the applicant must provide a justification and scientific evidence for
why those design parameters are not relevant and do not raise public
health concerns.
    (Comment 47) One comment stated that it would be arbitrary and
capricious to require manufacturers to submit the design parameters for
pipes because the terms used are ones that pipe manufacturers neither
know nor could they test for in pipes.
    (Response 47) FDA disagrees with the suggestion that requiring pipe
manufacturers to submit design parameters for their new tobacco
products in PMTAs would be arbitrary and capricious. FDA believes that
these design parameters are needed to fully characterize the product
and assess its impact on public health. Because these design parameters
are an important component of being able to determine a product's
health effects, FDA may refuse to accept or refuse to file a PMTA if it
lacks design parameters information required by Sec.  1114.7(i)(2)(ii).
For FDA to fully determine the precise product being reviewed and
understand the potential health effects associated with the product, we
are requiring that applicants provide all design parameters specific to
the new product tobacco category. The design parameters required for
pipes are measurable, and therefore test data should be easily
obtained. Even if the design parameter names were not familiar to
manufacturers, the manufacturers could supplement design parameter
information by providing labeled images of their product that associate
each component with the design parameter name used by the applicant or
as discussed above, provide the information needed is with an MDSS
document. FDA believes with the information provided in this rule,
manufacturers should now be familiar with the required design
parameters and can provide the necessary data. If FDA did not have the
design parameters for the product it was reviewing, it would be unable
to determine the precise product being reviewed, let alone whether the
data and information contained in a PMTA are applicable.
    (Comment 48) One comment stated that many of the items listed in
the ENDS design parameters section apply to components or parts that do
not provide a direct correlation to aerosol emissions when evaluated
independently or individually. The comment suggested that measuring
HPHCs is a better way to assess the product than by reviewing these
design parameters.
    (Response 48) Sections 1114.7(i)(1)(v) and (i)(2)(ii) require a
PMTA to include both a full statement of the constituents, including
HPHCs and other constituents, and of the design parameters for the new
tobacco product because both provide information that is important for
FDA's review. The design parameters are necessary to fully characterize
the new tobacco product, which is important to FDA's accurately
identifying and understanding of the product under review. As described
elsewhere in this document, these design parameters can also affect the
health risks of the new tobacco product. Information regarding the
constituents contained in and delivered from the new tobacco product is
also important because, as described in section VIII.B.13.a.iii, it
directly correlates to the health risks of the new tobacco product.
    (Comment 49) One comment stated that the costs associated with
generating design parameter data exceeds the potential marginal benefit
of the data to FDA's overall determination of whether permitting the
marketing of the new tobacco product would be APPH. The comment stated
that rather than providing information regarding a product's battery,
it should just be able to provide a certificate of compliance with the
Underwriters Laboratories 8139 standard, which would render further
review of the battery by FDA superfluous. The comment also stated that
even though information regarding the particles in the aerosol produced
by e-cigarettes is relevant to lung and cardiovascular function, FDA
does not need it to determine whether permitting the marketing of e-
cigarettes would be APPH because they are far less harmful than
combusted cigarettes.
    (Response 49) FDA disagrees with the comment's suggestion that FDA
should not require design parameters for ENDS. While FDA acknowledges
there is cost associated with generating design parameter data, the
design parameters of the product can change the health impact of the
tobacco product by affecting the level of constituents that reach
tobacco product users or nonusers and as such are an important part of
the APPH determination. This information is also necessary to fully
characterize a tobacco product. The differences in health risks that a
new tobacco product may present compared to one other product category
such as cigarettes is not, by itself, sufficient to demonstrate that
permitting the marketing of a new tobacco product would be APPH. As
explained in section IX.D., FDA interprets the APPH standard in
910(c)(2)(A) to require a showing that permitting the marketing of a
new tobacco product would likely have at least a net benefit to public
health based upon the risks and benefits to the population as a whole
(which includes youth, young adults, and other vulnerable populations).
Comparative health risk information is just one factor FDA may consider
in making this determination. Additionally, a comparison to just one
other product category may not be sufficient when current users of more
than one product category may begin using the new tobacco product.
    iii. Function. The rule requires the application to contain a
description of how the product is intended to function. For example,
this could include a description of how the energy or heating source is
used in or with the product, and how the delivery of the product's
output (e.g., smoke, aerosol, nicotine) is controlled. This information
can be critical to FDA's review of a tobacco product, including whether
the product functions as intended and whether the application contains
data and information that is relevant to the way in which it is
intended to function. For example, if an applicant states that a
product heats or aerosolizes, but does not combust tobacco or an e-
liquid, it would assist FDA in determining whether the information in
the PMTA shows the product functions as intended and whether the
application contains appropriate information regarding this function
(e.g., data regarding relevant HPHCs).
    iv. pH of product and nicotine formulation. The rule requires the
PMTA to specify the pH of the product. The pH of the product is
important for

FDA to review as part of a PMTA because it can affect the amount of
unprotonated nicotine delivered to the user (Refs. 96 and 97).
    The rule also requires the PMTA to specify the formulation of the
nicotine in the product. The nicotine formulation information is
required to state the type(s) and quantity of nicotine in the product.
Type(s) of nicotine include, but are not limited to, unprotonated
nicotine and nicotine salts (e.g., nicotine lactate, nicotine benzoate,
nicotine pyruvate). The quantity of unprotonated nicotine is important
for FDA to review because the amount and speed of nicotine delivered by
a tobacco product is related to the proportion of nicotine in a tobacco
product that is unprotonated (Refs. 98 and 99). The types and
quantities of nicotine salts in the product are important for FDA to
review because nicotine salt complexes can substantially increase
nicotine delivery relative to free-base nicotine in ENDS products
(Refs. 100-102).
    v. Fermentation process. For smokeless tobacco products and tobacco
products that contain fermented tobacco (including naturally fermented
tobacco), the rule requires an application to contain information on
the fermentation process. The rule requires this information because
the fermentation process can result in different degrees of change in
the chemical constituents of the tobacco (Refs. 103-105) and affect the
type and number of microorganisms in the final tobacco product, (Refs.
106-108) which could potentially affect the levels of TSNAs and
stability of the tobacco products during storage. In addition, the type
and amount of the fermentation inoculum can change the product as a
result of directed fermentation (Ref. 109). Therefore, the application
must contain the following information regarding the fermentation
process:
     A description of the fermentation process;
     composition of the inoculum (starter culture) with genus
and species name(s) and concentration(s) (if applicable);
     any step(s) taken to reduce microbes already present
during product processing (e.g., cleaning of product contact surfaces);
     specifications and test data for pH, temperature, and
moisture content, or water activity;
     frequency of aeration or turning (if applicable);
     duration of fermentation;
     added ingredients;
     method used to stabilize or stop fermentation. If the
applicant uses heat treatment, then it must provide the information
specified in the following subsection. If an applicant uses a method
other than heat treatment, it must provide the parameters of the method
(e.g., length of treatment, temperature) and method validation data;
and
     storage conditions of the fermented tobacco prior to
further processing or packaging and duration of storage (if
applicable).
    vi. Heat treatment process. In final rule, we have added a
requirement for information on the heat treatment process, if
applicable. For tobacco products that are heat treated, the rule
requires an application to contain information on the heat treatment
process. We have included this requirement for information because the
heat treatment process can potentially reduce the microbial load,
resulting in lower levels of carcinogenic TSNAs thereby altering
product composition (i.e., product characteristics) (Refs. 110-112).
Therefore, the application must contain the following information
regarding the heat treatment process:
     A description of the heat treatment process;
     the type of heat treatment;
     the conditions of heat treatment, including time,
temperature, and moisture; and
     method validation data, including microbial loads
(including bacteria, spores, yeast, and fungi) and TSNAs before and
after heat treatment.
    vii. Shelf life and stability information. In the proposed rule,
Sec.  1114.7(i)(2)(vii) would have required a PMTA for any category of
tobacco product to contain tobacco product storage and stability
information that establishes the microbial and chemical stability of
the tobacco product throughout the stated shelf life. Upon review of
public comments and further consideration, we are finalizing these
requirements (with specified changes) for products other than
cigarettes and RYO tobacco as explained in this section.
    Shelf life and stability information is important for FDA's review
of many tobacco products because bacterial communities and constituents
in tobacco products can change over time (Refs. 107, 108, 113 and 114).
Stability information is a particular concern with smokeless tobacco
products and other tobacco products that contain fermented tobacco
(including naturally fermented tobacco) because the characteristics of
these products can be affected by the manufacturing process, storage
conditions, and length of time on a shelf. Carcinogenic TSNA production
is critically influenced by the microbial communities associated with
the tobacco (Refs. 113 and 105). TSNA content in the finished tobacco
products is greatly affected by a variety of factors, such as tobacco
processing method(s) (e.g., curing, aging, sweating, fermentation, and
heat treatment), chemical additives added to control microbial activity
(e.g., humectants or preservatives), water activity (aw) of
the product, container closure system, and product storage conditions
(e.g., temperature, humidity), all of which could potentially alter
microbial activity and, in turn, affect the stability of the tobacco
products over the shelf life (Refs. 107, 108, 110, 113, 114, 115-120).
Furthermore, some tobacco products such as smokeless tobacco products
and e-liquids, have been shown to contain microbial cell wall
constituents ([1[rarr]3]-[beta]-D-glucan) and/or microbial toxins, such
as aflatoxins and endotoxins (Refs. 121 and 122). These microbial
components or toxins may result in increased risk to public health
because they are either carcinogenic in nature or associated with the
development of respiratory symptoms, reduced lung function,
inflammation and asthma (Refs. 121 and 122). In addition, based on our
experience, HTPs can contain high levels of humectants, which can
affect product stability; therefore shelf life and stability
information is required to support an application for HTPs. Humectants
function to keep a product moist, thereby impacting the moisture
content and water activity of the product, which in turn may impact
microbial growth and product stability (Ref. 116). Thus, for many
tobacco products, information obtained through stability testing and
shelf life is important for FDA to consider during its review to ensure
that the tobacco products are microbiologically and chemically stable
during the storage and do not result in an increased risk to public
health as the product sits in storage.
    Under the final rule, applicants submitting a PMTA for cigarettes
\29\ and RYO tobacco products do not need to provide the shelf life and
stability information under Sec.  1114.7(i)(2)(vii). In our review
experience, we have found that since the vast majority of cigarettes
and RYO tobacco products do not contain fermented tobacco, these
products generally do not present the same stability concerns as other
tobacco products. Thus, after further consideration, FDA is not
finalizing the shelf life and stability information

