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Summary
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). Smoking-related disease causes
more deaths than alcohol, illicit drug use, homicide, and suicide com-
bined (Mokdad et al., 2004). Another 8.6 million smokers in the United
States live with a smoking-attributable illness (CDC, 2009a). In total,
tobacco-related mortality amounts to approximately 5.1 million years of
potential life lost per year (CDC, 2008). 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).
The current prevalence of cigarette use is 20.6 percent among adults
and 19.5 percent in youth (CDC, 2010, 2011). 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). Between 1997 and 2003, smoking preva -
lence among high school students declined substantially from 36.4 percent
to 21.9 percent; this decline slowed from a 21.9 percent youth smoking
rate in 2003 to 19.5 percent in 2009 (CDC, 2011). 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).
1
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2 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
THE FAMILY SMOKING PREVENTION
AND TOBACCO CONTROL ACT
The Family Smoking Prevention and Tobacco Control Act of 2009
(FSPTCA)1 grants the Food and Drug Administration (FDA) broad author-
ity to regulate the manufacturing, distribution, and marketing of tobacco
products, including “modified risk tobacco products” (MRTPs). Gener-
ally, an MRTP is defined by the law as any tobacco product that is sold or
distributed for use to reduce harm or the risk of tobacco-related disease.
Under the FSPTCA, no MRTP may be marketed without an order for
sale from the U.S. Department of Health and Human Services (HHS). To
be marketed, the product must meet 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.
To meet the Modified Risk standard, the applicant must prove with
scientific evidence that the product, as actually used by consumers, will
(1) significantly reduce harm and the risk of tobacco-related disease to
individual users and (2) benefit the health of the population as a whole,
taking into account both users and nonusers of the product.
Under the Special Rule for Certain Products, the Secretary of HHS
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 but where the available evidence dem -
onstrates that a substantial reduction in morbidity and mortality is “rea -
sonably likely.”
In regard to both standards, the law further specifies that the Secre -
tary should also take into account how the marketing of the MRTP affects
the likelihood of current users continuing tobacco product use with an
MRTP who otherwise would have quit, nonusers initiating tobacco use
with an MRTP, and the risks and benefits compared to other smoking-
cessation products.
The concept of harm reduction informs the public health rationale
for permitting the development and potential marketing of modified risk
tobacco products. The basic premise of harm reduction is the continuation
of a potentially hazardous or dangerous behavior, with the aim of decreas-
ing the potentially adverse consequences of these behaviors (Marlatt,
2002). In the context of tobacco harm reduction, “a product is harm reduc-
ing if it lowers total tobacco-related morbidity and mortality, even though
use of that product may involve continued exposure to tobacco-related
toxicants” (IOM, 2001).
1 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat.
1776 (June 22, 2009).
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3
SUMMARY
Modification of the risk profiles of tobacco products is only one com-
ponent of a comprehensive, multifaceted strategy to minimize the nega -
tive health effects of tobacco use. Tobacco harm reduction efforts specifi-
cally target users that are unwilling or unable to quit. In conjunction with
tactics to prevent initiation of tobacco use and to promote immediate ces-
sation, 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.
REQUIREMENT FOR REGULATIONS, GUIDANCE, AND
CONSULTATION WITH THE INSTITUTE OF MEDICINE
The FSPTCA requires the FDA to issue guidance or regulation on the
scientific evidence required for the assessment and ongoing review of an
MRTP applicant. The law also specifically requires the FDA to consult
with the Institute of Medicine (IOM) in developing guidance and regula-
tion on the “design and conduct of such studies and surveillance.” Box S-1
provides the statement of task.
COMMITTEE APPROACH
The IOM convened a multidisciplinary committee of 15 experts with
backgrounds in addiction, cardiology, pulmonology, oncology, epidemiol-
ogy, study design methodology, biostatistics, risk perception, adolescent
behavior, drug or device regulation and law, population health, tobacco
initiation and cessation, and toxicology. Over the course of 10 months,
the committee held five meetings; extensively reviewed literature; heard
representatives from the tobacco industry, public health advocacy groups,
and regulatory agencies; and consulted with external subject area experts.
To fully grasp the nature of the task, the committee sought guidance
not only from the statement of task, but also from the enabling statutory
language of the FSPTCA Section 911(l)(2). While it is essential to address
BOX S-1
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 postmarket studies of approved products.
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4 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
minimum standards for scientific studies, the committee interpreted the
task more broadly than the simple rearticulation of basic scientific prin -
ciples or the review of current scientific methods. The committee was
particularly wary of making “perishable” recommendations that may lose
relevance as time passes and scientific methods and technologies evolve.
