initiation, switching, poly use, cessation) that may occur with the
marketing of the new tobacco product. We recommend an applicant compare
the health risks of its product to both products within the same
category and subcategory, as well as products in different categories
as appropriate. It is helpful for FDA to understand applicant's
rationale and justification for comparators chosen whether within the
same category or different categories of tobacco products. This
comparative health risk data is an important part of the evaluation of
the health effects of product switching. As set forth in proposed Sec.
1114.27(b)(1)(ii), a PMTA would be required to contain substantive
information regarding comparative health risks to be filed for review.
    Information about tobacco products in the same category or
subcategory is important to FDA's evaluation of a tobacco product's
potential effect on public health because current users may switch to
other products within the same category. When determining an
appropriate comparison product within the same category or subcategory
of product, FDA recommends applicants consider products consumers are
most likely to consider interchangeable between your proposed product
and other similar products. For example, for a PMTA for an e-liquid,
FDA recommends the product be compared to other e-liquids used in a
similar manner. This comparison is not meant to be a 1:1 comparison as
in a substantial equivalence report under section 905(j), rather, it is
meant to demonstrate how the proposed new product may be evaluated in
relation to similar products.
    Information about tobacco products in different categories is
important to FDA's evaluations because it can help demonstrate the
changes in health risks current tobacco users could face if they
switched to your new tobacco product or use it in conjunction with
their current tobacco product. For tobacco products that are not in the
same tobacco product category, but that may be appropriate for
examining health risk, FDA recommends determining the likely users of
the proposed new product to justify appropriate comparison products.
For example, if an applicant submitting a PMTA for an ENDS believes
that current users of cigarettes and ENDS will use its product, it
would be appropriate to compare the health risks of the ENDS to both
cigarettes and other similar ENDS products. Polytobacco use risks
should also be considered.
     Foreign Data. An application may contain health risk
investigations conducted outside of the United States. If the study
data concern a demographic that is different from the United States,
the applicant should provide a scientific rationale for why the results
of the study can be generalized to other demographic groups that are
representative of the U.S. population as whole.\12\ This could include
a discussion of the factors that would be expected to influence study
findings and whether they vary significantly across the U.S.
population. The applicant should also clearly describe any reasons why
study findings may not be generalized to the broader U.S. population.
---------------------------------------------------------------------------

    \12\ For a discussion of both intrinsic and extrinsic factors in
foreign data that might need to be addressed, please see the
International Council for Harmonisation (ICH) E5 guidance: Ethnic
Factors in the Acceptability of Foreign Clinical Data.
---------------------------------------------------------------------------

    Foreign clinical studies should be performed by clinical
investigators so that the rights, safety, and welfare of human subjects
have been protected in accordance with ethical principles acceptable to
the international community, such as those reflected in the
International Council for Harmonisation (ICH) Good Clinical Practice
standards.
    An application may be required to contain full reports of foreign
investigations even if they do not meet these criteria because of the
requirements of proposed Sec.  1114.7(k) that an application contain
all published studies regarding a new tobacco product. This could
include, for example, a published health risk investigation regarding
the product conducted outside the United States by someone other than
the applicant. Where data do not meet the recommendations described in
the preceding paragraph, an application should contain a description of
the ways in which the foreign data fails to meet those criteria and, if
applicable, describe whether FDA should still consider the data to be
valid.
    i. Health risks of the product. Proposed Sec.  1114.7(k)(1)(i)(A)
would require a PMTA to contain full reports of all investigations,
published or known to, or which should reasonably be known to, the
applicant regarding the potential health effects of their product. This
would include full reports of investigations on the constituents,
including HPHCs, in the specific product or formed during use of the
product, and at the quantitative levels that would be delivered to both
users and nonusers under the range of conditions under which the
specific product may be used. FDA is proposing to include these
investigations under its interpretation of the requirements of

section 910(b)(1)(A) of the FD&C Act because the health effects of
constituents at the levels delivered to both users and nonusers help
demonstrate the overall health risks of the product. Types of
investigations into the health effects of constituents that applicants
would be required to submit as part of a PMTA if published or known to,
or which should reasonably be known to an applicant include human
exposure studies, in silico computational toxicology techniques, risk
assessments, in vitro toxicology studies, published reports of in vivo
toxicology studies, and, if necessary, new in vivo toxicology studies.
    The proposed rule would not require an applicant to conduct any
particular type of studies regarding the health risks of the
constituents for the purposes of application acceptance and filing;
however, as set forth in proposed Sec.  1114.27(b)(1)(ii) and described
in section VIII.B., an application would be required to contain
substantive information regarding the health risks of the new tobacco
product to be filed. Where an applicant chooses to conduct its own
investigations, FDA is providing the following discussion of non-
binding recommendations for consideration.
    The health effect evaluation of tobacco constituents, including
HPHCs, in a PMTA should begin with an assessment of human exposure. For
tobacco product users, this assessment should include direct
measurements of exposure, estimates of exposure from analytical studies
of the tobacco product and its smoke or aerosol, or investigations that
combine both approaches. For nonusers of the tobacco product, exposure
estimates would include analytical studies. One source of this
information can be the HPHC data that would be required by proposed
Sec.  1114.7(i)(1)(v). FDA recommends that these investigations
specifically assess the levels of each HPHC to which users and nonusers
could be exposed and that direct measurements or estimates of exposure
use the same route of administration (e.g., inhalation, ingestion,
dermal contact) as the tobacco product they evaluate. Other aspects of
the exposure that FDA would recommend applicants define in the tobacco
constituent exposure assessment include exposure duration, inhalation
rate, consumption rate, body mass, and other similar relevant measures.
    Study reports regarding the health effects of product constituents
at both the exposure ranges estimated for user and nonuser exposure and
higher exposures are important in the toxicological evaluation of a
PMTA because it allows for a more thorough dose-response assessment.
Higher exposures may provide indication of toxicity potential from
lower exposure levels over longer exposure times. FDA recommends
including dose-response assessments across a range of exposures. For
noncarcinogenic constituents, FDA recommends including study reports
that define the threshold of toxicity, especially those that identify
the no-observable-adverse effect level and lowest-observable-adverse-
effects-level. For carcinogenic constituents, if only high-exposure
studies are available, an assumption of linearity should be made for
low-dose extrapolation. For both carcinogenic and noncarcinogenic
constituents, user and nonuser exposures should be compared to
available dose response information.
    FDA supports reducing the reliance on animal testing where adequate
and scientifically valid non-animal alternatives can be substituted.
FDA encourages sponsors to meet with CTP early in the development
process to discuss what, if any, animal testing is appropriate and the
suitability and acceptability of non-animal tests for their specific
new tobacco product. When animal-based nonclinical laboratory studies
are conducted, investigators should use appropriate animal models and
adhere to the best practices of refinement, reduction, and replacement
of animals in research and to applicable laws, regulations, and
policies governing animal testing, such as the Animal Welfare Act (7
U.S.C. 2131 et seq.) and the Public Health Service Policy of Humane
Care and Use of Laboratory Animals (available at https://olaw.nih.gov/policies-laws/phs-policy.htm).
    Under proposed Sec.  1114.7(k)(1)(i)(B), a PMTA would be required
to contain all investigations, published or known to, or which should
reasonably be known to, the applicant regarding the toxicological
profile of the new tobacco product related to the route of
administration, including, but not limited to, the genotoxicity,
carcinogenicity, respiratory toxicity, cardiac toxicity, reproductive
and developmental toxicity, and chronic (repeat dose) toxicity of the
new tobacco product relative to other tobacco products. The
toxicological profile also includes information regarding the
ingredients, additives, and HPHCs, relative to the route of
administration and the range of the potential levels of exposure
resulting from the use of or other exposure to the product. While FDA
is aware of the risk of harm posed by HPHCs generally, understanding
the toxicological effects of HPHCs in the product is important to FDA's
review because the levels and combinations of HPHCs to which a consumer
may be exposed can determine whether, and the severity with which, a
user may experience harm. For example, some constituents may only cause
harm above certain levels of exposure, while others may have no safe
level of exposure. Additionally, since there are potential complex
interactions between HPHCs and each tobacco product can produce a
different mixture of these HPHCs, FDA needs to determine the toxicity
of the specific mixture of HPHCs in a tobacco product in order to
compare that tobacco product to other similar products on the market
place and to use this comparison in the decision about whether
permitting the marketing of the product would be APPH. The
toxicological profile investigations covered by the proposed rule would
also include studies that discuss the toxicological effects of any
leachables and extractables from the container closure system and the
ingredient mixture, such as additive or synergistic effects.
    FDA is proposing to include the toxicological profile of the
tobacco as part of its interpretation of the health risk investigations
required under section 910(b)(1)(A) of the FD&C Act, where published,
known to, or which should reasonably be known to an applicant, because
it identifies the hazardous or harmful effects of product constituents
and allows for product comparisons that estimate the impact of the
assessed tobacco product on the health of both users and nonusers of
the tobacco product.
    The types of toxicological information or data regarding a tobacco
product that a PMTA would be required to contain if published or known
to, or should reasonably be known to, an applicant would generally
include the characterization of toxic effects of HPHCs to which users
and nonusers may be exposed. This evaluation can include identification
of the organs affected by constituents; the cancer and noncancer
effects of the constituents; dose response relationships between
exposure to constituents and health effects; and, when appropriate,
threshold levels of exposure above which noncancer effects occur. The
toxicological assessment of the product that is the subject of a PMTA
should focus on the HPHCs reported in proposed Sec.  1114.7(i)(1)(v),
the constituent reporting section. The types of studies or information
required by the proposed rule, if published or known to, or should
reasonably be known to an applicant, include toxicological

