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1
Introduction
TOBACCO HARM IN THE UNITED STATES
Smoking is the leading cause of preventable morbidity and mortality
in the United States, contributing to approximately 443,000 premature
deaths each year nationally (CDC, 2008). Cigarette smoking is the most
common form of tobacco use; there are an estimated 46.6 million current
adult smokers, and initial use of tobacco typically occurs in youth (CDC,
2010; HHS, 1994). Many of the approximately 1,000 adolescents who
initiate smoking each day continue use to become regular adult smokers
(SAMHSA, 2011).
Smoking-related disease causes more deaths than alcohol, illicit drug
use, homicide, and suicide combined (Mokdad et al., 2004). In total,
tobacco-related mortality amounts to approximately 5.1 million years
of potential life lost per year (CDC, 2008). Lung cancer, ischemic heart
disease, and chronic obstructive pulmonary disease (COPD) are the lead -
ing causes of smoking-attributable deaths (CDC, 2008). Smoking can also
increase a person’s risk for stroke and other forms of cancers. A list of
documented diseases and conditions that are caused by cigarette smok-
ing can be found in Table 1-1. In total, cigarette smoking accounts for
approximately 80 percent of deaths from COPD, and at least 30 percent
of deaths due to cancers (CDC, 2008). Another 8.6 million smokers in
the United States live with a smoking-attributable illness (CDC, 2009a).
Smoking also imposes enormous costs on the U.S. health care system and
economy, with an estimated $193 billion in losses due to health care costs
and productivity losses per year (CDC, 2008).
21
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22 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
TABLE 1-1 Diseases and Conditions Caused by Active Cigarette
Smokinga
Disease Effects
Tumor sites for which there is sufficient evidence:
Malignant
neoplasmsb
• ral cavity
O
• ropharynx, nasopharynx, and hypopharynx
O
• esophagus (adenocarcinoma and squamous-cell carcinoma)
O
• tomach
S
• olorectum
C
• iver
L
• ancreas
P
• asal cavity and paranasal sinuses
N
• arynx
L
• ung
L
• terine cervix
U
• vary (mucinous)
O
• rinary bladder
U
• idney (body and pelvis)
K
• reter
U
• one marrow (myeloid leukaemia)
B
Tumor site for which there is limited evidence:
• emale breast
F
Cardiovascular • oronary heart disease
C
diseases • erebrovascular disease
C
• therosclerosis
A
• ortic aneurysm
A
Respiratory • Chronic obstructive pulmonary disease (bronchitis, emphysema,
diseases in chronic airway obstruction)
adults • neumonia
P
• Premature onset of and an accelerated age-related decline in lung
function
• All major respiratory symptoms (e.g., coughing, phlegm, wheezing,
dyspnea)
• oor asthma control
P
Respiratory • mpaired lung growth
I
diseases in • Respiratory symptoms and asthma-related symptoms (e.g., wheezing)
young people in childhood and adolescence
• Early onset of lung function decline during late adolescence and
early adulthood
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23
INTRODUCTION
TABLE 1-1 Continued
Disease Effects
Reproductive • udden infant death syndrome
S
and perinatal • educed fertility in women
R
conditions • etal growth restriction
F
• ow birth weight
L
• remature rupture of the membranes
P
• lacenta previa
P
• lacental abruption
P
• reterm delivery and shortened gestation
P
• espiratory distress syndrome
R
Miscellaneous • ataracts
C
• ip fractures
H
• ow bone density
L
• eptic ulcer disease in persons who are Helicobacter pylori positive
P
• Diminished health status (i.e., increased absenteeism from work,
increased use of medical care services)
• Adverse surgical outcomes related to wound healing and
respiratory complications
SOURCE:
a Modified from Giovino (2007). Reprinted from American Journal of Preventive Medicine, Vol 6,
Supplement 1, Gary A. Giovino, The Tobacco Epidemic in the United States, S318-S326,
Copyright 2007, with permission from Elsevier.
b Data from Secretan et al. (2009).
Cigarette smoking is harmful for nonusers as well. Secondhand
smoke (also called environmental tobacco smoke, involuntary smoke, or
passive smoke) is responsible for approximately 50,000 annual deaths,
largely due to lung cancer, coronary heart disease, and sudden infant
death syndrome (HHS, 2006).
Other forms of tobacco use, such as smokeless tobacco products and
cigars, also have harmful consequences. Smokeless tobacco use—primarily
in the form of chewing tobacco and snuff—causes cancer of the oral cavity
and pancreas and other oral health problems such as gum recession and
leukoplakia (IARC, 2007).
The United States faces particular challenges with youth smoking. Of
the approximately 1 million people who start smoking regularly each year,
39.5 percent are under the age of 18 (SAMHSA, 2011). Like adult smokers,
quit rates remain low in adolescent smokers (Mermelstein, 2003). It is
estimated that 50 percent of those who start smoking in adolescence go
on to smoke for 16 to 20 years (Pierce and Gilpin, 1996).
Since the mid 1960s when smoking rates among adults in the United
States peaked at more than 42 percent, efforts to reduce cigarette use have
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24 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
made significant progress (CDC, 1999). The current prevalence of cigarette
use is 20.6 percent among adults and 19.5 percent in youth (CDC, 2010).