Rather, the committee sought to provide enduring insights into what con-
stitutes credible and meaningful evidence of the effect of tobacco products
on public health. The committee’s insights can be generally organized into
three categories:
1. Types of studies and evidence on MRTPs
2. Design of studies on MRTPs and decision making
3. Governance
EVIDENCE AND STUDIES
Generally, the evidence to support the marketing approval of an
MRTP will come from three categories: health effects of the MRTP, addic-
tive potential of the MRTP, and perceptions about the MRTP.
Evidence and Studies of Health Effects
Laboratory analysis of the performance and of the constituents
of tobacco products will be the first step in the evaluation of any new
product. These analyses involve standard methods of extraction, sample
cleanup, analyte identification, and quantitation. There are important
limitations to laboratory analysis of product performance and composi -
tion. First, laboratory analysis of constituents may not reflect constituent
uptake under conditions of use. In particular, smoking machines do not
replicate human smoking conditions. There is currently no proven way
to replicate the many ways humans use tobacco. As such, it is crucial to
describe the smoking regimen or other extraction methods employed.
Second, there may be other unidentified compounds in tobacco that con -
tribute in important ways to adverse health effects. Also, seemingly innoc-
uous compounds can exacerbate the effects of toxicants.
The second step in the evaluation of an MRTP will be preclinical
studies of toxicity. These assays are essential in identifying particularly
risky or toxic products that should not be tested in humans, and to iden -
tify products that have reasonable potential to reduce risk and harm and
therefore should proceed to clinical evaluation. In vitro assays for cyto-
toxicity, genotoxicity, apoptosis and cell proliferation, oxidative stress,
inflammation, mucus production, and endothelial activation are a stan -
dard step in evaluations of all combusted and noncombusted products.
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5
SUMMARY
Evaluation of products in vitro should precede in vivo assays. Further-
more, assays in animal models should precede human assays. Although
it is not possible to make laboratory animals use tobacco products the
way humans do, and there are inherent interspecies differences that pre -
vent meaningful extrapolation of human effects, it is still informative to
observe the effect of tobacco products in live animal models. Assays of
toxicity in humans will also be essential, in particular assays of urinary
mutagenicity and sister chromatid exchange in peripheral lymphocytes.
Biomarkers of exposure measure human exposure to constituents of
tobacco. Biomarkers of human exposure to specific constituents of tobacco
include the constituents themselves, their metabolites, or protein- or DNA-
binding products of the constituents or their metabolites. These biomarkers
have the potential to bypass many of the uncertainties in product compo-
sition analysis and provide a realistic and direct assessment of carcinogen
and toxicant dose in an individual. The first step in employing biomarkers
of exposure is analytical validation. The second step is validation with
respect to product use. Finally, biomarkers can be validated with respect to
disease risk; however, there is no proof that any individual constituent or
group of constituents is responsible for a given disease. For a biomarker of
exposure to be accepted as a biomarker of risk or a surrogate endpoint
of disease, there should be a strong biological rational as well as compelling
data from clinical and epidemiologic studies.
Experimental designs, in particular randomized controlled trials
(RCTs), provide data that can support the strong inferences about the
effect of an MRTP on human health relative to conventional tobacco prod-
ucts. The use of appropriately designed clinical trials will be important to
establish whether the use of the MRTP reduces exposure to toxicants or
induces positive changes in surrogate markers as claimed by the manu -
facturer. An RCT is an effective means of examining acceptability and
use of the MRTP, the ability of the MRTP to increase cessation in users of
conventional tobacco products, and the likelihood that availability of the
MRTP will lead to dual use. RCT methods can also produce evidence on
whether and how much individuals use an MRTP after they have used
it to help them quit conventional products, changes in perception of the
MRTP with its continued use, and the MRTP’s ability to suppress tobacco
withdrawal symptoms. It is important to recognize that no single RCT can
address all of these areas, and each study should have a focused objective
with a primary endpoint.
Observational epidemiologic studies play a critical and central role in
the evaluation of MRTPs. Although they will rarely, if ever, have the com-
pelling scientific credibility of experimental designs, these methods form
the basis for most evaluation studies of regulated products in the com-
munity. Long, intensive, and robust observational studies of actual health
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6 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
outcomes may be required to fully evaluate the net effects of MRTPs rela-
tive to conventional tobacco products.