assessments conducted in terms of both the whole tobacco product and
the individual HPHCs that the product contains or delivers to users and
nonusers.
    Because different tobacco products contain different ingredients
and additives, they may also have different HPHC yields. A tobacco
product that would result in increased exposure to a potent HPHC or set
of HPHCs, for example, may present higher health risks to users.
However, important aspects such as dose-response and whether the end
organ toxicity is carcinogenic or noncarcinogenic in nature could
affect whether this higher exposure results in an estimate of increased
risk. The information generated from the toxicological assessment of
tobacco products is part of the information that the applicant should
use in product comparisons to estimate the impact of the assessed
tobacco product on the public health.
    The toxicological profile includes information about, or
investigations into, the potential for a tobacco product or its
constituents to cause toxicity. For the specific toxicological profile
of a new tobacco product or constituents in or formed during use of the
new tobacco product, the applicant should address known tobacco target
organs of toxicity, as appropriate for the product and/or route of
administration. The profile should include data and thorough literature
reviews of the following health effects known to be caused by tobacco
products as applicable such as:
     Genotoxicity (the ability of a chemical agent to damage
DNA within a cell, causing mutations that may lead to cancer);
     Carcinogenicity (the ability of a chemical agent to
directly cause cancer in humans or animals after exposure);
     Cardiovascular toxicity (the ability of a chemical agent
to cause adverse effects on the cardiovascular system (i.e., heart and
blood vessels));
     Respiratory toxicity (the ability of a chemical agent to
cause adverse effects on the respiratory system, which comprises the
nasal passages, pharynx, trachea, bronchi, and lungs);
     Reproductive toxicity (the ability of a chemical agent to
cause adverse effects on the male or female reproductive systems such
that normal reproduction is impaired);
     Developmental toxicity (the ability of a chemical agent to
interfere with the development of the embryo or fetus); and
     Other diseases associated with use.
    While not required for application acceptance or filing under
proposed Sec.  1114.33, FDA recommends that an application contain a
discussion of the toxicological potential for the tobacco product to
cause additional chronic toxicities, other than those listed above,
such as any end-organ toxicity or route of administration effects.
These end-organ toxicities include, but are not limited to, the
potential toxicity on the liver, kidneys, immune system, digestive
system, and neurological system. An example of route of administration
effects that FDA recommends be addressed is the toxic potential of a
smokeless tobacco product to the oral cavity, including teeth.
    FDA also recommends the application address acute toxicity, which
concerns the ability of a chemical agent to cause adverse effects after
either a single exposure or multiple exposures in a short period of
time (usually less than 24 hours). If there are known acute toxicities
for product constituents at the levels to which an individual may be
exposed (e.g., carbon monoxide poisoning from waterpipe use, the
ingestion of nicotine contained in e-liquids) including through
accidental or unintended exposures, an applicant should justify how the
product could contain such constituents and how permitting its
marketing would be APPH. This could include a description of the design
features, such as child-resistant packaging for e-liquids, that would
prevent exposures to constituents that could result in acute toxicity
as part of proposed Sec.  1114.7(i)(1)(vi)(B). See the discussion in
section VII.B.9.a.vi. for more information about protective packaging.
    FDA recommends that an applicant compare the toxicity of its
product to the toxicity of other products in the same product category
or subcategory. Additionally, FDA recommends that applicants consider
use exposure in conjunction with the hazards posed by a particular
product to determine the most appropriate group of comparator products.
    While applicants are not required to conduct toxicological analyses
under the proposed rule, if an application does not contain substantive
information regarding either the health risks of the new tobacco
product or a comparison of the health risks compared to other tobacco
product categories, FDA intends to refuse to file a PMTA as set forth
in proposed Sec.  1114.27(b)(1)(ii) and described in section VIII.B..
Information about the product's toxicity and a comparison of its
toxicity to other tobacco products could satisfy this threshold
information requirement for filing; however, it should be noted that
information from nonclinical studies alone, including a product's
toxicological profile, is generally not sufficient to support a
determination that permitting the marketing of the product would be
APPH. An applicant should also consider the existing valid scientific
evidence regarding its new tobacco product to determine whether it
would need to conduct and submit a full report of toxicological
analyses to demonstrate the potential health risks of the new tobacco
product as part of its PMTA. If an application does not contain
sufficient information about the health risks of the new tobacco
product to allow FDA to make a determination regarding the potential
risks and benefits to the population as a whole under section 910(c)(4)
of the FD&C Act, FDA will issue a no marketing order for the new
tobacco product.
    Under proposed Sec.  1114.7(k)(1)(i)(C), a PMTA would be required
to contain all studies concerning the pharmacological profile of the
new tobacco product that are published or known to, or which should
reasonably be known to, the applicant, including investigations into
the pharmacokinetics, pharmacodynamics, metabolism, and elimination
profile, of each of the ingredients, additives, and HPHCs for the range
of potential levels of exposure resulting from the use of or exposure
to the product relative to other tobacco products. The applicant would
also be required to specify whether the studies were conducted in
vitro, in vivo, ex vivo, or in silico. The pharmacological profile of
the product and its constituents are important for FDA to consider when
evaluating the relationship between the dose of the product and the
body's response. FDA is proposing to include the pharmacological
profile of the tobacco product as part of the information required
under section 910(b)(1)(A) of the FD&C Act because it provides
important information regarding how the product constituents and human
body interact with each other, which directly impacts whether and what
health impacts the constituents can have on users and nonusers of the
product.
    The types of pharmacological information that the applicant would
be required to include in a PMTA if published or known to, or which
should reasonably be known to, the applicant include pharmacokinetics
and pharmacodynamics. Pharmacokinetics concern the movement of a
constituent into, through, and out of the body. Types of
pharmacokinetic information that an application would be required to
contain if published or known to, or which should reasonably be known
to, the applicant include absorption (the

rate and movement of a constituent into the bloodstream after
administration), bioavailability (the extent to which the constituent
reaches the site of action), distribution (the transfer of a
constituent from one location in the body to another), metabolism (the
breaking down of a constituent), and excretion (the elimination of a
constituent). Pharmacodynamics refers to the effects of the constituent
on the body including physiological (e.g., changes in blood pressure
and heart rate) and subjective effects (e.g., whether the product is
``liked'' or produces other changes in affect). Types of
pharmacodynamic information that an applicant would be required to
submit in a PMTA if published or known to, or which should reasonably
be known to, the applicant include physiological and subjective effects
data and information regarding drug-receptor interactions, chemical
interactions, and dose-response relationships.
    The pharmacological profile of the product provides important
information about the health risks of the product because it is
directly related to the health risks of the product as well as its risk
relative to other products. The pharmacological profile of nicotine,
for example, is particularly important for assessing product health
risk because its pharmacokinetic properties can enhance or reduce the
product's associated health risks. In general, the abuse potential of
nicotine increases when absorption is rapid because the rewarding
properties of the compound increase, and suppression of withdrawal
symptoms occurs more quickly. Nicotine's pharmacological profile
impacts use behavior that can then affect the overall exposure of the
user to HPHCs and other constituents in the product. Changes in use
behavior may result from the pharmacokinetic properties of the nicotine
and can result in increased or decreased exposure to the constituents
within a product. (Refs. 109-112).
    Under proposed Sec.  1114.7(k)(1)(i)(D), a PMTA would be required
to contain full reports of all investigations published or known to, or
which should reasonably be known to the applicant concerning the health
risks of the tobacco product compared to other tobacco products on the
market, never using tobacco products, quitting tobacco product use, and
using the tobacco product in conjunction with other tobacco products.
Under section 910(b)(1)(A) of the FD&C Act, an applicant must submit
investigations that have been made to show whether the tobacco product
presents less risks than other tobacco products. FDA is proposing under
section 910(b)(1)(G) of the FD&C Act to require applicants to submit
investigations that have been made to show whether the tobacco product
has the same or different potential health risks (not just less
potential health risks) than other tobacco products to capture
investigations that could potentially show a range of risks compared to
other tobacco products. FDA is proposing that applicants include
comparisons between the health risks of the tobacco product and never
using tobacco product under the authority of section 910(b)(1)(A) and
(G) of the FD&C Act because this information is relevant to determining
the health risks faced by nonusers who initiate tobacco use with the
tobacco product.
    FDA is also proposing to require that an application contain, if
published, known to or which should be reasonably known to the
applicant, comparisons between the health risks of the tobacco product
and using the tobacco product in conjunction with other tobacco
products as part of the required information because existing data
indicates that a significant number (approximately 40 percent or more
by some estimates) of individuals who currently use tobacco products
use more than one type of tobacco product (Refs. 113 and 114). This
information is important in determining the health risks faced by
individuals that may use the new tobacco product in conjunction with
other tobacco products because research indicates that individuals who
use a tobacco product with lower health risks in conjunction with a
tobacco product with potentially higher health risks may continue to
face the potentially higher health risks of the more dangerous product
above a certain threshold of usage (Refs. 115 and 116).
    The types of investigations that a PMTA would be required to
contain if published or known to, or which should reasonably be known
to the applicant in this section include, for example:
     Cross sectional and longitudinal surveys (such as market
analyses or publicly available national surveys such as NYTS);
     epidemiologic studies that are descriptive (which describe
the occurrence of a prespecified or unknown outcome), such as case
reports and case series; and
     analytic studies (which describe the association between
exposure and outcome) such as randomized controlled clinical trials,
cohort studies, and case control studies.
    Additionally, clinical studies that employ surrogate endpoints
(e.g., biomarker studies) may be used to draw conclusions regarding the
effects of the product on a clinical benefit endpoint and patient
reported outcome data (i.e., report of the status of health that comes
directly from the subject without interpretation from the subject's
response by a clinician) may be used as supportive evidence for health
outcomes or effects.
    For determining the health risks that are posed to a typical user
of a tobacco product for the purposes of comparison, FDA recommends
using an average of light, moderate, and heavy users. FDA also
recommends including evidence and a description supporting the range of
light, moderate, and heavy use an applicant includes in its PMTA,
including how they relate to the exposures in the submitted toxicology
studies. Where an applicant does not have data regarding light,
moderate, or heavy product use because the product has not been
commercially marketed, including outside the United States, an
applicant could, where applicable, bridge to data regarding a similar
tobacco product or conduct clinical studies under ad libitum (i.e.,
unrestricted use) conditions.
    As set forth in proposed Sec.  1114.27(b)(1)(ii) and described in
section VIII.B, for an application to be filed it must contain
substantive information comparing the new tobacco product's health
risks to those generally presented by the same product category and at
least one different product category that is used by the consumers an
applicant expects to use their new tobacco product. An applicant should
consider the appropriate comparative health information a PMTA may need
beyond this threshold requirement to provide FDA with a full
understanding of the potential risk and benefits to current tobacco
users. If a PMTA lacks sufficient information to demonstrate the
changes in risk to which current users of tobacco products would
potentially be exposed if they switched to the new tobacco product or
began using it in conjunction with their current product, FDA intends
to issue a no marketing order for the new tobacco product.
    For demonstrating the health risks that are posed by the product in
comparison to using other tobacco products, FDA recommends a comparison
to both products that are within the same category or subcategory of
tobacco product and also to other categories of tobacco products
currently on the market, as appropriate. As described in section
VII.B.13.a., when determining an appropriate comparison product within
the same category or subcategory of product, FDA recommends applicants
consider

products that consumers are most likely to consider interchangeable
between your proposed product and other similar products. For example,
for a PMTA for an e-liquid, FDA recommends the product be compared to
other e-liquids likely to be used in the same manner. When determining
appropriate comparator products that are not in the same tobacco
product category, FDA recommends comparing the health risks of the
product to categories of products that have a substantial market share
(e.g., cigarettes, smokeless tobacco, cigars). Because it is expected
that current consumers of products that are in the same category may
switch products and consumers of different categories of tobacco
product may also switch products or use a new product in conjunction
with their current product, this comparative health risk data is an
important part of the evaluation of whether switching could potentially
result in a lower or higher population health risks.
    ii. Impacts on tobacco use behavior of tobacco product users. FDA
interprets health risk investigations under section 910(b)(1)(A) of the
FD&C Act to include the effect of the product and its label, labeling,
and advertising on tobacco use behavior and tobacco use topography
because use behavior and topography are directly related to levels of
exposure to HPHCs, which, in turn, impacts health risks. For example,
changes in tobacco product use behavior and topography that result in
more frequent or intense use of the product will result in greater
exposure to HPHCs and may result in increased health risks. Aspects of
a product that could result in more frequent or intense use compared to
currently marketed products can include differences in the appeal and
design of the product, including ingredients; flavors; alteration in
the amount or delivery of nicotine; physical differences such as
changes in the velocity of the inhaled particles, the effort required
to inhale, or the density of the smoke, vapor, or aerosol; or other
changes which similarly affect user behavior (e.g., ventilation, filter
density).
    Proposed Sec.  1114.7(k)(1)(ii)(A) would require a PMTA to contain
full reports of investigations into the abuse liability of the new
tobacco product that are published or known to, or which should
reasonably be known to the applicant. However, as set forth in proposed
Sec.  1114.27(b)(1)(ii) and described in section VIII.B., if a PMTA
does not contain substantive information regarding the abuse liability
of a new tobacco product, FDA may refuse to file the application. This
means where there is no published information regarding the abuse
liability or information that is otherwise known to the applicant,
including information from investigations using other products that an
applicant could bridge to its product, an applicant would need to
conduct its own investigation and include a full report of the results
in its PMTA for filing.
    Abuse liability refers to the potential of a substance to result in
addiction and be used repeatedly or even sporadically resulting in
undesirable effects. The abuse liability of a new tobacco product is
important for FDA to evaluate because it indicates the degree to which
users of the tobacco product are likely to use and develop an addiction
to the product. Abuse liability may result in compulsive and continued
use despite harm or risk of harm, and craving of the product. FDA
proposes to require the submission of abuse liability information under
its interpretation of section 910(b)(1)(A) of the FD&C Act because it
indicates the likelihood of users to become addicted to the product and
face the health risks posed by product use over the long term, and may
provide insight into the use and adoption of the product, which is an
important part of FDA's assessment of the health risks of the new
tobacco product as part of its determination of the risks and benefits
to the population as a whole under section 910(c)(4) of the FD&C Act.
If FDA lacks sufficient information regarding the potential abuse
liability of the new tobacco product, it intends to issue a no
marketing order for the new tobacco product.
    The types of investigations that inform an evaluation of a
product's abuse liability can be wide ranging and are likely to overlap
with data submitted elsewhere as part of the PMTA, including data
regarding product chemistry, pharmacology, and pharmacokinetic
characteristics. Where the data are included elsewhere in a PMTA, FDA
recommends including content in this section by cross-reference to the
full reports of relevant investigations in other sections. Applicants
should analyze the results of all investigations included in the
application that impact the abuse liability of the product and
synthesize the findings in this section.
    While applications need to contain only a threshold amount of abuse
liability information under proposed Sec.  1114.27(b)(2)(ii) to be
filed, the abuse liability of a tobacco product is an important part of
FDA's finding of whether permitting the marketing of the new tobacco
product would be APPH and applicants would want to consider conducting
an abuse liability study if they do not believe there is sufficient
existing data regarding their product. The ``standard'' abuse liability
study is a double-blind, placebo-controlled, within-subject study
comparing several doses of a new product to a comparator product with a
known abuse liability. Generally, the primary outcome measure is peak
``liking'' (Emax) as reported via a visual analog scale. Applicants
that wish to conduct abuse liability studies examining tobacco products
may utilize a similar framework with additional assessments, although
evaluating multiple doses may not be applicable to some tobacco
products. These assessments may include use topography, and
pharmacokinetics and pharmacodynamics assessments under both prescribed
and ad libitum (i.e., unrestricted) use conditions. Real world, actual
use data may also provide outcomes relevant to the products' abuse
liability, including misuse. Abuse liability conclusions should be
considered as an integral assessment of all outcome measures important
to understanding the abuse liability of the new tobacco product both
independently and relative to other tobacco products with a known abuse
liability. FDA generally expects abuse liability studies to contain a
comparison to one or more tobacco products and applicants seeking to
market a new tobacco product for which little abuse liability data has
been established should ensure FDA has sufficient information to
understand how the abuse liability of such a product compares to other
relevant categories of tobacco products.
    Section 1114.7(k)(1)(ii)(B) of the proposed rule would require a
PMTA to contain investigations published or known to, or which should
reasonably be known to the applicant into how consumers actually use
the product, including use topography, the product use frequency, use
trends over time, and how such use affects the health risks of the
product to individual users. FDA is proposing to require this
information because the ways in which consumers actually use the
product, instead of relying only on how manufacturers intend the
product to be used, help to demonstrate the levels of constituents to
which the users will be exposed. Under proposed Sec.
1114.27(b)(1)(ii), FDA may refuse to file a PMTA that does not contain
substantive information regarding how consumers actually use the
product, including use topography, product use frequency, use trends
over

