[Federal Register Volume 83, Number 52 (Friday, March 16, 2018)]
[Proposed Rules]
[Pages 11818-11843]
[FR Doc No: 2018-05345]

Vol. 83

Friday,

No. 52

March 16, 2018

Part II

Department of Health and Human Services

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Food and Drug Administration

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21 CFR Part 1130

Tobacco Product Standard for Nicotine Level of Combusted Cigarettes;
Proposed Rule

Federal Register / Vol. 83 , No. 52 / Friday, March 16, 2018 /
Proposed Rules

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 1130

[Docket No. FDA-2017-N-6189]
RIN 0910-AH86

Tobacco Product Standard for Nicotine Level of Combusted
Cigarettes

AGENCY: Food and Drug Administration, HHS.

ACTION: Advance notice of proposed rulemaking.

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SUMMARY: The Food and Drug Administration (FDA) is issuing this advance
notice of proposed rulemaking (ANPRM) to obtain information for
consideration in developing a tobacco product standard to set the
maximum nicotine level for cigarettes. Because tobacco-related harms
ultimately result from addiction to the nicotine in such products,
causing repeated use and exposure to toxicants, FDA is considering
taking this action to reduce the level of nicotine in these products so
they are minimally addictive or nonaddictive, using the best available
science to determine a level that is appropriate for the protection of
the public health. FDA is using the term ``nonaddictive'' in this
document specifically in the context of a potentially nonaddictive
cigarette. We acknowledge the highly addictive potential of nicotine
itself depending upon the route of delivery. As discussed elsewhere in
this document, questions remain with respect to the precise level of
nicotine in cigarettes that might render them either minimally
addictive or nonaddictive for specific members or segments of the
population. We envision the potential circumstance where nicotine
levels in cigarettes do not spur or sustain addiction for some portion
of potential smokers. This could give addicted users the choice and
ability to quit more easily, and it could help to prevent experimenters
(mainly youth) from initiating regular use and becoming regular
smokers. The scope of products covered by any potential product
standard will be one issue for comment in the ANPRM. Any additional
scientific data and research relevant to the empirical basis for
regulatory decisions related to a nicotine tobacco product standard is
another issue for comment in the ANPRM.

DATES: Submit either electronic or written comments on the ANPRM by
June 14, 2018.

ADDRESSES: You may submit comments as follows. Please note that late,
untimely filed comments will not be considered. Electronic comments
must be submitted on or before June 14, 2018. The https://www.regulations.gov electronic filing system will accept comments until
midnight Eastern Time at the end of June 14, 2018. Comments received by
mail/hand delivery/courier (for written/paper submissions) will be
considered timely if they are postmarked or the delivery service
acceptance receipt is on or before that date.

Electronic Submissions

    Submit electronic comments in the following way:
     Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
     If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').

Written/Paper Submissions

    Submit written/paper submissions as follows:
     Mail/Hand delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
     For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
    Instructions: All submissions received must include the Docket No.
FDA-2017-N-6189 for ``Tobacco Product Standard for Nicotine Level of
Certain Tobacco Products.'' Received comments, those filed in a timely
manner (see ADDRESSES), will be placed in the docket and, except for
those submitted as ``Confidential Submissions,'' publicly viewable at
https://www.regulations.gov or at the Dockets Management Staff between
9 a.m. and 4 p.m., Monday through Friday.
     Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' The Agency will
review this copy, including the claimed confidential information, in
its consideration of comments. The second copy, which will have the
claimed confidential information redacted/blacked out, will be
available for public viewing and posted on https://www.regulations.gov.
Submit both copies to the Dockets Management Staff. If you do not wish
your name and contact information to be made publicly available, you
can provide this information on the cover sheet and not in the body of
your comments and you must identify this information as
``confidential.'' Any information marked as ``confidential'' will not
be disclosed except in accordance with 21 CFR 10.20 and other
applicable disclosure law. For more information about FDA's posting of
comments to public dockets, see 80 FR 56469, September 18, 2015, or
access the information at: https://www.gpo.gov/fdsys/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
    Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Gerie Voss, Center for Tobacco
Products, Food and Drug Administration, 10903 New Hampshire Ave.,
Silver Spring, MD 20993, 1-877-CTP-1373, [email protected].

SUPPLEMENTARY INFORMATION:

Table of Contents

I. Executive Summary
    A. Purpose of the ANPRM
    B. Summary of the Major Issues Raised in the ANPRM
II. Background

    A. Purpose
    B. Legal Authority
III. Health Consequences of Combusted Tobacco Products
    A. Nicotine in Combusted Tobacco Products and Its Impact on
Users
    B. Negative Health Effects of Combusted Tobacco Product Use
IV. Requests for Comments and Information
    A. Scope
    B. Maximum Nicotine Level
    C. Implementation (Single Target vs. Stepped-Down Approach)
    D. Analytical Testing Method
    E. Technical Achievability
    F. Possible Countervailing Effects
    G. Other Considerations
V. Potential Public Health Benefits of Preventing Initiation to
Regular Use and Increasing Cessation
    A. Smoking Cessation Would Lead to Substantial Public Health
Benefits for People of All Ages
    B. A Nicotine Tobacco Product Standard Could Lead to Substantial
Improvement in Public Health
VI. References

I. Executive Summary

A. Purpose of the ANPRM

    Tobacco use causes a tremendous toll of death and disease every
year, and these effects are ultimately the result of addiction to the
nicotine in combustible cigarettes which causes repeated use of such
products, thus repeatedly exposing users and non-users to toxicants.
This nicotine addiction causes users to engage in compulsive tobacco
use, makes quitting less likely, and, thus, repeatedly exposes them to
thousands of toxicants in combusted tobacco products. This is
especially true with respect to cigarette smoking. Through this ANPRM,
FDA indicates that it is considering the issuance of a product standard
to set a maximum nicotine level in cigarettes so that they are
minimally addictive or nonaddictive, using the best available science
to determine a level that is appropriate for the protection of the
public health. The Agency seeks information and comment on a number of
issues associated with such a potential product standard. Greatly
reducing or eliminating the addictiveness of cigarettes would have
significant benefits for youth, young adults, and adults. More than
half of adult cigarette smokers make a serious quit attempt each year
(quit for at least a day), many of whom do not succeed due to the
addictive nature of these products (Ref. 1). The establishment of a
maximum nicotine level in cigarettes not only could increase the
likelihood of successful quit attempts, but it also could help prevent
experimenters (mainly youth and young adults) from initiating regular
cigarette smoking. Therefore, rendering cigarettes minimally addictive
or nonaddictive (however that were achieved) could help current users
quit and prevent future users from becoming addicted and escalating to
regular use.

B. Summary of the Major Issues Raised in the ANPRM

    In this ANPRM, FDA is seeking information on a variety of issues
regarding the development of a tobacco product standard that would
limit the amount of nicotine in cigarettes. Specifically, FDA is
seeking your comments, evidence, and other information supporting your
responses to questions on the following topics:
     Scope--Cigarettes are the tobacco product category that
causes the greatest burden of harm to public health given the
prevalence of cigarette use, including among youth, and the toxicity
and addictiveness of these products and the resulting tobacco-related
disease and death across the population, including among non-users. If
FDA were to establish a nicotine tobacco product standard that covered
only cigarettes, some number of addicted smokers could migrate to other
similar combusted tobacco products to maintain their nicotine dose (or
engage in dual use with other combusted tobacco products), potentially
reducing the positive public health impact of such a rule. Because the
scope would impact the potential public health benefits of a nicotine
tobacco product standard, FDA is seeking comment on whether the
standard should cover any or all of the following products: Combusted
cigarettes (which FDA has previously interpreted to include kreteks and
bidis), cigarette tobacco, roll-your-own (RYO) tobacco, some or all
cigars, pipe tobacco, and waterpipe tobacco. FDA intends that any
nicotine tobacco product standard would cover all brands in a
particular product category and, therefore, those products currently on
the market and any new tobacco products would be expected to adhere to
the standard.
     Maximum Nicotine Level--FDA has considered the existing
peer-reviewed studies regarding very low nicotine content (VLNC)
cigarettes and the likely effects of reducing nicotine in combusted
tobacco products (i.e., cigarettes, cigars, pipe tobacco, roll-your-own
tobacco, and waterpipe tobacco). A 2013 survey paper noted that
researchers initially estimated that reducing the total nicotine
content of cigarettes to 0.5 milligrams (mg) per rod would minimize
addictiveness and that a ``more recent analysis suggests that the
maximum allowable nicotine content per cigarette that minimizes the
risk of central nervous system effects contributing to addiction may be
lower'' (Ref. 2). The study authors concluded that ``[p]reventing
children from becom[ing] addicted smokers and giving people greater
freedom to stop smoking when they decide to quit by reducing the
addictiveness of cigarettes is a policy that increasingly appears to be
feasible and warranted'' (id.). We specifically request comment
regarding this paper's conclusions and the possible impact of higher or
lower maximum nicotine levels in a potential nicotine tobacco product
standard. If FDA were to pursue a nicotine tobacco product standard, it
would be important for FDA to consider what maximum nicotine level for
such standard would be appropriate, how this maximum nicotine level
should be measured (e.g., nicotine yield, nicotine in tobacco filler,
something else), and how the threshold of nicotine addiction should be
measured, using the best available science to determine a level that is
appropriate for the protection of the public health. FDA seeks comment
on a potential maximum nicotine level that would be appropriate for the
protection of the public health, in light of scientific evidence about
the addictive properties of nicotine in cigarettes. FDA is particularly
interested in comments about the merits of nicotine levels like 0.3,
0.4, and 0.5 mg nicotine/g of tobacco filler, as well as other levels
of nicotine. FDA is also requesting any information on additional
scientific data and research which would provide information about
specific groups within the general population which may have an
increased sensitivity to nicotine's reinforcing effects, or who may
have otherwise not been captured in the literature on VLNC cigarettes.
In addition, FDA is considering and requesting information on
additional scientific data and research relevant to the empirical basis
for regulatory decisions related to a potential nicotine product
standard.
     Implementation--If FDA were to issue a product standard
establishing a maximum nicotine level for cigarettes, such a standard
could propose either a single target (where the nicotine is reduced all
at once) or a stepped-down approach (where the nicotine is reduced
gradually over time through a sequence of incremental levels and
implementation dates) to reach the desired maximum nicotine level.
     Analytical Testing Method--As part of its consideration
regarding a potential nicotine tobacco product standard, FDA is also
considering whether such a product standard should specify a method for
manufacturers to use to

