all records pertinent to the application may result in the issuance of
a marketing denial order because FDA would not be able to determine
whether permitting the marketing of the new tobacco product would be
APPH. During an inspection, an applicant should ensure that:
     All pertinent records can be viewed;
     documents written in a language other than English can be
translated into English, if requested. Documents that have been
translated from another language into English should be accompanied by
a signed statement by an authorized representative of the manufacturer
certifying that the English language translation is complete and
accurate, and a brief statement of the qualifications of the person
that made the translation; and
     if the tobacco product is in production (domestic or
foreign) and is intended for U.S. commercial distribution, FDA can view
the product being manufactured.

C. FDA Action on an Application (Sec.  1114.29)

    Section 1114.29 lists six actions that FDA may take after receiving
an application:
     First, FDA could refuse to accept the application, as
described in Sec.  1114.27(a);
     second, FDA could issue a letter administratively closing
the application. This could occur where an applicant fails to respond
to a request for an amendment within the time period specified in the
amendment request under Sec.  1114.9(b) or requests to withdraw an
application under Sec.  1114.11. In the proposed rule, FDA had
previously stated that ``this could occur where an applicant fails to
response to a request for an amendment within 180 days.'' FDA changed
this language in the final rule to be the time period to respond to the
amendment request to reflect that fact that the time for response might
vary according to the complexity of the amendment request and thus
could be a period other than 180 days (e.g., an amendment request for
relatively simple information might have a shorter response period).
     third, FDA could issue a letter canceling the application
if FDA finds it mistakenly accepted the application (e.g., the
application does not pertain to a new tobacco product, or the
application was submitted in error);

     fourth, FDA could refuse to file the application as
described in Sec.  1114.27(b);
     fifth, FDA could issue a marketing granted order as
described in Sec.  1114.31; or
     sixth, FDA could issue a marketing denial order as
described in Sec.  1114.33.

D. Issuance of a Marketing Granted Order (Sec.  1114.31)

1. The Requirements To Receive a Marketing Granted Order
    Under section 910(c)(1)(A)(i) of the FD&C Act, FDA will issue a
marketing granted order for a new tobacco product after its review of a
PMTA if it finds that none of the grounds for denial specified in
section 910(c)(2) of the FD&C Act applies to the application. This
means that in order for FDA to issue a marketing granted order for a
new tobacco product, FDA must be able to determine the following:
    a. There is a showing that permitting the marketing of the new
tobacco product would be APPH. Under section 910(c)(4) of the FD&C Act,
FDA's finding that permitting the marketing of a new tobacco product
would be APPH must be determined with respect to the risks and benefits
to the population as a whole, including users and nonusers of tobacco
products, and taking into account:
     The increased or decreased likelihood that existing users
of tobacco products will stop using such products and
     the increased or decreased likelihood that those who do
not use tobacco products (including youth and young adults) will start
using such products.
    Finding that there is a showing that permitting the marketing of a
new tobacco product would be APPH is a complex determination that must
be made with respect to risks and benefits to the population as a
whole, considering the likelihood of changes in tobacco product use
behavior (including initiation and cessation) caused by the marketing
of the new tobacco product. When determining whether the marketing of a
particular new tobacco product would be APPH, FDA will evaluate the
factors in light of available information regarding the existing
tobacco product market, tobacco use behaviors, and the associated
health risks at the time of review. As described in section 910(c)(5)
of the FD&C Act, the types of scientific data that FDA will consider in
making its determination can include well-controlled investigations
and, where appropriate, other valid scientific evidence that FDA
determines to be sufficient to evaluate the tobacco product. FDA will
consider the information supplied in the application together with any
other relevant sources of information, including a report or
recommendation from TPSAC, when applicable, in making its
determination.
    Section 910(c) of the FD&C Act requires FDA to consider an array of
potential risks and benefits of each new tobacco product with respect
to the population as a whole when determining whether permitting the
marketing of a new tobacco product would be APPH. As set forth in the
criteria for withdrawing a marketing granted order in section
910(d)(1)(A) of the FD&C Act, FDA must continue to find the product
meets the APPH standard over time.
    FDA received many comments regarding the requirements to obtain a
marketing granted order, as discussed below.
    (Comment 102) Several comments stated that FDA has failed to
explain or justify how it is interpreting and applying the APPH
standard when evaluating PMTAs and must do so to allow a determination
of whether its issuance of PMTA marketing orders is arbitrary and
capricious. In addition, some comments expressed concern that the lack
of articulated definitions and standards regarding the APPH standard
would leave applicants guessing at what might satisfy the standard. In
addition, another comment stated that failing to provide this essential
direction could increase the likelihood of arbitrary and inconsistent
decisions.
    (Response 102) FDA disagrees with the assertion that is has failed
to provide adequate information concerning the APPH standard in section
910(c)(2) of the FD&C Act. Similar to premarket standards for other
products, such as medical devices or drugs, FDA does not provide a
precise definition of the standard but instead provides information
regarding the types of information that can be used to demonstrate the
standard has been met. FDA intends to consider the marketing of a new
tobacco product to be APPH where a PMTA contains sufficient valid
scientific evidence to demonstrate that the potential risks and
benefits of the marketing of the new tobacco product would likely have
a net positive effect on the health of the population as a whole, which
includes youth, young adults, and other relevant vulnerable
populations. This could include a variety of different types of
evidence that may provide FDA with an overall assessment of the
potential effect permitting the product to be marketed may have on
tobacco-related morbidity and mortality. For example, FDA may consider
scientific evidence such as whether levels of HPHCs and other
constituents in the new tobacco product are similar or lower than
levels of similar tobacco products currently on the market (see section
VIII.B.9.a.v), whether the use of the tobacco product has a lower risk
of disease than the use of a similar product (see section
VIII.B.13.a.ii), whether consumers are likely to use the product in a
manner that will lead to possible lower risks (see section
VIII.B.13.a.iv), and whether the marketing of the new tobacco product
affects the likelihood of nonuser uptake, ways in which the product may
be designed to limit or prevent youth access and use, cessation rates
or other significant shifts in user demographics such that it decreases
morbidity and mortality from tobacco product use, including youth,
young adults, and other vulnerable populations (see section
VIII.B.6.b). As described in this section, the APPH standard requires a
balancing of product-specific potential risks and benefits. For
example, an applicant maybe able to demonstrate that their product is
APPH by providing sufficient valid scientific evidence to show, among
several key considerations, that the tobacco product reduces morbidity
and mortality. This could include showing the potential reductions in
disease risk as compared to other tobacco products and weighing that
against the potential for nontobacco users to use tobacco product and
the accompanying potential changes in disease risk among new tobacco
users. As a result, the factors that could help demonstrate that the
marketing of a particular new tobacco product would be APPH might not
support the marketing of a different new tobacco product. As a general
example, if an application demonstrates that using a new tobacco
product would present significantly less toxicological risk to
individual health than cigarettes in a marketplace where many addicted
users currently smoke cigarettes, it could likely, depending on other
factors, receive an order where the PMTA demonstrates that the vast
majority of individuals who would use the product would be current
users of cigarettes who otherwise would not have quit and would switch
to using the new product exclusively. This can be seen in FDA's
determination to authorize the marketing of a tobacco product that
demonstrated, among several key considerations, that the product
produced fewer or lower levels of some