time, and how such use affects the health risks of the product to
individual users. This means where there is no published information
regarding actual use or information that is otherwise known to the
applicant, including information from investigations using other
products that an applicant could bridge to its product, an applicant
would need to conduct its own investigation and include a full report
of the results in its PMTA for filing.
    An actual use study can include the use of actual product in either
a simulated use setting or in a real use environment. Actual use
studies are important to the evaluation of a PMTA because they provide
information regarding whether consumers will use the product as
intended. In addition, actual use studies help demonstrate whether
consumers are likely to misuse the product, including in ways that may
change the health risks that the product poses to users and nonusers.
For example, ENDS users have applied e-liquid directly onto an exposed
heater coil, a process known as dripping, which can lead to greater
exposure to volatile aldehyde and a resulting change in the health
risks of using the product. (Ref. 69). Actual use studies may be
conducted using outpatient protocols so that results are as close to
actual use as possible. The format of the study should reflect the
goals of the study and how the applicant believes the information will
inform FDA's decision.
    Use topography measures the way in which users consume a product.
Use topography is an important measure to consider in assessing a
product's health risk and abuse liability because the volume,
frequency, and duration of product use determines the amount of, and
manner in which, a user is exposed to HPHCs in a product and,
consequently, affects the health risks of the product. For combusted or
inhaled products, use topography could include measurements of the
number of puffs taken, puff duration, puff volume, duration of use, and
other relevant measures. For smokeless tobacco, use topography could
include measures such as the number of smokeless tobacco tins used per
week, the total dips per day, and the dip duration.
    Section 1114.7(k)(1)(ii)(C) of the proposed rule would also require
the PMTA to contain full reports of all investigations, published or
known to, or which should reasonably be known to the applicant,
regarding the likelihood that users will use the product in conjunction
with other tobacco products. Data indicate that a substantial number of
tobacco product users are poly-users of tobacco products (Ref. 113 and
114). FDA is proposing to require information regarding the likelihood
of dual or poly-use because such use may increase or decrease known
health risks and may pose risks that are not currently known (Refs. 115
and 116). The likelihood of tobacco product users using the new tobacco
product in conjunction with another tobacco product, when considered
with the health effects resulting from such poly use, will help FDA
determine the health risks that poly users may encounter.
    Section 1114.7(k)(1)(ii)(D)-(F) of the proposed rule would also
require the PMTA to contain full reports of investigations published or
known to, or which should reasonably be known to the applicant,
regarding the likelihood that current tobacco product users:
     Will start using the product;
     will starting using the product exclusively and then
switch to or switch back to other tobacco products that may present
increased risks to individual health; and
     will start or continue to use the product when they
otherwise would have quit using tobacco products.
    While proposed Sec.  1114.7(k)(1)(ii)(c)-(f) would require a PMTA
to contain only information published, known to, which would reasonably
be known to the applicant, as set forth in proposed Sec.
1114.27(b)(1)(ii), if a PMTA does not contain a threshold amount of
information regarding likelihood of changes to tobacco use behavior of
current tobacco users, FDA intends to refuse to file the application.
This means where there is no published information regarding the
likelihood of changes in tobacco use behavior by current users of
tobacco products or information that is otherwise known to the
applicant, including information from investigations using other
products that an applicant could bridge to its product, an applicant
would need to conduct its own investigations and include a full report
of the results in its PMTA to meet this requirement for application
filing. And while the rule would not require an applicant address each
potential change in tobacco product use behavior for the purposes of
filing, FDA must be able to determine the potential risks and benefit
to the population as a whole, including each of the potential risks and
benefits associated with changes in tobacco product use behavior by
current tobacco product users in order to issue a marketing order for
the product. If a PMTA lacks sufficient information needed for FDA to
make these determinations, FDA intends to issue a no marketing order
for the new tobacco product.
    FDA is proposing to require information regarding the tobacco use
behavior of current tobacco product users because these behavior
patterns affect the health risks posed to those individuals. Current
tobacco product users who start using the product may be switching from
a product that may present greater, lower, or equal levels of
individual health risk. Current tobacco product users that adopt the
product may not continue use of the product in the future, so FDA seeks
information regarding whether they are likely to switch back or switch
to a product that may present higher levels of individual risk.
Finally, current tobacco product users who otherwise would have
otherwise quit using tobacco may use the new tobacco product instead,
exposing them to health risks to which they might not have otherwise
been exposed. FDA is also proposing to require information regarding
current tobacco product user behavior because to determine whether the
product is appropriate for the protection of public health, FDA must
under section 910(c)(4)(A) of the FD&C Act take into account the
increased or decreased likelihood that current tobacco product users
will stop using tobacco products. The types of studies that will likely
fall into this category can include actual use studies and national
survey databases that could be used to bridge general data to the
specific product. Ideally, the studies would look at past, present, and
likely future behaviors of the tobacco product users.
    iii. Impacts on tobacco use initiation by nonusers, including youth
and young adults. The proposed rule would also require a PMTA to
contain full reports of investigations published or known to, or which
should reasonably be known to the applicant, regarding the likelihood
that consumers who have never used tobacco products, particularly youth
and young adults, will initiate use of the tobacco product and the
likelihood that consumers who have never used tobacco products and
adopt use of the tobacco product will switch to other tobacco products
that may present higher levels of individual health risk however, as
set forth in proposed Sec.  1114.27(b)(1)(ii), if a PMTA does not
contain a threshold amount of information regarding the likelihood of
changes to tobacco use by current nonusers of tobacco products, FDA
intends to refuse to file the application. This means that where there
is no published information or information that is otherwise known to
the applicant regarding the likelihood of changes in

tobacco use behavior by current nonusers of tobacco products, including
information from investigations using other products that an applicant
could bridge to its product, an applicant would need to conduct its own
investigations and include a full report of the results in its PMTA for
filing. And while the rule would not require an application to contain
more than a threshold amount of relevant information for filing, FDA
must be able to determine the potential risks and benefit to the
population as a whole, including the potential risks and benefits
associated with changes in tobacco product use behavior by current
tobacco product users in order to issue a marketing order for the
product. If FDA lacks sufficient information to make these
determinations, it intends to issue a no marketing order for the new
tobacco product.
    FDA is proposing to require information regarding likelihood of
tobacco use initiation and switching to potentially more harmful
tobacco products, including among youth and young adults, as part of
its interpretation of the requirements of section 910(b)(1)(A) of the
FD&C Act because it will help FDA determine the number of current
nonusers who will likely be exposed to the health risks presented by
the tobacco product, as well as the risks posed by potentially more
harmful products that individuals may go on to use. The information
regarding initiation and switching by current nonusers of tobacco
products is also being required under section 910(b)(1)(G) because FDA
must take into account the increased or decreased likelihood that those
who do not use tobacco products will start using tobacco products under
section 910(c)(4)(A) of the FD&C Act. The types of studies that would
likely fall into this category include survey studies and focus groups.
In order to assess whether permitting the marketing of a proposed
product would be APPH, FDA will need to understand how youth may use or
intend to use the proposed product because youth are a population of
particular concern for initiating tobacco use. However, FDA does not
require research to be conducted on youth. Inferences regarding youth
may potentially be extrapolated from young adults, as well as derived
from existing sources of data, reviews of published scientific
literature, and/or bridging information obtained from other sources.
Providing data from the published literature or marketing information
in your application with appropriate bridging information may be one
useful approach. If you take such an approach, FDA recommends that you
clearly explain how such data can be extrapolated to the target
population or populations of interest, including youth, for the product
that is the subject of the PMTA.
    If an applicant chooses to conduct a study in the United States
using minors, they must use appropriate parental consent procedures, as
well as follow the requirements of the Children's Online Privacy and
Protection Act (15 U.S.C. 6501-6505), the Pupil Rights Amendment (20
U.S.C. 1232h), and their implementing regulations (see 16 CFR part 312
and 34 CFR part 98, respectively). FDA strongly recommends that any
studies conducted outside of the United States are designed so that the
rights, safety, and welfare of human subjects, including minors, have
been protected in accordance with ethical principles acceptable to the
international community, such as those reflected in the ICH Good
Clinical Practice standards.
    Regardless of where a study is conducted, any studies using minors
should have a narrow research scope and be as focused as possible given
sensitivities around the conduct of research in youth populations.
Specifically, research priorities for youth should be focused on key
questions relating to use (e.g., prevalence of use, characteristics of
users, and patterns of use), risk perception, and intention to use/
susceptibility among non-users. Studies conducted among youth focusing
on issues beyond these key questions (e.g., exposing youth to
advertisements or marketing material for tobacco products) would
warrant a very strong justification to demonstrate that the risks of
conducting the research are minimal and do not outweigh the potential
benefits of collecting such information.
    The proposed rule would also require a PMTA to contain full reports
of investigations published or known to, or which should reasonably be
known to the applicant, regarding the likelihood that former users of
tobacco products will re-initiate use with the tobacco product. FDA is
proposing to include information regarding likelihood of re-initiation
by former users as part of its interpretation of the requirements of
section 910(b)(1)(A) of the FD&C Act and under its authority of
910(b)(1)(G) of the FD&C Act because it will help FDA determine the
health risks to which these former users may be exposed if they begin
using the new tobacco product. Survey studies are one type of
investigation that is likely to fall into this category.
    iv. Perceptions and use intentions. The proposed rule would require
a PMTA to contain full reports of investigations published or known to,
or which should reasonably be known to the applicant, regarding tobacco
product perceptions and use intentions, including the impact of the
product and its label, labeling, and advertising on individuals'
perception of the risks of the product, and the ability of individuals
to understand the labeling and instructions for use and use the product
in accordance with those instructions; however, as set forth in
proposed Sec.  1114.27(b)(1)(ii), if a PMTA does not contain
substantive information regarding the potential impact of the product
and its label, labeling, and advertising on individuals' perception of
the product, and their use intentions, FDA intends refuse to file the
application. This means where there is no published information or
information that is otherwise known to the applicant regarding the
potential impact of the product and its label, labeling, and
advertising on individuals' perception of the product, and their use
intentions, including information from investigations using other
products that an applicant could bridge to its product, an applicant
would need to conduct its own investigations and include a full report
of the results in its PMTA for filing. And while the rule would not
require an application to contain more than a threshold amount of
relevant information for filing, FDA must be able to determine the
potential risks and benefit to the population as a whole, including the
potential risks and benefits associated with changes in tobacco product
use behavior by current tobacco product users in order to issue a
marketing order for the product. As described in section VII.B.6.,
because the advertising, marketing, and promotion of a tobacco product
can have a significant impact on the potential for tobacco product
initiation, especially by youth, where FDA is unable to determine the
impact that the labeling, advertising, marketing, and promotion of the
new tobacco product may have on consumer perceptions and use
intentions, FDA intends to issue a no marketing order for the new
tobacco product.
    FDA is proposing to include perception and use intention studies as
part of its interpretation of the requirements of section 910(b)(1)(A)
and under its authority of 910(b)(1)(G) of the FD&C Act because
perception of the risk of the product may influence decisions to use
the product and the resultant