requirements for these products based upon its review experience with
the product categories under the SE pathway. However, since we lack
similar experience with novel tobacco products, such as ENDS and HTPs,
we need stability information for these types of products to determine
whether there is a difference in microbial factors or HPHC quantities
over time. Given the Agency's lack of experience reviewing applications
for novel tobacco products, at this time FDA believes information
regarding these products' shelf life and stability over time is needed
to ensure FDA fully understands the microbial and chemical stability of
the tobacco products throughout their stated shelf life.
---------------------------------------------------------------------------

    \29\ See the discussion in section VIII.B.3. about how products
should be categorized for purposes of PMTA review.
---------------------------------------------------------------------------

    In addition, after review of available scientific information
regarding stability testing as well as consideration of comments
received in responses to the proposed rule, the stability testing
requirements have been updated including changes such as the removal of
identification of microbiological organisms by genus and species and
removal of testing for pH, moisture content, nitrate and nitrite
levels, and preservatives and microbial metabolic inhibitors.
Specifically, the final rule requires an application to contain the
following shelf life and stability information:
     The length of the shelf life, a description of how the
shelf life is determined and a description of how shelf life is
indicated on the tobacco product, if applicable. The rule would not
require a tobacco product to indicate the product's shelf life;
however, if it is indicated on the product, the PMTA must describe how
it is determined. For example, if the tobacco product labeling has a
``use by,'' ``best by,'' or expiration date, a PMTA must contain a
description of how the date is determined (e.g., a certain number of
days after packaging);
     stability date assessed at the beginning (zero time),
middle, and end of the expected shelf life. If a tobacco product does
not have a defined shelf life, provide stability data over a specified
amount of time and a justification for why that time period is
appropriate. For example, if an applicant believes that 2 years after
the date of product manufacture is an appropriate shelf life, the
applicant should provide clear justification to support this time.
Stability testing must be performed for the chemical and microbial
endpoints for the following items:
    [cir] Microbial content data, including total aerobic microbial
count and total yeast and mold count;
    [cir] water activity (aw);
    [cir] TSNA yields (total N-nitrosonornicotine [NNN], and 4-
(methylnitrosamino)-1-(3-pyridyl)-1-butanone [NNK]); and
    [cir] preservative content (if applicable).
    If microbial activity during the product shelf life is detected,
further information, such as endotoxin or aflatoxin levels, should be
included in the PMTA.
    Accelerated studies for chemical endpoints, combined with basic
stability information on the components or parts and container closure
system (separately), or the tobacco product (as a whole) may be used to
support chemical stability of the tobacco product provided full shelf
life studies are not available and are being conducted. Where data from
accelerated studies are used to project a tentative shelf life that is
beyond a date supported by actual shelf life studies, stability studies
must be conducted under nonaccelerated conditions at appropriate
intervals, until the tentative expiration date is verified or the
appropriate expiration date is determined.
    As required by Sec.  1114.7(i)(4), the reported stability testing
must be performed on test samples that reflect the final tobacco
product composition and design (including the container closure system)
and be conducted using a sufficient sample size and number of
replicates to substantiate the results of the type of testing
conducted. Section 1114.7(i)(4) also requires the application to
contain the following information regarding stability testing:
     The mean quantity and variance with unit of measure;
     the number of samples and measurement replicates for each
sample;
     the methods used, including a deviation(s) from the
methods, associated reference(s), and full validation reports for each
method;
     the name and location of the testing laboratory or
laboratories and documentation showing that the laboratory or
laboratories is (or are) accredited by a nationally or internationally
recognized external accreditation organization;
     the length of time between dates of tobacco product
manufacture and date(s) of testing;
     the length of time between date of tobacco product
manufacture and date(s) of testing;
     the storage conditions of the tobacco product before it
was tested;
     a statement that the testing was performed on a tobacco
product in the same container closure system in which the tobacco
product is intended to be marketed; and
     full test data (including quantitative acceptance (pass/
fail) criteria, complete data sets, and a summary of the results) for
all stability testing performed.
    FDA received several comments regarding shelf life and stability
information, as discussed below.
    (Comment 50) One comment requested that FDA clarify, with regard to
shelf life and stability testing, whether changes to the product over
time will form the basis of FDA's decision to issue a marketing denial
order for a new tobacco product.
    (Response 50) Product stability information is important for FDA to
consider during its review because if a product changes over time, it
may affect the health risks presented by the new tobacco product. As
described in section IX.D, the health risks of a new tobacco product
forms part of the basis for FDA's determination of whether it should
issue a marketing granted order for the new tobacco product. This may
include the health risks of a new tobacco product as it changes over
time. For example, a product with a 24-month expiration date whose
stability testing data demonstrates that the product may be unstable
after manufacturing, with the levels of TSNAs (NNN and NNK) increasing
significantly over the 24-month period shelf life above what is
reasonably expected for similar products on the market, may raise
additional health risks. Because NNN and NNK are carcinogenic to humans
with no safe level of exposure, the increased levels of TSNAs may
increase the health risks to the users. Therefore, this type of
stability testing information is important for FDA to consider during
its review to ensure that the tobacco products are microbiologically
and chemically stable, and the product remains APPH, over the product's
shelf life.
    (Comment 51) One comment stated that where a product does not have
an established shelf life, the rule should require an applicant to
report stability data using the upper bound length of time the product
will remain in storage, such as the upper 95 percent confidence
interval, rather than relying on the typical period of time in which a
product is sold to consumers, which it interprets to be the median
time. The comment also stated that the rule should be amended to
require applicants to provide regular postmarket reports on how much
product has been removed because it was in storage for too long and how
that product was disposed of.