Prospective cohort studies are obvious candidates for the evaluation
of MRTPs, and will also be an essential tool to validating anticipated or
claimed effects of marketed MRTPs on both individuals and on the pub -
lic’s health. Cohort studies allow assessment of overall health status and
outcomes, as well as offering the following important strengths:
• Biochemical tobacco and MRTP exposure assessment can be made
at baseline, offering unbiased exposure assessment before health out-
comes occur.
• There is less of a problem with retrospective recall of product use,
because this information can be summarized at the start of the study, and
followed prospectively.
• Changing product use habits can be monitored as the study
progresses.
• Outcomes can be documented as they occur, and verification
becomes more efficient.
A wide variety of outcomes can be evaluated in the same study,
including both intermediate and clinical outcomes. In addition, other
epidemiological study designs will be necessary to evaluate MRTPs and
provide evidence on the public health effects of marketed MRTPs; these
include retrospective cohort studies, case-control studies, crossover or
case-crossover designs, and comparative effectiveness research methods.
Case-control studies are commonly used because of their efficiency in
assembling study participants, including when the disease outcomes are
not common in general populations (e.g., varying levels of biomarkers).
When the outcomes are short term and/or recurrent (particularly when
using intermediate endpoints), an observational crossover or case-
crossover design becomes feasible and informative. Comparative effective-
ness research methods more critically inform health care and policy deci-
sions, but these methods can also sharpen or extend observational studies
comparing health outcomes associated with use of conventional tobacco
products and use of certain MRTPs. Overall, different study designs will
be necessary depending on the circumstances and the research question.
Evidence and Studies of Addictive Potential
Evaluation of the likelihood of initiation, maintenance, and persis -
tence of use in both conventional tobacco users and nonusers is critical
to estimating the public health effect of marketing an MRTP. Specifically,
evaluation of the MRTP’s ability to promote initiation and continuation
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7
SUMMARY
of its regular use, switching to its use and cessation of the consumption of
more harmful products, dual use, and to promote relapse back to more
harmful tobacco use are all essential. All of these outcomes are logically
related to the reinforcing value of the MRTP (that is, how rewarding it is).
There is a continuum of reinforcement value. In theory, the MRTP
should be somewhat more reinforcing than nicotine replacement thera -
pies but perhaps less reinforcing than conventional cigarettes. Ideally, an
MRTP would be sufficiently reinforcing so as to attract smokers away
from conventional cigarettes but not enough to encourage the widespread
dependent use of the product by individuals who were previously non-
users, or who would have quit smoking.
Evaluation of the abuse and addiction potential of a product can be
accomplished with a variety of experimental designs and in a variety of
contexts, including subjective evaluations in laboratory contexts, acute
self-administration studies in laboratory contexts, use in extended resi -
dence facilities, and natural environment contexts where long-term use
can be studied in real-world circumstances via RCTs, cross-sectional sur-
vey studies, and longitudinal cohort studies.
Evaluation of reinforcement value in a laboratory setting is particu-
larly important because the results of these studies reliably correspond to
an agent’s addictive potential in real-world use. A standard with regard to
human abuse liability drug testing is acute dose-effect comparison studies,
because of the correspondence between subjective ratings of drug effects
and real-world abuse potential. Behavioral economic self-administration
studies will also be important in evaluating the reinforcement potency of
a product. The usefulness of all studies in forecasting the risk for initia -
tion and abuse of a product depends on study design factors. Important
design considerations include the size of the sample, the nature of the
sample (whether the sample includes heavy smokers or light smokers,
smokers who want to quit, and nonsmokers), the characterization of the
sample (age, sex, gender, ethnicity, educational attainment, socioeconomic
status, etc.), and the nature of the comparison product.
Evidence and Studies of Risk Perception and Communication
Judgments about risk, otherwise known as risk perceptions, are a
fundamental element to most theoretical models of health behavior and
behavioral decision making. In general, these models argue that indi -
viduals’ perceptions about the value and likelihood of behavior-related
positive and negative consequences and their vulnerability to those con -
sequences play a key role in behavioral choices. As such, understanding
individuals’ perceptions of tobacco-related products, including MRTPs,
whether such perceptions change over time, and whether such percep-
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8 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
tions play a role in tobacco behavior, is critical. It will be important to
identify consumers’ perceptions of disease risk, likelihood of addiction,
likelihood of reducing or increasing others’ exposure to potentially haz -
ardous compounds, and perceptions of risk compared to other products
already on the market. It is also important to assess intentions of using the
product. It is essential that the industry carefully crafts messages about
risks and benefits of any MRTP and demonstrates through rigorous test -
ing that people correctly understand and interpret the risks.