These tobacco control efforts have been recognized by the Centers for
Disease Control and Prevention (CDC) as a major public health achieve -
ment, both of the 20th century and of the first decade of the 21st century
(CDC, 2011a). Despite this improvement in the past half-century, however,
progress has stalled in recent years. After substantial declines in adult
smoking rates through the 1980s and 1990s, the rate of U.S. adult smokers
has remained relatively static, from 20.9 percent in 2004 to 20.6 percent
in 2009 (CDC, 2010). This lack of continued progress is also seen in youth
smoking rates. Between 1997 and 2003, smoking prevalence among high
school students declined substantially from 36.4 percent to 21.9 percent;
this decline slowed from a youth smoking rate of 21.9 percent in 2003 to
19.5 percent in 2009 (CDC, 2011a).
Current disparities in tobacco use patterns are another cause for con -
cern; trends in smoking show higher tobacco use rates among certain
ethnic and racial minority groups, persons with low socioeconomic status,
sexual minorities, and people in the South and Midwest of the United
States (CDC, 2011b; HHS, 1998).
In spite of the well-established health risks for smoking and other
forms of tobacco use, some individuals still choose to use tobacco for a
number of potentially desired effects or outcomes. These effects or out-
comes may range from perceived social benefits (Halpern-Felsher et al.,
2004), to discrete physiological effects (Vezina et al., 2007), or even the mere
enjoyment of the flavor and aroma of tobacco. Although the ultimate deci-
sion of whether the benefits outweigh the risks is up to the individual, the
committee firmly maintains that the individual and public health hazards
of tobacco use far outweigh any potentially desired effects of tobacco use.
HARM REDUCTION
The concept of harm reduction informs the public health rationale
for permitting the development and potential marketing of modified risk
tobacco products (MRTPs). The basic premise of harm reduction is the
continuation of a potentially hazardous or dangerous behavior, with the
aim of decreasing the potentially adverse consequences of these behaviors
(Marlatt, 2002). The reduced risk can be for either participants or non -
participants of the potentially harmful activity. Harm reduction is most
typically associated with illicit substance use, including opioid substitu -
tion therapies, needle exchange programs, and supervised injecting sites.
Harm reduction strategies can incorporate a wide spectrum of individual
tactics, from safer use, to managed use, to complete abstinence from the
risk behavior. In the context of tobacco harm reduction, “a product is
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25
INTRODUCTION
harm reducing if it lowers total tobacco-related mortality and morbidity,
even though use of that product may involve continued exposure to
tobacco-related toxicants” (IOM, 2001).
Modification of the risk profiles of tobacco products is only one of
several potential tactics to reduce the harm of tobacco. In addition to
preventing initiation of tobacco use and promoting cessation of tobacco
use, MRTPs with reduced risk profiles may potentially lessen the harm
of tobacco for the substantial portion of U.S. smokers who are unable
or unwilling to abstain. Of the 46 million adult smokers in the United
States, an estimated 70 percent of smokers wish to quit completely, and
approximately 45 percent of smokers attempt to quit each year (CDC,
2002, 2009b). However, only approximately 6 percent of the smokers who
attempt to quit are successful for 1 month or more (HHS, 2000). Tobacco
harm reduction efforts target users that are unwilling or unable to quit
as one component of a comprehensive, multifaceted strategy to minimize
the negative health effects of tobacco use.
In 2001 the Institute of Medicine (IOM) specifically addressed the
potential of tobacco harm reduction in Clearing the Smoke: Assessing
the Science Base for Tobacco Harm Reduction. The report articulated six
principle conclusions:
1. For many diseases attributable to tobacco use, reducing risk of
disease by reducing exposure to tobacco toxicants is feasible.
2. PREPs1 have not yet been evaluated comprehensively enough
(including for a sufficient time) to provide a scientific basis for conclud-
ing that they are associated with a reduced risk of disease compared to
conventional tobacco use.
3. Surrogate biological markers that are associated with tobacco-
related diseases could be used to offer guidance as to whether or not
PREPs are likely to be risk-reducing.
4. Currently available PREPs have been or could be demonstrated to
reduce exposure to some of the toxicants in most conventional tobacco
products.
5. Regulation of all tobacco products, including conventional tobacco
products as recommended in IOM (1994), as well as all other PREPs is
a necessary precondition for assuring a scientific basis for judging the
effects of using PREPs and for assuring that the health of the public is
protected.
6. The public health impact of PREPs is unknown. They are poten-
tially beneficial, but the net impact on population health could, in fact, be
negative.
1 PREPs or potential reduced-exposure products are defined in Box 1-2.
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26 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
In the report, the IOM also suggests a research agenda for evaluat-
ing the potential for harm reduction of PREPs (IOM, 2001). Since the
publication of Clearing the Smoke, significant advances have been made in
the science of evaluating tobacco products (Carter et al., 2009; Cohen et
al., 2009; Hatsukami et al., 2005, 2006, 2007, 2009; O’Connor et al., 2009;
Shields, 2002). Also, in following the report’s conclusion that harm reduc -
ing products might be possible, tobacco companies have developed a
large number of PREPs. Several products remain on the market; however,
no products have been proven to reduce harm or risk.