    (Response 51) FDA disagrees with this comment. As discussed
elsewhere in this document, a PMTA is required to contain product
storage and stability information that establishes the microbial and
chemical stability of the product throughout the product's shelf life.
For tobacco products with no established or defined shelf life, FDA
recommends that applicants provide details of stability over a
specified amount of time and justify why that time period is
appropriate. This time period should correspond to the expected storage
time of the tobacco product after the date of manufacture of the
product until it is sold to consumers, as determined by the applicant.
This information is product-specific, and the burden is on the
applicant to show that the product is stable for the entire duration
determined by the applicant. Since the expected storage time is
product-specific, FDA declines to establish requirements for postmarket
reports regarding product removal or disposal for all products. FDA
will monitor the marketing of the product, including review of periodic
reports required under Sec.  1114.41, to determine whether there are
product stability issues that were not addressed in the PMTA.
    (Comment 52) One comment stated that FDA's approach for stability
testing for microbiological endpoints in the form of total aerobic
microbial count (TAMC), total yeast and mold count (TYMC), and testing
for specific microbial organisms is not aligned with current scientific
approaches. The comment also noted that the proposed testing
requirements are not aligned with the current scientific approaches in
addressing microbiological quality in various industries (e.g.,
pharmaceuticals), which take into consideration the importance of water
for microbiological proliferation. The comment suggested that
applicants should be allowed to adopt a risk-impact assessment-based
approach, whereby results of a toxicological assessment of the product
taking into account its composition, manufacturing process, and typical
supply chain conditions shall be used by the applicant to define and
execute a stability program appropriate for the product category. The
comment stated that in particular, with regards to risks associated
with potential microbiological activity, scientifically justified
surrogate factors can be employed such as water activity
(aw). The comment concluded by stating that FDA should not
employ a one-size fits all approach for different categories of tobacco
products.
    (Response 52) FDA disagrees with this comment. During review of a
PMTA, FDA evaluates stability of the finished tobacco product during
storage. To determine the microbial and chemical stability of a tobacco
product during the expected storage period, FDA evaluates the
cumulative effect of all factors, such as tobacco processing (e.g.,
fermentation, heat-treatment, curing), product composition (e.g.,
humectants, preservatives, certain flavor compounds, metabolic
inhibitors), aw of the finished tobacco product, container
closure system, and product storage conditions (e.g., temperature,
humidity), that could potentially affect the stability of the product
during storage. Aw is a measure of the amount of water that
is available for microbial growth in a product. Therefore, it only
provides information on the potential of a product to support growth of
microbes present in the product. Fresh tobacco leaves are colonized by
a variety of microorganisms. Additionally, microbial contamination
could potentially occur during tobacco processing, finished tobacco
product manufacture, and/or storage. Some tobacco products such as
smokeless tobacco products and e-liquids, have been shown to contain
microbial cell wall constituents ([1[rarr]3]-[beta]-D-glucan) or
microbial toxins, such as aflatoxins and endotoxins (Refs. 121 and
122). These microbial components or toxins may result in increased risk
to public health because they are either carcinogenic in nature or
associated with the development of respiratory symptoms, reduced lung
function, inflammation and asthma. Therefore, TAMC and TYMC data
provide crucial information on the microbial load in the finished
tobacco product and serve as an indicator for the potential of presence
or absence of microbial toxins in the product. Additionally,
aw levels are influenced by several factors (e.g., humectant
levels, container closure system, storage conditions) and could
potentially change during storage. TAMC and TYMC data are important to
corroborate changes in aw during storage and therefore
crucial in evaluating the stability of the finished tobacco product
during storage. FDA will evaluate shelf life and stability information
of each tobacco product as part of its APPH determination.
    (Comment 53) Two comments expressed additional concerns about the
breadth of information required to be submitted regarding the stability
of smokeless tobacco products. One comment disagreed with the proposed
requirement to include analytical measurements of pH, moisture content,
aw, TAMC, TYMC, nitrate, nitrite, preservatives, and
microbial metabolic inhibitors in stability studies for new smokeless
tobacco products. The comment stated that because the ultimate endpoint
of stability testing is to determine whether TSNA formation occurs over
time, assessment of these additional parameters is burdensome, resource
intensive, and unnecessary. The comment noted that not only would they
have to develop validated methodologies and find laboratories to
conduct the testing, the analysis of the proposed parameters would only
indicate favorable conditions for increases of TSNAs and would not
yield a change in total TSNAs, which are also being measured. Another
comment expressed similar concerns and disagreed with the requirement
to provide microbial content data that identifies detected
microbiological organisms by genus and species names because it would
be costly and time intensive, yield highly variable results depending
on the method used, and would not alter the presence of TSNAs in the
tobacco product as measured at each stability timepoint.
    (Response 53) FDA has revised section Sec.  1114.7(i)(2)(vii) of
the codified to include aw, preservative content, TSNAs
(reported as separate amounts for the total TSNAs, NNN, NNK) and
microbial content data including TAMC and TYMC along with
identification of microbiological organisms by genus and species names.
FDA disagrees with the statement that the parameters would only
indicate favorable conditions for increases of TSNAs and would not
yield a change in total TSNAs. Microbial-mediated reduction of nitrate
results in production of nitrite, which further reacts with alkaloids
present in tobacco to produce carcinogenic TSNAs (Refs. 107 and 113).
Microbial-mediated nitrite production is a key determinant of TSNA
levels in the final tobacco product. Several nitrate-reducing bacterial
species (e.g., Bacillus, Enterobacter, Staphylococcus, Corynebacterium,
Escherichia) and fungal species (e.g., Candida, Fusarium, Aspergillus,
Alternaria) that are active across a wide temperature and pH range have
been identified in smokeless tobacco products (Refs. 107, 113, and
123). During tobacco processing and storage, these nitrate-reducing
microbial species could potentially convert nitrate to nitrite
resulting in increases in TSNA levels thereby affecting product
stability during storage. It is important for FDA to evaluate all of
the factors that affect

microbial growth and determine if any increases in TSNAs over tobacco
product storage are microbial-mediated. This information ensures that
the tobacco product is microbiologically and chemically stable during
the expected storage period and does not result in an increased risk to
public health as the product sits in storage.
    viii. Product and packaging design risks and misuse hazards. This
section of an applicant's PMTA is required to contain a review and
assessment of reasonably foreseeable risks associated with the design
of the tobacco product and its packaging that may occur during normal
use of the tobacco product or during any foreseeable misuse of the
product, including user error, which may cause illness, injury, or
death not normally associated with the use of the tobacco product. The
review and assessment must identify the measures taken to reduce or
eliminate each risk associated with the design of the tobacco product
and packaging. Examples of these design risks include, but are not
limited to: (1) Defects in the air permeability of fire standards
compliant banding on cigarette paper that is intended to allow
cigarettes to self-extinguish when left unattended; (2) software errors
or flaws (i.e., bugs) that occasionally result in the product
performing differently than designed; (3) failure of a safety switch to
shutoff a product if it exceeds a certain temperature; and (4) the
failure of a battery design feature to prevent battery from
overcharging. The PMTA must contain a review and assessment of each
defect, describing the potential to cause illness, injury, or death and
the measures taken to reduce or eliminate the defects and their
potential impact. FDA is requiring this information under section
910(b)(1)(G) of the FD&C Act, because the potential for the product
design or foreseeable misuse to cause illness, injury, or death
provides information that informs FDA's determination of whether
permitting the marketing of the product would be APPH.
    FDA received one comment regarding product and packaging design
risks and misuse hazards, as discussed below.
    (Comment 54) One comment stated that applicants should not be
required to report or assess the ways in which a tobacco product could
be misused because requiring companies to do so would require judgments
that are so wildly subjective that the results are unlikely to be valid
or relevant.
    (Response 54) FDA disagrees with this comment. As discussed above,
a PMTA would not be required to contain information regarding all
potential misuses; rather it would be required to contain an
identification and assessment of foreseeable misuses. Prospective
applicants should review section VII.13.a, which explains the ways in
which applicants can include this type of information, including
information bridged from investigations on similar products.
10. Principles of Operation
    Section 1114.7(i)(3) describes FDA's interpretation of the full
statement of the principle or principles of operation required by
section 910(b)(1)(B) of the FD&C Act and requires the PMTA to contain
full narrative descriptions of:
     The way in which a typical consumer will use the new
tobacco product. This includes a description of how a consumer operates
the product, how long a single unit of the product is expected to last
(e.g., total length of time of use to consume a unit, number of use
sessions expected per unit), and where applicable, whether and how a
consumer can change the product design and add or subtract ingredients,
such as:
    [cir] E-cigarettes that allow users to change performance features,
such as the temperature, voltage, or wattage;
    [cir] e-cigarettes that allow users to add or subtract e-liquid
ingredients, such as liquid nicotine and flavoring, including instances
where such manipulation is not intended by the manufacturer (e.g., ways
to misuse the product);
    [cir] e-cigarettes that allow users to add, subtract, or substitute
components or parts other than identical replacement parts; and
    [cir] waterpipes that allow users to add, subtract, or substitute
components or parts other than identical replacement parts, such as
stems and hoses;
     a justification for an applicant's determination of what
constitutes a single unit of product as described in the PMTA; and
     whether the product incorporates a heating source and, if
it does, a description of the heating source.
    FDA received several comments regarding these provisions, as
discussed below.
    (Comment 55) FDA received multiple comments in response to its
request for comment regarding how the rule should require measurement
of the length of time it takes a user to consume a single unit of the
product. One comment stated that FDA should not require any such
measurements with respect to e-cigarettes because it is the overall
exposures to HPHCs from repeated use of a product that informs health
risks, not the use of a single unit. Another comment had specific
suggestions as they relate to ENDS, stating that for a closed ENDS, a
single unit should be the amount of e-liquid in the closed ENDS; for an
open ENDS, a single unit should be the amount of liquid required to
fill the reservoir; and for open e-liquids, a single unit should be 2
milliliters (mL) of e-liquid regardless of the container size.
    (Response 55) FDA agrees that the overall exposures to HPHCs from
repeated use of a product provide the most relevant information about
health risk. However, because the overall exposures come from an
accumulation of individual use sessions over time, it is important for
FDA to understand how the new tobacco product is likely to be used by a
typical consumer in an individual use session as well as how frequently
they use the product (including variable use behaviors within sessions
and over time). It is also important to fully characterize the product
so that FDA can determine the differences in health risks between the
new tobacco product and other similar products on the market.
Therefore, FDA declines to exempt e-cigarettes from reporting the
length of time it takes for a user to consume a single unit of product.
    In terms of what should constitute a single unit for an ENDS, FDA
agrees with the comment's suggestions and recommends that applicants
consider a closed e-cigarette, such as a prefilled disposable cigalike,
or closed e-liquids, like cartridges or pods that are not intended to
be refillable, to constitute a single unit. For an open e-cigarette,
applicants consider a single unit to be the amount of e-liquid required
to fill the reservoir. FDA believes these measurements of a single unit
are appropriate because they are a consistent unit of measure set by
the manufacturer that could be useful in providing meaningful
information about product use; however, for open e-liquids, differences
in how consumers use the product may make a different unit of measure
more appropriate. Therefore, for open e-liquids, it may be more
appropriate to consider the volume of e-liquid required to fill the
container to be a single unit, rather than 2 mL of e-liquids. Due to
product variability and associated differences on what may be
appropriate as a single unit of a tobacco product, FDA declines to set
a required unit size and requires applicants to provide a scientific
justification for why the single unit used for the new tobacco product
is appropriate.