Studies evaluating risk perceptions and risk communication should be
performed both before the marketing of an MRTP and after the MRTP has
been marketed. Premarket research will play an essential role in develop-
ing the messages the tobacco industry can use to communicate informa-
tion about MRTPs to consumers. This research will determine consumers’
ability to accurately understand messages that communicate information
about the risks, benefits, and conditions of using an MRTP compared to
existing tobacco products. Studies should also test how these messages
influence consumers’ perceptions of the risks, benefits, and likelihood of
addiction related to an MRTP. The first stage of premarket research will
involve formative work using focus groups. The second stage should
include discussions with groups of similar individuals to assess how the
messages that were developed in the first stage are received by consumers.
Finally, the effects of these messages on consumer perceptions should be
tested. It will be important to evaluate consumer understanding and to
compare consumer perceptions of an MRTP to conventional products.
After the product is released on the market, it is vital to continue monitor-
ing consumer perceptions and behavior related to that product. Conduct-
ing nationally representative cohort-sequential longitudinal surveys will
be essential.
Table S-1 presents the evidence domains and example considerations
for using evidence from the different domains.
STUDY DESIGN AND DECISION MAKING
Study Design
Studies should be designed appropriately to create an evidence base
that can support a finding of public health benefit. The ultimate goal of
studying the effect of an MRTP on human health and behavior is to be
able to accurately predict the public health effects of allowing an MRTP
to be marketed. In other words, the ultimate goal of scientific studies is to
produce generalizable data. The “generalizability” of data, or the reliabil -
ity of predictions that can be made about the real world based on scientific
observations, will depend on the design of the studies.
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SUMMARY
TABLE S-1 Evidence Domains Relevant to an MRTP Application
and Examples of Types of Findings
Class of Evidence Examples of Types of Finding That May Be Required
Preclinical • Assurance of manufacturing quality control
• Significant and substantial reduction in toxicant and carcinogen
content in product
• Significant reduction in exposure to toxicants and carcinogens
in limited human study
• No significant evidence for offsetting increases in content of or
exposure to other toxicants
Clinical trial • Significant reduction in exposure to toxicants and carcinogens
in relation to continued use of traditional product, preferably
approaching nonsmoker levels
• Significant rates of cessation of conventional tobacco product
use, or significant decrease in the rates of conventional tobacco
product use
• Significant reduction in biomarkers or surrogates of disease
Abuse potential • No more liable for abuse than currently marketed products
• No significant evidence of attractiveness to nonusers of tobacco
Epidemiology • Clear and consistent evidence of reduction in disease risk (e.g.,
cancer, cardiovascular disease, chronic obstructive pulmonary
disease) or intermediate endpoint thereof
• No significant evidence of offsetting increased risk for other
diseases
• No significant evidence of uptake among nonusers or relapse
among former users (postmarketing)
Consumer and • Evidence for accurate understanding of product claim
nonconsumer • No significant evidence that consumers equate reduced
perceptions exposure with reduced risk
• No significant evidence of intention to use product among
nonusers (especially adolescents)
• No significant evidence of switching from MRTP to other
tobacco product usage
Populations at • No significant evidence of risk of initiation among nonusers
high risk for (especially adolescents)
tobacco use • Consistency of findings across relevant subpopulations of
interest (e.g., low socioeconomic status, racial/ethnic minorities)
Modeling and • Population predictions show reduction in smoking-related
synthesis morbidity and mortality following the introduction of an MRTP
with no significant evidence of uptake by nonusers (especially
adolescents)
NOTE: This table is not comprehensive and is not intended to be a guideline or framework
for the evaluation of MRTP applications.
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10 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
Elements of study design that should be carefully evaluated include
the size of the sample and the nature of the sample. Sample sizes should
be carefully determined and tailored to the study design and the effects
that are being studied. Statistically underpowered studies cannot sup -
port inferences or projections about the effects of a product. The nature
of the study sample is critical to the usefulness of study results. Results
from studies conducted in one population may not be applicable to other
populations because the characteristics that define the study population
either are related to or cause the responses to the product. As such, it is
important to study a wide range of populations. It is particularly impor-
tant to include populations that have a high risk of using tobacco and
populations that will be affected by the marketing of the product.
Study designs should also carefully consider the degree of control
imposed on experimental designs. Internal and external validity should
be balanced not only within studies, but also across studies of the same
product. Highly controlled experimental designs can eliminate many vari-
ables and confounders and support strong inferences, but simultaneously
they can lose relevance to the real world as the conditions of product
use do not reflect real-world circumstances and behaviors. Experimental
designs that are less controlled can emulate circumstances that reflect
real-world conditions and behaviors, and therefore they may be more
relevant in predicting real-world effects, but uncontrolled variables may
confound meaningful associations or inferences. Multiple complementary
study designs will be necessary to provide the evidence necessary to meet
the statutory public health standards.