HISTORY OF TOBACCO REGULATION IN THE UNITED STATES
The Family Smoking Prevention and Tobacco Control Act of 2009
(FSPTCA)2 grants the Food and Drug Administration (FDA) broad author-
ity to regulate the manufacturing, distribution, and marketing of tobacco
products. This law marks an important turning point in the history of
tobacco control in the United States. In fewer than 70 years, the profile of
tobacco has changed from that of a popular luxury item associated with
athletes, movie stars, and celebrities to that of a highly regulated public
health hazard. However, despite decades of heightened concern and pub-
lic awareness, smoking is still the leading cause of preventable death in
the United States.
Modern tobacco control began in the 1940s and 1950s with scientific
and public health authorities establishing through emerging evidence that
smoking causes disease. Prior to the 1940s, little existing evidence linked
tobacco use to disease. As late as the 1950s, certain cigarettes were still mar-
keted with explicitly positive health claims. The 2001 IOM report chronicled
the early health claims of tobacco manufacturers in response to the health
concerns of smokers (IOM, 2001).
Evidence collected in the 1940s and 1950s confirmed the link between
smoking and lung cancer. Landmark publications from Richard Doll and
Austin Hill, and from Ernst Wynder and Evarts Ambrose Graham, pro-
vided convincing evidence that smoking caused lung cancer (Doll and
Hill, 1950, 1956; Wynder and Graham, 1950). In 1962, a report from the
Royal College of Physicians of London reaffirmed findings that smoking
significantly increased the risk of death from lung and heart disease (Royal
College of Physicians, 1962). In 1964, the Surgeon General released a report
that authoritatively linked smoking to lung cancer, cardiovascular disease,
and emphysema (U.S. Public Health Service, 1964).
2 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat.
1776 (June 22, 2009).
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27
INTRODUCTION
In addition to authoritatively linking smoking to disease, the Royal
College of Physicians and the Surgeon General reports also directed
the evidence to policy makers and the public with recommendations to
reduce the harm of smoking. The Royal College report specifically recom-
mended preventive measures including filtration of smoke, modifications
of tobacco, and discouragement of smoking. The report also made specific
recommendations for government action, including public education,
taxation, and restrictions on advertisement and smoking in public places.
In response to the Surgeon General’s report, which stated that “ciga-
rette smoking is a health hazard of sufficient importance in the United
States to warrant appropriate remedial action” (U.S. Public Health Service,
1964), Congress passed the Federal Cigarette Labeling and Advertising Act
of 1965 requiring that the statement “Caution: cigarette smoking may be
hazardous to your health” be placed on every cigarette package. In 1970,
Congress strengthened the regulation through the Public Health Cigarette
Smoking Act, which banned cigarette advertisements on any medium of
electronic communication subject to the jurisdiction of the Federal Trade
Commission. In total between 1965 and 2000, Congress passed six pieces
of legislation to address the harm of tobacco use, including
• the Federal Cigarette Labeling and Advertising Act of 1965;3
• the Public Health Cigarette Smoking Act of 1970;4
• the Alcohol and Drug Abuse Amendments of 1983;5
• the Comprehensive Smoking Education Act of 1984;6
• the Comprehensive Smokeless Tobacco Health Education Act of
1986;7 and
• the Alcohol, Drug Abuse, and Mental Health Administration Reor-
ganization Act of 1992.8
Additional smoking-related regulations and interventions have fol-
lowed, with the recognition of secondhand smoke as a serious public
health hazard (IOM, 2010), including the restriction of smoking in govern-
ment facilities and on all commercial U.S. airline flights. (See Table 1-2 for
3 Federal Cigarette Labeling and Advertising Act of 1965 , Public Law 89-92, 79 Stat. 282
(July 27, 1965).
4 Public Health Cigarette Smoking Act of 1970, Public Law 91-222, 84 Stat. 87 (April 1, 1970).
5 Alcohol and Drug Abuse Amendments of 1983, Public Law 98-24, 97 Stat. 175 (April 26, 1983).
6 Comprehensive Smoking Education Act of 1984, Public Law 98-474, 98 Stat. 2200, 98th
Congress (October 12, 1984).
7 Comprehensive Smokeless Tobacco Health Education Act of 1986 , Public Law 99-252, 100 Stat.
30, 99th Congress (February 27, 1986).
8 Alcohol, Drug Abuse, and Mental Health Administration Reorganization Act of 1992 , Public
Law 102-321, 106 Stat. 323, 102nd Congress (July 10, 1992).
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28 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
TABLE 1-2 Summary of Milestones in Decreasing Indoor Tobacco
Smoke in the United States
Year Event
1971 The Surgeon General proposes a federal smoking ban in public places.
1972 The first report of the Surgeon General to identify secondhand smoke as
posing a health risk is released.
1973 Arizona becomes the first state to restrict smoking in several public places.
The Civil Aeronautics Board requires no-smoking sections on all commercial
airline flights.
1974 Connecticut passes the first state law to apply smoking restrictions in
restaurants.
1975 Minnesota passes a statewide law restricting smoking in public places.
1977 Berkeley, California, becomes the first community to limit smoking in
restaurants and other public places.
1983 San Francisco passes a law to place private workplaces under smoking
restrictions.