11. Product Testing and Analysis Information
    Section 1114.7(i)(4) requires that all testing and analyses of the
tobacco product required in Sec.  1114.7(i) be performed on test
samples that reflect the final tobacco product composition and design,
and that they be conducted using a sufficient sample size and number of
replicates to substantiate the results of the type of testing
conducted. This is required under FDA's authority in section
910(b)(1)(G), because the testing requirements are relevant to the
subject matter of the application in that they help FDA determine
whether the product testing and analyses are accurate and reliable. If
the product that is the subject of the PMTA is a component or part,
testing and analyses of the product should be performed with a range of
other components or parts with which a consumer is expected to use the
product (e.g., an e-liquid should be tested in a representative sample
of e-cigarettes in which it is may be used).
    Additionally, the applicant must provide the following information
about the testing and analysis:
     The name and location of the testing laboratory or
laboratories and documentation showing that the laboratory is (or
laboratories are) accredited by a nationally or internationally
recognized external accreditation organization;
     the length of time between dates of manufacture and
date(s) of testing;
     the storage conditions of the tobacco product before it
was tested;
     the number of samples and measurement replicates for each
sample;
     description of method procedure, method validation
information and rationale for selecting each test method, including
relevant voluntary testing standards;
     reports of all product formulation testing, including line
data, test protocols, quantitative acceptance criteria, and a summary
of the results, for each applicable parameter. Please note that an
applicant must retain source data under Sec.  1114.45; and
     complete descriptions of any smoking or aerosol-generating
regimens used for analytical testing that are not standardized or
widely accepted by the scientific community, if applicable. Where the
applicant is not using a widely recognized and standardized regimen,
such as the ISO or HCI regimens, the PMTA must contain a complete
description of the regimen.
    FDA received one comment regarding constituents and stability
testing, as discussed below.
    (Comment 56) One comment stated that the final rule must provide
greater detail regarding method validation and the number of samples
and measurement replicates required for constituent and stability
testing.
    (Response 56) FDA declines to set requirements for a specific
number of samples and replicates because the type of product and
methodology of testing will vary for a PMTA and the sample size and
number of replicates necessary to substantiate the type of testing may
vary. Thus, FDA does not find it appropriate to establish specific
requirements for testing in terms of validation methodologies, and the
number of samples and replicates at this time. While FDA generally
recommends testing across three batches with seven replicates per batch
as advised in the ENDS PMTA Guidance, varying numbers of batches and
replicates may be required to substantiate the results of testing. FDA
recommends that the validation report include sufficient information to
demonstrate method efficiency, specificity, sensitivity, accuracy, and
precision needed for the intended purpose. In addition, FDA recommends
that a PMTA contain an explanation of why the information used for
testing is sufficient to support the reliability of the results,
representative of their products, and does not cause public health
concerns.
12. Manufacturing
    Section 910(b)(1)(C) of the FD&C Act requires a PMTA to contain
full descriptions of the methods used in, and the facilities and
controls used for, the manufacture, processing, and, when relevant,
packing and installation of, the tobacco product. Section 1114.7(j)
provides FDA's interpretation of this requirement, together with its
authority under section 910(b)(1)(G) of the FD&C Act, stating that
these descriptions must include information regarding all manufacturing
facilities, include descriptions of design controls, and be
sufficiently detailed to demonstrate that the product meets
manufacturing specifications and can be manufactured in a manner
consistent with the information submitted in the PMTA.
    Additionally, because FDA must, under section 910(c)(2)(B) of the
FD&C Act, deny a PMTA that does not demonstrate compliance with
regulations issued under section 906(e) of the FD&C Act, the
descriptions contained in the manufacturing section must demonstrate
the means by which the processes comply with any applicable tobacco
product manufacturing practices regulation issued under section 906(e).
FDA has not yet issued a regulation under section 906(e) of the FD&C
Act, so demonstrating compliance with such regulations is not currently
required; however, FDA intends to issue regulations under section
906(e), and once such regulations are effective, applicants must
demonstrate that their methods, facilities, and controls comply with
that rule to receive a marketing granted order under section
910(c)(1)(i)(A) of the FD&C Act.\30\ Until a final rule issued under
section 906(e) of the FD&C Act is effective, FDA will evaluate the
manufacturing process information and consider whether the product can
be manufactured in a manner consistent with the information submitted
within the application as part of its determination of whether the
marketing of the new tobacco product would be APPH. As part of this
evaluation, FDA may conduct inspections as described in Sec.  1114.27
to verify the information and data submitted in the application.
---------------------------------------------------------------------------

    \30\ In establishing the effective date of a regulation under
section 906 of the FD&C Act, FDA must provide for a ``reasonable
period of time for . . . manufacturers to conform to good
manufacturing practices,'' and small tobacco product manufacturers
will have at least 4 additional years to comply. See section
906(e)(1)(B) of the FD&C Act. FDA anticipates that manufacturers
preparing PMTA applications before any regulation under 906(e) is
finalized will have sufficient time to prepare applications that
demonstrate that their methods, facilities, and controls comply with
such a rule before the applicable effective date. For PMTA
applications submitted before any regulation under 906(e) is
finalized, FDA generally expects the review of such applications
will be concluded prior to the effective date.
---------------------------------------------------------------------------

    FDA received one comment regarding this issue, as discussed below.
    (Comment 57) One comment stated that the proposed manufacturing
information requirements in Sec.  1114.7(j) exceed FDA's statutory
authority because they constitute the equivalent of a current good
manufacturing practice that must be issued in accordance with the
process specified in section 906(e) of the FD&C Act. The comment
further stated that FDA would, in effect, be requiring that applicants
demonstrate to its satisfaction that a new tobacco product conforms
with manufacturing criteria as precondition to placing that product on
the market. The comment requested that FDA significantly revise Sec.
1114.7(j) and establish regulations in accordance with section 906(e)
of the FD&C Act.
    (Response 57) FDA disagrees with the comment's conclusory assertion
that requiring the submission of information regarding whether an
applicant can manufacture the product described in its application
constitutes manufacturing practice requirements.

Section 906(e) requires that FDA, in applying manufacturing
restrictions to tobacco, follow a prescribed process to require
manufacturers to conform to current good manufacturing practices (CGMP)
or hazard analysis and critical control point (HACCP) methodology. In
issuing section Sec.  1114.7(j), FDA has neither created a requirement
to conform to a CGMP or HACCP methodology, nor set forth any
manufacturing practice requirements; rather, FDA has created a
requirement to submit information about the manufacturing process and
has identified the level of detail of such information that must be
submitted in the application. Drawing upon its experience with CGMP and
HACCP regulations for other regulated products, such as medical
devices, FDA has embraced a similar flexible approach that does not
prescribe in detail how a manufacturer must produce a specific tobacco
product but rather provides a framework to provide detailed information
regarding the manufacturing of a specific product.\31\ As described in
the following paragraphs, the process by which a tobacco product is
manufactured is important to FDA's determination of whether a new
tobacco product is APPH because it demonstrates the likelihood that the
tobacco product that will ultimately be used by consumers meets the
specifications set forth in the PMTA.
---------------------------------------------------------------------------

    \31\ See e.g., Medical Devices; Current Good Manufacturing
Practice (CGMP); Final Rule, 61 FR 52601 (October 7, 1996).
---------------------------------------------------------------------------