toxins than conventional cigarettes.\38\ On the other hand, where a
PMTA for a different tobacco product shows that individuals that would
use the new tobacco product are predominately current users of tobacco
products that have less toxicological risk to individual health,
including products within the same product category, the application is
likely, again depending on other factors, to result in the issuance of
a marketing denial order because the product is not likely to have a
net benefit to the population as a whole. As discussed in section
VIII.B.14, understanding of the effect the new tobacco product may have
on the health of the population as a whole, which includes youth, young
adults, and other vulnerable populations, such as effects on tobacco
use initiation, switching, and cessation, and reductions in premature
mortality, or increases in life-years lived, directly informs FDA's
determination as to whether permitting the marketing of the new tobacco
product would be APPH. The discussion should include all of the
information in the PMTA regarding the product and its potential effects
on health, including, but not limited to adverse experiences, tobacco
use behavior, and tobacco use initiation to provide an overall
assessment of the potential effect that permitting the product to be
marketed has or may have on overall tobacco-related morbidity and
mortality including on youth, young adults, and other vulnerable
populations.
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    In addition to the information provided throughout this document,
applicants may obtain information regarding how the APPH standard can
be met from marketing granted orders and decision memoranda that FDA
posts on its website.
    (Comment 103) One comment stated that where an applicant proposes a
restriction on the marketing of its product, such as a limitation on
sales, FDA should apply that restriction in making its APPH
determination.
    (Response 103) FDA will consider proposed restrictions on the sales
and distribution of a tobacco product as part of its review of a PMTA
and may determine that it should impose such restrictions where FDA
determines they are APPH. However, FDA's review is not constrained by
such proposals and FDA intends to consider a variety of factors in
determining whether it should include those restrictions, including,
but not limited to, whether it would be feasible or realistic for the
applicant to implement such restrictions, or the ease with which the
implementation of the restrictions may be monitored or enforced as they
pertain to all population groups, including among groups
disproportionately affected by tobacco product use. FDA will also
consider and may impose restrictions on sales and distribution
different from, or in addition to, those proposed by the applicant.
    (Comment 104) One comment stated that FDA should focus its
evaluation on the population segments most likely to be affected by the
marketing of the new tobacco product and require applicants to show a
public health benefit for those specific groups.
    (Response 104) FDA declines to make changes in response to this
comment. FDA is required by section 910(c)(4) of the FD&C Act to
determine its APPH finding based upon the risks and the benefits to the
population as a whole. This includes consideration of all parts of the
population, including those more likely to be affected by the marketing
of the new tobacco product, and it is not limited to only the effect on
specific population segments.
    (Comment 105) One comment requested a clear regulatory definition
of the APPH standard, with product category-specific guidance about
what is required to meet the target, noting that it is missing from the
proposed rule and is crucial for applicants as they develop the data
needed to substantiate that a new tobacco product meets the APPH
standard and prepare their applications. The comment recommended that
FDA provide further clarity in the final rule as to the factors to be
considered in an APPH analysis and how the Agency will weigh those
factors. The comment requested that FDA provide clarification as to
whether a showing of reduced morbidity and mortality is required to
receive a marketing order, asserting that the structure of the statute
and congressional intent make clear that Congress intended a marketing
order under section 910 of the FD&C Act to be a less burdensome
standard than the standard for a marketing order for a modified risk
product under section 911of the FD&C Act. The comment also requested
additional information regarding how FDA will determine whether a
product has had a net positive effect on the health of the population
as a whole, including whether each factor has a threshold finding.
    (Response 105) FDA declines to set static requirements that a new
tobacco product could meet and be considered to meet the APPH standard
because the tobacco product marketplace and trends in consumer behavior
that inform FDA's APPH determination are not static. The factors that
could demonstrate that permitting the marketing of a new tobacco
product would be APPH at one point in time might not support the same
determination with respect to a similar product in the future. For
example, FDA may consider, in conjunction with other available data
regarding the new tobacco product, information showing that a product
has reduced morbidity and mortality to help demonstrate that the
potential risks and benefits of marketing the new tobacco product would
have a net positive effect on the health of the population as a whole
(which includes youth, young adults, and other vulnerable populations).
    However, FDA does not make its APPH determination on one static set
of requirements. FDA makes its APPH determination in consideration of
the existing market (e.g., the products on the market, tobacco product
use behaviors) at the time the determination is made. For example, FDA
has authorized marketing of a product that would, among other things,
potentially reduce nicotine dependence in adult smokers who may also
benefit from decreasing nicotine exposure and cigarette consumption. In
consideration of the existing market and based on the information
provided by the applicant, FDA was able to determine that nonsmokers,
including youth, would also be unlikely to start using the product, and
those who experiment would be less likely to be become addicted than
people who experiment with conventional cigarettes. \39\ As the tobacco
product market changes over time, the potential risks and benefits of
marketing a new tobacco product to the population as a whole might also
change. A new tobacco product that receives a marketing granted order
under the current market conditions might not receive an order at a
future time in which fewer individuals are using products that present
higher levels of risk to individual health or such products are no
longer on the market. Due to the nature of the Federal rulemaking
process, if FDA were to codify what could satisfy the APPH standard
under market conditions that are current at the time, FDA may not be
able to update such standards in a timely manner.
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    (Comment 106) Several comments stated that FDA has failed to
explain or

justify how it is interpreting and applying the APPH standard when
evaluating PMTAs and must do so to allow a determination of whether its
issuance of PMTA marketing orders is arbitrary and capricious. In
addition, some comments were concerned that the lack of articulated
definitions and standards regarding the APPH standard would leave
applicants guessing at what might satisfy the standard. In addition,
another comment stated that failing to provide this essential direction
could increase the likelihood of arbitrary and inconsistent decisions.
    (Response 106) FDA disagrees with the assertion that is has failed
to provide direction concerning the APPH standard in section 910(c)(2)
of the FD&C Act. FDA describes its interpretation of the APPH standard
in details in this section, including the statement that FDA intends to
consider the marketing of a new tobacco product to be APPH where a PMTA
contains sufficient valid scientific evidence to demonstrate that the
potential risks and benefits of the marketing of the new tobacco
product would have a net positive effect on the health of the
population as a whole.
    (Comment 107) Multiple comments stated that FDA should require that
PMTAs contain information demonstrating that all available steps have
been taken to make the product as minimally harmful as possible in
order for the marketing of a tobacco product to be considered APPH.
    (Response 107) As described in section IX.D, FDA interprets the
APPH standard in section 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. Where an applicant meets this standard
along with the other criteria in section 910(c)(2) of the FD&C Act, FDA
will issue a marketing granted order.
    (Comment 108) Multiple comments stated that FDA should impose a
number of conditions that products must meet to receive a marketing
granted order. One comment stated FDA should apply a more rigorous
standard than it did in previous PMTA reviews by requiring an applicant
demonstrate, among other things that its product is significantly less
harmful than other products current on the market and that any increase
in health risks is significantly smaller than the likelihood and size
of the benefits it presents. Another comment stated FDA should impose
specific requirements that a flavored tobacco product must meet to
receive a marketing granted order, including requirements such as
having no appeal to youth, being substantially less harmful than
smoking, and promoting complete cessation of tobacco products.
    (Response 108) FDA declines to create a series of criteria that
either all products or a specific subset of products must meet be in
order for marketing of such products to be considered APPH as part of
this rule. As described elsewhere in this section, FDA intends to
consider marketing of a new tobacco product to be APPH where permitting
its marketing 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. While
this determination would involve consideration of many factors,
including some of the particular concerns cited by the comments, it
will be made with respect to the risks and benefits to the health of
the population as a whole, rather than whether a product meets each
item in a series of specific criteria.
    (Comment 109) Multiple comments made suggestions regarding how FDA
should consider the risks and benefits that the marketing of the new
tobacco product may have on specific groups of the population, with one
comment emphasizing social justice concerns and highlighting the
effects that the new tobacco product may have on disadvantaged or
vulnerable populations. Another comment stated that the FD&C Act does
not permit FDA to weigh the risks and benefits a product may have on
one group more strongly than another.
    (Response 109) Section 910(c)(4) of the FD&C Act requires the
finding of whether the marketing of a new tobacco product would be APPH
to be determined with respect to the population as a whole. As noted
elsewhere in this document, FDA has made edits to ensure the rule
addresses the potential effects of permitting the marketing of a new
tobacco product to vulnerable populations and FDA will consider the
potential effects on such groups as part of its assessment of the
effect on the population as a whole.
    It is important to note that in order for FDA to issue a marketing
granted order for a new tobacco product, section 910(c)(1)(A)(i) of the
FD&C Act requires FDA to find there is ``a showing'' that the marketing
of the new tobacco product would be APPH. FDA interprets this to mean
that an applicant must submit sufficient information in its PMTA for
FDA to be able to find whether the marketing of a product would be
APPH. While FDA may consider outside sources of information during PMTA
review, an applicant cannot rely on FDA to seek out or create
additional data to fill information gaps that may exist in a PMTA. As
discussed in section VIII.E., failure to submit sufficient information
that FDA needs to make its required findings would result in the
issuance of a marketing denial order.
    This rule focuses primarily on PMTA review procedures and content
requirements, particularly with respect to application acceptance and
filing. An application may meet the acceptance and filing requirements,
but still lack vital information that FDA needs to determine whether it
should issue a marketing granted order. The rule creates a requirement
to submit full reports of all existing health risk investigations;
however, where there is not sufficient existing evidence that an
applicant may utilize to demonstrate that the marketing of a new
tobacco product would be APPH, an applicant would need to conduct its
own investigations to ensure that FDA has sufficient valid scientific
evidence it needs to determine whether a marketing granted order should
be issued for the new tobacco product.
    Although an applicant may submit any type of evidence to FDA in an
attempt to substantiate that the new tobacco product should receive a
marketing granted order, FDA relies upon only valid scientific evidence
to determine whether the marketing of the new tobacco product would be
APPH.
    (Comment 110) One comment stated that FDA should require the full
report of each study to identify the source of funding and give less
weight to the results of industry research than to independent
scientific research and should explicitly consider bias in industry
studies.
    (Response 110) FDA declines to make changes as a result of this
comment FDA's determination of whether there's a showing that
permitting the marketing of a new tobacco product would be APPH must be
determined on the basis of valid scientific evidence. FDA assesses all
scientific evidence with the same rigor to determine whether it is
valid, regardless of the source.
    (Comment 111) One comment stated that FDA must require long-term
clinical studies because it impossible to determine the risks and
benefits of a tobacco product without them.
    (Response 111) Long-term clinical studies can provide information
that is important to FDA's review; however, the FD&C Act grants FDA the
authority to consider other valid scientific evidence in making its
APPH determination. Section 910(c)(5) of the

