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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