Decision Making
It is clear that no single class of evidence (e.g., preclinical, RCTs, con -
sumer perception, epidemiologic) in itself will be sufficient to support an
MRTP application. The portfolio of evidence brought to the FDA to justify
a modified risk or modified exposure claim will be substantial. To inform
regulatory decision making, the FDA will need to process the evidence
at a higher level, beyond merely amassing the evidence in support of the
MRTP claims.
A key challenge facing the FDA will be integrating the various
domains and levels of evidence provided by sponsors in support of an
MRTP application. It would be helpful to have a systematic, explicit
approach that weighs outcomes in terms of their public health impor-
tance, identifies the measures and data most relevant to those outcomes,
and combines the available evidence in a manner that is psychometrically
sound, objective, and reproducible. The approach to data integration
that the FDA takes will be highly influential in determining whether an
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SUMMARY
MRTP is marketed, and the approach should be transparent, objective,
and reproducible.
It is anticipated that modeling and simulation methods will play a
role in integrating evidence to inform regulatory decisions. For model-
ing and simulation to be transparent, detailed information on all aspects
of model structure, sources of evidence used, computational approach,
construction of summaries, and reporting of the results should be avail-
able. Such information is essential not only for a proper scientific under-
standing of the modeling, but also for allowing researchers and other
stakeholders in the regulatory process to critique and validate the model.
It is important to ensure that the methods for data integration that inform
decision making are neither arbitrary nor flawed.
Another critical factor in deciding whether to issue an order for the
marketing of an MRTP is the amount of harm reduction claimed by an
MRTP sponsor in an application. Harm reduction is inherently relative;
a reduction claim is, by definition, relative to a comparison product.
Selection of an appropriate comparison product is essential for informed
and accurate decision making. The FSPTCA recognizes this, giving the
Secretary of HHS authority to require product sponsors to compare their
product to a commercially marketed representative product. The choice
of appropriate comparison products will be driven by the type of MRTP
being tested, the anticipated claim, and the study design. The comparison
products may even differ between different classes of evidence. Two refer-
ence products come to the forefront in terms of integration and synthesis
of evidence: leading brands and smoking-cessation products.
“Leading brands” represent a set of products that accounts for a
significant portion of the market and could capture subgroups of interest
(e.g., those of low socioeconomic status, who tend to use discount brands,
and certain racial/ethnic minorities, who have higher rates of menthol
cigarette use). Using leading brands increases the likelihood that the find-
ings will have broader applicability to the population, which is crucial
given the public health standard against which MRTPs are evaluated.
Using leading brands as a comparator also avoids potential mischief in
allowing comparisons between an MRTP and a product that is little used
but inflates the apparent benefit of the MRTP.
Smoking-cessation products represent a standard (or tobacco-
cessation products in the case of smokeless tobacco users) as a compari -
son product, because these products pose very few, if any risks to health.
These products provide an aspirational goal for risk and exposure from
MRTPs. In principle, the closer the risks and exposures from the MRTP
are to cessation products, the more confident a regulator can be in the
chances for net public health benefit. Note that the use of this comparison
product is not the same as studying whether the MRTP acts as an aid to
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12 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
smoking cessation. Rather, the goal is to compare how the risk or exposure
reduction attained with use of the MRTP compares to smoking-cessation
product use of similar duration.
GOVERNANCE
The role of governance is to ensure the proper conduct of research. In
addition to the essential role of protecting the interests of human research
participants, governance of research is critical to the production of cred -
ible and reliable evidence. Governance and oversight of research conduct
can prevent unethical behavior such as the falsification and manipulation
of research data. Over time, the proper conduct of research can also build
credibility and public trust.
There is profound distrust of the tobacco industry and of research
supported by the tobacco industry. This distrust is the direct result of
the tobacco industry’s history of improperly influencing or manipulating
scientific findings and messaging about the health effects of tobacco. This
history and the lack of trust may prevent independent experts from partici-
pating in research on tobacco products and therefore may impede the pro-
duction of data on MRTPs necessary to assess public health impact. Partic-
ularly important illustrations of the lack of public trust include the fact that
many major universities have bans on the acceptance of tobacco industry
funding, and that many journals will not accept or publish research sup-
ported by the tobacco industry. Establishing the tobacco industry as a
legitimate participant in tobacco research is an important consideration in
the overall goal of producing evidence on the effects of MRTPs.