FD&C Act explains that APPH ``shall, when appropriate, be determined on
the basis of well-controlled investigations.'' This section also
explains that FDA may base its APPH determination on ``valid scientific
evidence (other than evidence derived from [well-controlled
investigations]) which is sufficient to evaluate the tobacco product.''
As discussed in this section, FDA does not expect that long-term
clinical studies will need to be conducted for each PMTA; instead, it
expects that it should be able to rely on other valid scientific
evidence to evaluate some PMTAs.
    FDA will determine whether the evidence submitted or otherwise
available to FDA is valid scientific evidence for the purpose of
determining the new tobacco product's impact on individual and
population health, and whether the available evidence, when taken as a
whole, is adequate to support a determination that permitting the new
tobacco product to be marketed would be APPH.
    Valid scientific evidence includes data from well-controlled
investigations, as well as other sources upon which FDA may base its
determinations under section 910(c)(5) of the FD&C Act. Other sources
may include partially controlled studies, studies and objective trials
without matched controls, and well-documented case histories conducted
by qualified experts. The other sources of study data may be considered
valid scientific evidence if they have been gathered using well-
established or standardized methodologies from which it can fairly and
responsibly be concluded by qualified experts that there is reasonable
assurance of the reliability of their findings. The evidence required
may vary according to the characteristics of the tobacco product, its
conditions of use, the existence and adequacy of warnings and other
restrictions, and the extent of consumer experience with its use.
Isolated case reports, anecdotal experiences, reports lacking
sufficient details to permit scientific evaluation, and unsubstantiated
opinions are not considered valid scientific evidence.
    As part of its determination of whether permitting the marketing of
a new tobacco product would be APPH, FDA must be able to determine the
likely health risks of the new tobacco product. While this rule does
not necessarily require applicants to conduct new studies for the
purposes of application acceptance and filing (beyond the requirements
of Sec.  1114.27(b)(1)(ii)), FDA expects that it could not issue a
marketing granted order unless an application contains data from a
variety of sources, including both clinical and nonclinical
investigations that give FDA comprehensive information about the
product's likely health effects in the U.S. market. Where
epidemiological evidence is available and comes from an investigation
using a different product or one that was conducted outside the United
States, FDA would examine whether the PMTA contains sufficient
information, or the applicant has conducted bridging studies when
needed, to demonstrate the data is applicable to the product and the
U.S. population or provides adequate justification for how the
information is relevant. FDA recognizes that this type of long-term
epidemiological data is not available for all categories of products
and does not expect that long-term clinical studies (i.e., those
lasting approximately 6 months or longer) will need to be conducted for
each PMTA; however, in the event long-term clinical study data should
become available for the new product or similar product while the
application is pending, this information should be submitted to FDA in
an amendment.
    Where a PMTA contains no long-term epidemiological evidence
regarding the product or that could be bridged to the product, FDA
would consider whether there are other sources of scientific evidence
that sufficiently demonstrate the potential health risks of the
product, such as actual use studies (e.g., clinical studies that assess
real-world use conditions and health outcomes, or clinical studies that
use scientifically valid endpoints as a predictor for potential long-
term health effects). Where a PMTA lacks human subject study data
regarding the product or that can be bridged to the product, FDA will
examine how a PMTA attempts to estimate the health effects of the
product on the U.S. population from the results of nonclinical
investigations; however, it should be noted that information from
nonclinical studies alone is generally not sufficient to support a
determination that permitting the marketing of the product would be
APPH.
    As part of FDA's consideration of the changes in tobacco product
use behavior that are likely to be caused by the marketing of the new
tobacco product, FDA will examine data regarding how the product, its
label, labeling, and any available advertising, and description of the
applicant's marketing plans will affect the tobacco use behavior of
both users and nonusers of tobacco products, including the behaviors
described in Sec.  1114.7(k)(1)(ii) and (iii). FDA needs sufficient
information to determine the potential changes in tobacco product use
behavior and the health risks and benefits associated with the changes
in user behavior will allow FDA to make a determination of whether
permitting the marketing of the new tobacco product would be APPH.
Where a PMTA does not contain sufficient information for FDA to make
these determinations, FDA will issue a marketing denial order for the
product because the PMTA lacks information necessary to determine the
risks and benefits to the population as a whole as required by section
910(c)(4) of the FD&C Act.
    (Comment 112) Multiple comments stated that a premarket assessment
of a new tobacco product can neither fully nor precisely predict future
tobacco use behavior patterns and recommended that FDA modify the rule
to acknowledge such limitations on premarket research. Another comment
expressed a similar opinion and noted that FDA has postmarket tools,
including the ability to withdraw a marketing granted order to address
unintended consequences.
    (Response 112) FDA disagrees with the implication that it should
discount the importance of information concerning the likelihood of
changes in tobacco product use behavior during application review and,
in essence, shift it to a postmarket determination. As discussed in the
following paragraphs, the burden is on the applicant to make a showing
that the marketing of its new tobacco product would be APPH. Section
910(c)(4) of the FD&C Act requires FDA to consider the likelihood of
changes in tobacco product use behavior in making its APPH
determination and if an application lacks sufficient information to
make this determination, FDA must issue a marketing denial order.
    b. The methods used in and the facilities and controls used for,
the manufacture, processing, or packing of such tobacco product conform
to the requirements of section 906(e) of the FD&C Act. As discussed in
section VII.B.12 regarding Sec.  1114.7(j), FDA has not yet issued a
regulation under section 906(e) of the FD&C Act, so demonstrating
compliance with such regulations in a PMTA is not currently required;
however, FDA plans to issue proposed rulemaking(s) under section
906(e), and once such regulations are effective, applicants must
demonstrate that their methods, facilities, and controls are in
conformance with applicable requirements to receive a marketing granted
order under section 910(a)(1)(i)(A) of the FD&C Act. Until such a final
rule issued under section 906(e) of the FD&C Act is effective, FDA

will evaluate the manufacturing process 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 is appropriate for the
protection of public health. As part of this evaluation, FDA will
consider whether the applicant would be able to consistently produce
the new tobacco product as described in the PMTA. The potential for an
applicant to produce nonconforming tobacco products that have higher
levels of HPHCs than intended, have dangerous foreign material, or
otherwise potentially presents a higher risk of harm than the product
described in the PMTA may affect FDA's determination of whether the
marketing of a product would be APPH.
    (Comment 113) One comment stated that FDA should amend the rule to
address how applicants will be able to address evolving requirements,
such as product standard and manufacturing practice requirements,
especially if changes become effective during application review.
    (Response 113) The regulatory processes that FDA must follow to
issue a product standard under section 907 of the FD&C Act or tobacco
product manufacturing practices under section 906(e) of the FD&C Act
are lengthy and would provide applicants with notice of proposed
requirements well in advance of any change becoming effective. FDA
generally intends to give applicants the opportunity to amend
previously submitted applications to demonstrate conformance with new
requirements under sections 906(e) or 907 of the FD&C Act; however, FDA
may provide directions regarding how to demonstrate conformance in the
text of any such rulemaking.
    c. Based on a fair evaluation of all material facts, the proposed
labeling is not false or misleading in any particular.
    d. The tobacco product is shown to conform in all respects to a
tobacco product standard in effect under section 907 of the FD&C Act or
there is adequate information to justify a deviation from such
standard. A PMTA submitted under the rule is required by Sec.
1114.7(d)(2) to contain a statement identifying all tobacco product
standards issued under section 907 of the FD&C Act that are applicable
to the new tobacco product and a brief description of how the new
tobacco product fully meets the identified tobacco product standard(s)
or justifies a deviation from such standards, if applicable. FDA must
be able to locate the data regarding the tobacco product's compliance
with the product standard and determine that the tobacco product does,
in fact, meet the requirements of the applicable product standard(s)
or, if applicable, deviates from such standards in a way that is
justified. For example, if an applicant submitted a PMTA for a product
that is subject to a product standard limiting the amount of an HPHC
that may be delivered to product users, FDA must be able to verify
though a review of the HPHC testing data contained in the product
formulation section that the product complies with that product
standard. Under section 910(c)(2)(D) of the FD&C Act, FDA will not
issue a marketing granted order for a tobacco product unless a PMTA
demonstrates that it meets any applicable product standard(s), or an
applicant has justified the deviation from such standard, if
applicable.
1. Restriction on the Sale and Distribution of a New Tobacco Product in
a Marketing Granted Order
    Section 1114.31(b) describes restrictions and additional
requirements that FDA may include as part of a marketing granted order.
Under section 910(c)(1)(B) of the FD&C Act, FDA may require the sale
and distribution of the tobacco product be restricted to the extent
that the sale and distribution of a tobacco product may be restricted
under a regulation under section 906(d) of the FD&C Act. Section
1114.31(b)(1) reiterates this authority as part of the rule and Sec.
1114.31(b)(2) allows FDA to include restrictions on sales and
distribution proposed by the applicant in its PMTA as part of a
marketing granted order.
    A number of comments suggested that FDA impose a number of specific
restrictions on the sales and distribution of tobacco products under
the rule, as discussed below.
    (Comment 114) One comment stated that the rule should be amended to
require age verification for all websites and social media, and to
prohibit the use of partners, sponsors, influencers, bloggers, or brand
ambassadors to market or promote the product.
    (Response 114) FDA declines to revise the rule in response to this
comment because, at this time, FDA intends to consider which
restrictions on sales and distribution should be included in a
marketing granted order for a new tobacco product on a case-by-case
basis.
    (Comment 115) One comment stated that FDA should amend the rule to
require preauthorization of all advertising and marketing materials
during an initial 5-year period that a new tobacco product is permitted
on the market.
    (Response 115) FDA declines to make this revision because it is in
conflict with section 903(b) of the FD&C Act.
    (Comment 116) One comment stated that FDA should require each
marketing granted order to include all available restrictions on the
product packaging, labeling, marketing, sale, including the use of
restrictions that require products to be sold with additional labeling
and marketing requirements that would reduce the risk of youth exposure
to the product or its advertising while also reducing the likelihood of
increased tobacco-related harms and risks for current users. For
example, FDA could require revisions to an ENDS product nicotine
warning statement to include information such as the product is meant
only as a complete substitute for traditional smoking and any other use
will increase harms or risks to the user's health. The comment further
stated that FDA must take advantage of readily accessible means in its
issuing of marketing granted orders to avoid or reduce any unnecessary
individual or public health harms or risks. The comment stated the
belief that FDA's failure to implement or consider these types of
restrictions to reduce the risk of harm of these products could lead to
FDA being found arbitrary and capricious under the Administrative
Procedure Act.
    (Response 116) FDA agrees with the comment's general point that
restricting the sales and distribution of a new tobacco product is an
important way in which FDA can potentially limit the health risks of a
new tobacco product. FDA intends to consider whether and which
restrictions are appropriate for the marketing of a new tobacco product
under section 910(c)(1)(B) on a case-by-case basis during substantive
review. FDA disagrees with the comment's broad assertion, which
suggests that FDA is required to impose certain restrictions in every
marketing order, when the FD&C Act does not so require.
    (Comment 117) One comment requested that FDA, in issuing a marketed
granted order, explicitly prohibit the marketing of a product in any
way that targets vulnerable populations unless it only reaches users of
more harmful tobacco products or users of more harmful products who
have already switched.
    (Response 117) FDA agrees with the general principle that a new
tobacco product should be marketed in ways that will not increase the
health risks to vulnerable populations. FDA declines to implement a
blanket restriction on the scope of permissible advertising as part