    The information required under Sec.  1114.7(j) is based on FDA's
interpretation of the manufacturing information required by section
910(b)(1)(C) of the FD&C Act as supplemented by FDA's section
910(b)(1)(G) authority. The statutory requirement to submit
manufacturing information under section 910(b)(1)(C) of the FD&C Act
exists independently of the requirements in section 906(e) of the FD&C
Act and FDA is in no way required to create a rule under section 906(e)
before requiring the submission of manufacturing information and
reviewing it as part of a PMTA. Only once FDA issues a regulation under
section 906(e) of the FD&C Act would an applicant have to demonstrate
it complies with any manufacturing practice requirements established by
FDA.
    The process by which a tobacco product is manufactured is important
to FDA's determination of whether a new tobacco product is APPH because
it demonstrates the likelihood that a tobacco product will be
manufactured in accordance with the specifications set forth in the
PMTA. A tobacco product that fails to conform to the PMTA's
specifications, referred to as a ``nonconforming tobacco product,''
could result in a defective product and increase the product's risk
compared to what would normally be expected from use of the product as
characterized in the PMTA. Additionally, a nonconforming tobacco
product constitutes a different tobacco product than the one authorized
in the marketing granted order, which would render a nonconforming
tobacco product adulterated under section 902(6)(B) of the FD&C Act. A
nonconforming tobacco product can be the result of a number of issues,
including design defects, failures of or problems with purchasing
controls, inadequate process controls, improper facilities or
equipment, inadequate training, inadequate manufacturing methods and
procedures, or improper handling of the tobacco product.
    Nonconforming tobacco products have been highlighted in the news.
For example, in 2017, a manufacturer of smokeless tobacco products
issued a voluntary recall of certain products after receiving
complaints of foreign metal material, including sharp metal objects, in
its smokeless tobacco products. After the recall, the manufacturer
investigated whether the contamination was a result of the
manufacturing practice or a deliberate act by an individual to
contaminate the product. FDA is also aware of other instances where
smokeless tobacco products contained rocks or metal shavings as well as
other nontobacco related materials (NTRMs) (e.g., glass, nails, pins,
wood, dirt, sand, fabric, cloth, and plastics) in finished tobacco
products. These NTRMs can cause cuts or lacerations to the lips and
gums or result in broken teeth.
    FDA also has observed during inspections that tobacco product
manufacturers have received complaints regarding nonconforming tobacco
products that contain contaminants and hazards such as biological
materials (e.g., mold, mildew, hair, fingernails) and chemical hazards
(e.g., ammonia, cleaning agents, and kerosene). Caustic cleaning
chemicals may cause the consumer to experience adverse health effects
not normally associated with tobacco use, such as vomiting, nausea,
allergic reactions, dizziness, numbness, or headaches.
    Nonconforming tobacco products may also contain higher levels of a
constituent than the consumer is expecting and that the product is
supposed to have as characterized by the PMTA, which may result in
increased risks to health. For example, FDA is aware of the variability
of nicotine among certain ENDS products and that the labeling may not
accurately reflect the actual levels of nicotine in those products. In
one study, researchers found that actual nicotine amounts differed from
labeled amounts by more than 20 percent in 9 out of 20 original e-
cigarette cartridges tested, and in 3 out of 15 refill cartridges
tested (Ref. 124). FDA has observed on inspections that some e-liquid
manufacturers do not have established procedures to conduct activities
or maintain records of their manufacturing processes, including but not
limited to calibration of equipment, documenting the identity or purity
of their ingredients, and testing final product to confirm that it
meets established specifications such as the concentration of nicotine.
A finished ENDS product that contains a nicotine concentration higher
than the established specification can be more addictive (Refs. 125 and
126). Similarly, a cigarette that does not conform to its pH
specification can deliver nicotine in a different speed and amount to
the user which can impact the tobacco product's toxicity and
addictiveness (Ref. 59). Exposure to nonconforming products in this
circumstance can result in user exposure to increased levels of
nicotine, which can lead to increased addictiveness.
    Nonconforming products may also contain defects that can cause the
tobacco product to be more harmful. For example, an ENDS product may
have a defect that contributes to an increased risk of fire and/or
explosion. The ENDS product, during use or foreseeable misuse, can
expose consumers to increased harm if the device catches fire or
explodes resulting in serious burns that would not be expected from use
of the product (e.g., Ref. 127).
    Given the dangers associated with nonconforming (including
contaminated) tobacco products, FDA will evaluate an applicant's
manufacturing process information to help determine whether the
marketing of a new tobacco product would be APPH, specifically
considering whether the manufacturer explains controls it would
establish and maintain to prevent the manufacture and distribution of
nonconforming products that may have an adverse effect on public
health.
    The manufacturing section of a PMTA must contain the following
information in the manufacturing section to meet the requirements of
Sec.  1114.7(j) and to help FDA determine if it conforms to the
requirements of section 906(e) of the

FD&C Act, when regulations are in effect:
     A listing of all manufacturing, packaging, storage, and
control facilities for the product, including the name, address, and
FEI number for each facility, if applicable, and a contact name and
telephone number for a representative from each facility;
     a narrative description, accompanied by a list and summary
of all standard operating procedures (SOPs) and examples of relevant
forms and records for the following categories of information for all
manufacturing, design controls, packing, and storage for the tobacco
product:
    [cir] Manufacturing and production process activities at each
establishment, including a description of each establishment, all
production steps, process controls, process specifications with
relevant acceptance criteria, and monitoring and acceptance activities;
    [cir] managerial oversight and employee training related to the
manufacture, processing, packing, and installation of the tobacco
product, as applicable;
    [cir] monitoring procedures and manufacturing controls for product
design, product characteristics, and changes in products,
specifications, methods, processes, or procedures, including a hazard
analysis that details the correlation of the product design attributes
with public health risk, as well as any mitigation strategies
implemented;
    [cir] activities related to identifying and monitoring suppliers
and the products supplied (including, for example, purchase controls
and product acceptance activities);
    [cir] handling of complaints, nonconforming products and processes,
and corrective and preventative actions;
    [cir] testing procedures carried out before the product is released
to market, including:
     A list and summary of any standards used for all testing
methods;
     validation or verification activities for all test methods
used to ensure that the tobacco product meets specifications;
     documentation of accreditation information for all testing
laboratories;
     complete description of smoking or aerosol-generating
regimes used for analytical testing, if any;
     tobacco product specifications (including any physical,
chemical, and biological specifications) and acceptance criteria for
those specifications; and
     reports of release testing performed on finished products
to demonstrate conformity with established specifications, including
test protocols, line data, and a summary of the results for each
applicable testing.
13. Health Risk Investigations
    Under section 910(b)(1)(A) of the FD&C Act, a PMTA must contain
full reports of all information, published or known to, or which should
be reasonably known to, the applicant concerning investigations which
have been made to show the health risks of the tobacco product and
whether the tobacco products present less risk than other tobacco
products. Section 1114.7(k) sets forth FDA's interpretation of this
requirement, together with its authority in section 910(b)(1)(G), in
three parts: (1) The types of investigations that are considered
investigations into the health risks of the product and whether the
tobacco product presents less risk than other products; (2) the
documentation an application must contain to demonstrate that the
application contains all published investigations; and (3) the
information that constitutes a full report of an investigation.
a. Types of Investigations and Analyses
    i. Interpretation of statutory language. FDA interprets the
information required under section 910(b)(1)(A) of the FD&C Act,
together with its authority under section 910(b)(1)(G) of the FD&C Act,
to include the health risk investigations specified in Sec.
1114.7(k)(1). Under the rule, applicants must submit full reports (as
described in Sec.  1114.7(k)(3)) of all information, both favorable and
unfavorable, published or known to, or which should reasonably be known
to, the applicant regarding the types of investigations described in
Sec.  1114.7(k)(1). Applicants are required to submit full reports of
these investigations, regardless of whether they support or are adverse
to the application, or are conducted within or outside the United
States.
    Section 1114.7(k)(1) requires an application to contain health risk
investigations that are published, known to, or should reasonably be
known to an applicant. This requirement ensures that FDA understands
the full scope of the health risk investigations for a new tobacco
product.
    Section 1114.7(k) interprets section 910(b)(1)(A) of the FD&C Act
broadly to ensure FDA has a complete understanding of the existing
information about a new tobacco product; it does not set requirements
for specific studies that must be contained in every single PMTA. The
description of the issuance of marketing denial orders (Sec.  1114.33),
discussed in section VIII.E, describes circumstances where FDA intends
to issue a marketing denial order. The description of the issuance of
marketing order (Sec.  1114.31) in section VIII.D contains information
regarding FDA's determination of whether there is a showing that the
marketing of a new tobacco product would be APPH.
    FDA received many comments regarding this provision, as discussed
below.
    (Comment 58) Multiple comments expressed concerns about what they
consider to be the breadth of the information required by proposed
Sec.  1114.7(k)(1). One comment stated that FDA should define the scope
of health risk investigations that must be submitted in every PMTA so
that applicants know exactly what to present in a PMTA and to reduce
potential burdens on both applicants and FDA. Another comment
interpreted the proposed rule as requiring information regarding
investigations for each of the topics described in Sec.  1114.7(k)(1)
and requested that FDA provide information about the expected design of
these studies as well as details regarding the ranges of acceptable
approaches to provide consistency and reliability to the PMTA review
process.
    (Response 58) FDA has made edits to the codified to further clarify
that FDA is not requiring an applicant to conduct an investigation into
each individual topic in Sec.  1114.7(k)(1). As described throughout
this document, a PMTA must contain at least some amount of substantive
information regarding each of the topic areas in Sec.
1114.27(b)(1)(ii) to be filed for substantive review. Additionally, a
PMTA must contain full reports of all investigations that are published
or known to, or which should reasonably be known to an applicant,
concerning the topics in Sec.  1114.7(k)(1) to be filed for substantive
review. FDA generally expects that applicants will be able to meet the
substantive information requirement in Sec.  1114.27(b)(1)(ii) by
submitting investigations that are published or known to, or which
should reasonably be known to, an applicant under Sec.  1114.7(k)(1);
however, in the event an application is lacking required substantive
information, an applicant may need to conduct its own investigation to
meet the filing requirements.
    (Comment 59) Other comments stated that FDA is providing too much
flexibility for applicants and should instead require applicants
conduct specific types of studies, allowing for exceptions only where
an applicant can demonstrate that a specific type of information is not
applicable.