detect the level of nicotine in their products. FDA believes that the
results of any test to measure the nicotine in such products should be
comparable across different accredited testing facilities and products.
It is critical that the results from the test method used demonstrate a
high level of specificity, accuracy, and precision in measuring a range
of nicotine levels across a wide variety of tobacco blends and
products. FDA is aware of a variety of methods being developed that
quantify nicotine in tobacco or tobacco product filler for various
products.
     Technical Achievability--If FDA were to move forward in
this area and proceed to the next step of issuing a proposed rule,
section 907(b)(1) of the Federal Food, Drug, and Cosmetic Act (the FD&C
Act) (21 U.S.C. 387g(b)(1) would require that FDA consider information
submitted in connection with that proposed product standard regarding
technical achievability of compliance. FDA continues to analyze the
technical achievability of a maximum nicotine level for cigarettes as
part of its broader assessment of how best to exercise its regulatory
authority in this area. Significant nicotine reductions in cigarettes
and other combusted tobacco products can be achieved principally
through tobacco blending and cross-breeding plants, genetic
engineering, and chemical extraction. Agricultural practices (e.g.,
controlled growing conditions, fertilization, and harvest) as well as
more recent, novel techniques also can help to reduce nicotine levels.
FDA is considering the feasibility of the current nicotine reduction
techniques--for cigarette and other combusted tobacco product
manufacturers of all sizes--to significantly reduce nicotine levels to
levels similar to those in existing VLNC cigarettes. FDA also is
considering the proper timeframe for implementation of a possible
nicotine tobacco product standard to allow adequate time for industry
to comply. In addition, FDA is seeking data and information regarding
the potential costs, including possible costs to farmers, to implement
such a standard.
     Possible Countervailing Effects--There may be possible
countervailing effects that could diminish the population health
benefits expected as a result of a nicotine tobacco product standard.
As part of any subsequent rulemaking, FDA would need to assess these
effects in comparison to the expected benefits, including among
population subgroups. One possible countervailing effect is continued
combusted tobacco product use. Current smokers of tobacco products
subject to a nicotine tobacco product standard could turn to other
combusted tobacco products to maintain their nicotine dependence, both
in combination with cigarettes (i.e., dual use) or in place of
cigarettes (i.e., switching). Coverage of other combusted tobacco
products, as FDA is considering, is one way to significantly limit this
product migration or transition to dual use with other combusted
tobacco products.
    Another possible countervailing effect is the potential for
increased harm due to continued VLNC smoking with altered smoking
behaviors (e.g., increase in number of cigarettes smoked, increased
depth of inhalation). Some studies of VLNC cigarettes with nicotine
levels similar to what FDA may consider including in a nicotine tobacco
product standard have not resulted in compensatory smoking and have
demonstrated reductions in cigarettes smoked per day and in exposure to
harmful constituents (e.g., Ref. 3; Ref. 4; Ref. 5).
    Another possible countervailing effect of setting a maximum
nicotine level for cigarettes could be users seeking to add nicotine in
liquid or other form to their combusted tobacco product. Therefore, FDA
is considering whether any action it might take to reduce nicotine in
cigarettes should be paired with a provision that would prohibit the
sale or distribution of any tobacco product designed for the purposes
of supplementing the nicotine content of the combusted tobacco product
(or where the reasonably foreseeable use of the product is for the
purposes of supplementing the nicotine content). FDA is also
considering other regulatory options to address this concern.
    FDA is also considering whether illicit trade could occur as a
result of a nicotine tobacco product standard and how that could impact
the marketplace. In addition, FDA is considering how, if FDA were to
issue a nicotine tobacco product standard that prompted an increase in
the illicit market, comprehensive interventions could reduce the size
of the illicit tobacco market through enforcement mechanisms and
collaborations across jurisdictions.
     Other Considerations--FDA also recognizes that, if FDA
were to proceed to the stage of proposing a rule in this area,
potential costs and benefits from a possible nicotine tobacco product
standard would be estimated and considered in an accompanying
preliminary impact analysis, including the potential impacts on growers
of tobacco and current users of potentially regulated products. Thus,
FDA is also seeking comments, data, research results, and other
information regarding economic impacts of a potential nicotine tobacco
product standard.
    Further, this ANPRM briefly describes the potential public health
benefits that could result from the increased cessation from and
decreased initiation to regular use of cigarettes that FDA expects
could occur with a nicotine tobacco product standard. FDA references
findings from a population-based simulation model that projects the
potential public health impact of enacting a regulation lowering
nicotine levels in cigarettes and certain other combusted tobacco
products to minimally addictive levels, utilizing inputs derived from
empirical evidence and expert opinion (eight subject matter experts
provided quantitative estimates for the potential outcomes of the
policy on smoking cessation, initiation, switching, and dual use
rates). Based on the experts' determinations that the reduction in
nicotine levels in combusted tobacco products would create substantial
reductions in smoking prevalence due to increased smoking cessation and
reduced initiation of regular smoking, the model calculates that by the
year 2100, more than 33 million youth and young adults who would have
otherwise initiated regular smoking would not start as a result of a
nicotine tobacco product standard. The model also projected that
approximately 5 million additional smokers would quit smoking 1 year
after implementation of the product standard, compared to the baseline
scenario, which would increase to approximately 13 million additional
former smokers within 5 years after policy implementation.

II. Background

A. Purpose

    On July 28, 2017, FDA announced a comprehensive approach to the
regulation of nicotine that includes the Agency's plan to begin a
public dialogue about lowering nicotine levels in combustible
cigarettes to minimally addictive or nonaddictive levels through
achievable product standards, including the issuance of an ANPRM to
seek input on the potential public health benefits and any possible
adverse effects of lowering nicotine in cigarettes. Tobacco use causes
a tremendous toll of death and disease every year, and these effects
are ultimately the result of addiction to the nicotine contained in
combustible cigarettes, leading to repeated exposure to toxicants from
such cigarettes. This nicotine addiction causes users to engage in
compulsive use, makes quitting less likely and, therefore,

repeatedly exposes them (and others) to thousands of toxicants in
combusted tobacco products. This is especially true with respect to
cigarette smoking. Researchers have found that the mortality rate from
any cause of death at any given age is 2 to 3 times higher among
current cigarette smokers, compared to individuals who never smoked
(Ref. 6).\1\ Through this ANPRM, FDA indicates that it is considering
the issuance of a product standard to set a maximum nicotine level in
cigarettes so that they are minimally addictive or nonaddictive, using
the best available science to determine a level that is appropriate for
the protection of the public health.\2\ The Agency seeks information
and comment on a number of issues associated with such a potential
product standard. Greatly reducing the addictiveness of cigarettes
would have significant benefits for youth, young adults, and adults.\3\
More than half of adult smokers make a serious quit attempt each year
(quit for at least a day), many of whom are not able to succeed due to
the addictive nature of these products (Ref. 1). The establishment of a
maximum nicotine level in cigarettes not only could increase the
likelihood of successful quit attempts, but it also could help prevent
experimenters (mainly youth) from initiating regular use. Therefore,
FDA hypothesizes that making cigarettes minimally addictive or
nonaddictive, using the best available science to determine a level
that is appropriate for the protection of the public health, would
significantly reduce the morbidity and mortality caused by smoking.
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    \1\ The discussion of scientific data discussed in this ANPRM is
not intended to cover all available information on this subject
matter. Rather, it is intended to provide only a sampling of some of
the current research that could be relevant to consideration of a
potential nicotine tobacco product standard.
    \2\ The Family Smoking Prevention and Tobacco Control Act
specifically prohibits the Agency from ``requiring the reduction of
nicotine yields of a tobacco product to zero'' but generally
authorizes FDA to issue a tobacco product standard setting a maximum
nicotine level. Section 907(C)(3)(B) of the FD&C Act.
    \3\ The definitions of ``youth,'' ``young adults,'' and
``adults'' can vary in scientific studies. The term ``youth''
generally refers to middle school and/or high school age students.
``Young adults'' generally refers to individuals 18 to 24 years of
age. In some studies, ``adults'' may encompass individuals age 18 to
24 but generally refers to those individual 24 to 65 years of age.
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    Preventing nonsmokers, particularly youth and young adults, from
becoming regular smokers due to nicotine addiction would allow them to
avoid the severe adverse health consequences of smoking and would
result in substantial public health benefits. In 2014, the Surgeon
General estimated that, unless this trajectory is changed dramatically,
5.6 million youth aged 0 to 17 years alive today will die prematurely
from a smoking-related disease (Ref. 7 at table 12.2.2). In 2009,
Congress estimated that a 50 percent reduction in youth smoking would
also result in approximately $75 billion in savings \4\ attributable to
reduced health care costs (see section 2(14) of the Family Smoking
Prevention and Tobacco Control Act; 21 U.S.C. 387 note). As further
explained in this ANPRM, if cigarettes were minimally addictive or
nonaddictive, it is expected that many fewer youth and young adults
would be subjected to the impacts of nicotine (which has a
significantly stronger effect on the developing brains of youth (e.g.,
Refs. 8 and 9)) from cigarettes, nor would they suffer from the health
and mortality effects of cigarette use.
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    \4\ Congress' estimate of approximately $75 billion in savings,
if adjusted for inflation, would amount to $83.63 billion in 2017.
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    Nicotine is powerfully addictive. The Surgeon General has reported
that 87 percent of adult smokers start smoking before the age of 18 and
half of adult smokers become addicted before the age of 18, which is
before the age at which they can legally buy a pack of cigarettes (Ref.
7). Nearly all smokers begin before the age of 25, which is the
approximate age at which the brain has completed development (Ref. 8).
Generally, those who begin smoking before the age of 18 are not aware
of the degree of addictiveness and the full extent of the consequences
of smoking when they begin experimenting with tobacco use (see, e.g.,
Ref. 10). Although youth generally believe they will be able to quit
when they want, in actuality they have low success rates when making a
quit attempt. For example, more than 60 percent of high school aged
daily smokers have tried to quit but less than 13 percent were
successful at quitting for 30 days or more (Ref. 11). In addition, one
study found that 3 percent of 12th grade daily smokers estimated that
they would ``definitely'' still be smoking in 5 years, while in reality
63 percent of this population is still smoking 7 to 9 years later (Ref.
12). Another survey revealed that ``nearly 60 percent of adolescents
believe that they could smoke for a few years and then quit'' (Ref.
13).
    Because it is such a powerful addiction, addiction to nicotine is
often lifelong (Ref. 14). Among adolescent tobacco users in 2012, over
half (52.2 percent) reported experiencing at least one symptom of
tobacco dependence (Ref. 15). FDA expects that making cigarettes
minimally addictive or nonaddictive (however that were achieved) may
have significant benefits for youth by reducing the risk that youth
experimenters progress to regular use of cigarettes as a result of
nicotine dependence.
    The adolescent brain is more vulnerable to developing nicotine
dependence than the adult brain; there are also data from animal
studies that indicate that brain changes induced by nicotine may have
long-term consequences (i.e., the long-term physical changes, caused by
the adolescent nicotine exposure, prevent the brain from reaching its
full potential, which could result in permanent deficiencies) (Refs. 8
and 9). Adolescent tobacco users who initiated tobacco use at earlier
ages were more likely than those initiating at older ages to report
symptoms of tobacco dependence, putting them at greater risk for
maintaining tobacco product use into adulthood (Ref. 15). Evidence from
animal studies indicate that exposure to substances such as nicotine
can disrupt brain development and have long-term consequences for
executive cognitive function (such as task-switching and planning) and
for the risk of developing a substance abuse disorder and various
mental health problems (particularly affective disorders such as
anxiety and depression) as an adult (Ref. 16). This exposure to
nicotine can also have long-term effects, including decreased attention
performance and increased impulsivity, which could promote the
maintenance of nicotine use behavior (id.). Further, the 2010 Surgeon
General's Report noted that symptoms of dependence could result from
even a limited exposure to nicotine during adolescence (Ref. 17).
    For all these reasons, FDA is considering limiting the
addictiveness of cigarettes by setting a product standard establishing
a maximum nicotine level of cigarettes, to help prevent experimenters
(who are mainly youth) from becoming addicted to tobacco and, thus,
prevent them from initiating regular use and from increasing their risk
of tobacco-related death and disease.
    FDA is also considering this action because age restrictions on the
sale of tobacco products, by themselves, are not entirely effective in
preventing youth from obtaining cigarettes or other combusted tobacco
products. Youth smokers get their cigarettes from a variety of sources,
including directly purchasing them from retailers, giving others money
to buy them, obtaining them from other youth or adults (with

or without their knowledge), or using illegal means (i.e., shoplifting
or stealing) (Ref. 18). The 2015 National Youth Risk Behavior
Surveillance Survey (YRBS) of high school students in grades 9 through
12 found that 12.6 percent of current cigarette smokers under age 18
had purchased their cigarettes directly from stores or gas stations
despite the Federal minimum age requirements for cigarettes (Ref. 19).
While continued vigorous enforcement of youth access restrictions is
critical to protecting public health, FDA is considering taking this
additional step to ensure that even if youth do obtain access to
cigarettes, they will be less likely to: (1) Become addicted to these
products; (2) initiate regular use; and (3) increase their risk of the
many diseases caused by, and debilitating effects of, combusted tobacco
product use (Ref. 20).
    Similarly, limiting the nicotine in cigarettes could have
significant benefits for adult tobacco product users, a large majority
of whom want to quit but are unsuccessful because of the highly
addictive nature of these products (see, e.g., Ref. 21). Data from the
2015 National Health Interview Survey show that 68 percent of current
adult cigarette smokers in the United States wanted to quit and 55.4
percent of adult cigarette smokers made a past-year quit attempt of at
least 1 day (Ref. 22). In high-income countries, about 7 of 10 adult
smokers say they regret initiating smoking and would like to stop (Ref.
23 at p. 2). Decreasing the nicotine in cigarettes so that they are
minimally addictive or nonaddictive (using the best available science
to determine a level that is appropriate for the protection of the
public health) could help users quit if they want to--as the large
majority of users say they do (e.g., Ref. 21).
    Although many factors contribute to an individual's initial
experimentation with tobacco products, the addictive nature of tobacco
is the major reason people progress to regular use, and it is the
presence of nicotine that causes youth, young adults, and adult users
to become addicted to, and to sustain, tobacco use (see, e.g., Refs. 24
and 25). While nicotine is the primary addictive chemical in tobacco,
sensorimotor stimuli that are repeatedly paired with nicotine through
the process of smoking also develop into conditioned reinforcers that
contribute to the persistent nature of nicotine dependence (Ref. 26).
In cigarette users, the sensory aspects of smoking, such as taste and
sensations of smoking (e.g., throat hit), are often reinforcing as they
have been paired repeatedly with nicotine exposure and have been found
to be reinforcing without concomitant nicotine exposure in experienced
users (Ref. 27). Once tobacco users become addicted to nicotine, they
require nicotine to avoid certain withdrawal symptoms. In the process
of obtaining nicotine, users of combusted tobacco products are exposed
to an array of toxicants in tobacco and tobacco smoke that lead to a
substantially increased risk of morbidity and mortality (see, e.g.,
Ref. 10). Although most current U.S. smokers report that they want to
quit smoking, have attempted to quit, and regret starting (see, e.g.,
Refs. 28 and 29), many smokers find it difficult to break their
addiction and quit. Because of nicotine addiction, many smokers lack
the ability to choose whether or not to continue smoking these toxic
combusted products despite their stated desire to quit (see, e.g., Ref.
17).
    Accordingly, FDA is considering whether to issue a tobacco product
standard to: (1) Give addicted users of cigarettes the choice and
ability to quit more easily by reducing the nicotine to a minimally
addictive or nonaddictive level and (2) reduce the risk of progression
to regular use and nicotine dependence for persons who experiment with
the tobacco products covered by the standard. FDA hypothesizes that
making cigarettes minimally addictive or nonaddictive, using the best
available science to determine a level that is appropriate for the
protection of the public health, could significantly reduce the
morbidity and mortality caused by smoking.