of this final rule and instead will consider restrictions on the sales
and distribution of a new tobacco product under Sec.  1114.31(b)(2) on
a case-by-case basis for each new tobacco product that meets the
requirements to receive a marketing granted order.
2. Requirements for Postmarket Records and Reports in a Marketing
Granted Order
    Section 1114.31(b)(3) allows FDA, using its authority in section
910(f) of the FD&C Act, to require an applicant to submit postmarket
reports in addition to those described in Sec.  1114.41, as
appropriate. This can include, but is not limited to, requirements that
an applicant provide information such as labeling, advertising,
marketing, promotional materials, or marketing plans not previously
submitted to FDA, and do so at least 30 days prior to the initial
publication, dissemination to consumers, or use in engaging or
communicating with consumers of such materials. Similar to what is
described in section VII.B.6, these items provide information that is
important to FDA's determination of whether the continued marketing of
the new tobacco product would be APPH or whether FDA must withdraw the
marketing granted order under section 910(d)(1)(A) of the FD&C Act
because the marketing of the new tobacco product is no longer APPH.
Receiving this information in advance of its first use is not for pre-
approval but will allow FDA to ensure it can appropriately track and
monitor the impact that the use of such information has on tobacco use
behavior. In addition, if needed, this information will allow FDA to
provide applicants with advisory comments, including any concerns about
possible impact on youth appeal and tobacco use initiation and with
regard to the finding that the continued marketing of the product is
appropriate for the protection of public health. FDA anticipates it
will use this authority on a case-by-case basis, especially as it
relates to novel tobacco products for which the body of knowledge is
still growing.

E. Issuance of a Marketing Denial Order (Sec.  1114.33)

    Section 1114.33 describes the circumstances under which FDA would
issue a marketing denial order for a new tobacco product after PMTA
review. Section 1114.33(a)(1) specifies that based on the information
submitted as part of the application and any other information before
FDA with respect to the new tobacco product, FDA will issue a marketing
denial order if any of the grounds for denial listed in 910(c)(2) of
the FD&C Act apply to the application. Any other information before FDA
may include, for example, information received from a TPSAC report,
toxicological information regarding a particular ingredient or
combination of ingredients (e.g., diacetyl) from peer reviewed research
results that were published after the PMTA was submitted, or
preliminary results from a study that FDA is aware of (e.g., a Tobacco
Centers of Regulatory Science study).
    As discussed elsewhere in this document, meeting the requirements
for application acceptance and filing does not mean that an application
has sufficient information to receive a marketing granted order. For
example, while FDA may accept and file an application that contains the
information in Sec.  1114.7(k), FDA will not issue a marketing granted
order unless that information also makes a showing that permitting the
marketing of a new tobacco product would be APPH. While the rule does
not necessarily require the applicant to conduct studies on its
product, applicants would need to do so for products for which
insufficient information exists to demonstrate whether marketing of the
product is APPH. Similarly, the information required in the
manufacturing section of the application is required for acceptance and
filing; however, unless the manufacturing process described ensures a
product will be consistently produced as described in a PMTA (e.g.,
implementing sufficient controls), an applicant would receive a
marketing denial order.
    Examples of when FDA would be required to issue a marketing denial
order for a lack of information necessary to make its required findings
and determinations under sections 910(c)(2) and (c)(4) of the FD&C Act
are contained throughout this document and include, but are not limited
to, a lack of sufficient information regarding:
     The health risks of the new tobacco product;
     a comparison of the new tobacco product to the health
risks of other tobacco products used by individuals that the applicant
expects to use the new tobacco product, including products both within
the same category as the new tobacco product and at least one different
product category;
     the abuse liability of the new tobacco product;
     potential changes to tobacco product use behavior of
current tobacco product users;
     the increased or decreased likelihood that those who do
not use tobacco products will start using tobacco products;
     the impact of the product and its label, labeling, and
advertising, to the extent that advertising has been developed and
studied, on individuals' perception of the health risks of the product
and their use intentions; and
     how human factors can influence the health risks of the
new tobacco product.
    Section 1114.33(a) also allows FDA to issue a marketing denial
order where the applicant does not permit an authorized FDA employee,
at a reasonable time and a reasonable manner, an opportunity to: (1)
Inspect the facilities and controls, and sites and entities involved
with clinical and nonclinical research (including third parties and
contract research organizations) described in the application or (2)
have access to, copy, and verify all records pertinent to the
application, where such refusal prevents FDA from making the required
findings in 910(c) necessary to issue a marketing granted order. FDA
would issue a marketing denial order where an applicant does not permit
these inspections because the ability to access and inspect the
facilities and controls and sites and entities involved with clinical
and nonclinical research, as well as pertinent records, is important to
FDA's ability to determine whether any of the denial criteria specified
in section 910(c)(2) of the FD&C Act and Sec.  1114.33(a)(1) apply to
the application. Inspecting the facilities and controls described in
the application will allow FDA to ensure the applicant can manufacture
the product in accordance with the manufacturing practices described in
the application. Inspecting records, including those required to be
kept under Sec.  1114.45, will allow FDA the opportunity to verify the
study findings and data that the applicant relies upon in the PMTA to
demonstrate that the new tobacco product should receive a marketing
granted order. As stated in Sec.  1114.45, the records would be
required to be legible and written in English.
    If FDA issues a marketing denial order, it will, where practicable,
identify measures to address the reasons for which the application is
being denied. While FDA will identify the deficiencies that resulted in
the marketing denial order, the deficiencies specified in the order
might not be an exhaustive listing of all deficiencies contained in the
PMTA.
    FDA received several comments regarding issuance of marketing
denial order, as discussed below.

    (Comment 118) One comment stated that Sec.  1114.33(a) should be
amended to provide that FDA will issue a marketing denial order if,
after considering outside sources of information during PMTA review,
FDA finds that the new tobacco product is not appropriate for the
protection of the public health.
    (Response 118) We have edited Sec.  1114.33 to make it clear that
FDA's issuance of a marketing denial order will be made, as required by
section 910(c)(2) of the FD&C Act, on the basis of information
submitted as part of an application and any other information before
FDA with respect to the new tobacco product. If, during substantive
review, FDA considers information outside of a PMTA that leads FDA to
find that one or more of the grounds for denial in section 910(c)(2) of
the FD&C Act apply, FDA intends to issue a marketing denial order for
the new tobacco product.
    (Comment 119) One comment stated that FDA should consider any
public comments submitted in response to MRTP applications for the same
new product that is the subject of the PMTA and FDA's assessment of
these public comments should be explicitly addressed in any PMTA
marketing order.
    (Response 119) Under section 910(c)(2) of the FD&C Act, FDA will
determine whether a PMTA should be denied on the basis of the
information in a PMTA and any other information before FDA with respect
to such tobacco product. Where public comments on an MRTPA for the same
product are before FDA during its consideration of a PMTA, FDA
generally intends to consider those comments where relevant and clearly
applicable to the marketing of the new tobacco product without modified
risk information. FDA declines to explicitly address its assessment of
public comments in a marketing granted order because it would further
delay FDA's action on an application and a marketing granted order is
not an appropriate venue to address comments to an MRTPA.
    (Comment 120) One comment stated that Sec.  1114.33 should be
revised to include dual use and deterrence of complete quitting of all
tobacco products as factors that FDA must explicitly consider when
deciding whether to issue a marketing denial order.
    (Response 120) Section 1114.33 incorporates the grounds for denial
set forth in section 910(c)(2) of the FD&C Act, which FDA interprets to
require consideration of these tobacco product use behaviors. In
determining whether permitting the marketing of the new tobacco product
would be APPH, FDA will consider dual use and potential changes to
cessation as part of its determination of the risks and benefits to the
health of the population as a whole.
    (Comment 121) One comment suggested that FDA amend Sec.  1114.33 to
specifically state that FDA will issue a marketing denial order where
FDA is unable to determine the impact that the labeling, advertising,
marketing, and promotion of the new tobacco product may have on
consumer perceptions and use intentions.
    (Response 121) FDA considers information regarding consumer
perceptions and use intentions to be an important part of PMTA review.
If a PMTA does not contain sufficient information for FDA to determine
that permitting the marketing of the product would be APPH, including
impact on tobacco product and use intentions, it cannot authorize the
marketing of the new tobacco product. FDA recently issued a draft
guidance for public comment regarding scientific issues for applicants
to consider as they design and conduct tobacco product perception and
use intention studies to support tobacco product applications. For more
information, please see the guidance for industry entitled ``Tobacco
Products: Principles for Designing and Conducting Tobacco Product
Perception and Intention Studies.'' \40\
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    \40\ Available at https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
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    (Comment 122) Several comments requested that FDA issue marketing
denial orders for all products that meet certain criteria or in certain
product categories, including flavored tobacco products, hookah,
cigarillos, and little cigars. The comments asserted that FDA should
deny all PMTAs for specific products because there is little or no
evidence of health benefits and they are attractive to youth.
    (Response 122) FDA declines to make revisions in response to these
comments because the FD&C Act requires FDA to make an individualized
determination of whether to deny an application based on the risks and
benefits of a specific tobacco product to the health of the population
as a whole (which includes youth, young adults, and other vulnerable
populations).