    (Response 59) We decline to require that an applicant conduct a
list of new studies as part of every application under this rule
because there may be other ways in which an applicant can provide
scientific information to inform FDA's review (e.g., bridging,
published literature). Additionally, while a PMTA must contain
substantive information regarding certain categories of information set
forth in Sec.  1114.27(b)(i)(ii) to be filed by FDA as described in
section VIII.B, an applicant has some flexibility in determining how to
use existing information to support a PMTA for their product and what
types of additional investigations it may need to conduct to provide
FDA with information that demonstrates that permitting the marketing of
its new tobacco product would be APPH. For example, information about
known problems and risks related to mouth ulcers in moist tobacco
products would be informative and could be used to extrapolate known
health risk information for a related type of product that is the
subject of the PMTA submitted to FDA. Applicants may want to review the
areas of scientific investigation listed in Sec.  1114.31 to determine
whether there are gaps in the existing scientific information regarding
its product that it may need to fill by conducting a new study
regarding its tobacco product. As discussed in the description of Sec.
1114.31 in section VIII.D, acceptance and filing of a PMTA does not
mean that it has sufficient scientific information necessary to obtain
a marketing granted order.
    (Comment 60) Another comment stated that FDA's interpretation of
section 910(b)(1)(A) of the FD&C Act set forth in Sec.  1114.7(k) is
both unclear and is potentially limitless in scope. The comment noted
that the requirements in Sec.  1114.7(k)(1) go far beyond the
information that is required to be submitted for other products
regulated by FDA, such as the requirements for new drug applications.
The comment recommended that rather than requiring information
concerning the product under the range of conditions under which the
product might be used, FDA should revise the rule to focus on normal,
customary, and ordinary conditions of use and permit the use of
customary scientific methods, such as bracketing and dose response
curves, to provide such information to FDA.
    (Response 60) FDA declines to revise Sec.  1114.7(k) in response to
the comment and disagrees with the claim that it is potentially
limitless in scope. Unlike the premarket approval standard for drugs or
devices, which requires the submission of information to show whether a
drug or device is safe and effective, section 910(b)(1)(A) of the FD&C
Act requires applications to include information regarding the health
risk of the tobacco product and whether the product presents less risk
than other tobacco products. As discussed in section VIII.B.13.a, FDA
interprets the information required under section 910(b)(1)(A) of the
FD&C Act, together with its authority under section 910(b)(1)(G) of the
FD&C Act, to include the health risk investigations specified in Sec.
1114.7(k)(1). This requirement ensures that FDA understands the full
scope of the health risk investigations for a new tobacco product as
well as provides FDA with crucial information when determining whether
permitting the marketing of the new tobacco product is APPH.
    FDA also declines to limit the required submission of information
to just what the applicant considers to be normal, customary, and
ordinary conditions of use because understanding the full range of
conditions under which a product may be used, including the potential
for misuse, is important to determining the health risks posed by a new
tobacco product. For example, in ENDS products, the heating element
configurations and the number of heating elements have been known to be
modified. Another misuse that has occurred includes modifying the
wicking materials and the amount of wicking materials in the ENDS
product. Information such as whether an applicant's product design
reduces the possibility that the product will be misused or used
outside of ordinary conditions of use are an important part of
demonstrating that the new tobacco product would be APPH.
    (Comment 61) Another comment requested clarification regarding what
constitutes information that is ``known to or which should reasonably
be known to an applicant,'' suggesting that documentation of a search
of its own files and a survey of its scientific staff should be
sufficient. Multiple comments also requested that FDA amend Sec.
1114.7(k)(2) to require that an applicant impose a reasonable time
limit on searches of its own files and available literature, such as a
limitation to what is currently available or what has recently been
published (e.g., within a specified time period).
    (Response 61) FDA declines to adopt an interpretation of documents
that should reasonably be known to an applicant as part of this
rulemaking because it is likely to be a fact specific determination.
FDA also declines to set a time limit for the literature search
requirement because there is no such limitation in the statutory
requirement to submit full reports of published investigations. Under
Sec.  1114.7(k)(2), the application must 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. If, for
example, an applicant limits the literature search to a certain time
period, the applicant must include the reason for such limitation in
their description of the literature search.
    ii. General recommendations related to health investigations. The
rule does not require an applicant to conduct any of its own studies
for the purposes of the application acceptance and filing requirements
in Sec.  1114.27, except as necessary to meet the filing requirements
of Sec.  1114.27(b)(2)(ii). Should an applicant choose to do so, FDA is
providing recommendations for consideration throughout this section of
the preamble. In addition to recommendations for specific types of
studies that follow, FDA is making recommendations for three general
topics related to health risk investigations that may help an applicant
prepare a PMTA in some instances: (1) Bridging data from an
investigation conducted using a different product to the product that
is the subject of the application; (2) choosing appropriate comparison
products; and (3) using foreign data.
    (Comment 62) One comment stated that because FDA is acknowledging
the acceptability of ``bridging,'' ``comparison products,'' and
``foreign data,'' it should define these terms in the final rule,
stating that it is not sufficient to just mention these terms in
passing.
    (Response 62) FDA declines to define the terms in the final rule.
We believe the discussion of these topics and the associated
recommendations that follow provide sufficient information to be useful
to applicants in preparing PMTAs.
 Bridging
    FDA recognizes that in preparing the health risk investigations
section of a PMTA, an applicant may choose to use data from a study
conducted using a different tobacco product in an attempt to
demonstrate the health risks of the product that is the subject of the
application. The submission of studies using different products is
optional. Ideally, a PMTA will contain studies conducted with respect
to the new tobacco product itself, but the bridging of data from a
different product to the