exposure to the health risks presented by the product (Ref. 117). If an
applicant uses advertising as stimuli in a tobacco product perception
and use intention study, the PMTA would be required to indicate, as
part of the full report of the study under proposed Sec.  1114.7(k)(3),
whether it is representative of advertising that the applicant intends
to use in marketing the product that is required by proposed Sec.
1114.7(f)(2). If the advertising is not representative of the
advertising an applicant intends to use in marketing the product, the
applicant would be required to indicate whether the study results are
still relevant to the likely impact of product advertising on tobacco
product perceptions and use intentions.
    Additionally, information about individuals' understanding
regarding the labeling is also relevant to determining whether the
labeling is misleading, which is a reason for which FDA would have to
deny an application under section 910(c)(2)(C) of the FD&C Act, and
also may provide information on the likelihood of individuals using the
product. Additionally, whether consumers understand the instructions
for use and use the product in accordance with those instructions can
help show whether consumers will be exposed to potentially greater
health risks by using the product improperly. Topics that should be
examined in tobacco product perception and intention investigations
overlap with the topics identified in the human factors section that
follows.
    v. Human factors. The proposed rule would also require a PMTA to
contain full reports of investigations, published or known to, or which
should reasonably be known to, the applicant regarding human factors
that influence the health risks of the product, which includes use
conditions, use environments, use related hazards, estimated use error
risk, potential unintended uses, risk controls to ensure that harms and
unintended consequences are minimized, and adverse experiences related
to such uses; however, as set forth in proposed Sec.
1114.27(b)(1)(ii), if a PMTA does not contain a threshold amount of
information regarding the potential impact of human factors on the
health risks of the product, FDA intends to refuse to file the
application. This means where there is no published information or
information that is otherwise known to the applicant regarding the
potential impact of human factors on product risk, including
information from investigations using other products that an applicant
could bridge to its product, an applicant would need to conduct its own
investigations and include a full report of the results in its PMTA for
filing. And while the rule would not require an application to contain
more than a threshold amount of relevant information for filing, FDA
must be able to determine the potential risks and benefits of the new
tobacco product to the population as a whole. If FDA lacks sufficient
information to make this determination, it intends to issue a no
marketing order for the new tobacco product. FDA is proposing to
require human factors information as part of its interpretation of the
requirements of section 910(b)(1)(A) of the FD&C Act because it
provides an assessment of use-related health hazards for the tobacco
product.
    In situations where it is critical for the end user to have
instructions on how to properly use the product, it is important for
applicants to demonstrate that the instructions for use are adequate.
FDA recommends that human factors studies focus on the particular
aspects of labeling that provide instructions for use. For example, it
may be appropriate for a human factors study to evaluate the tobacco
product user's:
     Ability to select the appropriate task from a set of
instructions that include different options;
     Understanding of how to identify a defective or expired
product;
     Awareness and understanding of the safety information
provided in the instructions for use;
     Recognition of any potential harms or dangers that would
signify the need to seek medical attention, such as shortness of
breath, allergic reaction, weakness, increased heart rate; and
     Understanding of diagrams, if provided as part of the
product labeling (which may overlap with investigations regarding
consumer perception and understanding).
    Analyzing use-related risks is a critical step in identifying use
related hazards associated with the product and in characterizing high-
risk hazards so that they can be mitigated or eliminated. FDA
recommends that a PMTA contain a use-related risk analysis to help
identify critical tasks that should be evaluated in human factors
studies and inform the priority of testing the tasks in a human factors
study, and determine if there are specific use scenarios to include in
testing. If an applicant conducts human factors testing to determine
use related risks, FDA recommends that the test considers potential
users of the product, use environments, similar products used within
the environments, and any associated medical factors or health
conditions that may affect whether users may experience serious or
unexpected adverse experiences. An applicant may also want to include
information on known use related problems with similar products or
previous versions of the product.
    As part of the risk analysis, FDA recommends that an application
first identify all users and use environments for the product, as well
unintended users who are likely to use the product and unintended
environments in which the product is likely to be used. For example,
intended users may be characterized within the application according to
their respective experience levels, skills, age ranges, and use
responsibilities. Use environments are an important factor to consider
because they can have diverse characteristics that affect the users'
interactions with the product. In some cases, use of the product may
actually be prohibited (e.g., laws prohibiting use of a product in the
workplace, public spaces, airplanes).
    FDA recommends that human factors investigations be conducted in
the form of actual use studies. Because it may be difficult in some
cases to simulate the conditions of use, physical characteristics of
the product, or environment of use, actual use studies allow for better
assessment of how users interface with the product. If errors or
failures or new findings are identified in the human factors validation
study, then these problems should be evaluated to determine the root
cause(s), potential for harm, and additional measures to eliminate or
mitigate risk.
    b. Literature search. Proposed Sec.  1114.7(k)(2) would require an
applicant to conduct a literature search for each type of information
described in proposed Sec.  1114.7(k)(1) and require the application to
contain a description of the literature search performed, including the
databases searched and the date searched, search terms, reasons for
inclusion or exclusion of documents, and the strategy for study quality
assessment. The PMTA would also be required to contain a bibliography
of all published studies and articles referenced in the application. If
a literature search was performed and resulted in no information found,
the application would also be required to contain a statement to that
effect. FDA is proposing to require that an application contain the
bibliography and literature search information because section
910(b)(1)(A) of the FD&C Act requires (in part) that a PMTA contain
full reports of all published health risk investigations. FDA is also
proposing to include these requirements in the rule under authority of
sections

701(a) and 910(b)(1)(G) of the FD&C Act because it would help FDA to
determine whether the application contains reports of all published
investigations in an efficient manner by helping FDA determine whether
the application contains all relevant published studies, rather than
having to follow up with the applicant about the inclusion or exclusion
of specific studies. FDA must determine whether the application
contains all published investigations because FDA needs to ensure it
has all relevant health risk data to determine whether permitting the
marketing of the product would be APPH. The description of the reasons
for inclusion or exclusion of documents, in particular, will facilitate
FDA's review of an application because it will explain, if applicable,
why some investigations that initially appear relevant were excluded
from the application and also why some investigations that do not
initially appear to be relevant were included in the application. For
ease of review, FDA recommends that an applicant include internal
hyperlinks to, or otherwise reference, the location of published
studies that are included in an application. If applicable, it is also
recommended that an application explain why an investigation that was
conducted using a product other than the one that is the subject of the
PMTA is relevant to the application to inform FDA's review of the PMTA.
    c. Study reports. Proposed Sec.  1114.7(k)(3) would set
requirements for the full report of each investigation that must be
included as part of an application. An application would be required to
contain each type of documentation listed in proposed Sec.
1114.7(k)(3) to the extent that it is applicable to the type of
investigation and to the extent that it is reasonably available to the
applicant. FDA considers a document to be reasonably available unless
it does not exist or obtaining the document is unduly burdensome due to
the effort or expense involved. Where an applicant considers a document
that would be required by this section to not be reasonably available,
the application would be required contain an explanation in the full
report that describes the actions taken to obtain the document and
specifies why the document is not reasonably available. It is important
to note that failure to submit documents may affect the extent to which
FDA is able to rely upon an investigation's findings during substantive
application review. A full report of the investigation would be
required to contain:
    i. Full copies of any published articles and other reference
materials. FDA is proposing to require that an application contain full
copies of published articles and other reference materials to
facilitate the review process. FDA is proposing this requirement to
enable it to review an application more quickly.
    ii. Documentation of all actions taken to ensure the reliability of
the study. The requirements for this item would differ based upon
whether the investigation is a clinical investigation or a nonclinical
laboratory investigation. For nonclinical laboratory investigations, an
application would be required to include documentation demonstrating
all actions taken to ensure the reliability of the study, including
whether the investigation was conducted using good laboratory practices
(GLPs), such as those specified in part 58 (21 CFR part 58). FDA
considers GLPs to be those that support the quality, reliability, and
integrity of nonclinical laboratory investigations. FDA is proposing
this requirement to help enable it to determine whether the study's
findings are accurate and reliable. While this rule on its own would
not require compliance with the GLP regulations found in part 58,\13\
FDA would consider a nonclinical laboratory investigation that contains
the documentation required by part 58 to satisfy the requirements of
proposed Sec.  1114.7(k)(3)(ii).
---------------------------------------------------------------------------

    \13\ It is important to note that in the Federal Register of
August 24, 2016 (81 FR 58341), FDA issued a proposed rule that, when
finalized, would require laboratory investigations regarding tobacco
products to comply with the requirements of part 58.
---------------------------------------------------------------------------