F. Withdrawal of a Marketing Granted Order (Sec.  1114.35)

    Section 1114.35 describes the grounds and procedures for
withdrawing a marketing granted order for a new tobacco product. FDA
will move to withdraw an order in the following situations:
1. Any of the Grounds for Withdrawal Under Section 910(d)(1) of the
FD&C Act Apply
    These grounds include situations in which FDA finds that the
continued marketing of the tobacco product is no longer APPH. The
marketing of a product may no longer be APPH in several situations,
including, for example, where there are changes to tobacco product use
behaviors that were not expected in FDA's assessment of the PMTA (e.g.,
more nonusers of tobacco products are initiating use with the product
than expected and/or fewer users of potentially more harmful products
are switching to the potentially less harmful new tobacco product).
Another example is where studies conducted after the issuance of the
marketing granted order show that the product presents greater risks to
health than FDA understood during application review and, as a result,
the product likely has or will have a net negative impact on the health
of the population as a whole (which includes youth, young adults, and
other vulnerable populations).
    FDA also interprets section 910(d)(1)(A) of the FD&C Act to provide
for the withdrawal of a marketing granted order where changes to the
tobacco product marketplace result in FDA finding that the marketing of
a product is no longer APPH:
     The application contained or was accompanied by an untrue
statement of material fact;
     the applicant has failed to establish a system for
maintaining records, or has repeatedly or deliberately failed to
maintain records or make reports required by part 1114 or another
applicable regulation under section 909 of the FD&C Act;
     the applicant has refused to permit access to, or copying
or verification of, records as required by section 704 of the FD&C Act;
     the applicant has not complied with the requirements of
section 905 of the FD&C Act;
     on the basis of new information before the Secretary with
respect to such tobacco product, evaluated together with the evidence
before the Secretary when the application was reviewed, that the
methods used in, or the facilities and controls used for, the
manufacture, processing, packing, or installation of such tobacco
product do not conform with the requirements of section 906(e) of the
FD&C Act and were not brought into conformity with such requirements
within a reasonable time after receipt of

written notice from the Secretary of nonconformity;
     on the basis of new information before the Secretary,
evaluated together with the evidence before the Secretary when the
application was reviewed, that the labeling of such tobacco product,
based on a fair evaluation of all material facts, is false or
misleading in any particular and was not corrected within a reasonable
time after receipt of written notice from the Secretary of such fact;
or
     on the basis of new information before the Secretary,
evaluated together with the evidence before the Secretary when such
order was issued, that such tobacco product is not shown to conform in
all respects to a tobacco product standard which is in effect under
section 907 of the FD&C Act, compliance with which was a condition to
the issuance of an order relating to the application, and that there is
a lack of adequate information to justify the deviation from such
standard.
    FDA received comments regarding grounds for withdrawal, as
discussed below.
    (Comment 123) Multiple comments requested that FDA provide more
clarity with regard to how the APPH standard may change over time with
respect to determining whether a marketing granted order should be
withdrawn. One comment noted concerns regarding the example FDA
provided in section IX.F of the preamble to the proposed rule that
appears to contemplate FDA withdrawing marketing orders under section
910(d)(1)(A) of the FD&C Act based on only the issuance of a product
standard. The comment also stated that FDA should use the PMTA pathway
to further the principles of tobacco product harm reduction and the
potential for marketing orders to be withdrawn after an unduly short
period of time or on an unpredictable basis may discourage
manufacturers from investing the significant resources necessary to
bring harm-reducing products to market.
    Another comment suggested that FDA develop a more systematized
approach to determining whether the marketing of a product is no longer
APPH. The comment suggested that because substantial shifts in consumer
use of tobacco products are unlikely in the short term, FDA should
determine whether marketing of a product is no longer APPH by comparing
the product to a single comparator product in the same product class as
the new tobacco product and that is used by the majority of likely
users of the new tobacco product. The comment also requested that FDA
reevaluate its APPH determination no sooner than 5 years after the
issuance of a marketing granted order, noting that this approach is
consistent with section 911 of the FD&C Act for the marketing of MRTPs
and would allow FDA to use its authority to temporarily suspend a
marketing order if significant health issues needed to be addressed
before the end of the 5-year period.
    (Response 123) FDA disagrees with the comment's characterization of
the APPH standard as changing over time. As described in this document,
FDA interprets the APPH standard in 910(c)(2) of the FD&C Act as
requiring the marketing of a new tobacco product to likely present a
net benefit to the health of the population as a whole to receive a
marketing order. FDA interprets section 910(d)(1)(A) of the FD&C Act
consistently to require that FDA withdraw a marketing granted order
where FDA is no longer able to find that the marketing of the new
tobacco product likely presents a net benefit to public health. Because
market conditions will change over time, what might be APPH at one
point in time may no longer be APPH in the future. Examples of changes
that could affect FDA's determination that the marketing of the product
is APPH could include the example from the proposed rule mentioned by
the comment: FDA's implementation of a tobacco product standard
pursuant to section 907 of the FD&C Act that alters the relative health
risks presented by other tobacco products. For instance, if FDA issued
a marketing granted order for a new (non-cigarette) tobacco product, in
part, because it presented significantly lower risks to individual
health than cigarettes, and FDA later implemented a product standard
that significantly lowered the health risks of cigarettes, FDA may
determine that the continued marketing of the new (non-cigarette)
tobacco product is no longer APPH. If FDA were to be unable to consider
changing market conditions when evaluating whether the marketing of a
new tobacco product continues to be APPH after it is granted a
marketing granted order, FDA would potentially be unable to address the
continued marketing of products that have higher levels of relative
health risks, thus undermining its core statutory mandate to reduce the
harm caused by tobacco product use. Accordingly, FDA declines to limit
its consideration of whether a product continues to be APPH to just one
comparator product in the same product category, as suggested by the
comment.
    The example regarding the issuance of a product standard that
changes the health risks to current tobacco product users is a general
example of a circumstance that could affect whether the marketing of a
new tobacco product continues to be APPH. This example does not dictate
that marketing orders for a different category of tobacco products must
be withdrawn should such a product standard be implemented; rather, the
determination of whether a marketing order should be withdrawn under
section 910(d)(1)(A) of the FD&C Act would be made on a fact-specific
basis for each new tobacco product based on whether its marketing
continues to be APPH and a change to the health risks presented by a
tobacco product category an applicant relied on to demonstrate a likely
net benefit to public health may affect this APPH determination.
    FDA also notes that marketing granted orders do not come with a
guaranteed time duration. Applicants concerned about the effect of
tobacco product standards on the PMTA pathway should consider the
process required under section 907 of the FD&C Act to issue and
implement product standards and make business decisions accordingly.
FDA also declines to establish a minimum 5-year period in which
applicants may market a new tobacco product without having its APPH
determination reassessed. FDA intends to review new information
regarding the health risks of tobacco products and changes in tobacco
product use behavior, including information submitted as part of
periodic and adverse experience reports, on an ongoing basis and
consider whether it affects FDA's APPH determination for any new
tobacco products that have received marketing granted orders. FDA also
notes that, contrary to the assertion in the comment, waiting 5 years
before reevaluating the issuance of a marketing granted order is not
consistent with section 911 of the FD&C Act because 911(j)(1), like
910(d)(1)(A), provides for withdrawal prior to expiration of the order
if standard for authorization is no longer met.
2. Any Postmarket Requirement Imposed by the Marketing Granted Order or
By This Part That Has Not Been Met and Results in FDA Finding That One
or More of the Grounds for Withdrawal Specified in Section 910(d)(1) of
the FD&C Act Apply
    This requirement will allow the withdrawal of a marketing granted
order where an applicant fails to meet requirements imposed by a
marketing granted order or part 1114, including postmarket restrictions
on the sales and distribution of the tobacco product as described in
section VIII.D and results

in FDA finding one or more of the grounds for withdrawal specified in
section 910(d)(1) of the FD&C Act apply.
    FDA received multiple comments on this issue, as discussed below.
    (Comment 124) Multiple comments stated that FDA should include
bright lines or triggers in all marketing orders that would result in
the automatic withdrawal of marketing authorization. One comment stated
that FDA should withdraw or temporarily suspend a marketing order if it
learns from any source that the tobacco product is impacting the health
of youth and young adults, including increases in the percentages of
youth and young adults who report use of the product. Another comment
stated that FDA should set a threshold for problems with nonconforming
products in the manufacturing process and require an order to be
withdrawn if these thresholds are exceeded.
    (Response 124) As set forth in Sec.  1114.35(a)(1), FDA will move
to withdraw a marketing granted order if FDA finds, after due notice
and opportunity for an informal hearing, that the continued marketing
of such tobacco product is no longer APPH. As described throughout the
preamble to the final rule, FDA must make its APPH determination with
respect to the risks and benefits of the population as a whole. FDA
agrees that the potential for nonconforming tobacco products and
underage use of tobacco products are an important consideration in
making this determination and FDA will give them due consideration as
part of its ongoing evaluation of whether the marketing of the tobacco
product is APPH.
    FDA may seek advice on scientific matters from any appropriate FDA
advisory committee in deciding whether to withdraw a marketing granted
order and may use information other than that submitted by the
applicant in deciding whether to withdraw a marketing granted order.
Prior to withdrawing a marketing granted order, FDA will notify the
holder of the marketing granted order of the opportunity for an
informal hearing under 21 CFR part 16. If the holder of the marketing
granted order does not request an informal hearing or if FDA decides to
withdraw the marketing granted order after the informal hearing is
held, FDA will issue an order withdrawing the marketing granted order.
FDA will notify the public that the marketing granted order for the
product has been withdrawn and state the basis for the withdrawal.