1986 A report of the Surgeon General focuses entirely on the health consequences
of involuntary smoking, proclaiming secondhand smoke a cause of lung
cancer in healthy nonsmokers. The National Research Council issues a
report on the health consequences of involuntary smoking. Americans
for Nonsmokers’ Rights becomes a national group; it had formed as the
California Group Against Smoking Pollution.
1987 The U.S. Department of Health and Human Services establishes a
smoke-free environment in all its buildings, affecting 120,000 employees
nationwide. Minnesota passes a law requiring all hospitals in the state to
prohibit smoking by 1990. A Gallup poll finds, for the first time, that a
majority (55 percent) of U.S. adults favor a complete ban on smoking in all
public places.
1988 A congressionally mandated smoking ban takes effect on all domestic
airline flights of 2 hours or less. New York City’s ordinance for clean
indoor air takes effect; the ordinance bans or severely limits smoking in
various public places and affects 7 million people. California implements a
statewide ban on smoking aboard all commercial intrastate airplanes, trains,
and buses.
1990 A congressionally mandated smoking ban takes effect on all domestic
airline flights of 6 hours or less. The U.S. Environmental Protection Agency
(EPA) issues a draft risk assessment of secondhand smoke.
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29
INTRODUCTION
TABLE 1-2 Continued
Year Event
1991 The National Institute for Occupational Safety and Health issues a bulletin
recommending that secondhand smoke be reduced to the lowest feasible
concentration in the workplace.
1992 Hospitals applying to the Joint Commission on Accreditation of Healthcare
Organizations for accreditation are required to develop a policy prohibiting
smoking by patients, visitors, employees, volunteers, and medical staff.
The EPA releases its report classifying secondhand smoke as a group A
carcinogen (known to be harmful to humans), placing secondhand smoke in
the same category as asbestos, benzene, and radon.
1993 Los Angeles passes a ban on smoking in all restaurants. The U.S. Postal
Service eliminates smoking in all facilities. Congress enacts a smoke-
free policy for Special Supplemental Food Program for Women, Infants,
and Children clinics. A working group of 16 state Attorneys General
releases recommendations for establishing smoke-free policies in fast-food
restaurants. Vermont bans smoking in all public buildings and in many
private buildings open to the public.
1994 The U.S. Department of Defense prohibits smoking in all indoor military
facilities. The Occupational Safety and Health Administration proposes a
rule that would ban smoking in most U.S. workplaces. San Francisco passes
a ban on smoking in all restaurants and workplaces. The Pro-Children
Act requires persons who provide federally funded children’s services to
prohibit smoking in their facilities. Utah enacts a law restricting smoking in
most workplaces.
1995 New York City passes a comprehensive ordinance effectively banning
smoking in most workplaces. Maryland enacts a smoke-free policy for
all workplaces except hotels, bars, some restaurants, and private clubs.
California passes comprehensive legislation that prohibits smoking in
most enclosed workplaces. Vermont’s smoking ban is extended to include
restaurants, bars, hotels, and motels except establishments holding a cabaret
license.
1996 The U.S. Department of Transportation reports that about 80 percent of
nonstop scheduled U.S. airline flights between the United States and
foreign points will be smoke free by June 1, 1996.
1997 President Clinton signs an executive order establishing a smoke-free
environment for federal employees and all members of the public visiting
federally owned facilities. The California EPA issues a report determining
that secondhand smoke is a toxic air contaminant. Settlement is reached in
the class-action lawsuit brought by flight attendants exposed to secondhand
smoke.
continued
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30 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
TABLE 1-2 Continued
Year Event
1998 The U.S. Senate ends smoking in the Senate’s public spaces. California
law takes effect banning smoking in bars that do not have a separately
ventilated smoking area. The Minnesota tobacco-document depository is
created as a result of a tobacco-industry settlement with Minnesota and
Blue Cross and Blue Shield of Minnesota. U.S. tobacco companies are
required to maintain a public depository to house more than 32 million
pages of previously secret internal tobacco industry documents.
2000 The New Jersey Supreme Court strikes down a local clean-indoor-air
ordinance adopted by the city of Princeton on the grounds that state law
preempts local smoking restrictions. A congressionally mandated smoking
ban takes effect on all international flights departing from or arriving in the
United States.
2002 New York City holds its first hearing on an indoor smoking ban that
would include all bars and restaurants. The amended Clean Indoor Air Act
enacted by the state of New York (Public Health Law, Article 13-E), which
took effect July 24, 2003, prohibits smoking in virtually all workplaces,
including restaurants and bars. The Michigan Supreme Court refuses to
hear an appeal of lower-court rulings striking down a local clean-indoor-
air ordinance enacted by the city of Marquette on the grounds that state
law preempts local communities from adopting smoking restrictions
in restaurants and bars that are more stringent than the state standard.
Delaware enacts a comprehensive smoke-free law and repeals a preemption
provision precluding communities from adopting local smoking restrictions
that are more stringent than state law. Florida voters approve a ballot
measure that amends the state constitution to require most workplaces and
public places—with some exceptions, such as bars—to be smoke free.
2003 Dozens of U.S. airports—including airline clubs, passenger terminals, and
nonpublic work areas—are designated as smoke free. Connecticut and New
York enact comprehensive smoke-free laws. Maine enacts a law requiring
bars, pool halls, and bingo venues to be smoke free. State supreme courts in
Iowa and New Hampshire strike down local smoke-free ordinances, ruling
that they are preempted by state law.