B. Legal Authority

    The Family Smoking Prevention and Tobacco Control Act (Tobacco
Control Act) was enacted on June 22, 2009, amending the FD&C Act and
providing FDA with the authority to regulate tobacco products (Pub. L.
111-31). Section 901 of the FD&C Act (21 U.S.C. 387a), as amended by
the Tobacco Control Act, granted FDA authority to regulate the
manufacture, marketing, and distribution of cigarettes, cigarette
tobacco, RYO tobacco, and smokeless tobacco to protect the public
health and to reduce tobacco use by minors. The Tobacco Control Act
also gave FDA the authority to issue a regulation deeming other
products that meet the statutory definition of tobacco product to be
subject to FDA's tobacco product authority under chapter IX of the FD&C
Act. On May 10, 2016, FDA issued the deeming rule (81 FR 28973),
extending FDA's tobacco product authority to all tobacco products,
other than the accessories of deemed tobacco products, that meet the
statutory definition of tobacco product.
    Among the authorities included in chapter IX of the FD&C Act is the
authority to establish tobacco product standards. The Act authorizes
FDA to adopt a tobacco product standard under section 907 of the FD&C
Act if the Secretary of Health and Human Services (HHS) finds that a
tobacco product standard is appropriate for the protection of the
public health. In making such a finding, the Secretary of HHS must
consider scientific evidence concerning: (1) The risks and benefits of
the proposed standard to the population as a whole, including users and
nonusers of tobacco products; (2) the increased or decreased likelihood
that existing users of tobacco products will stop using such products;
and (3) the increased or decreased likelihood that those who do not use
tobacco products will start using such products (section
907(a)(3)(B)(i) of the FD&C Act).
    Section 907(a)(4) of the FD&C Act states that tobacco product
standards must include provisions that are appropriate for the
protection of the public health. Section 907(a)(4)(B)(i) provides that
a product standard must include, where appropriate for the protection
of the public health, provisions respecting the construction,
components, ingredients, additives, constituents, including smoke
constituents, and properties of the tobacco product. Further, section
907(a)(4)(A)(i) states that provisions in tobacco product standards
must include, where appropriate, provisions for nicotine yields.
Section 907(a)(4)(B)(ii) also provides that a product standard must,
where appropriate for the protection of public health, include
``provisions for the testing (on a sample basis or, if necessary, on an
individual basis) of the tobacco product.'' In addition, section
907(a)(4)(B)(iv) provides that, where appropriate for the protection of
public health, a product standard must include provisions requiring
that the results of the tests of the tobacco product required under
section 907(a)(4)(B)(ii) show that the product is in conformity with
the portions of the standard for which the test(s) were required.
Finally, section 907(d)(3)(B) of the FD&C Act prohibits the Agency from
issuing a regulation that would require the reduction of nicotine
yields of a tobacco product to zero.
    The FD&C Act also provides FDA with authority to issue regulations
establishing restrictions on the sale and distribution of a tobacco
product (section 906(d)(1) of the FD&C Act (21 U.S.C. 387f(d)(1))).
These restrictions

may include restrictions on the access to, and the advertising and
promotion of, the tobacco product, if the Secretary of HHS determines
such regulation would be appropriate for the protection of the public
health.
    FDA intends to use the information submitted in response to this
ANPRM, its independent scientific knowledge, and other appropriate
information, to further inform its thinking about options, including
the scope, for a potential product standard that would set a maximum
nicotine level for cigarettes, and restrictions prohibiting the sale
and distribution of any product that violates such a standard.

III. Health Consequences of Combusted Tobacco Products

A. Nicotine in Combusted Tobacco Products and Its Impact on Users

    Tobacco products are addictive, primarily due to the presence of
nicotine, and the magnitude of public health harm caused by tobacco
products is inextricably linked to their addictive nature (Ref. 13 at
p. xi). Cigarettes are the most widely used tobacco products among
adults and are responsible for at least 480,000 premature deaths in the
United States each year (Ref. 7). Other combusted tobacco products that
are possible targets of product migration (i.e., switch candidates for
smokers to maintain their nicotine addiction) or dual use have similar
adverse health effects and can cause nicotine dependence (Refs. 30 and
31). For example, researchers have found that current exclusive cigar
smokers and current exclusive pipe smokers have an increased risk for
lung cancer and tobacco-related cancers overall, as compared to those
who reported never using any type of combusted tobacco product (Ref.
32). We note that there is a dose-response relationship between the
number of cigars and pipes smoked and the risk of disease (i.e., the
larger the number of cigars or pipes smoked, the higher the risk of
disease) (Ref. 31 at 110), but cigar and pipe users are still subject
to the addictive effects of nicotine through nicotine absorption (and
to the health impacts of long-term use that may follow from regular use
due to addiction) even if they report that they do not inhale (Refs.
33-35).
    The Surgeon General has reported that ``most people begin to smoke
in adolescence and develop characteristic patterns of nicotine
dependence before adulthood'' (Ref. 36 at p. 29). Adolescents develop
physical dependence and experience withdrawal symptoms when they try to
quit smoking (id.). The 2014 Surgeon General's Report states that 5.6
million youth currently 0 to 17 years of age are projected to die
prematurely from smoking-related illnesses (Ref. 7 at pp. 666-667).
Accordingly, using the best available science to determine a level that
is appropriate for the protection of the public health, making
cigarettes minimally addictive or nonaddictive would limit the number
of youth and young adults who progress from experimentation to regular
use and who, thereby, increase their risk for dangerous smoking-related
diseases.
    Researchers have determined that almost one-third of adolescents
aged 11 to 18 (31 percent) are ``early experimenters,'' meaning that
they have tried smoking at least one puff of a cigarette (but smoked no
more than 25 cigarettes in their lifetime) (Ref. 37). The Centers for
Disease Control and Prevention (CDC) and other researchers have
estimated that 30 percent or more of experimenters become established
smokers (Ref. 37, citing Refs. 38 and 39). Given these past trends, if
one applies the 30 percent estimate to the adolescents who were early
experimenters in 2000, then 2.9 million of these early experimenters
have now or will become established smokers (Ref. 37). Based on the
number of persons aged 0 to 17 in 2012, the Surgeon General estimated
that 17,371,000 of that group will become future smokers and 5,557,000
will die from a smoking-related disease (Ref. 7 at T. 12.2.1). These
high numbers speak to the extreme vulnerability of today's children and
adolescents to the health harms of tobacco use resulting from
addiction.
    Nicotine addiction is a critical factor in the transition of
smokers from experimentation to sustained smoking and in the
continuation of smoking for those who want to quit (Ref. 7 at p. 113;
Ref. 17). Intermittent smokers, even very infrequent smokers, can
become addicted to tobacco products (Ref. 40). Longitudinal research
has shown that smoking typically begins with experimental cigarette use
and the transition to regular smoking can occur relatively quickly by
smoking as few as 100 cigarettes (Ref. 8). Other research found that
among the 3.9 million middle and high school students who reported
current use of tobacco products (including cigarettes and cigars) in
2012, 2 million of those students reported at least one symptom of
dependence (Ref. 15).
    Although the majority of adolescent daily smokers meet the criteria
for nicotine dependence, one study found that the most susceptible
youth lose autonomy (i.e., independence in their actions) regarding
tobacco within 1 or 2 days of first inhaling from a cigarette (Refs. 41
and 42). Another study found that 19.4 percent of adolescents who
smoked weekly also were considered to be nicotine dependent (Ref. 43).
In a study regarding nicotine dependence among recent onset adolescent
smokers, individuals who smoked cigarettes at the lowest levels (i.e.,
smoking on only 1 to 3 days of the past 30 days) experienced nicotine
dependence symptoms such as loss of control over smoking (42 percent)
and irritability after not smoking for a while (23 percent) (Ref. 44).
Researchers in a 4-year study of sixth grade students also found that
``[e]ach of the nicotine withdrawal symptoms appeared in some subjects
prior to daily smoking'' (Ref. 42) (emphasis added). Ten percent of the
subjects showed signs of addiction to tobacco use within 1 or 2 days of
first inhaling from a cigarette, and half had done so by the time they
were smoking seven cigarettes per month (Ref. 42).
    It is clear that many adult cigarette smokers want to quit. Data
from the 2015 National Health Interview Survey show that 68 percent of
current adult smokers in the United States wanted to quit and 55.4
percent of adult smokers made a past-year quit attempt of at least 1
day (Ref. 22). According to an analysis of this survey, only 7.4
percent of former adult cigarette smokers had recently quit (id.).
    For adult smokers who report quit attempts, many of these attempts
are unsuccessful. For example, among the 19 million adults who reported
attempting to quit in 2005, epidemiologic data suggest that only 4 to 7
percent were successful (Ref. 28 at p. 15). Similarly, the Institute of
Medicine (IOM), considering data from 2004, found that although
approximately 40.5 percent of adult smokers reported attempting to quit
in that year, only between 3 and 5 percent were successful (Ref. 13 at
p. 82). Adult smokers may make as many as thirty or more quit attempts
before succeeding (Ref. 45). FDA also notes that adults with education
levels at or below the equivalent of a high school diploma have the
highest smoking prevalence levels but the lowest quit ratios (i.e., the
ratio of persons who have smoked at least 100 cigarettes during their
lifetime but do not currently smoke to persons who report smoking at
least 100 cigarettes during their lifetime) (Ref. 46). Nicotine
addiction and associated withdrawal symptoms make it difficult for
smokers to quit without using cessation counseling and/or cessation
medications.

    Adolescents also experience low success rates when attempting to
quit. As we have noted, most Americans who use tobacco products begin
using when they are under the age of 18 and become addicted before
reaching the age of 18 (Refs. 36 and 47). Although many adolescents
believe ``they can quit [smoking] at any time and therefore avoid
addiction,'' nicotine dependence can be rapidly established (Ref. 13 at
p. 89; see also Ref. 28 at p. 158). Research has shown that some
adolescents report symptoms of withdrawal and craving within days or
weeks of beginning to smoke (Ref. 48). As a result, many adolescents
are nicotine dependent despite their relatively short smoking histories
(Ref. 11). An analysis of data from the 2015 YRBS found that, of those
currently smoking cigarettes, 45.4 percent had tried to quit smoking
cigarettes during the previous year (Ref. 19). Likewise, an analysis of
the 2012 National Youth Tobacco Survey (NYTS) revealed that 51.5
percent of middle and high school student smokers had sought to quit
all tobacco use in the previous year (Ref. 49).
    Relapse is the principal limiting factor in the transition of
smoking to nonsmoking status (Ref. 17). Relapse refers to the point
after an attempt to stop smoking when tobacco use becomes ongoing and
persistent (Ref. 17, citing Ref. 50). Most smokers who ultimately
relapse do so soon after their quit attempt (Ref. 17). One study found
that 80 to 90 percent of those individuals who were smoking at 6 months
following a quit attempt had resumed smoking within 2 weeks following
their quit attempt (Ref. 51). Long-term studies of individuals trying
to quit smoking reveal that 30 to 40 percent of those who quit smoking
for 1 year eventually relapsed (id.). In fact, one study following 840
participants for more than 8 years found that approximately one-half of
smokers who stopped smoking for 1 year relapsed to regular smoking
within the subsequent 7 years (Ref. 52). Researchers have found that a
higher frequency of smoking predicts more severe withdrawal symptoms
and earlier relapse after an attempt to quit smoking and is associated
with early lapses after cessation (Ref. 17 at p. 119). FDA specifically
requests comment as to whether higher frequency smokers would
experience more severe withdrawal symptoms from the use of VLNC
cigarettes.
    FDA expects that, if cigarettes were minimally addictive or
nonaddictive, the nicotine level in cigarettes would be self-limiting
(i.e., smokers would be unable to obtain their nicotine dose from
cigarettes no matter how they smoked them and eventually would stop
trying to do so) (e.g., Refs. 4, 5, and 53), making it potentially
easier for smokers to make more successful quit attempts and likely
leading to a potentially substantial reduction in the rate of relapse
compared to current levels.\5\ Former smokers that choose to switch
completely to a potentially less harmful nicotine delivery product
(e.g., electronic nicotine delivery systems (ENDS)) to maintain their
nicotine dose also would, to the extent that those products result in
less harm, significantly reduce their risk of tobacco-related death and
disease. Accordingly, rendering cigarettes minimally addictive or
nonaddictive (however that were achieved) would be expected to address
the principal reason that smokers are unable to quit smoking.
---------------------------------------------------------------------------