G. Temporary Suspension of a Marketing Granted Order (Sec.  1114.37)

    Section 1114.37 describes the grounds and procedures by which FDA
will temporarily suspend a marketing granted order under section
910(d)(3) of the FD&C Act. FDA is required by section 910(d)(3) to
initiate a temporary suspension of a marketing granted order when it
determines that there is a reasonable probability that the continued
distribution of the product will cause serious, adverse health
consequences or death, that is greater than what is ordinarily caused
by tobacco products on the market. FDA interprets this language to mean
serious, adverse health consequences at a rate or of a severity, or
death at a rate, that is greater than what is ordinarily caused by
tobacco product currently on the market. Under the rule, FDA will
notify the holder of the marketing granted order of the opportunity to
hold an informal hearing. If FDA determines after the opportunity for
the informal hearing that the marketing granted order for the tobacco
product should be temporarily suspended, the Agency will issue an order
temporarily suspending the marketing granted order. FDA recommends that
the applicant submit a plan demonstrating how it intends to comply with
the temporary suspension, including a description of how the applicant
will ensure that the tobacco product will not cause or continue to
cause the serious, adverse health consequences or death (or reasonable
probability of such events) that resulted in the temporary suspension,
and the steps the applicant plans to take to ensure that the product is
not further distributed, imported, sold, marketed, or promoted in the
United States. Once FDA temporarily suspends a marketing granted order,
it will proceed expeditiously to withdrawal. Where appropriate, FDA may
combine the notices and hearings for temporary suspension of a
marketing granted order and withdrawal of a marketing granted order
into one notice and hearing. Whether the determinations occur
separately or in one combined proceeding, the determination regarding
temporary suspension and the determination regarding withdrawal will be
made separately by the Agency as the findings are separate and
distinct.

X. Postmarket Requirements (Part 1114, Subpart D)

A. Postmarket Changes (Sec.  1114.39)

    Section 1114.39 describes the scope of a marketing granted order.
FDA issues marketing granted orders for the specific new tobacco
product described in the PMTA.
    FDA received several comments regarding this section, as discussed
below.
    (Comment 125) One comment stated that FDA should issue marketing
orders for e-cigarettes that allow for the independent sale of
components and parts that are identical to the ones contained in the
authorized e-cigarette for use as replacements. The comment stated that
because the components and parts would have already been reviewed as
part of the complete e-cigarette, it would be redundant and unduly
costly to require a company to submit a separate PMTA for an individual
component or part.
    (Response 125) FDA declines to make the revisions suggested by this
comment. Unless an applicant otherwise satisfies the requirements of
premarket review in section 910(a)(2) of the FD&C Act, it must submit a
PMTA and receive a marketing granted order prior to introducing a new
tobacco product, or delivering it for introduction, into interstate
commerce. This requirement applies to both an entire e-cigarette and
its components and parts where sold separately. Applicants seeking to
market an e-cigarette and its components and parts in such a manner
should consider whether a bundled submission containing the information
required to support multiple PMTAs would be appropriate.
    An applicant may not make any modification to the specific product
that is the subject of the order, as any modification to the tobacco
product results in a new tobacco product under the definition in
section 910(a)(1) of the FD&C Act. Changes that do not result in a new
tobacco product, such as manufacturing process changes that do not
modify the finished tobacco product, must be reported under Sec.
1114.41.
    (Comment 126) One comment stated that the proposed requirement in
Sec.  1114.39 is redundant and unnecessary because it is no different
from the plain meaning of section 910(a)(1)(B) of the FD&C Act and,
therefore, should not be included in the final rule.
    (Response 126) FDA declines to remove Sec.  1114.39 because it
serves to emphasize that the requirements of premarket review apply to
modifications to new tobacco products that have already received a
marketing granted order.
    (Comment 127) One comment stated that FDA should clarify the
circumstances in which ``changes'' are considered ``modifications,''
and the

pathways available when modifications are made. The manufacturer stated
that based on its interpretation of the rule, FDA would not require
reporting of any changes that do not rise to the level of modifications
resulting in a new tobacco product, other than the specific types of
manufacturing-related and labeling changes described in proposed Sec.
1114.41.
    (Response 127) FDA has provided numerous examples throughout this
document, and guidance documents,\41\ regarding modifications that
result in a new tobacco product. Under section 910(a)(1)(B) of the FD&C
Act, new tobacco products include those that are new because they have
been rendered new through any modification (including a change in
design, any component, any part, or any constituent, including a smoke
constituent, or in the content, delivery or form of nicotine, or any
other additive or ingredient) of a tobacco product where the modified
product was commercially marketed in the United States after February
15, 2007. The discussion of the definition of the term ``new tobacco
product'' in section VII.B. contains information about what constitutes
a new tobacco product, including the description of modifications to
cigarette paper, container closure systems (e.g., change from glass to
plastic e-liquid vials or from plastic to tin container closures),
product quantity, or tobacco cut size as some examples of changes that
result in a new tobacco product.
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    \41\ Please see ENDS PMTA Guidance and the guidance for industry
entitled ``Demonstrating the Substantial Equivalence of a New
Tobacco Product: Responses to Frequently Asked Questions,'' both of
which are available at https://www.fda.gov/tobacco-products/rules-regulations-and-guidance/guidance.
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    Where an applicant seeks to modify a new tobacco product that has
received a PMTA marketing order, it may choose to seek premarket
authorization through any of the three premarket pathways described in
section VII.B; however, we note that the requirements of the PMTA
pathway are distinct from those of the SE pathway. Under the SE
pathway, an applicant must rely on a tobacco product that was
commercially marketed (other than for test marketing) in the United
States as of February 15, 2007, or a tobacco product that FDA has
previously found substantially equivalent under section 910(a)(2)(A)(i)
of the FD&C Act; the issuance of a PMTA marketing order would not
independently create a valid predicate product for use in the SE
pathway. Therefore, an applicant seeking to modify a new tobacco
product that has received a PMTA marketing order (and does not have a
corresponding SE order), has three options to receive premarket
authorization: (1) It could submit a new PMTA for the product with the
modifications; (2) depending on the type of modification, it could seek
authorization through the SE exemption pathway; or (3) it could seek
authorization through the SE pathway relying on a valid predicate,
i.e., a product FDA has previously found SE or a product that was
commercially marketed in the United States (other than for test
marketing) as of February 15, 2007. The modifications for which an SE
exemption request may be submitted are set forth in Sec.  1107.1. The
circumstances under which an applicant may submit a supplemental PMTA
for a new tobacco product that results from a modification or
modifications to the original tobacco product that received a marketing
granted order are described in section VIII.F.
    Marketing a new tobacco product without required premarket
authorization would render the product adulterated under section
902(6)(A) of the FD&C Act and misbranded under section 903(a)(6) of the
FD&C Act and subject to an FDA enforcement action.

B. Reporting Requirements (Sec.  1114.41)

    Section 1114.41 requires applicants that receive a marketing
granted order to submit postmarket reports. FDA is requiring postmarket
reports under the authority of section 910(f) of the FD&C Act, which
requires applicants to establish and maintain records and make reports
that FDA requires as necessary to determine or facilitate a
determination of whether there may be grounds to withdraw or
temporarily suspend a marketing granted order. In addition, under
section 909 of the FD&C Act, FDA is permitted to require the reporting
of information to assure that a tobacco product is not adulterated or
misbranded and to otherwise protect public health. Section Sec.
1114.41 describes the reports that FDA requires through this
regulation; however, FDA may require additional reporting in an
individual applicant's marketing granted order.
    Applicants are required under Sec.  1114.41 to submit two types of
reports after receiving a marketing granted order: Periodic reports and
adverse experience reports. Applicants must submit periodic reports
within 60 calendar days of the reporting date specified in the
marketing granted order (or potentially sooner if they choose to use
the application as the basis for a supplemental PMTA under Sec.
1114.15). FDA anticipates that the reports will be required on an
annual basis, but FDA may require, by a specific order, that reports be
made more or less frequently depending upon a number of factors (e.g.,
the novelty of the type of product).

C. Requirements for Periodic Reports

    Applicants must submit the following information electronically
together with the appropriate form (Ref. 140) as part of each periodic
report under Sec.  1114.41(a)(1). The materials provided in these
reports can provide important information regarding whether the
marketing of the product is no longer APPH under section 910(d)(1)(A)
of the FD&C Act or whether the marketing granted order should be
temporarily suspended under section 910(d)(3) of the FD&C Act:
     A cover letter that includes basic identifying
information, such as the product name(s) (including the original
product name, if different) and application STN;
     a full description of the changes made to the methods used
in, and the facilities and controls used for, the manufacture,
processing, and, when relevant, packing and installation of, such
tobacco product, if any, during the reporting period. This description,
which we are requiring under section 909 of the FD&C Act, must include
sufficient information for FDA to determine whether a change to methods
used in, and the facilities and controls used for, the manufacture,
processing, and, when relevant, packing and installation of, such
tobacco product results in a new tobacco product or do not conform to
the requirements of section 906(e) and potentially be a basis to
withdraw or temporarily suspend the marketing granted order. This
information includes a comparison to the methods used in, and the
facilities and controls used for, the manufacture, processing, and,
when relevant, packing and installation of, such tobacco product,
described in the PMTA, the rationale for making the change, and an
explanation of why the change does not result in a new tobacco product
and why there are no grounds for FDA to withdraw or temporarily suspend
the marketing granted order on the basis of the change (i.e., the
marketing of product continues to be APPH, the manufacturing process
complies with the requirements of section 906(e) of the FD&C Act, and
the product still conforms to any product standards under section 907
of the FD&C Act);
     An inventory of all ongoing and completed studies about
the tobacco product conducted by, or on behalf of, the applicant that
are within the scope of Sec.  1114.7(k) and were not already submitted
as part of the PMTA or