The need for academic institutions or other experts to conduct
research on tobacco products is particularly important in the current
regulatory environment. First, the tobacco industry currently lacks the
infrastructure and expertise to independently produce the necessary evi -
dence to support an application to market an MRTP. The FSPTCA now
requires tobacco products to undergo a premarket approval process simi -
lar to drugs and devices. Prior to the passage of the FSPTCA, the tobacco
industry lacked robust regulation, and as a consequence, the industry
may lack the institutional and organizational capacity to assemble a com -
plete application to meet the requirements of the law. In addition, there
are significant domains of evidence that should be addressed in an appli-
cation to market an MRTP wherein the tobacco industry either lacks the
expertise or the willingness to independently conduct the research. In
particular, research involving populations with a high risk for tobacco
use such as behavioral research, studies of adolescents, research on abuse
liability, and observational studies of health effects will be very challeng-
ing for the tobacco industry.
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SUMMARY
The committee recommends several strategies to create an environ-
ment conducive to the production of reliable and credible evidence, in
spite of the tobacco industry’s reputation and currently limited infra-
structure and expertise. The first strategy is to create a mechanism to dis -
tance the reputation and influence of the tobacco industry from experts,
researchers, and institutions that will be critical to the production of evi -
dence on MRTPs. Fear, either real or perceived, of being influenced by or
aiding the tobacco industry prevents many institutions, researchers, and
journals from having any association with the tobacco industry. Provid-
ing independence, autonomy, and separation from the industry addresses
these fears. An independent third party that conducts research, pro-
vides oversight of research, distributes funding for research or manages
research contracts, or otherwise provides governance of research may be
a useful mechanism for reengaging the experts and institutions necessary
to producing high-quality evidence on the effects of MRTPs. Relevant
examples of third-party partnerships between industry and government
include the Health Effects Institute and the Reagan-Udall Foundation.
Currently, there are no independent entities that fulfill these roles for the
tobacco industry.
The second strategy is to require that the conduct of research in sup -
port of MRTPs conform to ethical standards and that study information be
made publicly available. Transparency and the proper conduct of research
not only protect the interests of research participants, but also improve
data quality. Requiring transparency and ethical conduct of research may
also help change public perceptions of the tobacco industry, and subse-
quently engagement and support from key stakeholders may be more
likely. Over time, requiring adherence to codes of ethics, and requiring the
publication of study information and results, will improve the quality and
availability of evidence about the effects of MRTPs on health.
FINDINGS AND RECOMMENDATIONS
In the committee’s view, the fundamental problem that confronts the
FDA is a shortage of credible and reliable evidence about the effects of
MRTPs on both individual and public health. The history of deceptive
behavior by the tobacco industry undermined the trust of the public as
well as the public’s confidence in the industry’s ability to rigorously con-
duct studies that will generate the data needed to evaluate these products.
Therefore, the committee’s recommendations are designed to articulate the
minimum standards for producing credible and reliable evidence to dem-
onstrate that the marketing of an MRTP is consistent with the protection
of public health. The committee articulates a strategy for the production of
scientific evidence by making recommendations in three areas:
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14 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
1. Types of evidence and studies
2. Design and integration
3. Governance of studies
Types of Evidence and Studies
Finding 1: Types of Evidence. The public health standard articulated by
the FSPTCA requires collection of scientific evidence from a wide range
of disciplines and research domains. Although the committee respects the
FDA’s independence and discretion in regulating MRTPs, the committee
maintains there is a minimum range of research domains required to
evaluate the effect of MRTPs on individuals and public health. Individual
methods may change as the technology or state of the science may evolve,
but the minimum standards for the domains of evidence will be relevant
regardless of the state of the science in the future.
Recommendation 1: The FDA should require that studies submitted
in support of an MRTP application address all key research domains
needed to forecast and monitor the product’s public health impact,
including
• product composition and performance;
• addiction potential and likelihood for initiation or persistence of
use;
• human exposure to harmful and potentially harmful constituents;
• perceptions about the product’s effects and likelihood of addic-
tion; and
• effects of the product on human health and surrogates of human
health.
Finding 2: Phased Approach to New MRTPs. Many novel MRTPs are
likely to be developed for marketing in the near future. There are inher-
ent uncertainties and risks with new products that should be addressed.
Risks should be minimized before new products are tested in humans. To
address the risk of new products, a phased approach, similar to the New
Drug Application framework for the regulation and control of new drugs,
is appropriate for the evaluation of new MRTPs. A phased approach will
help the FDA ensure that only products that are unlikely to be unsafe and
have a reasonable expectation of reducing harm relative to conventional
tobacco products will be used in human studies.