    \5\ As stated throughout the document, FDA expects that, to
maintain their nicotine dose, some number of addicted cigarette
smokers could migrate to other similar, combusted products (or
engage in dual use with such products) after the standard went into
effect, reducing the benefits of the product standard. Since the
scope would impact the potential public health benefits of such a
nicotine tobacco product standard, FDA is seeking comment on whether
the standard should cover any or all of the following products:
Combusted cigarettes (which FDA has previously interpreted to
include kreteks and bidis), cigarette tobacco, roll-your-own
tobacco, some or all cigars, waterpipe tobacco, and pipe tobacco.
---------------------------------------------------------------------------

B. Negative Health Effects of Combusted Tobacco Product Use

    Nicotine is a powerfully addictive chemical. The effects of
nicotine on the central nervous system occur rapidly after absorption
(Ref. 25 at p. 12). Users of combusted tobacco products absorb nicotine
readily from tobacco smoke through the lungs (id. at p. iii). Nicotine
introduced through the lungs is rapidly distributed to the brain (id.
at p. 12). With regular use, nicotine levels accumulate in the body
during the day from the tobacco product use and then decrease overnight
as the body clears the nicotine (id. at p. iii). Mild nicotine
intoxication even occurs in first-time smokers (Ref. 25 at pp. 15-16).
Tolerance to the effects of nicotine develops rapidly.
    The addiction potential of a nicotine delivery system varies as a
function of its total nicotine dosing capability, the speed at which it
can deliver nicotine, the palatability and sensory characteristics of
the system, how easy it is for the user to extract nicotine, and the
cost of the delivery system (Ref. 54). A cigarette is an inexpensive
and extremely effective nicotine delivery device, which maximizes the
cigarette's addicting and toxic effects (id.). The amount of nicotine
delivered and the means through which it is delivered can either reduce
or enhance a product's potential for abuse and physiological effects
(Ref. 17 at p. 113). Quicker delivery, higher rate of absorption, and
higher resulting concentration of nicotine increase the potential for
addiction (id. at p. 113). The ultimate levels of nicotine absorbed
into the blood for different tobacco products (e.g., cigarettes and
cigars) can be similar in magnitude even though individuals may smoke
them differently and the rate of absorption may be different (Ref. 25).
    The significant negative health effects from cigarettes are a
consequence of long-term use. Children and adults continue using
cigarettes primarily as a result of their addiction to nicotine (e.g.,
Ref. 7). Almost all adult smokers started smoking cigarettes as
children or young adults, and half of adult smokers became addicted
before turning 18 (id.).
    Cigarettes are responsible for hundreds of thousands of premature
deaths every year from many diseases, put a substantial burden on the
U.S. health care system, and cause massive economic losses to society
(Ref. 7 at pp. 659-666; another perspective on this issue is provided
by Sloan et al. (Ref. 55)). Cigarette smoking causes more deaths each
year than AIDS, alcohol, illegal drug use, homicide, suicide, and motor
vehicle crashes combined (Ref. 47). Every year, cigarette smoking is
the primary causal factor for 163,700 deaths from cancer, 160,600
deaths from cardiovascular and metabolic diseases, and 131,100 deaths
from pulmonary diseases (Ref. 7 at p. 659). In the United States, about
87 percent of all lung cancer deaths, 32 percent of coronary heart
disease deaths, and 79 percent of all cases of chronic obstructive
pulmonary disease (COPD) are attributable to cigarette smoking (id.).
The 2014 Surgeon General's Report states that 5.6 million youth
currently 0 to 17 years of age are projected to die prematurely from
smoking-related illnesses (id. at pp. 666-667).
    Data from the CDC's Smoking-Attributable Mortality, Morbidity, and
Economic Costs system for 2005-2009 (the most recent years for which
analyses are available) indicate that cigarette smoking and exposure to
cigarette smoke are responsible for at least 480,000 premature deaths
each year (id. at p. 659). However, this estimate does not include
deaths caused by other combusted forms of tobacco, such as cigars and
pipes (id. at 665).\6\

The three leading causes of smoking-attributable death for current and
former smokers were lung cancer, heart disease, and COPD (id. at p.
660). For every person who dies from a smoking-related disease,
approximately 30 more people will suffer from at least one smoking-
related disease (Ref. 58).
---------------------------------------------------------------------------

    \6\ As discussed in Ref. 56, regular cigar smoking was
responsible for approximately 9,000 premature deaths and more than
140,000 years of potential life lost among adults aged 35 years or
older in 2010. The 2014 Surgeon General Report states that the
methodology for estimating the current population burden for use of
combusted tobacco products other than cigarettes remains under
discussion, but the number of added deaths is expected to be in the
thousands per year (Ref. 7 at 665, 14 SG; citing Ref. 57).
---------------------------------------------------------------------------

    Cigarettes also have deadly effects on nonsmokers. From 2005 to
2009, an estimated 7,330 lung cancer and 33,950 heart disease deaths
were attributable to exposure to secondhand smoke (Ref. 7 at p. 660).
It is also well established that secondhand tobacco smoke causes
premature death and disease in children and in adults who do not smoke
(see, e.g., Ref. 59 at p. 11). According to the Surgeon General's
Report, ``50 Years of Progress: A Report of the Surgeon General,
2014,'' which summarizes thousands of peer-reviewed scientific studies
and is itself peer-reviewed, smoking remains the leading preventable
cause of disease and death in the United States, and cigarettes have
been shown to cause an ever-expanding number of diseases and health
conditions (Ref. 7 at pp. 107-621). As stated in the 2014 Report,
``cigarette smoking has been causally linked to disease of nearly all
organs of the body, to diminished health status, and to harm to the
fetus . . . [and] the burden of death and disease from tobacco use in
the United States is overwhelmingly caused by cigarettes and other
combusted tobacco products'' (Ref. 7 at p. 7).
    Other combusted tobacco products, particularly those that could be
cigarette alternatives if users were unable to continue smoking
cigarettes, cause similar negative health effects. For example, there
is a long-standing body of research, including reports from the Surgeon
General and National Cancer Institute (NCI), demonstrating that cigar
use can cause serious adverse health effects (Ref. 31 at 119-155; Refs.
60, 61, and 33). NCI's Smoking and Tobacco Control Monograph No. 9
(``Cigars: Health Effects and Trends''), which provides a
comprehensive, peer-reviewed analysis of the trends in cigar smoking
and potential public health consequences, as well as other research,
demonstrates that cigar smoking leads to an increased risk of oral,
laryngeal, esophageal, pharyngeal, and lung cancers, as well as
coronary heart disease and aortic aneurysm, with the magnitude in risk
a function of the amount smoked and depth of inhalation (Ref. 31 at
119-155). Research indicates that most cigar smokers do inhale some
amount of smoke, even when they do not intend to inhale, and are not
aware of doing so (Refs. 33 and 34). Even when cigar smokers do not
breathe smoke into their lungs, they are still subject to the addictive
effects of nicotine through nicotine absorption (Refs. 33 and 35). This
is because cigar smoke dissolves in saliva, allowing the smoker to
absorb sufficient nicotine to create dependence, even if the smoke is
not inhaled (Refs. 35 and 62).
    Regular cigar smoking (which, in this study, constituted use on at
least 15 of the past 30 days) was responsible for approximately 9,000
premature deaths and more than 140,000 years of potential life lost
among adults aged 35 years or older in 2010 (Ref. 56). Researchers also
have found that the risk of dying from tobacco-related cancers is
higher from current exclusive pipe smokers and current exclusive cigar
smokers than for those who reported never using combusted tobacco
products (Ref. 32).

IV. Requests for Comments and Information

    To aid in its consideration regarding development of a nicotine
tobacco product standard, FDA is seeking comments, data, research
results, and other information related to questions under the following
topics: Scope of products to be covered, maximum nicotine level for a
nicotine tobacco product standard, implementation, analytical testing,
technical achievability, possible countervailing effects (including the
potential for an illicit market), and other considerations. We ask that
commenters clearly identify the section and question associated with
their responsive comments and information.

A. Scope

    A tobacco product standard limiting the nicotine level in
cigarettes could address one of our nation's greatest public health
challenges: The death and disease caused by cigarette use.
Approximately 480,000 people die every year from smoking cigarettes
(Ref. 7). Cigarettes are the tobacco product category that causes the
greatest burden of harm to public health as a result of the prevalence
of cigarette use and the toxicity and addictiveness of these products.
FDA hypothesizes that a tobacco product standard limiting the nicotine
level in cigarettes could significantly increase the number of
successful quit attempts by the majority of smokers seeking to quit
smoking every year and potentially prevent experimenters from becoming
regular smokers. However, if a standard were to apply to cigarettes
only, it could be substantially less effective. Specifically, FDA
expects that, to maintain their nicotine dose, some number of addicted
cigarette smokers could migrate to other similar, combusted products
(or begin to engage in dual use with such other products) after the
standard went into effect, reducing the benefits of the product
standard. Former smokers that choose to switch completely to a
potentially less harmful nicotine delivery product (e.g., ENDS) to
maintain their nicotine dose also would, to the extent that those
products result in less harm, significantly reduce their risk of
tobacco-related death and disease. Since the scope would impact the
potential public health benefits of such a nicotine tobacco product
standard, FDA is seeking comment on whether the standard should cover
any or all of the following products: Combusted cigarettes (which FDA
has previously interpreted to include kreteks and bidis), cigarette
tobacco, RYO tobacco, some or all cigars, pipe tobacco, and waterpipe
tobacco. FDA intends that any nicotine tobacco product standard would
cover all brands in a product category and, therefore, those products
currently on the market and any new tobacco products would be expected
to adhere to the standard.
    FDA is continuing to weigh several factors as it considers the
scope of products that should be subject to any potential nicotine
tobacco product standard--including the strength and breadth of the
available data derived from studies of VLNC cigarettes on the likely
effects of reducing nicotine \7\ (as discussed in section IV.B);
current prevalence and initiation rates for different classes of
tobacco products; the available data on the toxicity, addictiveness,
and appeal of the products; the use topography of the products
(including quantity, frequency, and duration of use); and the potential
for migration to, and dual use of, different products. Current VLNC
cigarette literature indicates that reduction of nicotine in cigarettes
would make it more likely for smokers (even those not currently
expressing a desire to quit) to cease cigarette use (e.g., Refs. 4, 5,
63, and 64). In light of these data, FDA also believes that reduction
of nicotine could help prevent

experimenters from becoming addicted to tobacco, resulting in regular
tobacco use.
---------------------------------------------------------------------------

    \7\ VLNC cigarettes do not contain uniform amounts of nicotine.
---------------------------------------------------------------------------

    Based on these considerations, FDA is seeking comment on whether
any nicotine tobacco product standard should cover any or all of the
following products:
     Combusted cigarettes (which FDA has previously interpreted
to include kreteks and bidis),
     Cigarette tobacco,
     RYO tobacco,
     Cigars (some or all categories; i.e., small cigars, large
cigars, cigarillos, and/or so-called premium cigars),
     Pipe tobacco, and
     Waterpipe tobacco.
    Please explain your responses and provide any evidence or other
information supporting your responses to the following questions:
    1. If FDA were to propose a product standard setting a maximum
nicotine level, should such a standard cover other combusted tobacco
products in addition to cigarettes? If so, which other products? If FDA
were to propose to include additional categories of combusted tobacco
products in a nicotine tobacco product standard, should the standard be
tailored to reflect differences in these products? What criteria should
be used to determine whether, and which, products should be covered?
    2. Some suggest that large cigars and those cigars typically
referred to as ``premium'' cigars should be regulated differently from
other cigars, asserting that they are used primarily by adults and
their patterns of use are different from those of regular cigars (81 FR
28973 at 29024). FDA requests information and data on whether large
and/or so-called premium cigars should be excluded from a possible
nicotine tobacco product standard based on asserted different patterns
of use, and whether large and/or so-called premium cigars would be
migration (or dual use) candidates if FDA were to issue a nicotine
tobacco product standard that excluded premium cigars from its scope.
FDA also requests data and information on whether and how there is a
way that, if FDA were to exclude premium cigars from the scope of a
nicotine tobacco product standard, FDA could define ``premium cigar''
to include only unlikely migration or dual use products and thereby
minimize such consequences.
    3. Should waterpipe tobacco products, which are different from
regular pipe tobacco, be included in such a standard? Are there data
showing different use topographies or that they are not likely to be
migration substitutes or dual use candidates? If FDA were to issue a
nicotine tobacco product standard that did not include waterpipe
tobacco products within the scope, what would be the likelihood that
former smokers would switch to waterpipe tobacco to maintain their
nicotine addiction? What are the relative risk consequences of
switching to waterpipe tobacco?