2004 Massachusetts and Rhode Island enact comprehensive smoke-free laws.
The International Agency for Research on Cancer issues a new monograph
identifying secondhand smoke as “carcinogenic to humans.”
2005 North Dakota, Vermont, Montana, and Washington enact 100 percent
smoke-free workplace and/or restaurant and/or bar regulations.
2006 New Jersey, Colorado, Hawaii, Ohio, and Nevada enact 100 percent smoke-
free workplace and/or restaurant and/or bar regulations.
2007 Louisiana, Arizona, New Mexico, New Hampshire, and Minnesota enact 100
percent smoke-free workplace and/or restaurant and/or bar regulations.
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31
INTRODUCTION
TABLE 1-2 Continued
Year Event
2008 Illinois, Maryland, Iowa, and Pennsylvania enact 100 percent smoke-free
workplace and/or restaurant and/or bar regulations.
2009 Oregon and Nebraska enact 100 percent smoke-free workplace and/or
restaurant and/or bar regulations.
2010 Wisconsin, Michigan, North Carolina, and Kansas enact 100 percent smoke-
free workplace and/or restaurant and/or bar regulations.
As of Across the United States, 21,875 municipalities are covered by a 100 percent
Oct. 7, smoke-free provision in workplaces and/or restaurants and/or bars by a
2011 state, commonwealth, or local law; this represents 79.6 percent of the U.S.
population.
The District of Columbia and 39 states have local laws in effect that require
100 percent smoke-free workplaces and/or restaurants and/or bars.
SOURCE: Derived from IOM (2010) with additional information from the American Non -
smokers’ Rights Foundation (2011) and the Robert Wood Johnson Foundation (2011).
a summary of significant milestones in addressing indoor tobacco smoke
exposure in the United States.)
In 1996, 13 years before the passage of the FSPTCA, the FDA unsuc-
cessfully attempted to assert regulatory authority over tobacco. The
FDA argued that tobacco products fell within its purview, claiming that
nicotine is a drug, and that cigarettes and smokeless tobacco are combina-
tion products that consist of the drug (nicotine) and device components
intended to deliver nicotine to the body.9 Based on this framework, the
FDA issued a regulation that included
• prohibiting the sale of tobacco products to individuals under age 18;
• prohibiting free samples and the sale of tobacco products through
vending machines and self-service displays, except in facilities that ensure
that no person under age 18 is present;
• restricting advertising exposed to children and adolescents to
black-and-white, text-only displays;
• prohibiting billboards and outdoor advertising within 1,000 feet of
schools and public playgrounds;
• prohibiting the sale or distribution of brand identified promotional
nontobacco items; and
• prohibiting sponsorship of sporting and other events in the name
of a product.
9 61 Federal Register 44396-45318; 21 CFR Parts 801, 803, 804, 807, 820, and 897.
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34 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
products (IOM, 2001). In 2007, an IOM report gave extensive and detailed
recommendations for federal regulation, including the specific recom -
mendation that “Congress should confer upon the FDA broad regula-
tory authority over the manufacture, distribution, marketing, and use of
tobacco products” (IOM, 2007).
FSPTCA OVERVIEW
The FSPTCA codified the recommendation from the 2007 IOM report,
amending the Food, Drug and Cosmetic Act (FD&C Act) to grant the
FDA broad authority to regulate tobacco products. Under the FSPTCA,
a tobacco product is defined as “any product made or derived from
tobacco that is intended for human consumption, including any compo-
nent, part, or accessory of a tobacco product (except for raw materials
other than tobacco used in manufacturing a component, part, or accessory
of a tobacco product).” Under Section 301 of the FD&C Act, any adulter-
ated or misbranded product is prohibited from being introduced into
interstate commerce. Chapter IX articulates the definitions of adulterated
or misbranded tobacco products. Among other things, Chapter IX gives
the FDA authority to regulate the sale, distribution, labeling, and advertis-
ing of tobacco products, to set product standards, and to require reporting
and disclosure of tobacco product ingredients and components.
SECTION 911
This report provides advice to the FDA on the minimum scientific
standards for studies on MRTPs. Under Section 911 of the FSPTCA, the
FDA is required to develop regulations or guidance, in consultation with
the IOM, on the evidence that product sponsors should submit in filing an
application to market an MRTP. This committee and the report adopt the
definitions used in the legislation (see Box 1-2) and also take into account
the regulatory framework established by the act in making any conclu -
sions or recommendations.
Pursuant to the FSPTCA, no MRTP may be marketed without an order
for sale from the Secretary of the U.S. Department of Health and Human
Services (HHS). Under the FSPTCA, an MRTP is defined as any tobacco
product that is sold or distributed for use to reduce harm or the risk of
tobacco-related disease. The FSPTCA also specifies that a product will be
categorized as an MRTP, and therefore be regulated under Section 911,
if any labeling or advertising represents implicitly or explicitly that a
product is reduced in risk or harm, or is free of or contains a reduced
amount of a substance. Furthermore, any action that a tobacco product
sponsor takes directed toward consumers through the media that would
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35
INTRODUCTION
be reasonably expected to result in consumers believing a product is
reduced in risk or exposure, or contains a reduced amount of a substance,
renders the product subject to regulation under Section 911. A product
must also obtain FDA approval to market or advertise the product using
descriptors such as light, low, mild, or other similar descriptors. Smokeless
tobacco products are not considered an MRTP solely because they use
the word smokeless or other similar descriptors; if the smokeless tobacco
product sponsor wishes to make additional modified risk claims, then
the product must first apply for this claim. A product that is intended for
tobacco cessation that is regulated by Chapter V of the FD&C Act cannot
be considered an MRTP (for further detail, see Box 1-2).