previous postmarket reports. These reports can provide important
information regarding health risks or changes in tobacco product use
behavior, including initiation, which helps FDA determine whether the
marketing of the product is no longer APPH under section 910(d)(1)(A)
of the FD&C Act;
     full reports of information (as described in Sec.
1114.7(k)(3)) published or known to, or which should reasonably be
known to, the applicant concerning scientific investigations and
literature about the tobacco product that would be required in a PMTA
under Sec.  1114.7(k)(1) not previously submitted as part of the PMTA
or previous postmarket reports, including significant findings from
publications not previously reported;
     a summary and analysis of all serious and unexpected
adverse experiences associated with the tobacco product that have been
reported to the applicant or that the applicant is aware of,
accompanied by a statement of any changes to the overall risk
associated with the tobacco product, including the nature and frequency
of the adverse experience, and potential risk factors;
     a summary of sales and distribution of the tobacco
product, to the extent that the applicant collects or receives such
data, for the reporting period, including:
    [cir] total U.S. sales reported in dollars, units, and volume with
breakdowns by U.S. census region, major retail markets, and channels in
which the product is sold. Sales and distribution information may
constitute confidential commercial information under Sec.  20.61 that
is exempt from public disclosure. See Sec.  1114.47 and part 20 for
more information about the confidentiality of information submitted to
FDA;
    [cir] the Universal Product Code that corresponds to the product(s)
identified in the PMTA; and
    [cir] Demographic characteristics of product purchasers, such as
age, gender, race or ethnicity, geographic region, and tobacco use
status. After reviewing and considering comments received in response
to the proposed rule, FDA has updated this language here and throughout
the rule as the consideration of vulnerable populations is an important
part of determining whether permitting the continued marketing of a new
tobacco product is APPH;
     a summary of the implementation and effectiveness of
policies and procedures regarding verification of the age and identity
of purchasers of the product;
     a summary of all formative consumer research studies
conducted (if any), among any audiences, in the formation of new
labeling, advertising, marketing, or promotional materials, not
previously submitted, including qualitative and quantitative research
studies used to determine message effectiveness, consumer knowledge,
attitudes, beliefs, intentions and behaviors toward using the products,
and including the findings or these studies and copies of the stimuli
used in testing;
     a summary of all consumer evaluation research studies
conducted (if any), among any audiences, not previously submitted, to
determine the effectiveness of labeling, advertising, marketing, or
promotional materials and shifts in consumer knowledge, attitudes,
beliefs, intentions, and behaviors toward using the products, and
including the findings of these studies and copies of the stimuli used
in testing;
     a summary of the creation and dissemination of the
products' labeling, advertising, marketing, and promotional materials
(if any), including a list of all entities involved and a description
of their involvement, including a description of contractual agreements
with such entities. For example, a list of entities involved in the
creation and dissemination of marketing materials might include the
names of advertising agencies, media companies, public relations firms,
market research companies, partners, sponsors, bloggers and social
media influencers;
     specimens of all labeling that has not been previously
submitted in the PMTA, prior postmarket reports, or under section
905(i) of the FD&C Act and descriptions of all labeling changes
including the date the labeling was first disseminated and the date
when dissemination was completely terminated. This labeling information
can help FDA determine whether the withdrawal grounds under section
910(d)(1)(E) of the FD&C Act apply;
     full color copies of all advertising, marketing, and
promotional materials for the tobacco product that have not been
previously submitted, the original date the materials were first
disseminated, and the date when their dissemination was completely
terminated. FDA is requiring the submission of this information under
authority of section 910(f) because as discussed in section
VIII.B.6.b., the way in which a tobacco product is advertised,
marketed, and promoted can play an important role in FDA's
determination of whether the marketing of a tobacco product is APPH. A
substantial body of evidence illuminates the powerful impact of tobacco
product labeling, advertising, marketing, and promotion on youth
perceptions of tobacco products, youth appeal of tobacco products, the
likelihood of youth initiation and use of tobacco products, even when
said marketing is purportedly targeted or designed to appeal to adults.
Youth are a significant population of concern as their current stage of
brain development makes them especially susceptible to nicotine
addiction. Thus, for FDA to help ensure that the continued marketing of
a new tobacco product is appropriate for the protection of public
health, it is critical for FDA to conduct ongoing review and evaluation
of the product's labeling, advertising, marketing, and promotional
materials and activities to assess any possible effects on perceptions,
appeal, intentions, and behaviors among intended and unintended
audiences, especially youth. The information, together with other
postmarket information concerning the marketing of the tobacco product,
will facilitate determination of whether there are or may be grounds to
withdraw a marketing granted order under section 910(d)(1)(A) of the
FD&C Act;
     a description of the implementation of all advertising and
marketing plans, not previously submitted to FDA (whether conducted by
the applicant, on its behalf, or at its discretion), including
strategic creative briefs and paid media plans by channel and by
product, and the dollar amount(s) and flighting of such plans, by
channel and by product, including a description of any of the following
activities that an applicant may have engaged in:
    [cir] Use of competent and reliable data sources, methodologies,
and technologies to establish, maintain, and monitor highly targeted
advertising and marketing plans and media buys, including a list of all
data sources used to target advertising and marketing plans and media
buys;
    [cir] Targeting of specific group(s) by age-range(s), including
young adults, ages 21-24, and other demographic or psychographic
characteristics that reflect the intended audience including the source
of such data;
    [cir] with respect to individuals below the minimum age of sale,
actions taken to restrict access to the product and limit exposure to
the product labeling, advertising, marketing, promotion, or other
consumer-directed activities;
    [cir] use of owned, earned, shared, or paid media to create
labeling for, advertise, market, or promote the product;
    [cir] use of partners, influencers, bloggers, or brand ambassadors
to create labeling for, advertise, market, or promote the product;
    [cir] consumer engagements--whether conducted by an applicant, on
its

behalf, or at its direction--including events at which the product was
demonstrated and how access was restricted to individuals at or above
minimum age of sale; or
    [cir] use of public relations or other communications outreach to
create labeling for, advertise, market, or promote the products;
     a summary of media tracking and optimization (e.g.,
assessment of marketing campaigns in market, and adjustments to a media
buy to improve or correct delivery of advertising to the intended
audience) by channel, by product, and by audience demographics (e.g.,
age, gender, race/ethnicity, geographic region), including a summary of
any real-time digital media monitoring (e.g., tracking the use of a
specific hashtag, reviewing audience engagement metrics such as
``likes'', ``comments'', and ``shares'') and including a summary of
implementation of any corrective and preventive measures to identify,
correct, and prevent delivery of advertising to individuals below the
minimum age of sale, not previously submitted;
     a report or summary of the actual delivery of advertising
impressions (e.g., instances where the intended audience had the
opportunity to view or consume the product's advertising and
marketing), by channel, by product, and by audience demographics (e.g.,
age, gender, race/ethnicity, geographic region), not previously
submitted. This report or summary must be based on post-launch
delivery-verification reports submitted to the tobacco product company
from an accredited source, where applicable;
     additional information required to be reported under the
terms of a marketing granted order (if applicable); and
     an overall assessment of how the marketing of the tobacco
product continues to be APPH.
    Postmarket information concerning the marketing of a tobacco
product is critical to FDA's evaluation of whether the continued
marketing of the product is APPH under section 910(d)(1)(A) of the FD&C
Act. Determining whether the continued marketing of the tobacco product
is APPH requires FDA to consider the likelihood that those who do not
use tobacco products, including youth, will start using the product. As
discussed in section VIII.B.6.b., youth exposure to tobacco product
advertising, marketing, and promotion has a direct and powerful impact
on youth trial and uptake of tobacco product use, making it directly
relevant to FDA's determination of the likelihood that nonusers and
users of other products switching to the new product, including youth
will use the product. Accordingly, section Sec.  1114.41(a)(1) seeks
information that directly informs FDA's evaluation of youth exposure to
marketing materials for the product and youth access to the product.
Information regarding paid media plans for the product, such as the
channels used and the dollar amount(s) and flighting of the plans, as
well as information regarding the use (or nonuse) of competent and
reliable data sources, methodologies, and technologies to establish,
maintain, and monitor highly targeted advertising and marketing plans
and media buys, allows FDA to estimate the scale and potential reach of
advertising, marketing, and promotion for the product and thereby
directly informs its determination of the likelihood that youth will be
exposed to such marketing materials. For example, the use of social
media platforms known to reach youth, such as Twitter, Instagram, and
YouTube, without use of methods to restrict and monitor youth access to
marketing on those platforms may indicate a higher likelihood of youth
exposure to marketing for the tobacco product and youth use of the
tobacco product (see, e.g., Refs. 12-14 and 16). Additionally, use of
partners, influencers, bloggers, or brand ambassadors to create
labeling for, advertise, market, or promote a tobacco product may also
indicate a higher likelihood of youth exposure to marketing materials
for the product and youth use of the product, given studies
demonstrating that such methods, including the use of ``organic''
depictions of tobacco use and endorsements of tobacco products by
cultural icons and other influencers, are especially effective among
youth who are particularly susceptible to social influences (Ref. 9).
Moreover, information regarding actions taken to restrict access to the
product and limit exposure to the product labeling, advertising,
marketing, promotion, or other consumer-directed activities for
individuals below the minimum age of sale directly informs FDA's
evaluation of youth access to the product.