B. Maximum Nicotine Level

    As discussed throughout this document, nicotine is addictive and is
the primary reason why many smokers who want to quit are unable to do
so. Accordingly, FDA is considering developing a proposed product
standard to make cigarettes minimally addictive or nonaddictive by
setting a maximum nicotine level, using the best available science to
determine a level that is appropriate for the protection of the public
health. FDA has considered several peer-reviewed studies regarding very
low nicotine content (VLNC) cigarettes \8\ and the likely effects of
reducing nicotine in combusted tobacco. A 2013 survey paper noted that
researchers initially estimated that reducing the total nicotine
content of cigarettes to 0.5 mg per rod would minimize addictiveness
and that a ``more recent analysis suggests that the maximum allowable
nicotine content per cigarette that minimizes the risk of central
nervous system effects contributing to addiction may be lower'' (Ref.
2). The study authors concluded that ``[p]reventing children from
becom[ing] addicted smokers and giving people greater freedom to stop
smoking when they decide to quit by reducing the addictiveness of
cigarettes is a policy that increasingly appears to be feasible and
warranted'' (id.). We specifically request comment regarding this
paper's conclusions and the possible impact of higher or lower maximum
nicotine levels in a potential nicotine tobacco product standard.
---------------------------------------------------------------------------

    \8\ Scientific studies regarding VLNC cigarettes use both
``yield'' and ``content'' to describe the amount of nicotine in
research cigarettes. ``Yield'' is the International Organization for
Standardization (ISO) machine-generated nicotine smoke yield, and
``content'' refers to the nicotine in the tobacco filler of the
entire finished product. ``Yield'' and ``content'' are not
interchangeable terms. If neither ``yield'' nor ``content'' is used,
the nicotine levels in these studies refer to content.
---------------------------------------------------------------------------

    Early ``light'' cigarettes achieved a reduction in machine-measured
nicotine yield through a variety of means, including through the use of
ventilation holes (although the actual nicotine content was not low).
This increase in ventilation led to lower yields of nicotine in smoke
as measured by smoking machines, and these products were marketed as
low nicotine delivery or ``light'' cigarettes. However, cigarette users
could modify their use behaviors to compensate for this increase in
ventilation. For example, the vent holes could be easily blocked by
users' fingers or mouths, and larger or more frequent puffs could be
taken by consumers (Ref. 65). As a result, these products were designed
to make them ``appear'' light to the user but could deliver as much
nicotine to the user as high nicotine delivery cigarettes. The
compensatory behaviors of the cigarette user were able to overcome the
changes in ventilation in these higher ventilated products.
    VLNC cigarettes, in contrast, have relied on reducing nicotine
content in the tobacco filler rather than engineering changes to the
cigarette. Patents reveal that more than 96 percent of nicotine can be
successfully extracted while achieving a product that ``was
subjectively rated as average in smoking characteristics'' (Ref. 66)
and that up to a 75 percent reduction in the nicotine contained in a
tobacco leaf can be achieved with an ``effective and economical system
for producing tobacco products . . . while maintaining other desirable
ingredients for good taste and flavor'' (Ref. 67).
    In conventional cigarettes manufactured in the United States,
nicotine accounts for approximately 1.5 percent of the cigarette
weight, or 10-14 mg of nicotine per cigarette (Refs. 68-71) and
generally have nicotine yields in the 1.1 mg to 1.7 mg (Ref. 31 at p.
67). Certain VLNC cigarettes have much lower nicotine yields than
conventional cigarettes--in the 0.02-0.07 mg nicotine/cigarette range--
due to product changes that the user cannot overcome (Ref. 72).
Reducing the nicotine in the finished tobacco product places an
absolute maximum limit on the amount of nicotine that can be extracted
by the user in a given cigarette, unlike modifications such as
ventilation holes, which affect nicotine yield in smoke but can be
overcome through user behavior. See section IV.C of this document for a
discussion of possible compensatory smoking under a single target
approach or a stepped down approach to nicotine reduction.
1. VLNC Cigarettes
    The first VLNC cigarettes studied by researchers were produced by
Philip Morris and marketed under the brand name ``Next,'' which was
reported to contain 0.4 mg nicotine/g of tobacco filler (Ref. 73).
Later, the National Institute for Drug Abuse (NIDA) contracted with the
Ultratech/Lifetech

Corporation \9\ to produce VLNC cigarettes for research purposes (Ref.
74; Ref. 75). The two types of cigarettes produced were: (1) 1.1 mg/
cigarette (cig) ISO smoke nicotine (7.2 mg nicotine/cig in filler) and
(2) 0.07 mg/cig ISO smoke nicotine (filler levels were reported as 0,
but FDA has estimated these levels to be between 0.4 and 0.5 mg/cig)
(Ref. 74).
---------------------------------------------------------------------------

    \9\ Both Ultratech and Lifetech have been reported as being the
company through which NIDA manufactured research cigarettes.
---------------------------------------------------------------------------

    Researchers also have used Quest cigarettes, produced by Vector
Tobacco, to study the impact of reduced nicotine (Ref. 76). To provide
consumers with reduced risk tobacco products, companies like 22nd
Century are using genetic engineering and plant breeding to produce
very low nicotine tobacco for incorporation into cigarettes. In 2014,
the company was granted patents for its process to virtually eliminate
the nicotine in tobacco plants (Ref. 77). Further, low-nicotine
cigarettes are produced and distributed for research purposes by
Research Triangle Institute (RTI), under a contract for the NIDA's Drug
Supply Program (Ref. 78). 22nd Century is acting as a vendor for RTI
for this contract manufacturing Spectrum cigarettes that contain 0.4 mg
nicotine/gram (g) of tobacco filler (id). Finally, Philip Morris
manufactured cigarettes with varying nicotine levels for research only
(Ref. 79). FDA requests data and information regarding the risks to
smokers from inhalation of VLNC cigarette smoke.
    Table 1 includes a list of VLNC cigarettes used in research studies
and their reported nicotine levels.

 Table 1--Filler Nicotine and ISO Nicotine Delivery for Low and Very Low
    (*) Nicotine Cigarettes Made Available Either Commercially or for
                                Research
------------------------------------------------------------------------
                                       Filler nicotine     ISO Nicotine
         Type of cigarette           level (mg/g or mg/    delivery (mg/
                                            cig)               cig)
------------------------------------------------------------------------
Quest 1...........................  12.5 mg/g; 8.9 mg/               0.6
                                     cig.
Quest 2...........................  6.4 mg/g; 5.1 mg/cig             0.3
Quest 3...........................  1.0 mg/g; 0.4 mg/cig            *0.5
Ultratech/Lifetech................  10.3 mg/g \1\; 7.2               1.1
                                     mg/cig.
Ultratech/Lifetech\2\.............  0.6-0.7 mg/g \1\;             *<0.06
                                     0.4-0.5 mg/cig.
Next..............................  0.4 mg/g............           *0.08
Spectrum high nicotine............  11.4-12.8 mg/g......         0.6-1.0
Spectrum intermediate nicotine....  5.7-5.8 mg/g........             0.3
Spectrum low nicotine.............  0.4 mg/g............          *<0.04
Philip Morris 12 mg (for research   14.4 mg/g \1\; 10.1              0.9
 only).                              mg/cig.
Philip Morris 8 mg (for research    10.6 mg/g \1\; 7.4               0.6
 only).                              mg/cig.
Philip Morris 4 mg (for research    5 mg/g \1\; 3.5 mg/              0.3
 only).                              cig.
Philip Morris 2 mg (for research    2.1 mg/g \1\; 1.5 mg/            0.2
 only).                              cig.
Philip Morris 1 mg (for research    0.9 mg/g \1\; 0.6 mg/            0.1
 only).                              cig.
------------------------------------------------------------------------
\1\ mg/g or mg/cigarette (cig) was calculated based on an estimate of
  0.7 g of tobacco per cigarette (Ref. 80).
\2\ Filler nicotine level was reported as 0 mg/cig, but FDA estimates
  the cigarette contained 0.4-0.5 mg/cig.

2. Estimate of Addiction Threshold Levels
    In 1994, certain scientists proposed the idea of federal regulation
of nicotine content, which could result in lower intake of nicotine and
a lower level of nicotine dependence (Ref. 81). However, FDA
acknowledges that there is individual variability in dose sensitivity
to all addictive substances, making it difficult to determine a single
addiction threshold which would apply across the population. A proposal
to lower the nicotine in conventional cigarettes, or any tobacco
product, could merit consideration only if there were a threshold
nicotine exposure level below which the nicotine did not produce
significant reinforcing effects or sustain addiction in a majority of
the population. FDA continues to assess VLNC cigarette studies
analyzing addiction threshold levels, as discussed in this section.
    Four primary study types speak to the level of nicotine in tobacco
that could significantly reduce product addictiveness. The first type
uses indirect estimates based on information in humans regarding
nicotine intake in smokers who appear not to be addicted to nicotine to
estimate a likely threshold level. A second type includes studies of
VLNC use by study participants that have reported increased quit
attempts and cessation even in smokers not interested in quitting. A
third type includes studies that have revealed reduced positive
subjective effects and increased negative effects in VLNC smokers. The
fourth type includes studies measuring nicotine receptor binding, which
indicate that use of VLNC cigarettes yields significantly lower
nicotinic acetylcholine receptor (nAChR) occupancy and cerebral
response.
    a. Indirect estimates of an addiction threshold. In 1994,
researchers conducted a review to explore indirect estimates of an
addiction threshold by focusing on the smoking habits of a small
population of smokers who demonstrate reduced nicotine dependence, as
compared to other smokers (a group sometimes referred to as tobacco
``chippers'') (Ref. 81, citing Ref. 82,). In the 1994 review,
researchers suggested that a threshold level of nicotine per cigarette
should be low enough to prevent or limit the development of nicotine
addiction in most young people, while providing enough nicotine for
taste and sensory sensation (e.g., Ref. 81). These researchers found
that based on existing studies at the time, ``an absolute limit of 0.4
to 0.5 mg of nicotine per cigarette should be adequate to prevent or
limit the development of addiction in most young people. At the same
time, it may provide enough nicotine for taste and sensory
stimulation'' (id.), which FDA interprets to mean that there would be
enough nicotine for an experienced user to tell that there is nicotine
in the tobacco product.
    In another study seeking to estimate a reinforcement threshold,
scientists reviewed several studies, including one in which abstinent
smokers received intravenous nicotine injections by pulling a lever in
a fixed ratio task (Ref.