To obtain an order for the sale of any new product, or for a new
modified risk claim on an existing product, the manufacturer is required
to submit an application to the FDA, which must include comprehensive
documentation about the intended advertising and labeling, conditions of
use, formulation, all documents relating to the product’s effect on health,
and information on how consumers actually use the product.
Under the FSPTCA the Secretary may only issue an order for the
sale of an MRTP if the Secretary finds that the product that is the sub-
ject of the application meets one of two public health standards: either
(1) an empirically demonstrated Modified Risk claim or (2) a Special Rule
for Certain Products claim, specifying a reduced exposure product. The
determination of whether an order is granted under either the Modified
Risk standard or the Special Rule for Certain Products must be based on
scientific evidence submitted by the applicant.
To issue an order pursuant to the Modified Risk standard, the Secre-
tary must find that the applicant has demonstrated that the product, as
actually used by consumers, will (1) significantly reduce harm and the
risk of tobacco-related disease to individual tobacco users and (2) benefit
the health of the population as a whole, taking into account both users
and nonusers of the product. Under the Modified Risk standard, the
orders expire after a time specified within the order.
Under the Special Rule for Certain Products, the Secretary may issue
an order for the sale of a reduced-exposure product for which there is
inadequate long-term epidemiologic data to support a finding under
the Modified Risk standard. The specific conditions that must be met
for approval under the Special Rule for Certain Products are outlined
in Section 911(g)(2). Orders granted under the Special Rule for Certain
Products cannot last longer than 5 years.
The law also specifies public health considerations that the Secretary
must take into account when evaluating whether to issue an order, either
under the Modified Risk standard or the Special Rule for Certain Prod-
ucts. These considerations are outlined in Section 911(g)(4) and include
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36 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
BOX 1-2
Definitions and Historical Comparisons
Definition of MRTP from FSPTCA Section 911, Subsection (b), “Definitions”:
(1) MODIFIED RISK TOBACCO PRODUCT- The term “modified risk tobacco
product” means any tobacco product that is sold or distributed for use to
reduce harm or the risk of tobacco-related disease associated with commer-
cially arketed tobacco products.
m
(2) SOLD OR DISTRIBUTED-
(A) IN GENERAL- With respect to a tobacco product, the term “sold or distrib-
uted for use to reduce harm or the risk of tobacco-related disease associated
with commercially marketed tobacco products” means a tobacco product—
(i) the label, labeling, or advertising of which represents explicitly or
implicitly that—
(I) the tobacco product presents a lower risk of tobacco-related dis-
ease or is less harmful than one or more other commercially mar-
keted tobacco products;
(II) the tobacco product or its smoke contains a reduced level of a
substance or presents a reduced exposure to a substance; or
(III) the tobacco product or its smoke does not contain or is free of
a substance;
(ii) the label, labeling, or advertising of which uses the descriptors “light,”
“mild,” or “low” or similar descriptors; or
(iii) the tobacco product manufacturer of which has taken any action
directed to consumers through the media or otherwise, other than by
means of the tobacco product’s label, labeling, or advertising, after the
date of enactment of the Family Smoking Prevention and Tobacco Con-
trol Act, respecting the product that would be reasonably expected to
result in consumers believing that the tobacco product or its smoke may
present a lower risk of disease or is less harmful than one or more com-
mercially marketed tobacco products, or presents a reduced exposure
to, or does not contain or is free of, a substance or substances.
(B) LIMITATION- No tobacco product shall be considered to be “sold or dis-
tributed for use to reduce harm or the risk of tobacco-related disease associ-
ated with commercially marketed tobacco products,” except as escribed
d
in subparagraph (A).
(C) SMOKELESS TOBACCO PRODUCT- No smokeless tobacco product
shall be considered to be “sold or distributed for use to reduce harm or the
risk of tobacco-related disease associated with commercially marketed
tobacco products” solely because its label, labeling, or advertising uses
the following phrases to describe such product and its use: “smokeless
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37
INTRODUCTION
tobacco,” “smokeless tobacco product,” “not consumed by smoking,” “does
not produce smoke,” “smokefree,” “smoke-free,” “without smoke,” “no smoke,”
or “not smoke.”*
From Subsection (c), “Tobacco Dependence Products”:
A product that is intended to be used for the treatment of tobacco dependence,
including smoking cessation, is not a modified risk tobacco product under this
section if it has been approved as a drug or device by the Food and Drug
A
dministration and is subject to the requirements of Chapter V.