Recommendation 2: The FDA should establish guidance that conveys
an expected sequencing of studies, such that preclinical work is com-
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SUMMARY
pleted and submitted to the FDA before clinical (human subjects)
work commences, and that there is a reasonable expectation based
on preclinical work that a reduction or lack of harm will be seen in
humans.
Finding 3: Clinical Trial Studies. Although the use of randomized con-
trolled trial methods will be constrained for a number of reasons (includ -
ing the practical limitations of study cost, size, and follow-up, and ethical
constraints on randomizing study participants to harmful exposures),
they will continue to play an essential role in creating an evidence base on
the public health effects of MRTPs. Randomized controlled trial methods
can provide highly reliable data on the likelihood of addiction and initia -
tion or cessation of product use. Also, these methods can provide reliable
evidence on human exposure.
Recommendation 3: The FDA should require randomized controlled
trials in the following domains:
• Exposure reduction
• Self-administration of the MRTP
• Effects on use of conventional tobacco products
These randomized controlled trials should include multiple compari-
son products (such as nicotine replacement products, conventional ciga-
rettes or smokeless tobacco, placebo preparations, and alternative nicotine
delivery systems). These trials should also assess the effect of the MRTP on
human exposure and on human health and surrogates of human health.
Finding 4: Requirement for Postmarket, Prospective Epidemiologic
Studies. Postmarket studies of MRTPs will be critical to evaluating the
effect of MRTPs on both individuals and the public’s health. In particular,
the prospective cohort design will be an essential tool to validating antici-
pated or claimed effects of marketed MRTPs. These studies have several
important strengths: (1) biochemical tobacco and MRTP exposure can
be assessed at baseline, offering “unbiased” exposure assessment before
health outcomes occur; (2) there is less of a problem with retrospective
recall of product use, because this information can be summarized at
the start of the study and followed prospectively; (3) changing product
use habits can be monitored as the study progresses; (4) outcomes can
be documented as they occur, and verification is more efficient; and (5)
a wide variety of outcomes can be evaluated in the same study, particu -
larly outcomes that are more common. Furthermore, cohort studies allow
assessment of overall health status and outcomes.
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16 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
Recommendation 4: The FDA should require prospective epidemio-
logic studies to commence upon issuance of a marketing order to
confirm reduced exposure and reduced risk claims, and to examine
effects of MRTP availability on the population as a whole, includ -
ing the likelihood of initiation and cessation. The FDA should issue
guidance on the design, conduct, and analysis of such studies.
Finding 5: Modeling of Public Health Outcomes. Mathematical model-
ing and simulation analysis provides a complementary approach to
the conduct of empirical studies that can be useful at each stage of the
regulatory process for MRTPs. Model-based analyses can (1) synthesize
the available information from empirical studies of MRTPs; (2) enable
researchers and decision makers to explore complex interactions and
systems that may be impractical to evaluate in empirical studies; (3) allow
researchers and decisions makers to explore “what if” questions relevant
to decision making, which would not be practical to assess in empirical
studies; and (4) be used to make projections about the short- and long-
term effects of the introduction of MRTPs.
Recommendation 5: The FDA should issue guidance on the develop-
ment and use of simulation and modeling approaches to predict pub-
lic health impact through the systematic integration of information
about relevant assumptions and influences. Such approaches should
be tested for robustness with regard to results and assumptions,
they should be public and transparent, and they should be validated
against postmarketing epidemiologic research.
Design and Integration of Studies
Finding 6: Standards for Sampling in MRTP Studies. To have regulatory
usefulness, studies of MRTPs must be generalizable to the overall popula-
tion of interest and to specific populations, including populations at high
risk for tobacco use. Failure to include relevant populations in studies will
result in incomplete evidence on the effect of an MRTP on the public’s
health and, therefore, will be inadequate to support regulatory decisions
about the marketing of MRTPs.
Recommendation 6: The FDA should require studies to include pop-
ulations of special relevance, including (but not limited to)
• users of tobacco products, including users who are and are not
interested in quitting;
• in certain circumstances, nonusers of tobacco products;
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SUMMARY
• former smokers;
• beginning smokers;
• adolescents; and
• populations at a high risk for tobacco use, including, but not
limited to, those low in socioeconomic status and educational attain -
ment, and certain ethnic minorities.
Finding 7: Quality of Studies. The usefulness of a study to inform a regu-
latory decision hinges on the quality and appropriateness of the design.
