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
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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 Administration of the U.S. 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: 978-0-309-22398-0
International Standard Book Number-10: 0-309-22398-9
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Copyright 2012 by the National Academy of Sciences. All rights reserved.
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Suggested citation: IOM (Institute of Medicine). 2012. Scientific Standards for Studies on Modified Risk Tobacco Products. Washington, DC: The National Academies Press.
THE NATIONAL ACADEMIES
Advisers to the Nation on Science, Engineering, and Medicine
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. 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 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 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.
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.
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
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
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 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:
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
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 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 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 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.
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” cigarettes. 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
consultation with the Institute of Medicine (IOM), regulations and guidance 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 populations 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 behavior. 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 product’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 standards set by the law. In the report, the committee explores the possibility
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 development. It is hoped that this report will provide guidance not only to the FDA but also to all stakeholders (the tobacco industry, academic researchers, 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 appreciative. 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 consultants. 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
Acronyms and Abbreviations
|ARISE||Associates for Research into the Science of Enjoyment|
|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|
|CONSORT||Consolidated Standards of Reporting Trials|
|COPD||chronic obstructive pulmonary disease|
|CSC||cigarette smoke condensate|
|CSE||cigarette smoke extract|
|CTP||Center for Tobacco Products|
|CTR||Council for Tobacco Research|
|DMC||data monitoring committee|
|DMEM||Dulbecco’s Modified Eagle Medium|
|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|
|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|
|HSV-1||herpes simplex virus 1|
|IAPS||International Affective Picture System|
|ICAM-1||inter-cellular adhesion molecule-1|
|IOM||Institute of Medicine|
|IRB||institutional review board|
|IVR||interactive voice response|
|LC-MS/MS||liquid chromatography-tandem mass spectrometry|
|MAPK||mitogen-activated protein kinase|
|MCP-1||monocyte chemotactic protein-1|
|MHBMA||1-hydroxy-2-(N-acetylcysteinyl)-3-butene and 1-(N-acetylcysteinyl)-2-hydroxy-3-butene|
|MRTP||modified risk tobacco product|
|MSA||Master Settlement Agreement|
|NACDA||National Advisory Council on Drug Abuse|
|NCI||National Cancer Institute|
|NF-kB||nuclear factor kappaB|
|NIDA||National Institute on Drug Abuse|
|NNK||nicotine-derived nitrosamine ketone|
|NRC||National Research Council|
|NRT||nicotine replacement therapy|
|OSMB||observational study monitoring board|
|PAMP||pathogen-associated molecular patterns|
|PBS||phosphate buffered saline|
|PCR||polymerase chain reaction|
|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|
|STE||smokeless tobacco extract|
|STROBE||Strengthening the Reporting of Observational Studies in Epidemiology|
|TRADD||tumor necrosis factor receptor type 1-associated death domain protein|
|TRGE||tobacco research governance entity|
|TUNEL||terminal deoxynucleotidyl transferase dUTP nick end labeling|
|VCAM-1||vascular cell adhesion molecule 1|
|VEGF-A||vascular endothelial growth factor A|