From Clearing the Smoke: Assessing the Science Base for Tobacco Harm Reduction:
The etymology of the term “Potential reduced-exposure products” or “PREP”:
Many tobacco and cigarette-like products have been introduced in the distant and
recent past that do, under measurement systems such as the smoking machine,
result in decreased emission of some toxicants compared to conventional prod-
ucts. These products could, therefore, potentially, results in reduced exposure
to toxicants. The committee uses “potentially,” because whether exposure to
tobacco toxicants is reduced depends on the user’s behavior, such as frequency
and intensity of use. Reduced exposure, however, does not necessarily assure
reduced risk to the user or reduced harm to the population. Therefore, and
in order to avoid misinterpretation, the committee will use the generic phrase
“potential reduced-exposure products,” or PREPs, when discussing modified
tobacco products, cigarette-like products (whether tobacco containing or not)
developed for their tobacco harm reduction potential (IOM, 2001).
Comparison of “PREPs” and “MRTPs”:
The term PREPs is not used by the committee and will not be included in this
report. The term “PREPs” was coined in Clearing the Smoke to describe a cat-
egory of products that theoretically could be used for tobacco harm reduction.
While the term “PREPs” has been adopted within the academic literature fol-
lowing Clearing the Smoke, the passing of the FSPTCA has created a statutory
definition that relates to PREPs. PREPs might be understood as a category of
potential MRTPs that have not yet been shown to reduce exposure or risk. The
task of this committee is essentially to advise the FDA in identifying scientific
standards for studies to produce evidence showing that a PREP actually does
reduce exposure, harm to users, and can protect public health. An MRTP may
be thought of as a PREP that has been validated according to standards set
in the FSPTCA and by the judgment of the FDA.
* It should be noted that some products, including some existing smokeless tobacco products,
may be marketed without an order if they do not make a reduced risk or exposure claim.
Products that do not make a claim or representation of reduced risk or exposure are not subject
to regulation under section 911, and are not addressed in this report.
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38 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
the health risks to individual current users, the likelihood that users will
quit or that nonusers will start using the product, and the risks compared
to cessation products.
If an order is approved, product sponsors are required to comply with
certain conditions for marketing, as well as requirements to conduct post-
market surveillance and studies of the product to determine the impact
of the order on consumer perception, behavior, and health. Results of the
postmarket surveillance and studies must be submitted to the Secretary
annually. Additionally, the Secretary can withdraw authorization, after an
opportunity for hearing, if the product sponsors either fail to fulfill their
obligations under the law, or if new evidence demonstrates that market -
ing of the product is not consistent with protecting the public’s health.
COMPARISON OF REGULATORY FRAMEWORKS
The statutory framework established by the FSPTCA for regulation of
MRTPs shares certain similarities with the existing regulatory frameworks
for pharmaceuticals, biologics, and devices. For instance, the power of
the FDA to inspect facilities and records, to require record keeping and
reporting of data on health effects, and to require good manufacturing
practices are generally consistent. In particular, all potential MRTPs must
undergo a premarket approval process similar to new drugs and high-risk
devices. However, tobacco products, including MRTPs, are fundamentally
different than other products regulated by the FDA: tobacco products
are inherently hazardous, addictive products. As a result, there are sev-
eral significant differences in the regulatory standards and requirements
established by the FSPTCA that are worth mention.
First, the standard to issue an order for the marketing of an MRTP
is a public health standard. According to the FSPTCA, the Secretary’s
actions regarding tobacco products, such as setting product standards or
restricting sales of certain products and advertising, must be based on a
finding that the action is “appropriate for the protection of public health.”
In Section 911 the law specifies that the Secretary must take into account
the effect of the product on nonusers when evaluating whether to issue
an order for the sale of an MRTP.12 The law also requires the Secretary
take into account the increased or decreased likelihood of tobacco users
quitting and nonusers initiating, and the risks and benefits compared to
other smoking cessation products.
This public health standard is a significant departure from the stan-
dards for drugs and devices. Generally, to obtain approval, drugs and
devices must be shown to be “safe and effective” for the individual
12 911(g)(1)(b) and 911(g)(2)(B)(4).
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39
INTRODUCTION
research participant or consumer. In contrast, MRTPs are potentially haz -
ardous to the user and are never truly “safe” or “effective” in the sense
that the product will improve the health of the user. The rationale for
issuing an order for the sale of an MRTP is not that the products are safe
and may improve health for individual users, but rather, that marketing
the products may reduce the overall negative health effects in a popula -
tion. To obtain an order to sell an MRTP, an MRTP candidate sponsor
must demonstrate to the FDA that the overall burden of tobacco-related
disease and death will be lower with the MRTP on the market than if it
were not on the market.
Second, product sponsors are required as a condition of obtaining an
order to market an MRTP to conduct postmarket studies and surveillance,
and to report the data to the FDA annually. In contrast, at this point in
time, drug and device manufacturers are generally not required to con-
duct postmarket studies of their products as an obligatory condition of
approval.
Third, orders for the marketing of an MRTP must expire, and manu-
facturers must reapply for additional orders to allow for the ongoing sale
of a product. MRTPs granted orders to market under the Special Rule for
Certain Products are given a maximum of 5 years, while the terms of the
orders granted under the Modified Risk standard are unspecified by
the law. Following the expiration of an order, MRTP sponsors may obtain
a renewal based on the filing of a new application. In contrast, drug and
device sponsors do not have to reapply and essentially repeat the pre-
market approval process after a specified period of time.