new tobacco product that is the subject of the application may be
feasible for a subset of products or for certain types of studies. If
an applicant lacks data on the product from one or more of the types of
studies listed in this section, the applicant could bridge data
regarding another product, or an earlier version of the product where
appropriate. For example, ``X-flavor'' e-liquids with nicotine
concentrations ranging from 1 milligram per milliliter (mg/mL) to 24
mg/mL may be able to show the health risks of each of the e-liquids
without having to conduct a unique study for each nicotine
concentration of the ``X-flavor'' product if data from a subset of
nicotine concentrations (e.g., low, middle, high) of ``X-flavor''
products may be bridged to other nicotine concentrations of ``X-
flavor'' products. Other examples where data from studies on a smaller
number of products could potentially be bridged to a larger number of
products include smokeless tobacco products available in various pouch
sizes or e-liquids available in various container volumes.
    FDA received multiple comments regarding bridging information in a
PMTA, as discussed below.
    (Comment 63) Multiple comments expressed concerns related to the
use of bridging in a PMTA. One comment requested that FDA prohibit the
use of bridging information from an investigation conducted using a
different tobacco product to the new tobacco product that is the
subject of the PMTA. The comment stated that specifically with regard
to ENDS, even minor variations in e-liquids and battery outputs affect
the production of toxicants. Another comment stated that the health
effects of a given product can differ dramatically because of
individual differences among consumers. Both comments suggested instead
that FDA require applicants to conduct product-specific research.
Another comment stated that FDA should issue a marketing granted order
for a PMTA based on bridged data only where FDA concludes that there is
compelling evidence that the differences between the product studied
and the new tobacco product that is the subject of the application are
immaterial to FDA's review of the application.
    (Response 63) FDA declines to prohibit the use of bridging in a
PMTA because it can be used to provide information that is relevant to
FDA's review of a PMTA. Where an applicant chooses to bridge to data
from a general study or a study conducted using a different tobacco
product, it would need to provide a scientific rationale to justify why
the study findings apply to its new tobacco product and any study
limitations that may be relevant. Failure to provide a sufficient
justification that such data can be used to evaluate the new tobacco
product would result in FDA being unable to rely upon it in evaluating
the PMTA. There may be circumstances when an applicant would need to
submit additional substantive information, including bridging studies,
as appropriate, to justify that the results of a general study or a
study using a different tobacco product is relevant to evaluation of
its new tobacco product. Where an applicant seeks to use information
from a study conducted using a different tobacco product in the same
product category, it may need to provide comparative product
information or potentially a bridging study to show the results apply
to its specific new tobacco product. For instance, if an applicant
wants to use the results of an abuse liability study that was conducted
on a different product, an applicant should justify how key
similarities between the products (e.g., product design, nicotine
formulation and content) demonstrate the results of the study apply to
its tobacco product. As another example, national surveys, such as the
NYTS, provide information about trends in tobacco product use by youth
and typically do so for product categories as a whole, rather than
specific products. If an applicant intends to use such survey data to
help show the likelihood of youth initiation with its product, it would
need to explain why results about a product category in general apply
to its specific product.
    Another example of when a justification or a bridging study may be
needed is when the location or region of a study differs from the
intended locations or regions where the product will be used, which is
further described in the foreign data section.
 Comparison Products
    As part of FDA's consideration under 910(c)(4) of the FD&C Act of
the risks and benefits of permitting the marketing of the new tobacco
product to the population as a whole, including users and nonusers of
tobacco products, FDA reviews the health risks associated with changes
in tobacco product use behavior (e.g., initiation, switching, polyuse,
cessation) that may occur with the marketing of the new tobacco
product. Applicants must 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. Additionally, as
likely users of a new tobacco product will vary dependent on the type
of product, and product use patterns vary across different populations,
the appropriate comparison product(s) may vary. When identifying the
likely users of the product and appropriate comparator products, FDA
recommends that applicants specifically consider product use patterns,
including abuse liability and unintended use, among youth, young
adults, and other relevant vulnerable populations. It is helpful for
FDA to understand the 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 Sec.  1114.27(b)(1)(ii), a PMTA must 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 with the new tobacco 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 to 1 comparison
as in a SE report under section 905(j); rather, it is meant to
demonstrate how the new tobacco 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 the 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 new
tobacco 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.
    FDA received many comments regarding comparison products, as
discussed below.
    (Comments 64) Multiple comments discussed comparison products. One
comment stated that the rule should specifically require PMTAs to
compare the health risks of new tobacco products to the health risks of
all other tobacco products on the market. Another comment stated that
Sec.  1114.7(k)(1)(i) is unclear regarding the tobacco products to
which an applicant must compare the new tobacco product that is the
subject of an application and stated that requiring a comparison to
just cigarettes could disincentivize the development of new, lower risk
e-cigarettes, not just to combustible cigarettes.
    (Responses 64) As described in the preceding paragraphs,
comparative health risk information is an important part of FDA's
review of a PMTA because it can demonstrate the potential risks and
benefits that current tobacco users could face if they switched to the
new tobacco product or used it in conjunction with their current
tobacco product. As required by Sec.  1114.27(b)(1)(ii)(B), applicants
must compare the health risks of its product to both products within
the same category and subcategory, as well as products in at least one
different category that are used by the consumers an applicant expects
will use its new tobacco product. FDA declines to require comparisons
to all other products in every instance because not every application
will necessarily require comparisons to all other categories and the
determination of which comparison products are necessary to consider in
determining the risks and benefits to the health of the population as a
whole is more appropriately considered during substantive review. We
also disagree with the suggestion that the comparative health risk
information requirements in the rule would disincentivize development
of lower risk products because FDA requires each PMTA to compare the
health risk of its product to other tobacco products in the same
product category. Because FDA's APPH determination considers changes in
health risks to users of other products in the same category that
switch to the new tobacco product, applicants have an incentive to
ensure its product does not pose greater health risks than other
products in the same category.
    (Comment 65) One comment stated that section 910 of the FD&C Act
does not permit FDA to require a PMTA to contain a comparison to other
products in the same product category and, as a result, FDA should
remove the requirement to do so in Sec.  1114.27(b)(2)(ii)(B). The
comment stated that interpreting the phrase ``other tobacco products''
in section 910(b)(1)(A) to include products in the same category would
defeat the congressional intent of the APPH standard, which the
comment, citing a statement from a 1998 Senate committee report, argues
is to ensure FDA issues PMTA marketing orders for only those products
that do not introduce more risk than conventional tobacco products.
    (Response 65) FDA disagrees with this comment. The determination of
whether the marketing of a new product would be APPH under section
910(c) of the FD&C Act is required to be based on the risks and
benefits to the health of the population as a whole, and not limited to
a determination of on whether a new tobacco product presents less risk
than conventional tobacco products. As described in this section,
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. Not only does this constitute
information regarding ``other tobacco product'' that falls under
section 910(b)(1)(A), it is relevant to the subject matter under
910(b)(1)(G) of the FD&C Act because it informs FDA's consideration of
the risks and benefits of the product to the health of the population
as a whole.
 Foreign Data
    Foreign clinical studies should be performed by clinical
investigators so that the rights, safety, and welfare of human subjects
are 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 Sec.  1114.7(k) that an application contain all
published studies regarding the health risks of a new tobacco product
and other topics. 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.
    FDA received one comment regarding foreign data, as discussed
below.
    (Comment 66) One comment stated that FDA should be required to
provide its own rationale as to why any foreign data in an application
are relevant to the U.S. population and why FDA concluded that specific
data from U.S. studies are not required. The comment stated that FDA
should not assume that consumers in the U.S. market will respond the
same way as consumers in a different country.
    (Response 66) FDA declines to make the requested revision. 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 burden is on the applicant to
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.\32\ 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.
---------------------------------------------------------------------------

    \32\ 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.''
---------------------------------------------------------------------------

    iii. Health risks of the product. Section 1114.7(k)(1)(i) requires
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 includes
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 includes 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 must 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.
    As set forth in Sec.  1114.27(b)(1)(ii) and described in section
VIII.B, an application must contain substantive information regarding
the health risks of the new tobacco product as described in either
Sec.  1114.7(k)(1)(i)(A), (B), or (C) as well as substantive
information regarding the health risks of the new tobacco product
compared to the health risks generally presented by products in the
same category as described in Sec.  1114.7(1)(i)(D). While the rule
does 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, the applicant would be required to
do so where it is not aware of existing studies that could be used to
support the application or where additional information is necessary to
ensure the application contains substantive information regarding the
health risks of the new tobacco product. Where an applicant chooses to,
or must, conduct its own investigations, FDA is providing the following
discussion of nonbinding recommendations for consideration. The
adequacy of the studies provided and whether they help demonstrate that
a product is APPH will be determined during FDA's review of the
application. The study recommendations, provided here and throughout
this document, are intended to help an applicant develop a more robust
application, which would facilitate FDA making a determination as to
whether the product is APPH.
    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 required by 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
recommends 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 received several comments regarding this issue, as discussed
below.
    (Comment 67) One comment stated that because FDA notes that
clinical studies would typically be a necessary part of a PMTA, FDA
should not allow applicants to conduct animal studies, which the
comment states are unethical.
    (Response 67) Restrictions on the types of investigations that an
applicant is allowed to conduct are outside the scope of this rule. FDA
supports reducing the reliance on animal testing where adequate and
scientifically valid nonanimal 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 nonanimal 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 Sec.  1114.7(k)(1)(i)(B), a PMTA must 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.
    (Comment 68) One comment stated that FDA should revise all of the
PMTA requirements to give more prominence to heart and lung disease
effects and in particular, Sec.  1114.7(k)(1)(i)(B) should be amended
to require applicants to prioritize submission of information regarding
the cardiovascular and respiratory effects of the new tobacco product,
and additionally include effects on blood and intergenerational health
effects caused by epigenetic changes.
    (Response 68) FDA agrees that heart and lung disease effects are
important considerations, which is why they are part of the information
required by Sec.  1114.7(k)(1)(i)(B). However, the rule does not set
forth requirements in order of importance and moving a particular item
would not affect the importance of any requirements.
    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
and to use this comparison in its determination of whether permitting
the marketing of the product would be APPH. The toxicological profile
investigations covered by the rule also includes

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 includes the toxicological profile of the tobacco product 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 must contain if published or known to, or should
reasonably be known to, an applicant 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 Sec.  1114.7(i)(1)(v), the
constituent reporting section. The types of studies or information
required by the 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 types of toxicological information that the applicant must
include in a PMTA if published or known to, or should reasonably be
known to, the applicant include 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 Sec.
1114.27, 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 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 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 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 substantive 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 marketing denial order for the new tobacco product.