In many cases, complementary studies might be needed to provide a
breadth of evidence for an informed regulatory decision with appropriate
control of confounders and internal and external validity.
Recommendation 7: For all studies of the effects of MRTPs on human
health and behavior, the FDA should require a range of designs that
are properly powered, balance internal and external validity, and
comprise multiple populations appropriate to the experimental ques-
tions being addressed.
Finding 8: Standards for Good Research Practice. A significant amount
of guidance on minimum standards for scientific studies directly relevant
to the evaluation of MRTPs has already been developed. Guidelines for
formatting, design, conduct, and reporting of science are articulated in
consensus statements, such as the Consolidated Standards of Reporting
Trials (CONSORT) reporting criteria for clinical trials, the Strengthen -
ing the Reporting of Observational Studies in Epidemiology (STROBE)
statement for observational studies, the publication criteria of the Inter-
national Council of Medical Journal Editors, and the reporting criteria of
the International Conference on Harmonization. These existing guidelines
represent robust standards for the conduct of science across many of the
research domains relevant to the evaluation of MRTPs.
Recommendation 8: The FDA should issue guidance to the industry
regarding the format, design, conduct, and reporting of studies in
support of MRTP applications that is based upon current generally
accepted principles for scientific investigation.
Finding 9: Standards for Integration of Evidence. Regulatory decisions
regarding MRTPs will be based on a wide range and variety of scientific
evidence, and the integration of scientific evidence will play a pivotal
role in that decision making. The assessment of MRTPs will typically
require the evaluation and integration of evidence on risks and ben -
efits across multiple diverse outcomes, such as measures of toxicity, bio -
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18 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS
markers, addictiveness, and disease endpoints. Modeling and simulation
approaches are relevant to estimating public health effects of tobacco
and, therefore, the FDA will likely engage in various methods of data
integration, synthesis, and analysis, including, but not limited to, simula -
tion and modeling. It is critical that these approaches are transparent and
reproducible.
Recommendation 9: The FDA should develop and use an approach
to data integration that is explicit and transparent with regard to the
importance of the different outcomes, that uses optimal available
evidence, and that employs objective and reproducible methods for
data integration.
Governance of Studies
Finding 10: Independent Oversight and Conduct of Studies. It has been
established in public records and as a matter of law that the tobacco
industry has engaged in illegal and improper practices, including the
destruction and manipulation of scientific data. As a result, the tobacco
industry is profoundly isolated from the mainstream scientific commu-
nity. Many major universities have policies against acceptance of tobacco
funding, and many high-impact scientific and medical journals will not
accept tobacco industry-supported manuscripts. The consequence of this
isolation is a lack of the expertise and the resources necessary to produce
high-quality science across the range of disciplines to support an applica -
tion to market an MRTP. Use of a trusted third party, particularly for prod-
ucts developed by the tobacco industry, could provide an avenue for the
production of credible evidence needed by the FDA to evaluate tobacco
products. Ultimately, such a research structure could encourage and sup-
port the production and dissemination of credible and reliable evidence
about the effects of tobacco products on the public’s health.
Recommendation 10: MRTP sponsors should consider use of inde-
pendent third parties to undertake one or more key functions,
including the design and conduct of research, the oversight of spe-
cific studies, and the distribution of sponsor funds for research.
Such independent third parties should be approved by the FDA in
advance of the research.
Finding 11: Public Disclosure of Research. Public availability of data
not only builds credibility and public trust, but also benefits the public
because it allows for independent analysis of study methods and data.
The model of Clinicaltrials.gov is particularly compelling and relevant,
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SUMMARY
and a similar model of public accounting and open disclosure should be
expected of the tobacco industry.
Recommendation 11: The FDA should require all MRTP sponsors
to place all data generated in the development and marketing of the
MRTP in a public repository selected by the FDA.
Finding 12: Proper Conduct of Research. Standards for the conduct of
science and the protection of human research participants have been
established for biomedical research enterprises not only in academics
but also in commercial research. The FDA has the tools to ensure studies
adhere to established standards in the drug development framework,
which can be applied to the development of MRTPs. Those standards not
only protect human participants, but they also build credibility into any
data that are provided to the FDA, particularly by the tobacco industry.
Institutional credibility and trustworthiness is particularly relevant in this
context, given the history of unethical and illegal practices of the tobacco
industry.
Recommendation 12: The FDA should require studies offered in
support of an MRTP application to adhere to established standards
and principles of good research governance, including appropri-
ately qualified investigators, transparency, independent institutional
review board or ethical review, and adherence to the Common Rule
(21 CFR parts 50 and 56).
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