BURDEN OF PROOF
The Secretary’s decisions on whether an action will be appropriate
for the protection of public health must be based on scientific evidence.
According to the FSPTCA, a determination to allow for the marketing of
an MRTP can be based on scientific evidence submitted by the product
sponsor and on other scientific evidence made available to the Secretary.
The committee maintains that the burden of proof rests on the appli-
cant. That is, the product sponsor that is applying for an order to market
an MRTP bears the responsibility of producing evidence in support of an
application, including the evidence necessary to demonstrate that an order
is appropriate for the protection of public health. Without evidence, the
Secretary cannot determine that issuing an order for the sale of an MRTP
is appropriate for the protection of public health.
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40 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
COMMITTEE CHARGE AND STATEMENT OF TASK
Origin of Task
In Section 911(l)(2) of the FSPTCA, Congress specifies that regulations
and guidance on the scientific evidence required for the assessment and
review of applications for a modified risk claim for a tobacco product
must be developed in consultation with the IOM. The law states:
The regulations or guidance issued under paragraph (1) shall be devel-
oped in consultation with the Institute of Medicine, and with input of
other appropriate scientific and medical experts, on the design and con -
duct of such studies and surveillance.
Statement of Task
Pursuant to the legislation, the FDA Center for Tobacco Products
(CTP) engaged the IOM to advise the agency. In discussing the scope
of the report, the CTP and the IOM agreed that the committee would
address premarket and postmarket studies in support of MRTPs and that
postmarket surveillance would be excluded from the report to maintain
appropriate focus and depth within the study time frame (see Box 1-3).
Scope of Task
The committee’s interpretation of the task was informed by the text of
the legislation and by input from the project sponsor in a public meeting.
The law specifically states that regulation or guidance shall be developed
in consultation with the IOM on both the design and conduct of studies. As
such, the committee found authority to address issues not only concerning
research methods and scientific standards, but also research conduct and
governance.
The CTP also provided direction about the task to the committee
during an open session of the first committee meeting. In a presentation
BOX 1-3
Statement of Task
The Institute of Medicine will establish a committee of 15 public health and
medical experts to advise the Food and Drug Administration on the minimum
standards for scientific studies to support the marketing of modified risk tobacco
products and for post market studies of approved products.
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41
INTRODUCTION
to the committee, CTP Director Dr. Lawrence Deyton, emphasized that
the committee should advise the CTP on the “types and characteristics”
of evidence needed to evaluate an application for an order to market an
MRTP. The director also specifically reminded the committee that it must
take into account the population health regulatory standard described
in the law. Finally, Dr. Deyton described tasks that he regarded as out -
side the committee’s charge. Specifically, he indicated that he did not
expect the committee to
• assess the evidence for any particular product;
• opine on whether any tobacco product or class of products is a
potential candidate for modified risk determination;
• offer regulatory principles;
• define or recommend a conceptual or regulatory framework for
modified risk assessment; and
• define terms from the act, such as “reasonably likely” or “measur-
able and substantial reduction.”
The statutory mandate and the limits articulated by the sponsor pre -
sented a challenge to the committee. On the one hand, the law clearly
placed the conduct of scientific studies within the scope of the IOM’s
task; on the other hand, the director indicated that the committee should
not address regulatory principles. Furthermore, the state of tobacco sci-
ence and regulation was well developed, with a significant existing body
of literature on the evaluation and regulation of tobacco. As such, the
committee concluded it would be inefficient and unproductive to sim -
ply reiterate basic scientific principles and review existing literature on
tobacco. Accordingly, the committee sought to provide insight and direc-
tion to the CTP without usurping the judgments that should be left to the
agency and the Secretary.
COMMITTEE PROCESS
With this task in mind, the IOM convened a committee of 15 experts.
The committee conducted five meetings between February and September
2011. During these meetings, committee members heard from a wide vari-
ety of experts and stakeholders, including individuals representing the
tobacco industry, researchers, public health experts and advocates, and
government. The committee also extensively reviewed literature includ -
ing original peer-reviewed research articles and published reports. In
the course of deliberations, the committee commissioned work from and
consulted with external experts to gain additional expertise.
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42 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
OVERVIEW OF THE REPORT
This report is organized into six chapters. Chapter 2 discusses the
standards for governance and the conduct of studies that are necessary to
produce reliable and credible data to support a tobacco product’s applica-
tion for a modified risk claim. Chapters 3 through 5 then address the types
and designs of studies available to assess these products’ impact on an
individual’s health and on the population’s health. Chapter 3 discusses
studies on the health effects of the products, such as product composi -
tion, biomarkers, preclinical studies, clinical studies, and epidemiologic
studies. Chapter 4 reviews the research methods to study the addictive
potential of the product. This information provides evidence on the impli-
cations for human behavior patterns and public health risks. Chapter 5
outlines the standards for studies needed to address both consumer and
nonconsumer risk perceptions and communication surrounding modi -
fied products. Issues of participant recruitment, measurement, and data
analysis are also detailed in Chapter 5. In the final chapter, Chapter 6,
the committee discusses the integration of these various classes of evi -
dence required for informed decision making by the FDA. The commit -
tee presents its overarching findings and recommendations at the end of
Chapter 6.
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