    FDA recommends that an application contain a final report of each
nonclinical laboratory investigation that contains the following items,
at minimum, to show that the study was accurate and reliable:
     Name and address of the facility performing the study and
the dates on which the study was initiated and completed;
     Objectives and procedures stated in the approved protocol,
including any changes in the original protocol;
     Statistical methods employed for analyzing the data;
     The test and control articles identified by name, chemical
abstracts number or code number, strength, purity, and composition or
other appropriate characteristics;
     Stability of the test and control articles under the
conditions of administration;
     A description of the methods used;
     A description of the test system used. Where applicable,
the final report should include the number of animals used, sex, body
weight range, source of supply, species, strain and substrain, age, and
procedure used for identification;
     A description of the dosage, dosage regimen, route of
administration, and duration;
     A description of all circumstances that may have affected
the quality or integrity of the data;
     The name of the study director, the names of other
scientists or professionals, and the names of all supervisory
personnel, involved in the study;
     A description of the transformations, calculations, or
operations performed on the data, a summary and analysis of the data,
and a statement of the conclusions drawn from the analysis;
     The signed and dated reports of each of the individual
scientists or other professionals involved in the study;
     The locations where all specimens, raw data, and the final
report are stored;
     The statement prepared and signed by the quality assurance
unit, if any, a description of the quality control review performed and
its results;
     The study director's signature and date upon completion of
the final report; and
     Any corrections or additions to a final report, clearly
identifying the part of the final report that is being added to or
corrected and the reasons for the correction or addition, and bearing
the dated signature of the person responsible.
    The proposed rule would require full reports of investigations
(both clinical and nonclinical) to contain, to the extent reasonably
available, a certification that the investigators do not have, or
documentation fully disclosing, any potential financial conflicts of
interest, such as the financial arrangements specified in the financial
disclosure by clinical investigators regulation in part 54 (21 CFR part
54). While FDA does not currently require compliance with part 54 for
tobacco product investigations, complying with those requirements for
both clinical and nonclinical investigators would satisfy the financial
disclosure requirements of the proposed rule. Financial conflicts
information is important for FDA to consider because it addresses a
potential source of bias in investigations. Applicants would be able to
use these disclosures as well as appropriate procedures in the design
and conduct of the study to demonstrate that a potential bias that may
affect the results of the investigation has been minimized. FDA would
use the information contained in

these disclosures, in conjunction with information about the design and
purpose of the study, as well as on-site inspections (if necessary) in
its assessment of the reliability of the data.
    The investigator financial arrangements that the applicant should
disclose and describe, include:
     Any financial arrangement entered into between the sponsor
of the study and the investigator involved in the conduct of a clinical
trial, whereby the value of the compensation to the investigator for
conducting the study could be influenced by the outcome of the study;
     Any significant payments of other sorts from the sponsor
of the study, such as a grant to fund ongoing research, compensation in
the form of equipment, retainer for ongoing consultation, or honoraria;
     Any proprietary interest in the tested product held by any
investigator involved in a study;
     Any significant equity interest in the sponsor of the
study held by any investigator involved in any clinical study; and
     Any steps taken to minimize the potential for bias
resulting from any of the disclosed arrangements, interests, or
payments.
    iii. A copy of all protocols and amendments that were used in the
study;
    iv. Copies of all investigator instructions, if any were produced
in addition to the protocol;
    v. The statistical analysis plan. The statistical analysis plan,
including a detailed description of the statistical analyses used
(including all variables, confounders, and subgroup analyses), the
scientific rationale for the choice of sample sizes, and any amendments
to the plan;
    FDA is proposing to require the protocol, investigator
instructions, and statistical analysis plan as part of the full report
of a study because they would enable FDA to understand a study's
design, conduct, and analysis in its entirety and to evaluate the
validity of a study.
    vi. Line data. To facilitate FDA's review, the application should
contain line data in SAS-transport file in XPT format, created by a
procedure that allows the files to be readily read by the JMP software.
FDA also recommends that an application contain data definition files
that include the names of the variables, codes, and formats used in
each dataset, and copies of SAS programs and necessary macro programs
used to create derived datasets and the results reported in the study
reports. Such data are important for FDA to replicate applicant
findings or conduct alternative statistical analyses. FDA intends to
provide technical specifications on its website for submitting
information, such as line data, in an electronic format that FDA can
review, process, and archive (e.g., method of transmission, media, file
formats, preparation, organization of files, accompanying metadata)
(https://www.fda.gov/tobacco-products);
    vii. Sites and clinical investigators. A list of sites and clinical
investigators that conducted the study, including contact information
and physical address(es);
    viii. The location of all source data. If the site that conducted
the study has not maintained all of the source data, indicate where the
data are located;
    ix. Format. The format of the records and data (e.g., electronic or
hard copy);
    x. Early termination sites. A list of all sites that had early
termination and the reason for early termination, along with any audit
certificates and inspection results, if applicable;
    xi. Contractors. A list of contractors who participated in the
study, the role of each contractor, and the initiation and termination
dates of the participation of each contractor;
    xii. Signed report. A signed full report of all findings; and
    xiii. Study materials and case report forms. For human subject
studies, all versions of study materials and case report forms used,
and all individual case report forms associated with participant
deaths, other serious and unexpected adverse experiences, withdrawals,
and discontinuations from the study. The proposed rule would require
the application to contain one blank copy of each version of the study
materials (including, but not limited to, consent forms,
questionnaires, and stimuli) and case report form, and only those
completed individual case report forms regarding deaths, serious and
unexpected adverse experiences, withdrawals, and discontinuations for
individuals that were exposed to the tobacco product, or for
individuals who were exposed to a similar or related product that the
applicant is using to help demonstrate the health effects of its
product. An example of where such case report forms from a study
regarding a similar product would be required is where a clinical
biomarker study on a product that is similar to the proposed product in
terms of design, ingredients, and HPHCs is used to provide information
about the anticipated health risks of the proposed product. As
described in proposed Sec.  1114.45, applicants would be required to
keep each questionnaire and case report form from the study as part of
its own internal records, which FDA may inspect, as described in
proposed Sec.  1114.27, or request that the applicant submit to
facilitate its review of an application. If an applicant fails to keep
such records, FDA may be unable to rely upon an investigation's
findings during substantive application review.
    Additionally, while clinical investigations for tobacco products
are not required to be conducted in accordance with the requirements
for the protocol and procedures implemented to protect human subjects
in the Institutional Review Boards regulation in part 56 (21 CFR part
56) and the Protection of Human Subjects regulation in part 50 (21 CFR
part 50), FDA plans to issue regulations requiring compliance with
those parts for tobacco products. Until FDA takes such action, FDA
strongly encourages applicants to follow the requirements of parts 50
and 56 or take sufficient actions to ensure that the investigation is
conducted in a manner that comports with the ethical and moral
considerations involved with conducting studies using human subjects.
Each clinical investigation included in the PMTA should have been
reviewed and approved by an Institutional Review Board (IRB) operating
to safeguard the rights, safety, and well-being of all trial subjects,
with special attention being paid to vulnerable subjects. FDA
recommends applicants retain documentation concerning efforts related
to the protection of human subjects, including documents related to the
IRB, such as:
     Copies of all research proposals reviewed, scientific
evaluations, if any, that accompany the proposals, approved sample
consent documents, progress reports submitted by investigators, and
reports of injuries to subjects;
     Minutes of IRB meetings in sufficient detail to show
attendance at the meetings; actions taken by the IRB; the vote on these
actions including the number of members voting for, against, and
abstaining; the basis for requiring changes in or disapproving
research; and a written summary of the discussion of controverted
issues and their resolution;
     Records of continuing review activities;
     Copies of all correspondence between the IRB and the
investigators;
     A list of IRB members identified by name; earned degrees;
representative capacity; indications of experience such as board
certifications, licenses, etc., sufficient to describe each member's
chief anticipated contributions to IRB deliberations; and any
employment or other relationship between each

member and the institution (e.g., full-time employee, part-time
employee, a member of governing panel or board, stockholder, paid or
unpaid consultant);
     Written procedures for the IRB; and
     Statements of significant new findings provided to
subjects, such as those discussed in Sec.  50.25.
    FDA also recommends, but does not currently require, maintaining
documentation of the protocol and procedures implemented to protect
human subjects, such as those set forth in the protection of human
subjects regulation in part 50. Each clinical investigation included in
the PMTA should have been conducted using only human subjects who gave
their informed consent to participate in the study. As described in
Sec.  50.20, informed consent is consent that is obtained from the
subject or the subject's authorized representative under circumstances
that provide the prospective subject or representative with sufficient
opportunity to consider whether to participate and that minimize the
possibility of coercion or undue influence. The information that is
given to the subject or the subject's representative should be in
language understandable to the subject or the representative. The
informed consent should not include any exculpatory language through
which the subject or representative is made to waive or appear to waive
any of the subject's legal rights, or releases or appears to release
the investigator, the sponsor, the institution, or its agents from
liability for negligence.
    xiv. Perception and use intention studies. For perception and use
intention studies that use a label, labeling, or advertising as
stimuli, the proposed rule would require the full report of the study
to contain a statement regarding whether the label, labeling, or
advertising used is representative of advertising that the applicant
intends to use in marketing the product. If the advertising used as
stimuli is not representative of the advertising an applicant intends
to use in marketing the product, the applicant would be required to
indicate whether and how the study findings are still relevant to the
likely impact of product advertising on consumer tobacco product
perceptions and use intentions. For more information about tobacco
product perception and use intention studies, please see the
description of proposed Sec.  1114.7(k)(1)(iv) in section
VII.B.13.a.iv.
    d. The effect on the population as a whole. The proposed rule would
require a PMTA to contain an in-depth analysis and discussion of how
the data and information contained in the application establish that
the proposed product is appropriate for the protection of public
health. This discussion must include the effect that the new tobacco
product may have on the health of the population as a whole by
integrating all of the information (both qualitative and quantitative
as available) regarding the product, its potential effects on health,
as well as tobacco use behavior, including likelihood of cessation and
initiation, to provide an overall assessment of the potential effect
that the marketing of the tobacco product may have on overall tobacco-
related morbidity and mortality. Relevant outcomes measures could
include reductions in serious medical conditions and premature
mortality and gains in life-years lived in the population. FDA is
proposing this requirement because it directly informs FDA's
determination under section 910(c)(2)(A) of the FD&C Act of whether
permitting the marketing of the new tobacco product would be APPH.
    e. Certification statements. Proposed Sec.  1114.7(m) would require
that the application contain a specific statement certifying that the
applicant would maintain all records to substantiate the accuracy of
the application consistent with the record retention requirements in
proposed Sec.  1114.45, that the information and accompanying
submission are true and correct, that no material fact has been
omitted, that the signer is authorized to submit the information on the
applicant's behalf, and that the signer understands that anyone who
knowingly and willfully makes a materially false, fictitious, or
fraudulent statement to the Government of the United States is subject
to criminal penalties under 18 U.S.C. 1001. This certification would
help ensure that the applicant understands the responsibilities related
to the application (including the potential consequences of submitting
false information to the U.S. Government), the applicant intends to
submit the PMTA, and the PMTA is ready for review.

C. Amendments (Proposed Sec.  1114.9)

    FDA generally expects that when an applicant submits a PMTA, the
submission will include all information required by section 910(b)(1)
of the FD&C Act and proposed part 1114 to enable FDA to determine
whether it should authorize the marketing of a new tobacco product.
However, FDA recognizes that additional information may be needed to
complete the review of a PMTA and, therefore, is proposing Sec.  1114.9
to allow the submission of amendments to a pending application.
    Proposed Sec.  1114.9 provides that FDA may request, and an
applicant may submit, an amendment to a pending PMTA together with the
appropriate form (Ref. 11). Because FDA tracks PMTAs using the STN, an
amendment must specify the STN that is assigned to the PMTA. An
amendment would also be required to include the certification statement
set forth in Sec.  1114.7(m), with the appropriate information
inserted, and signed by an authorized representative of the applicant.
FDA may, at any time after it receives and before it acts on an
application, request that an applicant submit additional information
that is necessary to complete the review of a PMTA. Similarly, an
applicant may submit an amendment on its own initiative that is
necessary for FDA to complete its review of the pending PMTA. These
amendments may include information such as newly completed or published
studies that are relevant to the PMTA, clarifications, or a transfer in
ownership of the PMTA as described in proposed Sec.  1114.13.
    Proposed Sec.  1114.9(b) describes how the submission of an
amendment may affect the time required for the review (as described in
proposed Sec.  1114.27(c)(1)) of the application. FDA intends to notify
applicants regarding changes to the review period, including pausing,
resuming, and resetting the review period for amendments as described
in this section. If the applicant submits a major amendment to an
application, either at FDA's request or on its own initiative, FDA may
restart the 180-day review period. FDA considers major amendments to be
those that will require substantial FDA review time. Examples of major
amendments include substantial new data from a previously unreported
study, detailed new analyses of previously submitted data or
substantial new manufacturing information. When an applicant submits a
major amendment, FDA would consider the applicant to have submitted a
new PMTA with the review period beginning on the date which FDA
receives the amendment. Because section 910(c)(1) of the FD&C Act
requires FDA to complete its review of an application meeting the
requirements of section 910(b)(1) within 180 days of its receipt, under
proposed Sec.  1114.9(b)(1) a new 180-day review period would begin on
the date FDA receives a major amendment.
    Proposed Sec.  1114.9(b)(2) describes the effect that minor
amendments would have on the 180-day review period. FDA