83). The authors found that studies using intravenous nicotine
administration suggest that the nicotine reinforcement threshold (i.e.,
the minimum amount of nicotine intake required to initiate or maintain
self-administration) is between 1.5 to 6.0 micrograms/kg in humans and
3 to 10 micrograms/kg in rats (Ref. 84). Although the study's authors
noted potential limitations (i.e., intravenous delivery does not mimic
inhalation, administration of nicotine alone omits other psychoactive
constituents in tobacco smoke, and other factors such as age, sex, and
genetic variations may influence nicotine's reinforcing properties)
(Ref. 84), the lowest dose in the study overlaps with the upper limit
of an addiction threshold estimated by the 1994 study (Ref. 81).
Despite the study limitations of both these estimates, they help
provide a range on which to potentially base a nicotine level
threshold.
    b. Findings of increased cessation for VLNC cigarettes. Several
studies indicate that people using significantly reduced nicotine
content cigarettes (as low as 0.4 mg nicotine/g of tobacco filler) are
more likely to consider cessation (i.e., consider reducing cigarette
intake as a step towards cessation or consider fully ceasing cigarette
intake), even if they had not previously considered quitting (see,
e.g., Refs. 4, 5, 63, and 64). These studies were not investigating
VLNC cigarettes as cessation aids.
    Some studies showed that switching to VLNC cigarettes results in a
reduced number of cigarettes smoked per day (Ref. 4; Ref. 76), reduced
nicotine dependence (Refs. 4, 84, and 85), and minimal evidence of
withdrawal distress and increased depression (Ref. 64, Ben 12; Refs.
85-87). On the other hand, other researchers have reported the use of
VLNC cigarettes did not change the number of cigarettes smoked per day
(Refs. 86 and 88), but they did observe reductions in cotinine and
carbon monoxide levels. For example, in the Benowitz et al. 2015 study
(Ref. 86), where researchers progressively lowered nicotine content
over 7 months, the authors found that, after the 7 months of VLNC
cigarette use, nicotine intake remained below baseline (i.e., plasma
cotinine at 149 ng/ml vs. 250 ng/ml). The Mercincavage et al. study
(Ref. 88), a randomized study of smokers progressively decreasing
nicotine content over three ten day periods, also yielded mixed results
regarding harm exposure. The researchers found that certain biomarkers
of exposure to toxic tobacco-related constituents (i.e., cotinine and
NNAL) decreased with decreases in nicotine content, but there was no
effect on the biomarker 1-hydroxpyrene (1-HOP) (Ref. 88). One
limitation of these studies is that they were conducted in an
unregulated environment in which smokers continued to have access to
the normal nicotine content (NNC) cigarettes.
    One of the more recent studies (Ref. 85) on this issue was a
double-blind, parallel, randomized clinical trial conducted between
June 2013 and July 2014 that evaluated 840 participants (780 completed
the 6-week study) who were not interested in quitting smoking. During
the sixth week of the study, the average number of cigarettes smoked
per day was lower for participants randomly assigned to cigarettes
containing 2.4, 1.3, or 0.4 mg of nicotine per gram of tobacco (16.5,
16.3, and 14.9 cigarettes per day, respectively) than for those
assigned to their usual cigarette brand or those cigarettes containing
5.2 or 15.8 mg per gram (22.2 and 21.3 cigarettes per day,
respectively) (Ref. 85). Those participants using cigarettes with the
lowest nicotine content (0.4 mg per gram nicotine/gram of tobacco
filler, demonstrated reduced dependence, and use of reduced nicotine
cigarettes, including the VLNC cigarettes, with minimal evidence of
withdrawal-related discomfort or safety concerns (id.). The authors
concluded that this study provides ``preliminary-short term data . . .
[that] suggest that if nicotine content is adequately reduced, smokers
may benefit by smoking fewer cigarettes and experiencing less nicotine
dependence, with few negative consequences'' (id.).
    While these results, taken together with other studies, are
promising, FDA acknowledges the inherent limitations of the available
research on changes in smoking as a function of VLNC cigarettes use. As
noted by the investigators of the 2015 double-blind, parallel,
randomized clinical trial, ``no large-scale clinical trials of reduced
nicotine cigarettes have been conducted. Furthermore, little is known
about the dose-related effects of reduced nicotine. Data derived from
trials assessing a range of reduced-nicotine cigarettes are critical
for providing an empirical basis for regulatory decisions pertaining to
nicotine product standards'' (Ref. 85). As a result, FDA requests
submission of additional data that may be used to explore further the
hypotheses presented in this ANPRM (e.g., extended duration studies)
and supports the development of additional studies to further analyze
these conclusions.
    c. Subjective effects and relief of withdrawal symptoms associated
with VLNC cigarettes. Individuals who smoke VLNC cigarettes experience
some of the same subjective effects as those individuals who smoke
traditional, NNC cigarettes. For example, VLNC users report
experiencing reductions in certain physiological withdrawal symptoms
(e.g., craving, anxiety, irritability, depression) but do not
experience other symptoms associated with full nicotine content
cigarettes (e.g., relief of physical withdrawal symptoms, increased
stimulation and alertness, reduction in restlessness) (Refs. 44, 72,
74, 75, 89-93). Exposure over multiple days generally leads to a
reduction in cigarettes smoked per day (Ref. 87). Furthermore,
physiological responses after VLNC cigarettes, such as the increase in
heart rate that is typically observed following nicotine
administration, are less than those seen with higher nicotine
cigarettes and are absent in some cases (Ref. 74, 94, and 95). Thus, it
appears that transitioning to VLNC cigarettes (from NNC cigarettes) may
result in some behavioral and physiological responses commonly
experienced when using standard NNC cigarettes (e.g., reduced appetite,
increased alertness). These responses, where present, are lower than
those seen with standard nicotine cigarettes and get progressively
lower over time.
    d. Lower nAChR occupancy and cerebral response from the use of VLNC
cigarettes. VLNC cigarettes contain some nicotine, albeit at very low
levels. Although there is enough nicotine in VLNC cigarettes to bind to
acetylcholine receptors in the brain, there is not enough to
consistently produce the full range of subjective responses (i.e.,
those responses based on or influenced by individual, internal
perceptions or experiences) observed following use of NNC cigarettes
(Refs. 74, 92, 96, and 97). Therefore, VLNC cigarettes may not produce
the full range of subjective effects as NNC cigarettes. This supports
the hypothesis that many subjective and physiological effects observed
following exposure to smoke from VLNC cigarettes could be due to
repeated pairing of nicotine with sensory and conditioned cues or to
other psychoactive chemicals. Given that these subjective and
physiological effects have been directly linked to nicotine, it is
likely that they are learned responses through repeated pairing with
nicotine and not due to other chemicals in the smoke.
    Please explain your responses and provide any evidence or other
information supporting your responses to the following questions:
    1. The Tobacco Control Act prohibits FDA from reducing nicotine
yields in any combusted tobacco product to zero

(section 907(d)(3) of the FD&C Act). If FDA were to propose a maximum
nicotine level for cigarettes, what should be the maximum level to
ensure that the product is minimally addictive or nonaddictive, using
the best available science to determine a level that is appropriate for
the protection of the public health? Rather than establishing a
nicotine target to make products ``minimally addictive'' or
``nonaddictive,'' should FDA consider a different threshold (e.g., less
addictive than current products on the market)? How should the maximum
level be measured (e.g., nicotine yield, nicotine in cigarette filler,
something else)? What would be the potential health impacts of
requiring a maximum nicotine level such as 0.4 mg nicotine/g of tobacco
filler? FDA is interested in public health impacts of requiring
different maximum nicotine levels, such as 0.3, 0.4, and 0.5 mg
nicotine/gram of tobacco filler, as well as other maximum nicotine
levels and solicits comments about the potential health impacts of
different maximum levels.
    2. FDA lists four types of studies to estimate the threshold of
nicotine addiction (i.e., indirect estimates; findings of increased
cessation for VLNC cigarettes; subjective effects, craving, and
withdrawal associated with VLNC cigarettes; and lower nAChR occupancy
and cerebral response from the use of VLNC cigarettes). Should FDA rely
on some or all of these types of studies? Why or why not? Is there a
different method that FDA should investigate or use to determine the
threshold for nicotine addiction?
    3. In addition to nicotine, minor tobacco alkaloids (including
nornicotine, cotinine, anabasine, anatabine, and myosamine) and tobacco
smoke aldehydes (such as acetaldehyde) are pharmacologically active and
may contribute to addiction (see, e.g., Refs. 98 and 99). Researchers
have investigated the abuse potential of nornicotine, cotinine,
anabasine, and acetaldehyde in animals (Ref. 100). However, many of
these compounds are only present in tobacco smoke at low levels and are
likely less potent than nicotine in mediating pharmacological response
and, therefore, reinforcement (Refs. 101 and 102). In addition to
setting a maximum nicotine level, should the product standard also set
maximum levels of other constituents (e.g., nornicotine, acetaldehyde,
anabasine) that may have the potential to produce dependence and be
addictive? If so, at what levels?
    4. If FDA were to finalize a nicotine tobacco product standard,
what is the potential that adults and adolescents would perceive these
VLNC cigarettes as ``safe''--and how could youth and adult risk
perceptions of these cigarettes impact initiation, use, and cessation
habits of combusted tobacco products?

C. Implementation (Single Target vs. Stepped-Down Approach)

    If FDA were to issue a product standard establishing a maximum
nicotine level for cigarettes, such a standard would need to either
propose a single target (where the nicotine is reduced all at once) or
a stepped-down approach (where the nicotine is gradually reduced over
time through a sequence of incremental levels and implementation dates)
to reach the desired maximum nicotine level. Some have suggested that
any maximum nicotine level should be established as a single target
(rather than a stepped-down approach) to limit exposure to harmful
tobacco while providing similar cessation rates to those that could
occur with a stepped-down approach. Some level of compensatory smoking
behavior (i.e., smokers seeking to obtain the amount of nicotine they
need to sustain their addiction by smoking more cigarettes per day,
taking more and deeper puffs, and/or puffing with a faster draw rate)
theoretically could occur under either a single target or stepped-down
approach and could impact the public health benefits of a possible
nicotine tobacco product standard. According to studies involving VLNC
cigarettes and other reduced nicotine cigarettes, researchers expect
there could be very little or no compensatory smoking with a single
target approach and that it would be self-limiting (i.e., smokers would
be unable to obtain their nicotine dose from cigarettes no matter how
they smoke them and eventually would stop trying to do so), which could
maximize the benefits of such a tobacco product standard (Refs. 3-5).
If individuals were to engage in compensatory smoking with a single
target approach, researchers find that any compensatory smoking at the
maximum nicotine levels that FDA is considering here could only be
minimal and transient (e.g., Refs. 103, 104, 92, and 93).
    In contrast, during a stepped-down approach, tobacco users may
attempt to compensate for the loss of nicotine during the early stages
of a stepped-down approach by smoking additional tobacco products or by
smoking more intensely, since the intermediate-stage products could
allow for extraction of nicotine through such efforts in a way that
VLNC cigarettes would not (e.g., Refs. 64, 76, and 105).\10\
---------------------------------------------------------------------------

    \10\ However, the IOM has cited one study showing that when
nicotine content is stepped down, smokers do not engage in
compensatory smoking when nicotine is extracted from tobacco and,
therefore, do not increase their toxic exposures (Ref. 13 at p.
349).
---------------------------------------------------------------------------

    FDA is aware of several studies that have demonstrated the impact
of an immediate (e.g., Refs. 53, 106-108) or a stepped-down approach
(Ref. 64) to nicotine reduction on smoking cessation outcomes.
Researchers have found that the single target approach may be
associated with better cessation outcomes. Data from the International
Tobacco Control Policy Evaluation 4-Country Survey, a telephone survey
of more than 8,000 adult smokers in the United States, the United
Kingdom, Canada, and Australia, illustrates the cessation benefits from
abrupt abstinence from cigarettes (``cold turkey'') when compared to a
gradual reduction of smoking prior to complete abstinence (``cut
down'') (Ref. 109). While this differs from the approaches considered
in this ANPRM, it provides helpful insight into the effects of a
gradual vs. single change in nicotine intake. Researchers concluded
that immediate nicotine cessation was ``clearly associated with more
successful outcomes'' (Ref. 109). Scientists also found higher
abstinence rates for those using the single target approach in studies
comparing two levels of commercial low-yield nicotine cigarettes and
nicotine lozenges (Ref. 4).
    Nevertheless, some studies have found that both reduction
strategies increase a smoker's probability of cessation. For example,
in a study of smokers with no strong preference for a quitting method
who were randomly assigned to study arms requiring either that they
quit immediately or gradually reduce their cigarette consumption over 2
weeks, both the immediate and gradual cessation methods produced
similar results (Ref. 110). Likewise, in a meta-analysis of 10 studies
to determine the impact of stepped reduction of nicotine versus a
single nicotine target in participants interested in quitting smoking,
scientists determined that a stepped reduction in nicotine ``provides
similar quit rates to abrupt quitting with no evidence that one method
is significantly superior to the other in adults trying to quit
smoking'' (Ref. 111 at p. 13) and concluded that there were no
additional cessation benefits for the stepped-down approach (Ref. 111
at p. 2).
    FDA understands the argument that a stepped-down approach to
limiting the nicotine levels in tobacco products

could undermine the public health goals of such a standard by allowing
for prolonged exposure to tobacco-related toxicants during the step-
down period. Although both approaches likely would result in comparable
quit rates eventually, some studies have indicated a greater likelihood
of cessation success with the use of a single target. In addition,
preliminary studies show that a single target approach could limit
further exposure to harmful tobacco (when compared with the stepped-
down approach to limiting nicotine levels). FDA continues to weigh
these factors, and will consider the information submitted in response
to this ANPRM, as it decides the appropriate approach for a potential
nicotine tobacco product standard.
    Please explain your responses and provide any evidence or other
information supporting your responses to the following questions:
    1. What data are available to demonstrate that a single target
approach to reach a maximum nicotine level would or would not result in
any unintended consequences?
    2. In the alternative, what data are available to demonstrate that
a stepped-down approach involving a sequence of incremental levels and
implementation dates to reach a proposed nicotine level would or would
not result in any unintended consequences?
    3. If FDA were to select a stepped-down approach for a nicotine
tobacco product standard, what scientific evidence exists to support
particular interim nicotine levels and the appropriate number of steps
that would be needed to reach the target level?
    4. Would a single target and a stepped-down approach for
implementation result in comparable quit rates or reduced initiation
rates?
    5. What would be the likely implementation differences, including
implementation timelines and transition costs, between a single target
approach or a stepped-down approach involving a sequence of incremental
levels and implementation dates?