    Under Sec.  1114.7(k)(1)(i)(C), a PMTA must 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 also must 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. As such, where
published or known to, or which should reasonably be known to the
applicant, the pharmacological profile of the tobacco product is 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 must
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 must 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 must 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.
    FDA received several comments regarding toxicological information,
as discussed below.
    (Comment 69) One comment stated that the pharmacological profile of
many of the ingredients or constituents in a tobacco product might not
be helpful to FDA's determination of health risks and that FDA should
recommend inclusion of this information rather than require it. The
comment noted that some constituents, such as nicotine, have already
had their pharmacological profile established in literature and that
other constituents are delivered at such low levels that they would not
permit evaluation of their pharmacological profile.
    (Response 69) FDA declines to revise the rule as a result of this
comment. The pharmacological profile of the product and its
constituents provide important information about the health risks of
the product as well as its risk relative to other products.
Specifically, this information is important for FDA to consider when
evaluating the relationship between the dose of the product and the
body's response. While the pharmacological profile of some ingredients
and constituents, such as the nicotine pharmacokinetic (PK) profile, is
well characterized for some general classes of tobacco products, slight
changes in product features (e.g., cigarette ventilation (Ref. 128),
tobacco pH and nicotine absorption site (Ref. 68), ENDS voltage (Refs.
129-133)) affect the nicotine PK profile. 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. 4 and 132-134). Because this
profile directly impacts use behaviors and abuse liability, it remains
a critical piece to understanding a tobacco product's impact on public
health.
    (Comment 70) One comment stated that in addition to describing the
health risks of the tobacco products contained within the new tobacco
product, FDA should require applicants to present evidence that the
product does not interfere with the pharmaceutical drugs that expected
users of the new tobacco product may be taking.
    (Response 70) As required under Sec.  1114.7(k), a full report of
each health risk investigation that is published or known to, or which
should reasonably be known to, an applicant concerning the potential
for interaction between drugs and the new tobacco product must be
included as part of a PMTA in order for it to be filed for review. FDA
intends to consider the implications of such health risk information,
or a lack thereof, during substantive review, as appropriate.
    Under Sec.  1114.7(k)(1)(i)(D), a PMTA must 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. Under section 910(b)(1)(G) of the
FD&C Act, FDA requires 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 requires
applicants to 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 also requires 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 because existing
data indicates that a significant number (approximately 40 percent or
more by some estimates) of both adults and youth who currently use
tobacco products use more than one type of tobacco product (Refs. 135
and 136). 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.
137 and 138).
    The types of investigations that a PMTA must 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 of 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 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.
    (Comment 71) One comment stated that Sec.  1114.7(k)(1)(i) is
unclear regarding the tobacco products to which an applicant must
compare the new tobacco product that is the subject of an application.
The comment stated requiring a comparison to just cigarettes could
disincentivize the development of new, lower risk e-cigarettes.
    (Response 71) FDA disagrees with the suggestion that the rule
requires a comparison to cigarettes in each application. Section
1114.27(b)(1)(ii) requires a PMTA to contain substantive information
regarding the health risks of the new tobacco product compared to the
health risks generally presented by both products in the same product
category and products in at least one different category that are used
by the consumers an applicant expects will use its new tobacco product.
While this could require a comparison to cigarettes for at least some
applications, it would not be required in all applications. For the
comparison to other products in the same category, this could include,
for example, comparing an e-liquid to other e-liquids used in a similar
manner. We also disagree with the suggestion that the comparative
health risk information requirements in the rule would disincentivize
development of lower risk products because FDA also requires each PMTA
to compare the health risk of its product to other tobacco products in
the same product category. Because FDA's APPH determination considers
changes in health risks to users of other products in the same category
that switch to the new tobacco product, applicants have an incentive to
ensure its product does not pose greater health risks than other
products in the same category.
    An applicant should consider the appropriate comparative health
information a PMTA may need beyond the minimum requirement for
substantive information 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 marketing denial
order for the new tobacco product.
    For demonstrating the health risks that are posed by the product in
comparison to using other tobacco products, a PMTA must contain, under
Sec.  1114.27(b)(1)(ii), 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 with the new tobacco 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, in
addition to the requirements of Sec.  1114.27(b)(1)(ii), comparing the
health risks of the product to categories of products that users are
likely to switch to. Applicants may compare to comparator products that
have a substantial market share (e.g., cigarettes, smokeless tobacco,
cigars); however, such comparisons may only be appropriate if users are
likely to switch to the comparator products. 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.
    iv. Impacts on tobacco use behavior of tobacco product users. FDA
interprets the health risk investigations that must be provided under
section 910(b)(1)(A) of the FD&C Act (where published or known to, or
which should reasonably be known to the applicant) to include the
effect of either the product or its label, labeling, or advertising, to
the extent that advertising has been studied, 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).
    (1). Abuse liability. Section 1114.7(k)(1)(ii)(A) requires 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 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 or should
reasonably be known to an 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 craving of the product
and compulsive and continued use despite harm or risk of harm. FDA
requires the submission of abuse liability information under its
interpretation of section 910(b)(1)(A) and (G) 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
provides 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 marketing
denial 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 some amount of substantive
information concerning abuse liability under 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 should 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.
    FDA received comments regarding abuse liability, as discussed
below.
    (Comment 72) One comment objected to the inclusion of a statement
in numerous places throughout the preamble to the proposed rule
indicating that an applicant would be required to conduct
investigations in certain circumstances. The comment stated that the
requirement should appear in the codified, rather than the preamble,
and requested additional information regarding how a company that does
not have a product on the market could meet such requirements.
    (Response 72) FDA disagrees with the characterization that it is
creating a requirement for the submission of information in the
preamble rather than in the codified. The instances identified by the
comment in which FDA references the potential need for applicants to
conduct their own investigations for submission in a PMTA are each a
part of a discussion regarding the substantive information required by
Sec.  1114.27(b)(1)(ii) for application filing. These portions of the
preamble identified by the comment, make it clear that where there is
no existing substantive information regarding these topics that an
applicant could include in its PMTA, including published investigations
or investigations it could bridge to its new tobacco product, the
applicant would need to conduct its own investigation to generate such
substantive information for inclusion in its application or have FDA
refuse to file its application for failing to meet the requirement of
Sec.  1114.27(b)(1)(ii).
    (Comment 73) One comment stated that the rule is overly broad in
that it requires the submission of information regarding abuse
liability and also contains recommendations concerning abuse liability
studies that align with how FDA assesses abuse liability for drugs. The
comment stated that because tobacco products are legal, there are no
defined parameters regarding abuse or misuse. The comment also noted
that there are a number of factors concerning individual users that
affect whether they will develop dependence and that a number of social
factors drive individual's decisions to start using and continue to
regularly use tobacco products and these factors cannot be simulated in
a premarket setting. The comment recommended that FDA use the term
``dependence potential'' and that FDA should limit the scope of
required information only to the product that is the subject of the
application and a comparator.
    (Response 73) As described in the preceding paragraphs, 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 or
develop an addiction to the product. Despite tobacco products being
marketed legally in the United States, nicotine is an addictive drug
and there are diagnostic criteria for tobacco use disorder in the
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition.
There are a number of factors that contribute to the abuse liability of
a substance and there are methodologies widely accepted to evaluate
abuse liability in a research setting. These methodologies can be used
to inform FDA about the abuse liability of product described in a PMTA.
FDA requires the submission of abuse liability information 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
product. Given the importance of this information in FDA's
understanding of the abuse liability of the new product both
independently and relative to other products with a known abuse
liability, FDA declines to use the term ``dependence potential'' or
limit the scope of required information to only the product that is
subject of the application and a comparator product. FDA generally
expects abuse liability studies to contain a comparison to one or more
tobacco products to ensure that FDA has sufficient information to
understand how the abuse liability of a product compares to other
relevant categories of tobacco products.
    (Comment 74) One comment stated that FDA should prioritize evidence
about real-world actual use over clinical trials or laboratory studies
and proposed revisions that appear to require the submission of actual
use data that is relevant to the abuse liability of the new tobacco
product.
    (Response 74) We agree that information regarding actual use of a
product and its abuse liability are important to FDA's review of an
application, which is why, under Sec.  1114.27(b)(1)(ii), FDA may
refuse to file a PMTA that does not contain substantive information
regarding those topics. We decline to require ``real-world actual use
data'' concerning abuse liability as part of FDA's acceptance and
filing requirements, because a determination of whether the data in an
application adequately demonstrate the abuse liability of a product is
more appropriately considered during substantive review on a case-by-
case basis.
    (2). Use Topography, Frequency, and Trends. Section
1114.7(k)(1)(ii)(B) of the rule requires 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 requires 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.
    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. 83). 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.
    FDA received one comment regarding this issue, as described below.
    (Comment 75) One comment requested that FDA clarify what
information an applicant would be required to submit under Sec.
1114.7(k)(1)(2)(ii)(B) to demonstrate 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. The comment noted that the rule seemed to
require actual use studies and requested that FDA clarify whether this
needs to be real-world studies or they could be in a simulated setting.
    (Response 75) Under 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, or how such use affects the health
risks of the product to individual users. Thus, 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.
However, FDA does not require a particular type of actual use study.
For example, applicants may conduct and submit results from an actual
use study in a real or simulated setting. The types of studies that may
provide this information on current tobacco use behavior can include,
but are not limited to, actual use studies and national survey