considers minor amendments to be any amendments that are not major
amendments. Minor amendments can be clarifications or other information
that FDA needs to complete its review of a PMTA, but will not require
substantial review time. If FDA determines that a minor amendment is
necessary to complete its review of a pending submission and requests
that the applicant submit the amendment, FDA may pause the review
period on the date that it issues the amendment request to the
applicant. FDA will resume the review period on the date that it
receives a written response from the applicant either submitting the
requested information or declining to submit the amendment. For
example, if FDA requests a minor amendment on day 80 of its review, the
date FDA receives the amendment would be day 81, even though weeks or
months may have passed from the date of request to receipt. An
applicant may notify FDA that it is declining to submit an amendment;
however, if an applicant declines to submit an amendment to FDA, and
FDA is not be able to determine whether the PMTA meets the requirements
to receive a marketing order without the amendment, it would issue a no
marketing order.
    If FDA requests an amendment, either major or minor, and the
applicant neither submits the amendment nor notifies FDA that it is
declining to submit the amendment within 180 days of FDA's request, FDA
may, as described in proposed Sec.  1114.9(c), consider the applicant
to have submitted a request to voluntarily withdraw its PMTA and issue
an acknowledgement letter stating that the application has been
withdrawn under Sec.  1114.11. FDA will consider requests for more time
to submit an amendment and may grant reasonable requests. FDA is
proposing Sec.  1114.9(c) under authority of section 701(a) of the FD&C
Act to efficiently enforce section 910 of the FD&C Act because it would
allow FDA to dedicate its resources to reviewing PMTAs that are more
likely to receive a marketing order, rather than continuing to review a
PMTA submitted by a nonresponsive applicant that is unlikely to provide
FDA with the information it needs to complete its review.
    If an application has been closed under Sec.  1114.29 or withdrawn
under Sec.  1114.11, proposed Sec.  1114.9(d) would prevent the
applicant from amending the application. If an applicant wishes to make
changes to an application after it is closed or withdrawn, it would
have to do so through submission of a new application.

D. Withdrawal by Applicant (Proposed Sec.  1114.11)

    Proposed Sec.  1114.11 discusses the ability of an applicant to
withdraw a pending PMTA. At any time prior to FDA acting on the
application (i.e., taking one of the actions described in proposed
Sec.  1114.29), the applicant may request to withdraw its application
by using the appropriate form (Ref. 11) to specify the name of the new
tobacco product, the STN of the application, and stating whether the
withdrawal request is related to a health concern. If the request is
related to a health concern, the applicant must describe the
concern(s), including the extent, duration, and frequency of the health
effects, and identify what gave rise to the concerns, such as adverse
experience reports. FDA would require information about health concerns
under authority of section 909 of the FD&C Act because the information
would help FDA protect the public health (e.g., identifying a problem
that could be present in similar currently marketed products) and
section 701(a) of the FD&C Act because it would allow FDA to
efficiently enforce provisions of the FD&C Act (e.g., more quickly
ensure an identified health concern was addressed if an application for
the same product is submitted again). Once FDA receives and processes
the withdrawal request, it would issue an acknowledgment letter to the
applicant, at which time the application would be considered withdrawn.
Withdrawing an application would not prejudice a future submission.
    The application is an Agency record even if withdrawn. Thus, under
proposed Sec.  1114.11(c), FDA would retain the withdrawn application
consistent with Agency record retention schedules and policies and,
under the Agency's public information regulations in 21 CFR part 20
(part 20), would provide a copy to the applicant upon request subject
to Sec.  20.45.

E. Change in Ownership of an Application (Proposed Sec.  1114.13)

    Proposed Sec.  1114.13 describes the steps that an applicant would
be required to take when it transfers ownership of a PMTA. This
proposed section is intended to facilitate transfers of ownership and
help ensure that FDA has current information regarding the ownership of
a PMTA. An applicant may transfer ownership of its PMTA at any time,
including when FDA has yet to act on it. Under proposed Sec.  1114.13,
at the time of the transfer, the new and former applicants (or owners)
of the PMTA would be required to use the appropriate form (Ref. 11) and
submit certain information to the Agency. First, the former applicant
would be required to submit a notice to FDA identifying the new
applicant and stating that all rights to the PMTA have been transferred
to the new applicant. Second, the new applicant would be required to
submit a signed notice to FDA containing the following information:
     To the extent applicable, the new applicant's commitment
to agreements, promises, and conditions made by the former applicant
and contained in the PMTA (e.g., certifications, proposed restrictions
on the sales and distribution of the tobacco product);
     The date that the change in ownership is effective;
     Either a statement that the new applicant has a complete
copy of the PMTA (including any amendments, or any records required to
be kept under proposed Sec.  1114.45); or a statement of intent to
request a copy of the PMTA filed with FDA under the Freedom of
Information Act (FOIA) (FDA's implementing regulations are in part 20);
and
     A certification that no modifications have been made to
the new tobacco product since the PMTA was submitted to FDA.
    Although FDA expects that the new applicant would have a copy of
the PMTA from the former applicant, if the new applicant requests a
copy of the PMTA filed with FDA, FDA would provide a copy to the new
applicant, subject to the FOIA requirements as implemented by FDA at
part 20 and under the fee schedule in Sec.  20.45.
    The new applicant also would be required to make available all
required records upon inspection by FDA (proposed Sec.  1114.45 would
impose a recordkeeping requirement).

F. Supplemental Application Submission (Proposed Sec.  1114.15)

    Proposed Sec.  1114.15 discusses the availability of supplemental
PMTAs. Supplemental PMTAs are an alternative format of submitting a
PMTA that meets the requirements of proposed Sec.  1114.7 that would
reduce the burden associated with the submission and review of an
application. Specifically, supplemental PMTAs are a standardized cross-
referencing format that FDA would implement under its authority of
section 701(a) of the FD&C Act to efficiently enforce section 910 of
the FD&C Act for submissions that are based on a PMTA that FDA has
previously reviewed. Applicants that have received a marketing order
would be able to submit a supplemental PMTA to seek marketing

authorization for a new tobacco product that results from a
modification or modifications to the original tobacco product that
received the marketing order. The applicant would be able to submit a
supplemental PMTA only for a modification or modifications that require
the submission of limited information or revisions to the PMTA to make
it apply to the modified tobacco product. FDA is proposing to restrict
the use of supplemental PMTAs to only changes that require the
submission of limited information or revisions to ensure that FDA is
able to efficiently review the application. An applicant would also be
able to submit a supplemental PMTA for modifications made to comply
with a product standard issued under section 907 of the FD&C Act where
FDA specifies that the submission of supplemental PMTAs would be
appropriate.
    As discussed in proposed Sec.  1114.15(a), an applicant would not
be able to submit a supplemental PMTA where the modifications to the
original tobacco product require the submission of new information or
revisions to the extent that review of the PMTA for the new tobacco
product in the supplemental PMTA format would be confusing, cumbersome,
or otherwise inefficient and submitting a standard PMTA under Sec.
1114.7(b) would better facilitate review. Because supplemental PMTAs
are based on a cross-referencing system that is supposed to reduce the
burden of preparing and reviewing a PMTA, FDA is proposing this
limitation to ensure PMTAs are submitted in the format that is the
easiest to review, process, and archive. Changes that require multiple,
sweeping, or difficult-to-trace changes to the PMTA for the original
tobacco product would be more efficient to review in the full text
format of Sec.  1114.7.
    Applicants that have questions about whether it would be
appropriate to submit a supplemental PMTA for the modifications they
are seeking to implement should contact FDA for more information. To
further illustrate when a supplemental PMTA could be submitted, FDA has
prepared the following examples of modifications to ENDS products that
are likely appropriate to be submitted using the supplemental PMTA
format and likely not appropriate to be submitted using the
supplemental PMTA format.

------------------------------------------------------------------------
          Potentially Appropriate for Supplemental PMTA Format
-------------------------------------------------------------------------
 Changes in connection type/thread size (e.g., 510).
 Minor Software Changes not affecting device functionality.
    [cir] Changes to user interface.
    [cir] Changes in recording/data capture properties.
 Minor changes in e-liquid volume, viscosity or boiling
 temperature.
 Minor changes in draw resistance.
 Minor changes in air flow rate.
 Changes to coil configuration if number of coils, coil gauge,
 material, and overall coil resistance remain unchanged.
 Changes to amount of wicking material.
 Minor changes in wick ignition temperature.
------------------------------------------------------------------------
           Likely Not Appropriate for Supplemental PMTA Format
------------------------------------------------------------------------
 Any modification that might increase risk of harm to individual
 health from the product.
 Modifications that may alter tobacco product use behavior and
 initiation, such as modifications that have strong youth appeal.
 Design modifications that change the category or subcategory of
 the product (e.g., modifying a closed e-cigarette to be an open e-
 cigarette).
------------------------------------------------------------------------

    Additionally, FDA is proposing two other limitations on the
submission of a supplemental PMTA. Under proposed Sec.  1114.15(a), a
supplemental PMTA could not be submitted where the marketing order for
the original tobacco product has been withdrawn or has been temporarily
suspended or is the subject of temporary suspension or withdrawal
proceedings by FDA, except where authorized by FDA in writing following
a presubmission meeting. FDA is proposing to restrict the submission of
supplemental PMTAs in this situation because it can signal that the
PMTA for the original tobacco product contains information that is not
sufficient or reliable such that a marketing order could be issued. If
the reason for the temporary suspension or withdrawal is unrelated to
the sufficiency or reliability of information contained in a PMTA, an
applicant may request, and FDA may grant, authorization to use a
supplemental PMTA under these circumstances.
1. Required Format
    Under proposed Sec.  1114.15(b) the supplemental PMTA format would
be the same as the format for standard PMTAs submitted under Sec.
1114.7(b), except that applicants would be required to include content
in a supplemental PMTA by cross-referencing content in the PMTA and
postmarket reports for the original tobacco product. FDA believes that
including content in an application by cross-referencing to a PMTA for
the original tobacco product is appropriate for supplemental
applications because the referenced information will be presented in
the proper context and format, and will facilitate application review.
2. Required Content
    The required content for a supplemental PMTA is divided into two
general categories: New content sections and content sections cross-
referenced from the PMTA for the original tobacco product. A
supplemental PMTA must contain the full text or a cross-reference to
text in a master file for the following new content sections under
proposed Sec.  1114.15(c)(1):
     General information (as described in Sec.  1114.7(c));
     New product information (as described in Sec.
1114.15(c));
     Statement of compliance with 21 CFR part 25 (as described
in Sec.  1114.7(g));
     Labeling (as described in Sec.  1114.7(f)) if the labeling
is not identical to the labeling submitted in the PMTA or postmarket
reports for the original tobacco product;
     Postmarket information (as described in Sec.  1114.15(d));
and
     Certification statement (as described in Sec.
1114.15(e)).
    A supplemental PMTA must also contain application sections that
comprise information included by cross-reference to the PMTA for the
original tobacco product. It is important to note that these cross-
referenced sections must be accompanied by the full text of any updates
or supplemental information that are necessary to tailor this
information to the new tobacco product. These updates or supplemental