D. Analytical Testing Method

    As part of its consideration regarding a potential nicotine tobacco
product standard, FDA is also considering whether such a product
standard should specify a method for manufacturers to use to detect the
level of nicotine in their tobacco products. FDA believes that the
results of any test method to measure the nicotine in combusted tobacco
products should be comparable across different accredited testing
facilities and products. It is critical that the results from the test
method demonstrate a high level of specificity, accuracy, and precision
in measuring a range of nicotine levels across a wide variety of
tobacco blends and products.
    A variety of methods have been in development that allows nicotine
in tobacco or tobacco product filler to be quantified for various
products. For example, two Cooperation Centre for Scientific Research
Relative to Tobacco (CORESTA) methods have undergone round-robin method
validation studies in accordance with ISO 5725-1 through ISO 5725-2:
(1) Continuous flow analysis (CFA) and (2) gas chromatography-flame
ionization detector (GC-FID). The CFA method measured a nicotine range
of 0.69-3.30 percent (or 6.9-33 mg/g) in burley and flue-cured tobaccos
and exhibited a repeatability range of 0.03-0.17 and a reproducibility
range of 0.12-0.67, dependent on the mean (Ref. 112). A GC-FID method
for determining nicotine in fermented extractions from tobacco leaves
was validated in accordance with FDA and International Council for
Harmonization of Technical Requirements for Registration of
Pharmaceuticals for Human Use specifications, including specificity,
linearity, precision, accuracy, and robustness (Ref. 113). Gas
chromatography-mass spectrometry (GC-MS) was used as the confirmation
technique in this study, in which a recovery of 117.8 percent was
achieved; recovery was within FDA guidelines (<120 percent) (Ref. 113).
Nicotine content of 0.43 percent (4.3 mg/g) in the extract was reliably
measured and stability testing on this same extract was conducted for
360 days (id.). In addition, the WHO's Tobacco Laboratory Network
(TobLabNet) has developed a standard operating procedure for
determination of nicotine in cigarette tobacco filler using gas
chromatography (Ref. 114). The WHO's TobLabNet determined that this
method is suitable for the quantitative determination of nicotine in
cigarette tobacco filler by gas chromatography (GC) (id.).
    We also note that ISO 10315 and CORESTA Method No. 62 have been
used in substantial equivalence reports submitted to the Agency. ISO
10315 is a method for analyzing nicotine in smoke. With this method,
conditioned cigarettes are smoked under ISO 4387 conditions and smoke
is captured on a Cambridge filter pad and extracted in propan-2-ol
containing internal standard such as n-heptadecane or quinaldine
(carvone or n-octadecane are other alternatives to internal standards)
and analyzed immediately using GC coupled with flame ionization
detection (Ref. 115).
    CORESTA Method No. 62 is a standard method used to analyze nicotine
in tobacco filler and smokeless tobacco products (Ref. 116). This
method describes extraction of nicotine in solid tobacco in basified
extraction solution (using sodium hydroxide to deprotonate the nicotine
in solution) of either hexane containing n-heptadecane or quinaldine
internal standards or basified extraction solution (using sodium
hydroxide) of methyl-t-butyl ether solution containing quinoline
internal standard (id.).
    FDA is also aware of other methods that have been used to analyze
nicotine levels. Such methods include GC combined with various
detectors, GC-MS with solid-phase microextraction as a preconcentration
step for low detection, other formats of GC-FID, capillary
electrophoresis combined with either ultraviolet (UV) or
electrochemical detection, and alternative chromatography techniques
including supercritical fluid chromatography-ion mobility detection
(Ref. 117), reversed phase ion-pair liquid chromatographic extraction
(Ref. 118), and high-pressure liquid chromatography with UV detection
(Ref. 119).
    Please explain your responses and provide any evidence or other
information supporting your responses to the following questions:
    1. If FDA were to issue a product standard, should the Agency
require a standard method of product testing to analyze the nicotine
levels in products subject to the standard? If so, what method or
methods should FDA use?
    2. Should the Agency require manufacturers to sample their products
in a specific manner to ensure that products do not contain excess
levels of nicotine? Should manufacturers be required to test each
manufactured batch to ensure compliance with a product standard
limiting nicotine levels? What criteria should be used to determine if
a batch passes or fails testing?

E. Technical Achievability

    FDA continues to analyze the technical achievability of a maximum
nicotine level for cigarettes as part of its overall assessment of how
best to implement this authority and is seeking comments from
interested parties regarding this issue, including with respect to the
technical achievability of such a standard for small cigarette and/or
small combusted tobacco product manufacturers.

    The industry and consumer product companies have developed versions
of denicotinized cigarettes and a range of brands with differing
nicotine levels. By blending tobaccos based on nicotine levels, tobacco
companies have manufactured their products to specifications that
ensure the final product will have precise levels of nicotine and have
ensured that nicotine levels vary only minimally within cigarette packs
and from pack to pack (60 FR 41453 at 41505, 41509, August 11, 1995).
In fact, the tobacco industry has had programs in place since the 1960s
to obtain ``any level of nicotine desired'' (Ref. 120, citing Ref.
121). The industry also has recognized that the techniques it has used
to increase nicotine levels can be used to reduce nicotine levels as
well (60 FR 41453 at 41722).
    As previously described, VLNC cigarettes have been produced since
the 1970s. During this time, NCI contracted for production of a line of
cigarettes with widely varying nicotine concentrations (Ref. 122, 81
SG). In the late 1980s, a major cigarette manufacturer had plans to
develop VLNC cigarettes with a reduction in mainstream nicotine yields
of greater than 95 percent (Ref. 123). More recently, 22nd Century,
acting as vendor for RTI's contract with NIDA, has developed
cigarettes, not currently commercially available, that are similar in
many sensory characteristics to conventional cigarettes but with
extremely low nicotine levels (Refs. 54, 124, and 125).
    Significant reductions of nicotine in combusted tobacco products
can be achieved principally through tobacco blending and cross-breeding
plants, genetic engineering, and chemical extraction. Agricultural
practices (e.g., controlled growing conditions, fertilization, harvest)
as well as more recent, novel techniques also can help to reduce
nicotine levels. One or a combination of these processes could be used
to achieve the nicotine levels that FDA is considering for a nicotine
tobacco product standard.
1. Tobacco Blending/Cross Breeding
    Most of the cigarettes sold in the United States are blended
cigarettes (Ref. 126). A tobacco industry executive previously
testified that the main component of a cigarette that contributes to
nicotine delivery is the tobacco blend and that year-to-year crop
variation does not determine the nicotine content in a cigarette (Ref.
127). The term ``leaf blending'' describes the selection of tobaccos to
be used in a product by tobacco type (e.g., flue-cured, burley,
oriental), geographical origin, year, and grade of the tobacco (Ref.
128). Blend differences can produce significant variations in nicotine
concentration in the tobacco rod, leading to differences in smoke
composition and yield (Ref. 120 at p. 469). Grading, which is used to
evaluate and identify differences within tobacco types and is a
function of both plant position (i.e., higher or lower on the stalk)
and of quality (i.e., ripeness), and segregation of grades by nicotine
content, already has become common practice (Ref. 128 at p. 2-3).
    Many tobacco lines are available, including approximately 1,000
different tobacco varieties (Ref. 126). The tobacco industry has used
breeding and cultivation practices to develop high nicotine tobacco
plants to give manufacturers greater flexibility in blending and in
controlling the amount of nicotine to be delivered (60 FR 41453 at
41694). These practices could be used to develop low nicotine plants as
well. In fact, tobacco industry documents show that in the 1960s,
tobacco companies recognized the increasing demand for low nicotine
tobacco and began instituting projects that found that low nicotine
cigarettes can be made by selecting grades of tobacco with low nicotine
content (Ref. 128; citing Ref. 129; Ref. 130).
    Because the nicotine content of tobacco plants varies,
manufacturers could replace more commonly used nicotine-rich varieties
like Nicotiana rustica with lower nicotine varieties (Ref. 131).
Oriental Turkish-type cigarettes also deliver substantially less
nicotine than cigarettes that contain air-cured Burley tobacco (Ref.
120; citing Ref. 132). In addition, manufacturers could select specific
tobacco seedlings that are low in nicotine and plant only those low
nicotine seedlings (Ref. 133). Even without this selective breeding,
manufacturers could use careful tobacco leaf purchasing plans to
control the nicotine content in their products (60 FR 41453 at 41694).
By maintaining awareness of the differences and monitoring the levels
in purchased tobacco, companies could produce cigarettes with nicotine
deliveries consistent to one-tenth of one percent (despite variations
of up to 25 percent in the nicotine content of the raw material grown
in the same area, from year to year) (60 FR 41453 at 41694).
    The position of leaves on the plant stalk also affects nicotine
levels; tobacco leaves located near the top of the plant can contain
higher concentrations of nicotine and lower stalk leaves generally
contain lower nicotine levels (Ref. 114; Ref. 120). For example, flue-
cured tobacco leaves harvested from the lowest stalk position may
contain from 0.08 to 0.65 percent nicotine, whereas leaves from the
highest positions may contain between 0.13 and 4.18 percent nicotine
(Ref. 126, citing Ref. 134). Therefore, substituting leaves found lower
on the plants could reduce the nicotine content of tobacco products
(Ref. 131).
    A number of internal tobacco industry documents describe the use of
leaf blending and tobacco selection to control the nicotine content of
cigarettes (Ref. 128 at p. 3). For example, one company project
determined that low nicotine cigarettes can be made by selecting grades
of tobacco with low nicotine content (Ref. 128 at p. 3, citing Ref.
135). Another observed that the demand for low nicotine tobacco has
increased worldwide and necessitated a shift in purchasing standards
(Ref. 128 at p. 3, citing Ref. 136).
2. Chemical Extraction
    Nicotine also can be removed from tobacco via chemical extraction
technology. By the 1970s, tobacco manufacturers regularly practiced
nicotine extraction as a method to control nicotine delivery (Ref. 128,
citing Ref. 137; Refs. 138 and 139). Extraction methods include water
extraction (coupled with steam or oven drying), solvent extraction, and
extractions of nicotine without usable leaf (Ref. 128). Supercritical
fluid extraction also yielded success in the 1990s, allowing for
optimum extraction times and the elimination of more time-consuming
steps (Refs. 140 and 141). FDA notes that there are existing patents
for chemical extraction of nicotine in tobacco, which reveal that more
than 96 percent of nicotine can be successfully extracted while
achieving a product that ``was subjectively rated as average in
nicotine characteristics'' (Refs. 142 and 66).
    In addition, a major tobacco manufacturer has used a high-pressure
carbon dioxide process similar to the process used to decaffeinate
coffee. In this process, tobacco leaf is treated with ammonium salt,
then treated with carbon dioxide/water vapor, which has achieved a 95
to 98 percent reduction in nicotine (Ref. 133, citing Ref. 143)
Although some manufacturers believe that previous water extraction
practices may have rendered the tobacco ``unsuitable for use,'' other
water extraction projects yielded suitable smoking material with
sizeable nicotine reductions (80 to 85 percent reduction in leaf
nicotine) (Ref. 128, citing Ref. 144; Refs. 145 and 146).

