless Tobacco Products, 98 3-3 Summary of Preclinical Studies for the Evaluation of Toxicity from Cigarette Smoke Products, 105 3-4 Selected Studies of Carcinogenicity in Response to Exposure to Cigarette-Smoke Condensate in Mouse, Rat, and Rabbit, 111 4-1 CONSORT 2010 Checklist of Information to Include When Reporting a Randomized Trial, 169

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xvi CONTENTS 6-1 Evidence Domains Relevant to an MRTP Application and Examples of Types of Findings, 230 6-2 Four Broad Scenarios for an MRTP Application, 231

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Acronyms and Abbreviations 1-HOP 1-hydroxypyrene 3HdT tritiated thymidine 4-NQO 4-Nitroquinoline 1-oxide ARISE Associates for Research into the Science of Enjoyment BaP benzo[a]pyrene bp base pair 5′-bromodeoxy-uridine BrdU CDC Centers for Disease Control and Prevention CER comparative effectiveness research CFR Code of Federal Regulations CIAR Center for Indoor Air Research CISNET Cancer Intervention and Surveillance Modeling Network CO carbon monoxide CONSORT Consolidated Standards of Reporting Trials COPD chronic obstructive pulmonary disease CRP C-reactive protein CS cigarette smoke CSC cigarette smoke condensate CSE cigarette smoke extract CTP Center for Tobacco Products CTR Council for Tobacco Research xvii

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xviii ACRONYMS AND ABBREVIATIONS 4′,6-diamidino-2-phenylindole DAPI DMBA dimethylbenz[a] anthracene DMC data monitoring committee DMEM Dulbecco’s Modified Eagle Medium DMSO dimethyl sulfoxide DSMB data and safety monitoring board DSM-IV Diagnostic and Statistical Manual of Mental Disorders, 4th Edition ELISA enzyme-linked immunosorbent assay EPA Environmental Protection Agency FD&C Act Food, Drug, and Cosmetic Act FDA Food and Drug Administration FDAAA Food and Drug Administration Amendments Act FSPTCA Family Smoking Prevention and Tobacco Control Act of 2009 FTC Federal Trade Commission GC-MS gas chromatography-mass spectrometry GC-MS/MS gas chromatography-tandem mass spectrometry H1N1 Influenza A HBMA 4-hydroxybut-2-yl mercapturic acid HBSS Hanks buffered salt solution HEI Health Effects Institute HEMA 2-hydroxyethyl mercapturic acid HHS U.S. Department of Health and Human Services HONC Hooked on Nicotine Checklist HPMA 3-hydroxypropyl mercapturic acid hr hour HSV-1 herpes simplex virus 1 IAPS International Affective Picture System ICAM-1 inter-cellular adhesion molecule-1 IL-8 interleukin 8 INS-GAS insulin-gastrin IOM Institute of Medicine IRB institutional review board IVR interactive voice response LC-MS/MS liquid chromatography-tandem mass spectrometry

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xix ACRONYMS AND ABBREVIATIONS MAPK mitogen-activated protein kinase MCA methylcoanthrene MCP-1 monocyte chemotactic protein-1 MHBMA 1-hydroxy-2-(N-acetylcysteinyl)-3-butene and 1-(N-acetylcysteinyl)-2-hydroxy-3-butene mRNA messenger RNA MRTP modified risk tobacco product MSA Master Settlement Agreement MTS 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)- 2-(4-sulfophenyl)-2H-tetrazolium MTT 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide NACDA National Advisory Council on Drug Abuse NCI National Cancer Institute NF-kB nuclear factor kappaB NG not given NIDA National Institute on Drug Abuse NNAL 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol NNK nicotine-derived nitrosamine ketone NNN N-nitrosonornicotine NRC National Research Council NRT nicotine replacement therapy OSMB observational study monitoring board OTC over-the-counter PAMP pathogen-associated molecular patterns PBS phosphate buffered saline PCR polymerase chain reaction poly(I:C) Polyinosinic:polycytidylic acid ppm parts per million PREP potential reduced-exposure product RCT randomized controlled trial RFA requests for application RICO Racketeer Influenced and Corrupt Organizations RNS reactive nitrogen species ROS reactive oxygen species RUF Reagan-Udall Foundation SPMA S-phenylmercapturic acid ST smokeless tobacco

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xx ACRONYMS AND ABBREVIATIONS STE smokeless tobacco extract STROBE Strengthening the Reporting of Observational Studies in Epidemiology TI Tobacco Institute TRADD tumor necrosis factor receptor type 1-associated death domain protein TRGE tobacco research governance entity TSNA tobacco-specific N-nitrosamines TUNEL terminal deoxynucleotidyl transferase dUTP nick end labeling VCAM-1 vascular cell adhesion molecule 1 VEGF-A vascular endothelial growth factor A wk week yrs years