information should consist of changes to application content that is
not otherwise included as part of the new product information section.
For example, if a new health risk investigation on the product is
published and it is not contained in the new product information
section, a full report (as described in Sec.  1114.7(k)(3)) of the
investigation must be included in full text together with a cross-
reference to the health risk investigations section in the PMTA for the
original tobacco product. The cross-reference-based sections that must
be included under proposed Sec.  1114.15(c)(2) are:
     Descriptive information (as described in Sec.  1114.7(d));
     Product samples (as described in Sec.  1114.7(e)). Please
note, however, that FDA may, request the submission of product samples
after receipt of a supplemental PMTA;
     Labeling (as described in Sec.  1114.7(f)) if the labeling
is identical to the labeling submitted in the PMTA or postmarket
reports for the original tobacco product;
     Summary of all research findings (as described in Sec.
1114.7(h));
     Product formulation (as described in Sec.  1114.7(i));
     Manufacturing (as described in Sec.  1114.7(j)); and
     Health risk investigations (as described in Sec.
1114.7(k)).
3. New Product Information
    Under proposed Sec.  1114.15(d), the application must contain the
following information concerning modifications to the original tobacco
product, including:
     Full descriptions of the modification(s) to the original
tobacco product and comparisons of such modification(s) to the
unmodified version(s) described in the PMTA for the original tobacco
product.
     A statement as to whether the new tobacco product is
intended to replace the original tobacco product if the new product
receives a marketing order, is intended to be a line extension of the
original tobacco product, or is intended to be introduced as an
additional product by the same manufacturer.
     All data and information relating to the modification(s)
that would be required in an application under Sec.  1114.7. This is
data and information that can span across a number of application
sections. A change in the connection type or thread size for an ENDS
product, for example, may require a change in the design parameters and
the manufacturing sections.
     A concluding summary of how the new tobacco product meets
the requirements to receive a marketing order. This summary must
describe how the data and information concerning the product
modification when viewed together with the information cross-referenced
from the previously submitted PMTA demonstrate that the new tobacco
product meets the requirements of section 910(c) of the FD&C Act to
receive a marketing order.
4. Postmarket Information
    Under proposed Sec.  1114.15(e), a supplemental PMTA would be
required to contain postmarket information. Where an applicant has
submitted postmarket reports for the original tobacco product, it must
incorporate those reports by cross-reference. Where an applicant has
yet to submit a postmarket report for the original tobacco product, it
must submit a report as part of the supplemental application that
contains all the information that would otherwise be required in a
report under proposed Sec.  1114.41, covering the period in time from
when it received its marketing order for the original tobacco product
to when it submitted the supplemental PMTA. Because information that is
contained in a postmarket report is likely to be required content of a
standard PMTA for the modified tobacco product, FDA is allowing
applicants to cross-reference this content to avoid the burden of
resubmitting information that FDA has previously reviewed.
5. Certification Statement
    Proposed Sec.  1114.15(f) would require the application to contain
a specific certification statement signed by an authorized
representative that, in addition to the certification required under
Sec.  1114.7(m) for a standard PMTA, certifies that the modifications
identified in the certification are the only modification(s) to the
original tobacco product.

G. Resubmissions (Proposed Sec.  1114.17)

    Proposed Sec.  1114.17 describes resubmissions, which are an
alternative format for submitting an application that meets the
requirements of Sec.  1114.7(b) or Sec.  1114.15 to seek a marketing
order for a tobacco product by responding to the deficiencies outlined
in a no marketing order. An applicant may submit a resubmission for the
same tobacco product that received a no marketing order or for a
different new tobacco product that results from changes necessary to
address the deficiencies outlined in a no marketing order. This
application format allows an applicant to address the deficiencies
described in a no marketing order without having to undertake the
effort of submitting a standard PMTA. The resubmission format is
available to resubmit an application that received a no marketing order
because FDA has completed its review of such PMTAs and can rely on the
findings of these reviews to save time when reviewing a resubmission.
The resubmission format is not available for PMTAs that FDA refused to
accept, refused to file, cancelled, or administratively closed, or that
the applicant withdrew, because FDA has not previously completed
reviews of such applications upon which it can rely, and such
applications may need significant changes to be successfully
resubmitted. It is important to note that, as discussed in section
VIII.E regarding proposed Sec.  1114.33, while FDA will identify the
deficiencies that resulted in the no marketing order, the deficiencies
specified in the order might not be an exhaustive listing of all
deficiencies contained in the PMTA.
    Similar to a supplemental PMTA, an applicant would not be able to
submit a resubmission to the extent that review would be confusing,
cumbersome, or otherwise inefficient and submitting a standard PMTA
under Sec.  1114.7 would better facilitate review. Where responding to
the deficiencies outlined in the no marketing order would require broad
or sweeping changes to the original PMTA, an applicant would need to
submit a standard PMTA under Sec.  1114.7 to better facilitate review.
Where possible, FDA will specify in the no marketing order if an
applicant may not pursue a resubmission to address the identified
flaws.
1. Format
    Under proposed Sec.  1114.17(b) the resubmission format
requirements would be the same as the format in Sec.  1114.7(b) for
standard PMTAs, except that applicants would be required to include
content in a resubmission by cross-referencing content in the PMTA. FDA
believes that including content in a PMTA by cross-referencing to a
PMTA for the original tobacco product is appropriate for resubmissions
applications because the referenced information will be presented in
the proper context and format, and will facilitate application review.
2. Content
    The required content for resubmission is divided into two general
categories: new content sections and cross-referenced content sections.
The resubmission must contain the full text or cross-referenced text
from a master file of the following new content sections under proposed
Sec.  1114.17(c)(1):

     General information (as described in paragraph Sec.
1114.7(c));
     Response to deficiencies (as described in Sec.
1114.17(d)); and
     Certification statement (as described in Sec.
1114.17(e)).
    A resubmission must also contain application sections that comprise
information included by cross-reference to the PMTA for the original
tobacco product. It is important to note that these cross-referenced
sections must be accompanied by the full text of any updates or
additional information that are necessary to tailor this information to
the new tobacco product. These updates or additional information should
consist of changes to application content that is not otherwise
included as part of the response to deficiencies section. This
information could include, for example, full reports of health risk
investigations published after the applicant submitted the PMTA that
received the no marketing order. The cross-reference-based sections
that must be included under proposed Sec.  1114.17(c)(2) are:
     Descriptive information (as described in Sec.  1114.7(d));
     Product samples (as described in Sec.  1114.7(e)). Please
note that FDA may require the submission of product samples after it
has received your application;
     Labeling (as described in Sec.  1114.7(f)), together with
updates to the labeling made by the time of submission, if any;
     Statement of compliance with 21 CFR part 25 (as described
in Sec.  1114.7(g));
     Summary of all research findings (as described in Sec.
1114.7(h));
     Product formulation (as described in Sec.  1114.7(i));
     Manufacturing (as described in Sec.  1114.7(j)); and
     Health risk investigations (as described in Sec.
1114.7(k)).
3. Response to Deficiencies
    As described in proposed Sec.  1114.17(d), the application must
contain a section that lists and provides a separate response to each
deficiency described by FDA in the no marketing order, including all
data and information necessary to complete each response, as well as
any applicant-identified deficiencies. The deficiencies should be
addressed in the order in which they are listed in the no marketing
order, followed by applicant-identified deficiencies. Where an
applicant modifies the original tobacco product to address the
deficiencies outlined in the no marketing order, the applicant must
also include: (a) A full description of each modification to the
product and comparisons of that change to the original version
described in the PMTA for the original tobacco product; and (b) all
data and information relating to each modification to the product that
would be required in an application under Sec.  1114.7.
4. Certification Statement
    Proposed Sec.  1114.17(e) would require the applicant to include
one of two certification statements signed by an authorized
representative that, in addition to the certification required under
Sec.  1114.7(l) for standard PMTA, certifies either: (a) That the
application addresses all deficiencies specified in the no marketing
order and is being submitted for a tobacco product that is identical to
the product for which FDA issued a no marketing order or (b) the
application addresses all deficiencies and the tobacco product is
distinct from the original tobacco product, but the only modifications
to the original tobacco product are those identified in the
certification.
5. Resubmission Meeting
    Under proposed Sec.  1114.17(f), applicants may request a meeting
with FDA prior to submitting a resubmission to determine whether it may
utilize the resubmission format and to discuss any issues related to
the application, such as application organization and format. For
example, applicants that have questions about whether it would be
appropriate to pursue a resubmission for the modifications they are
seeking to implement to respond to deficiencies identified in a no
marketing order may contact FDA for more information.

VIII. FDA Review (Proposed Part 1114, Subpart C)

A. Communications Between FDA and Applicants (Proposed Sec.  1114.25)

    Proposed Sec.  1114.25 would set forth general principles for the
communications between FDA and applicants and is intended to provide
more information to applicants about FDA communications. Proposed Sec.
1114.25 explains that during the course of FDA's review of an
application, FDA may seek to communicate with applicants about relevant
matters including scientific, medical, and procedural issues that arise
during the review process. Communications regarding human risk issues
may arise if adverse experience reports exist for the tobacco product.
FDA may use a variety of methods to communicate with applicants such as
telephone conversations, letters, emails, or face-to-face meetings
depending on the circumstances and issues. FDA would document any
communications regarding a PMTA in accordance with 21 CFR 10.65. While
applicants may contact FDA with questions, as a general matter, FDA
does not provide applicants with predecisional details about an ongoing
application review, such as whether an initial submission is sufficient
to receive a marketing order or the date and time at which FDA will act
on an application.

B. Review Procedure (Proposed Sec.  1114.27)

    Proposed Sec.  1114.27 describes the procedures by which FDA would
review a PMTA. When an applicant submits a PMTA, FDA performs an
acceptance review of the submission. Currently, FDA performs it
acceptance review of all premarket submissions based upon the criteria
set forth in Sec.  1105.10. The proposed rule would incorporate and
build upon these general criteria to set PMTA-specific acceptance
criteria. Under the proposed rule, FDA may refuse to accept an
application for further review if, upon initial review, it:
     Does not comply with the applicable format requirements
for the type of PMTA (i.e., Sec.  1114.7(b) for a standard PMTA, Sec.
1114.15 for a supplemental PMTA Sec.  1114.17 for a resubmission);
     Is not administratively complete because it does not
appear to contain the information required by the applicable
application content requirements section. This means that the content
required for the type of PMTA must be readily and easily identifiable
as part of a cursory review of the application (i.e., a standard PMTA
must appear to contain information required by Sec.  1114.7, a
supplemental PMTA must appear to contain information required by Sec.
1114.15, and a resubmission must appear to contain information required
by Sec.  1114.17). The acceptance review would assess the facial
completeness of a submission only, and would not be an in-depth,
technical review. Examples of submissions that FDA would refuse to
accept under this rule include, but are not limited to, applications
that do not appear to contain:
    [cir] Labeling (as required by Sec.  1114.7(f));
    [cir] Design parameter information (as required by Sec.
1114.7(i)(2)(ii));
    [cir] An environmental assessment (as required by Sec.  1114.7(g));
or
    [cir] A literature search (as required by Sec.  1114.7(k)(2)).
     Does not pertain to a tobacco product that is subject to
chapter IX of