3. Genetic Engineering
    Tobacco industry scientists have long recognized the potential for
genetic engineering to control nicotine content (Ref. 147). The first
practical application of biotechnology by a major tobacco manufacturer
was the development of low nicotine tobacco in the 1980s, which led to
the receipt of a patent for biotechnology for altering nicotine in
tobacco plants (Refs. 133 and 148). Other tobacco researchers and major
manufacturers also recognized the value of biotechnology for developing
low nicotine tobacco for cigarettes, including for use as part of a
smoking cessation program (Ref. 149).
    Several American and international tobacco companies genetically
engineered low nicotine varietals in the 1960s and 1970s, including a
strain with nicotine levels as low as 0.15 percent (Ref. 128; citing
Refs. 150-155). During that time period, the Kentucky Tobacco Research
Board worked on genetic strains of low nicotine tobacco (with a
nicotine content of 0.2 percent) to be used for experimental studies on
the role of nicotine in smoking behavior (Ref. 128, citing Refs. 156-
159). In addition, Canadian researchers examined low nicotine strains
of tobacco, particularly in association with efforts to develop a
strain of flue-cured or air-cured tobacco that would be suitable as the
base material for reconstituted tobacco (Ref. 128, citing Refs. 151 and
160). In 2003, Vector Tobacco began marketing the Quest cigarette,
which was produced from genetically modified tobacco and contained only
trace amounts of nicotine (Ref. 133) (this product is no longer on the
market). Genetic engineering has resulted in reductions of nicotine
levels in the range of 80 to 98 percent (id.). In 2014, the U.S. Patent
and Trademark Office granted two patents for two genes that may be
suppressed to achieve a substantial decrease in nicotine in tobacco
plants (Ref. 161).
4. Other Practices
    Industry studies have shown that changes to growing and harvesting
practices affect the development of tobacco chemistry, including
nicotine content (Ref. 128). Some manufacturers have revised their
agricultural practices specifically to meet new product development
goals, such as the production of low nicotine tobacco (id.). For
example, one manufacturer evaluated various experimental agricultural
practices that could affect the tobacco's chemistry, including bulk-
curing, once-over harvesting, and high plant density (id., citing Ref.
162). In other cases, chemical agents were observed to reduce nicotine
content (Ref. 128 citing Refs. 163-165).
    After growers harvest tobacco, it is cured and aged before use in
tobacco products. The aging process naturally changes the chemistry of
the tobacco, including some reduction in nicotine content (Ref. 128).
At least one manufacturer has explored efforts to speed up the process
of aging tobacco, in part to alter or limit the changes in chemistry
that naturally occur (id., citing Ref. 166). Other approaches to curing
and fermenting tobacco were explored as a method for altering nicotine
content (Ref. 128). For example, in one manufacturer's report,
researchers observed that the properties of tobacco, including nicotine
content, could be altered without the need for nontobacco additives by
modifying curing practices (id., citing Ref. 167). In addition,
manufacturers have explored approaches to identify microbial bacteria
that actively degraded nicotine while leaving other components of the
leaf intact (Ref. 128, citing Refs. 168 and 169). Consumer product
testing showed that the ``product acceptability'' of that tobacco was
equal to that of untreated tobacco (Ref. 128, citing Ref. 170).
    Researchers have developed novel approaches to reducing the
nicotine in tobacco products in recent years. For example, a salivary
excretion produced by a caterpillar (containing the enzyme glucose
oxidase) is applied to tobacco plant leaves and can reduce the nicotine
in tobacco leaf by up to 75 percent and provide an ``effective and
economical system for producing tobacco products which contain about
0.01 mg nicotine per cigarette or less . . . while maintaining the
other desirable ingredients for good taste and flavor'' (Ref. 67).
    Please explain your responses and provide any evidence or other
information supporting your responses to the following questions:
    1. What methods are tobacco product manufacturers currently using
to maintain consistency of the nicotine in their products, given the
variability of nicotine levels over growing seasons and crop type? How
could these methods be adapted to ensure that certain combusted tobacco
products meet a potential nicotine tobacco product standard?
    2. What is the feasibility of using the techniques discussed in
this section, or other nicotine reduction techniques, to reduce the
nicotine in cigarettes?
    3. What is the feasibility of using the techniques discussed in
this section, or other nicotine reduction techniques, for non-cigarette
combusted tobacco products (e.g., cigarette tobacco, RYO tobacco,
little cigars, large cigars, cigarillos, pipe tobacco, and waterpipe
tobacco) that FDA is considering covering under a nicotine tobacco
product standard?
    4. If FDA were to propose a tobacco product standard setting a
maximum nicotine level, how, if at all, would such a product standard
impact tobacco farmers' growing and/or curing practices? If FDA were to
finalize a nicotine tobacco product standard, what would be the costs
and benefits for tobacco farmers and tobacco processors, particularly
regarding how any such rulemaking might affect them in light of new
technologies and business opportunities that are foreseeable, but not
now in place? In addition, if FDA were to finalize a nicotine tobacco
product standard, what would be the costs for farmers in light of such
a standard?
    5. Section 907(d)(2) of the FD&C Act provides that a tobacco
product standard must set forth the effective date of the standard,
which may not be less than 1 year after publication of a final rule
unless FDA determines that an earlier effective date is necessary for
the protection of the public health (and that such effective date be
established ``to minimize, consistent with the public health, economic
loss to, and disruption or dislocation of, domestic and international
trade''). This section also provides that the effective date be a
minimum of 2 years after publication of a final rule if the tobacco
standard can be met only by requiring ``substantial changes to the
methods of farming the domestically grown tobacco used by the
manufacturer.'' Therefore, if FDA were to propose a product standard
setting a maximum nicotine level, when should this standard become
effective? What implementation timeframe would allow adequate time for
industry to comply? Should the same timeframe be required for all
tobacco product manufacturers, regardless of their number of employees
and/or annual revenues? \11\ Given the currently available processes to
reduce the nicotine in tobacco products (e.g., chemical processes,
genetic engineering), what do manufacturers

and others with relevant expertise consider an appropriate timeframe to
implement a product standard to reduce nicotine? Would a 2-year, 4-
year, or 6-year timeframe be appropriate?
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    \11\ The Tobacco Control Act defines ``small tobacco product
manufacturer'' to be a tobacco product manufacturer that employs
fewer than 350 employees (21 U.S.C. 387(16)). In the preamble to the
deeming rule, FDA defined ``small-scale tobacco product
manufacturers'' to be a manufacturer of any regulated tobacco
product with 150 employees or fewer and annual total revenues of $5
million or less (81 FR 28973 at 28980). If you are providing
comments or information relevant to these definitions or a different
definition, please note that definition in your comments.
---------------------------------------------------------------------------

    6. Should the standard include provisions that would allow
manufacturers, distributors, or retailers to sell off existing
nonconforming inventory of manufactured combusted tobacco products? If
so, what would be a reasonable sell-off period?
    7. What are the potential outcomes of implementing methods to
reduce nicotine content in cigarettes in terms of impact on
characteristics of cigarettes (flavor, taste, aroma, etc.) and user
experience?

F. Possible Countervailing Effects

    Section IV. B discusses some of the potential benefits that FDA
expects could occur as a result of one possible nicotine tobacco
product standard. There may be possible countervailing effects that
could diminish the population health benefits expected as a result of a
nicotine tobacco product standard. As part of any subsequent rulemaking
FDA would need to assess these effects in comparison to the expected
benefits, including among population subgroups.
    One possible countervailing effect is continued combusted tobacco
product use. Current smokers of tobacco products covered by a nicotine
tobacco product standard could turn to other tobacco products to
maintain their nicotine dependence, both in combination with cigarettes
(i.e., dual use) or in place of cigarettes (i.e., switching). For those
users seeking to switch to a potentially less hazardous tobacco product
(e.g., electronic nicotine delivery systems), FDA expects that the
increase in consumer demand for such other products likely would be met
by the tobacco industry, which has a history of being responsive to
market shifts (see FDA's Draft Concept Paper published elsewhere in
this issue of the Federal Register). For example, traditional cigarette
manufacturers began to expand into the smokeless market when
restrictions on where smokers were allowed to smoke were in enacted in
the 1980s, 1990s, and early 2000s (id., citing Ref. 171). FDA also
wishes to better understand whether users would switch to premium
cigars if these products were excluded from the scope of a nicotine
tobacco product standard. FDA has requested data and information on
whether large and/or so-called premium cigars would be migration or
dual use candidates, or whether and how there is a way to define
``premium cigar'' to minimize such consequences.
    While FDA believes that some consumers would be satisfied with VLNC
cigarettes, the Agency expects that there would be a subset of
consumers uninterested in switching to VLNC cigarettes or quitting
tobacco products altogether. This subset of consumers may seek to
obtain illicit tobacco products after a standard becomes effective (see
FDA's Draft Concept Paper). As a result, FDA is considering whether an
increase in illicit trade might occur as a result of a nicotine tobacco
product standard and how that could impact the marketplace and public
health. The analysis of possible illicit trade includes considerations
regarding the sources of tobacco, how illicit tobacco products might be
manufactured, possible workarounds (such as adding nicotine in liquid
or other form to a product with minimally addictive or nonaddictive
nicotine levels), the ability to distribute illicit products, the
development of consumer awareness, and how illicit trade sales might
take place (id.). The capacity to produce illicit tobacco products
would depend upon a variety of factors, including the ease of acquiring
the raw materials (particularly tobacco), the sophistication required
to construct the desired product, and the purpose (whether it is for an
individual's personal use, or for wider distribution and sale). Large,
commercial, tobacco product manufacturers have the resources,
sophistication, and ability to manufacture illicit tobacco products
(id.). Illicit tobacco products also may be smuggled and sold through
the internet. It is unclear, however, to what extent such companies
would be willing to risk their businesses (and resulting profits) to
manufacture illicit tobacco products (id.). Tribal manufacturers are an
additional source of tobacco products, having relatively high
sophistication and machinery in some instances, but they are also
subject to the same disincentives as large manufacturers and generally
lack widespread distribution and sales capabilities (id.).
    The IOM has explored the issue of possible illicit trade if FDA
were to issue a tobacco product standard limiting the levels of
nicotine in cigarettes. The IOM found that although there is
insufficient evidence to draw firm conclusions regarding how the U.S.
illicit tobacco market would respond to regulations requiring a
reduction in the nicotine content of cigarettes, limited evidence
suggests that the demand for illicit conventional cigarettes would be
``modest'' (Ref. 172). The IOM suggests that demand would be limited,
because some smokers may quit and other will use modified products or
seek legal alternatives (id.). Although some smokers may seek to
purchase illicit products if available and accessible, the IOM finds
that this ``would require established distribution networks and new
sources of product (which would either have to be smuggled from other
countries or produced illegally) to create a supply of cigarettes with
prohibited features'' (id.). Given that individuals have utilized
distribution networks to smuggle cigarettes and avoid higher taxes, FDA
is considering whether there might be additional incentive to create or
obtain the prohibited cigarettes that are not available elsewhere in
the United States. In addition, the report explains that comprehensive
interventions by several countries show that it is possible to reduce
the size of the illicit tobacco market through enforcement mechanisms
and collaborations across jurisdictions (id.).
    If a nicotine tobacco product standard were to prompt the
development of an illicit market, FDA would have the authority to take
enforcement actions regarding the sale and distribution of illicit
tobacco products. The FD&C Act provides FDA with several tools that it
may use against noncompliant parties. For example, FDA could issue a
Warning Letter, an advisory action in which FDA notifies a regulated
entity that FDA has found evidence that the party violated the law. A
Warning Letter is used to achieve prompt voluntary compliance. In a
Warning Letter, FDA informs the regulated entity that failure to comply
with the requirements of the FD&C Act and its implementing regulations
may result in FDA enforcement action. These actions may include
initiating administrative actions or referring cases to the Department
of Justice for initiation of judicial action. FDA may seek to initiate
an administrative legal action against a regulated entity that can
result in the imposition of a fine or civil money penalty. Possible
judicial actions may include seizures, injunctions, and criminal
prosecution.
    Another possible countervailing effect is the potential for
increased harm due to continued VLNC smoking with altered smoking
behaviors. Some studies of VLNC cigarettes with nicotine levels similar
to what FDA is considering have not found compensatory smoking behavior
and have found reductions in the number of cigarettes smoked per day
and, consequently, decreased exposure to harmful constituents (as
discussed in

section IV.B of this document). If FDA decides to pursue a proposed
nicotine product standard, FDA will continue to consider this potential
countervailing effect.
    Another possible countervailing effect of setting a maximum
nicotine level for cigarettes could be that users would seek to add
nicotine in liquid or other form to their combusted tobacco products.
Therefore, FDA is considering whether any action it might take to
reduce nicotine in combusted tobacco products should be paired with a
provision that would prohibit the sale or distribution of any tobacco
product designed for the purposes of supplementing the nicotine content
of a combusted tobacco product (or any product where the reasonably
foreseeable use is for the purposes of supplementing this nicotine
content). FDA is also considering what other regulatory options may be
available to address this concern and requests comments on such
options.
    Please explain your responses and provide any evidence or other
information supporting your responses to the following questions:
    1. In addition to a nicotine tobacco product standard, should FDA
consider any additional regulatory action to address the possibility of
migration to, or dual use with, other tobacco products?
    2. If FDA were to issue a product standard setting a maximum
nicotine content for cigarettes, would smokers seek to add liquid
nicotine to their VLNC cigarettes? Therefore, should such a regulation
include provisions prohibiting the sale or distribution of any tobacco
product designed for the purposes of supplementing the nicotine content
of a combusted tobacco product (or any product where the reasonably
foreseeable use is to supplement this nicotine content)? How could such
a provision be structured to efficiently and effectively achieve this
purpose? Should FDA consider other means to prevent supplementing the
nicotine content of a combusted tobacco product subject to a nicotine
tobacco product standard?
    3. Would a nicotine tobacco product standard affect the current
illicit trade market, and, if so, to what extent? How would users
obtain their sources of tobacco in an illicit market? How would
manufacturers distribute their illicit products and develop consumer
awareness of such products? How would such sales take place?
    4. FDA hypothesizes that, based on currently available research,
nicotine levels like those levels that FDA would consider with a
possible nicotine tobacco product standard would be self-limiting
(i.e., smokers would be unable to obtain their nicotine dose from
cigarettes no matter how they smoke them and eventually would stop
trying to do so). Do any peer-reviewed studies demonstrate that
lowering the nicotine content of cigarettes to minimally addictive
levels might encourage consumers to smoke more VLNC cigarettes to
achieve the higher nicotine doses currently delivered by NNC
cigarettes?
    5. If a nicotine tobacco product standard were in effect, the
following outcomes could occur: (1) Smokers could continue to smoke but
use the low nicotine products; (2) smokers could completely switch to,
or dual use low nicotine products with, other legal tobacco or nicotine
products; (3) smokers could quit using any nicotine or tobacco product;
or (4) smokers could seek to buy illegal cigarettes in an illicit
market. Are there data that would provide information on which of these
outcomes is most likely? Is there some other outcome that could occur?
    6. If an illicit market developed, what percentage of current
smokers would switch to illicit conventional cigarettes rather than
quitting or switching to other legal products? How would this change if
illicit conventional cigarettes were more expensive and/or harder to
obtain? How would this change with the implementation of improved
monitoring and enhanced enforcement by FDA and its partners?
    7. If a nicotine tobacco product standard prompted growth of an
illicit market, how long would it likely last? Would demand likely
decrease over time, stay the same, or increase?
    8. If a nicotine tobacco product standard prompted growth of an
illicit market, what effect, if any, would this have on the market for
illegal drugs? Are there data showing a relationship between illicit
tobacco use and illegal drug use?
    9. What mechanisms may be used to prevent, control, or contain
illicit markets in conventional cigarettes that may develop if FDA
establishes a product standard? What State and Federal entities may be