the FD&C Act, as required by Sec.  1105.10(a)(1). Under this provision
FDA would refuse to accept the PMTA if it does not pertain to a product
that is subject to the jurisdiction of CTP. CTP has premarket review
jurisdiction over products that meet the definition of ``tobacco
product'' in section 201(rr) of the FD&C Act and are subject to chapter
IX of the FD&C Act either in section 901(b) of the FD&C Act or by
regulation. This means that FDA will refuse to accept submissions for a
product that is a drug under the definition in section 201(g)(1), a
device under section 201(h), a combination product as described in
section 503(g) of the FD&C Act, or otherwise does not meet the
definition of a tobacco product.
     May otherwise be refused under Sec.  1105.10.
    Once FDA has completed its acceptance review under proposed Sec.
1114.29(a)(1), FDA will issue a letter to the applicant informing it of
FDA's decision. If FDA accepts the application for further review, it
will issue an acceptance letter to the applicant that specifies the STN
for the PMTA. If FDA refuses to accept the application, it will issue a
letter to the applicant that identifies the reasons, where practicable,
that prevented FDA from accepting the application. The applicant may,
after FDA has refused to accept a PMTA, correct the deficiencies and
submit a new PMTA under proposed Sec.  1114.7. Because FDA is not
issuing a no marketing order under Sec.  1114.33 when it refuses to
accept a submission, an applicant would not be able to utilize the
resubmission format described in proposed Sec.  1114.17 to address the
flaws outlined by FDA.
    FDA is proposing to implement the acceptance review procedures
under authority of sections 701(a) and 910 of the FD&C Act. The
content, format, and jurisdiction requirements that an application
would have to meet to be accepted for review will ensure that FDA will
be able to efficiently review applications and consider only
applications that meet quality and content standards. By refusing to
accept submissions that have clear deficiencies, FDA will be able to
focus its resources on those submissions that are more likely to be
filed for substantive review.
    After FDA accepts a PMTA for review, FDA may request product
samples as described in Sec.  1114.7(e) and will conduct a filing
review to determine whether the application contains sufficient
information to permit a full substantive review of the application. FDA
may refuse to file a PMTA if:
     The PMTA does not include sufficient information required
by section 910(b)(1) of the FD&C Act and by Sec. Sec.  1114.7, 1114.15,
or 1114.17, as applicable, to permit a substantive review of the
application. These requirements include a sufficient EA for each type
of PMTA, the absence of which is an existing reason for which FDA may
refuse to file an application under Sec.  25.15. The filing
requirements would also include product samples if required by FDA
after application acceptance. FDA's filing review is an examination of
the submission to ensure it contains adequate technical information for
FDA's substantive review of the application to proceed. Unlike the
acceptance review, which considers whether a submission meets quality
elements and appears to be facially complete, the filing review is a
more in-depth review to ensure the technical elements contain
sufficient information for initiating substantive review. For example,
during acceptance review, FDA would check whether the PMTA appears to
contain product design parameters, but during filing review, FDA would
review to determine whether it contains the correct design parameters
for the product category and has a value for each design parameter
required by Sec.  1114.7(i)(2)(ii). FDA is proposing to conduct the
filing review under authority of section 701 of the FD&C Act to improve
the efficiency of the PMTA review process. By determining whether a
PMTA contains sufficient technical information prior to conducting
substantive review, FDA can commit the considerable resources necessary
to conduct substantive review of a PMTA to only those submissions that
are prepared for review;
     The application does not contain substantive information
regarding certain specified broad categories of information that must
be addressed in every PMTA for FDA to determine whether permitting the
marketing of the new tobacco product would be APPH. FDA considers
substantive information to be information that is relevant to the
subject it claims to support and has evidentiary support. Bare
statements that the marketing of the tobacco product is unlikely to
result in tobacco product initiation or that it has no abuse liability
without supporting information would not constitute the types of
substantive information necessary for application filing. This
information can come from a variety of sources including investigations
conducted by the applicant, investigations conducted using a different
product that the applicant can bridge to its new tobacco product (as
described in section VII.B.13.a.), or published reports of
investigations that apply to, or are bridged to, the new tobacco
product (such as those found in the literature search that would be
required by proposed Sec.  1114.7(k)(2)). Proposed Sec.
1114.27(b)(1)(ii) would require a PMTA to contain substantive
information regarding certain categories of investigations described in
proposed Sec.  1114.7(k)(1). While FDA retains discretion to file
applications as set forth in proposed Sec.  1114.27(b)(1), we generally
intend to refuse to file each application that does not meet the
information threshold requirement in paragraph (ii). Where there is no
substantive information that is published or known to an applicant
regarding any of the categories of information outlined in this
section, including information in scientific literature or an
investigation that an applicant could bridge to its product, an
applicant would be required to conduct its own investigations and
include the resulting full report in its PMTA in order to meet the
requirements for filing. In general, FDA expects that manufacturers
seeking to market a new product in accordance with the requirements of
the statute will have access to information to meet these requirements
for filing.\14\
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    \14\ Information that is available to applicants includes, for
example, the studies FDA has funded, published, and made available
to the public, which are consolidated FDA's our website. This
database includes many ENDS related studies and can be searched by
key terms (e.g., e-cigarettes): https://www.fda.gov/tobacco-products/research/ctp-supported-tobacco-regulatory-research-projects.
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    FDA is proposing this application filing requirement under its
authority in sections 910(b)(1)(G) and 701(a) of the FD&C Act. As
described in section VIII.D., FDA needs information regarding the
potential health risks of the new tobacco product, the likelihood of
changes in tobacco product use behavior, and the potential health
consequences associated with those changes in behavior to determine the
potential risk and benefits to the population the health of the
population under section 910(c)(4) of the FD&C Act. Refusing to file
PMTAs that contain no information regarding these broad categories of
information would allow FDA to efficiently enforce the premarket review
requirements of section 910 of the FD&C Act by avoiding the significant
expenditure of resources it would otherwise commit to the substantive
review of applications that clearly lack sufficient information to
receive a marketing order. FDA expects that this efficiency would
significantly

benefit those applicants seeking timely consideration of complete,
high-quality applications.
    Proposed Sec.  1114.27(b)(1)(ii) would require PMTAs to contain
substantive information regarding:
     The health risks of the new tobacco product (as described
in Sec.  1114.7(k)(1)(i)(A)-(C)). Information regarding the health
risks of the new tobacco product is a basic piece of information that
FDA needs to determine the potential risks and benefits to the
population as a whole associated with changes in tobacco use behavior.
     The health risks of the new tobacco product compared to
the health risks that are generally presented by both tobacco products
in the same category and tobacco products in at least one different
category that are used by the consumers an applicant expects to use
their new tobacco product (as described in portions of Sec.
1114.7(k)(1)(i)(D)). This would require a comparison to the risks
generally presented by a product category as a whole. However, a
comparison to specific products that are generally representative of
the risks of the product category as a whole (e.g., products that
represent a significant share of the market for the product category)
would also be sufficient. Comparative health risk information is a
required part of FDA's review of an application because, as described
in section VII.B.13.a., it can demonstrate the potential risks and
benefits that current tobacco users could face if they switched to the
new tobacco product or use it in conjunction with their current tobacco
product.
     The abuse liability of the new tobacco product (as set
forth in Sec.  1114.7(k)(1)(ii)(A)). Information regarding abuse
liability indicates the likelihood of users to become addicted to the
product and face the health risks posed by product use over the long
term, and may provide insight into the use and adoption of the product,
which FDA must consider as part of its determination of the risks and
the benefits of the marketing of the new tobacco product to the
population as a whole under section 910(c)(4) of the FD&C Act.
     How consumers actually use the product, including use
topography, product use frequency, use trends over time, and how such
use affects the health risks of the product to individual users (as set
forth in Sec.  1114.7(k)(1)(ii)(B)). Information regarding how
consumers will actually use the new tobacco product is necessary to
FDA's review of a PMTA because it helps demonstrate the health risks of
the new tobacco product by showing the levels, and frequency, of
exposure to HPHCs and other toxic substances contained in and delivered
from the new tobacco product.
     The potential impact that the marketing of the new tobacco
product would have on the likelihood that current tobacco product users
would start using the new tobacco product, use the product in
conjunction with other tobacco products, and, after using the product,
switch to or switch back to other tobacco products that may present
increased risks to individual health (as described in Sec.
1114.7(k)(1)(ii)(C)-(F)). Information regarding potential changes to
tobacco product use of current tobacco product users is a required
basis for FDA's findings under 910(c)(4)(A).
     The potential impact that the marketing of the new tobacco
product would have on tobacco product initiation by current nonusers of
tobacco products (as described in Sec.  1114.7(k)(1)(iii)). Information
regarding potential impact that the marketing of the new tobacco
product would have on tobacco product initiation by current nonusers of
tobacco products is a required basis for FDA's findings under
910(c)(4)(B).
     The potential impact of the product and its label,
labeling, and advertising on individuals' perception of the product,
and individuals' use intentions (as described in Sec.
1114.7(k)(1)(iv)). This information is important to FDA's review of a
PMTA because perceptions of the health risk of the product can
influence decisions to use the product and, as described in section
VII.B.6., exposure to advertising can have a significant impact on the
likelihood that nonusers of tobacco products, particularly youth, will
initiate tobacco product use. Without information regarding perceptions
and use intentions, FDA will be unable to complete its required
determination under section 910(c)(4)(B) of the FD&C Act of the
increased or decreased likelihood that nonusers of tobacco products
will initiate tobacco product use.
    FDA invites comment on the information threshold requirements in
proposed Sec.  1114.27(b)(1)(ii), including comments on: Whether the
information would be best included in the final rule as a request or a
requirement; whether FDA should request or require additional
information as a threshold for filing and the basis for any such
additional provisions; and how these and other potential requests or
requirements related to the information threshold requirement for
filing relate to specific provisions of the FD&C Act, as well as other
applicable law(s).
     The PMTA contains a false statement of material fact; or
     The PMTA is a supplemental PMTA that does not comply with
Sec.  1114.15 or the PMTA is a resubmission that does not comply with
Sec.  1114.17. FDA may refuse to file a supplemental PMTA or a
resubmission that, although administratively complete, does not meet
the requirements for when a supplemental PMTA or a resubmission may be
submitted. For both supplemental PMTAs and resubmissions, this could
occur when, as discussed in Sec. Sec.  1114.15(a) and 1114.17(a), the
modifications to the original tobacco product are not appropriate to
review in these formats. As described in proposed Sec.  1114.15(a), FDA
may also refuse to file a supplemental PMTA where the marketing order
for the original tobacco product has been temporarily suspended (except
where authorized in writing by FDA) or has been withdrawn. As described
in proposed Sec.  1114.17(a), FDA would refuse to file a resubmission
where the no marketing order for the original tobacco product states
that the applicant may not use the resubmission format. If FDA refuses
to file an application, it will send a letter to the applicant
identifying, where practicable, the deficiencies that prevented FDA
from filing the application.
    After FDA files an application, it will begin its substantive
review of the PMTA. Within 180 days after receipt of an application
described in section 910(b)(1) of the FD&C Act, FDA intends to complete
its review of a PMTA and, as described in proposed Sec.  1114.29, act
on the application, except as described in proposed Sec. Sec.  1114.9
and 1114.27(c)(4) & (5). To determine when the 180-day period begins,
FDA generally relies on the date the last piece of information
necessary to complete the submission is received by CTP's Document
Control Center or the FDA laboratory (for product samples), not the
date that the applicant sent it. It is important to note the event that
starts the 180-day review clock is the receipt of an application that
meets the requirements of section 910(b)(1) of the FD&C Act which would
also include information required by the proposed rule including
product samples if required. Because the proposed rule would require
the submission of samples in accordance with FDA instructions that are
likely to be issued after a PMTA is accepted by FDA, the review clock
would begin, at the earliest, when FDA receives product samples if it
has required samples and those samples are the last piece needed

to complete an application. Similarly, if an application is missing
other pieces of required information, the review clock would begin only
upon receipt of that information. FDA intends to provide applicants
with notice of the date on which the 180-day review period begins, as
well as notice of when it is paused, resumed, or reset.
    FDA is proposing four instances in which the 180-day review period
after receipt of a complete PMTA would not run over a period of 180
consecutive calendar days. First, as described in Sec.  1114.9, the
submission of or request for amendments may result in changes to the
number of calendar days in the review period. Where FDA requests a
minor amendment, the issuance of this request would result in a pause
of the review period and receipt of the amendment would resume the
review period. As described in section VII.C., the submission of a
major amendment would be considered to be the submission of a new PMTA,
which would reset the 180-day review clock.
    The second instance in which FDA's 180-day review period would not
run over 180 consecutive calendar days after receipt of a complete PMTA
is where a new tobacco product, if introduced or delivered for
introduction into interstate commerce, would be adulterated or
misbranded due to the domestic manufacturer or importer being in
violation of the user fee requirements of part 1150 (21 CFR part
1150).\15\ Situations in which a new tobacco product would be
adulterated or misbranded for failure to comply with user fee
requirements are described in Sec.  1150.17(a) and (b), which include
failure to pay user fee assessments and failure to submit required
reports. In this situation, FDA intends to pause the 180-day review