D. Serious and Unexpected Adverse Experience Reporting

    Applicants must report all serious and unexpected adverse
experiences associated with the tobacco product that have been reported
to the applicant or of which the applicant is aware under Sec.
1114.41(a)(2). The serious and unexpected adverse experience reports
must be submitted to CTP's Office of Science through the Health and
Human Services (HHS) Safety Reporting Portal or in another manner
designated by FDA (if applicable) within 15 calendar days after
receiving or becoming aware of a serious or unexpected adverse
experience. FDA notes that the submission of a report under this
section (and any release by FDA of that report) will not constitute an
admission that the tobacco product caused or contributed to an adverse
experience.
    FDA received several comments regarding the requirements for
periodic reports, as discussed below.
    (Comment 128) One comment stated that section 910 of the FD&C Act
does not authorize FDA to require postmarket reporting for
manufacturing changes. The comment stated that if a manufacturing
change of the nature described by the proposed rule results in a new
product, then there can be no ``postmarket'' information for FDA to
evaluate because such a product cannot be placed on the market until a
new marketing order has been obtained. The comment further stated that,
if the manufacturing change does not result in a new tobacco product,
then this change cannot alter FDA's prior determination that the
marketing of the product is appropriate for the protection of public
health nor would it enable FDA to determine, or facilitate a
determination, that there are any other statutory grounds for
withdrawing or suspending a marketing order. The comment concluded that
in the future, manufacturing changes may result in a withdrawal or
suspension but as no manufacturing regulations exist under section
906(e) of the FD&C Act, this does not seem applicable.
    (Response 128) FDA declines to make any changes as a result of this
comment. As discussed in the rule, whether the applicant can
consistently manufacture the new tobacco product described in the PMTA
is important to FDA's determination of whether a tobacco product is
APPH, and given the dangers associated with nonconforming tobacco
products, reviewing manufacturing changes on a postmarket basis is
necessary for FDA to determine whether the continued marketing of the
product is APPH. Additionally, reviewing manufacturing changes would
allow FDA to determine whether they would result in a modification
(intended or unintended) to the product and is therefore a different
new tobacco product without premarket authorization, which would render
that tobacco product adulterated under section 902(6)(A) of the FD&C
Act and misbranded under section 903 of the FD&C Act. FDA is requiring
such information, in part, under its section 909 of the FD&C Act
authority, which

allows FDA to require the reporting of information to assure that a
tobacco product is not adulterated or misbranded and to otherwise
protect public health.
    (Comment 129) One comment stated that section 910 of the FD&C Act
does not authorize FDA to require postmarket reporting of sales and
marketing information. The comment noted that while FDA states that
this information will inform a determination of whether the marketing
of the new tobacco product continues to be APPH, it claimed that this
statement does not establish that all of the information required in
the proposed rule is necessary for FDA to make its determination and,
as such, many of the postmarket reporting requirements should be
deleted in the final rule.
    (Response 129) FDA disagrees with the statement that this reporting
is not authorized by the FD&C Act. As discussed throughout this
document, this postmarket information is necessary to help inform FDA's
determination of whether the continued marketing of the tobacco product
is APPH. FDA requires applicants to submit sales data under its
authority in section 910(f) of the FD&C Act to help inform its
determination of whether the continued marketing of the product is
APPH. Sales data in conjunction with other data such as demographics of
purchasers and information on retail channels can provide information
that can help indicate trends in tobacco use behavior across the United
States and potential changes in tobacco use behaviors among certain
subsets of the population. For example, if tobacco use of a specific
product was previously low among a certain demographic and, through the
postmarket reporting, is now being reported at higher levels of tobacco
use that also correlates with sales of the new product among the same
demographic group, this type of information would be important to FDA's
determination of whether the continued marketing of the tobacco product
is APPH. In addition, sales of tobacco products by retail channel,
combined with other required data, can help FDA understand where
products are being sold as well as help FDA better understand the
potential for youth access to the products. In particular, the data
help FDA to assess whether the information regarding likely tobacco
product use behavior described in the PMTA was consistent with actual
use after authorization. For example, data that indicate significantly
higher rates of youth initiation with the tobacco product than among
other nonusers than anticipated in the PMTA could result in FDA finding
that continued marketing of the tobacco product is no longer APPH and
the marketing granted order should be withdrawn under section
910(d)(1)(A) of the FD&C Act. Furthermore, because youth exposure to
tobacco product labeling, advertising, marketing, and promotion has a
direct and powerful impact on youth trial and uptake of tobacco product
use, information regarding the marketing of the tobacco product and
potential youth exposure to marketing directly informs FDA's
consideration of the likelihood that youth will use the product, which
is relevant to determining whether continued marketing of a product is
APPH and consistent with its statutory mandate to protect youth from
the dangers of tobacco use. In addition, as discussed below,
information regarding the marketing of the product can help FDA
determine whether the withdrawal grounds under section 910(d)(1)(E) of
the FD&C Act apply.
    (Comment 130) One comment requested that the rule require the
submission of postmarket information to demonstrate that all labeling,
instructions for use, and other communications related to the product
have been carefully designed and tested to ensure they will provide
accurate, not misleading, information and guidance to all consumers,
including those with less education, or weaker or non-existent English
literacy, and will not encourage harm-increasing uses of the product
among any subpopulations.
    (Response 130) FDA intends to consider the labeling, advertising,
and marketing, and promotion for a new tobacco product, including
labels, instructions for use and other advertising and marketing
materials, that an applicant uses after receiving a marketing granted
order as part of FDA's evaluation of whether the continued marketing of
a new tobacco product is APPH. FDA is not requiring formal testing of
advertising and marketing materials. However, when determining whether
the continued marketing of a new tobacco product is APPH, under section
910(d)(1)(E) of the FD&C Act, FDA is required to consider whether the
labeling of the tobacco product is false or misleading. In addition,
FDA will review advertising and marketing materials with consideration
of the potential for use among nonusers, including youth, as well as
product misuse and dual use among current tobacco product users (see
section VII.B.6 regarding Sec.  1114.7(f) for a discussion of the
impact of advertising).
    (Comment 131) One comment stated that FDA should, similar to
language FDA uses for other regulated product categories, make it clear
that submission of required postmarket reports, including adverse
experience reports, does not reflect a conclusion or admission by the
applicant or FDA that the product at issue caused or contributed to the
adverse experience.
    (Response 131) In section X.B., FDA has amended this document to
clarify that reporting an adverse experience will not constitute an
admission that the tobacco product caused or contributed to the adverse
experience.

E. Submission of Additional Information

    As part of its review of a postmarket report, FDA could require the
applicant to submit additional information to enable it to determine
whether a change results in a new tobacco product, or to facilitate a
determination of whether there are or may be grounds to withdraw or
temporarily suspend the marketing granted order. FDA may notify an
applicant that FDA has determined that a change described in a periodic
report made under this section results in a new tobacco product outside
the scope of the marketing granted order, requiring the submission of a
new PMTA under Sec.  1114.7 or a supplemental PMTA under Sec.  1114.15
and issuance of a marketing granted order if the applicant seeks to
market the new tobacco product, unless the new tobacco product can be
legally marketed through a different premarket pathway. Failure to
obtain marketing authorization for a new tobacco product would render
it adulterated under section 902(6) of the FD&C Act and misbranded
under section 903(a)(6) of the FD&C Act and could be subject to
enforcement action.
    FDA received one comment on this issue, as discussed below.
    (Comment 132) One comment stated that they expected some e-liquid
manufacturers to join controlled distribution networks to show youth
access to tobacco products would be limited. The comment recommended
that the rule be amended to allow third party entities (e.g.,
controlled distribution networks or their auditing agents) to submit
reports directly to the Agency that reference and link to participants'
approved PMTAs. This would allow applicants or their designated
distribution networks and auditors to submit to FDA all information
required.
    (Response 132) We decline to make this change. The rule concerns
the postmarket reports that applicants are required to make, rather
than the information that third parties or other entities may submit to
FDA about a tobacco product; however, note that

where an applicant obtains sales data about its product from a third
party, the applicant would need to report it to FDA as required by
Sec.  1114.41. As noted in section VIII.B.2, applicants have the
ability to cross-reference third-party owned information through TPMFs,
including in the submission of postmarket reporting requirements.

XI. Miscellaneous (Part 1114, Subpart E)

    Subpart E describes other procedures and requirements related to
PMTAs, including record retention, electronic submission requirements,
and confidentiality considerations.

A. Record Retention (Sec.  1114.45)

    Consistent with the authority to require recordkeeping under
sections 909 and 910(f) of the FD&C Act, Sec.  1114.45 requires
applicants receiving a marketing granted order to maintain all records
necessary to facilitate a determination of whether there are or may be
grounds to withdraw or temporarily suspend the marketing granted order
and ensure that such records remain readily available to the Agency
upon request. The records must be legible, written in English, and
available for inspection and copying by officers or employees
designated by the Secretary.
1. Record Retention by the Applicant
    Under Sec.  1114.45(a)(1), an applicant must retain all documents
submitted to FDA as part of an application and postmarket reports. An
applicant must also retain any additional documentation supporting the
application and postmarket reports that was not submitted to FDA. This
additional documentation includes information that demonstrates:
     Nonclinical laboratory studies were conducted using
laboratory practices that ensure the reliability and validity of the
study. This information includes documents that were generated during
the performance of nonclinical studies, but were not required to be
submitted as part of a full study report under Sec.  1114.7(k)(3). One
way that an applicant may satisfy this requirement is to retain all of
the documentation described in part 58 and
     whether any investigators had financial conflicts of
interest. One approach to satisfying this requirement is to retain all
of the documentation described in part 54 for both clinical and
nonclinical investigations.
    Applicants must also retain all other documents generated during
the course of a study that are necessary to substantiate the study
results (e.g., certain communications, case reports) including:
     Communications related to the investigation between the
investigator and the sponsor, the monitor, or FDA and
     all source data and related summaries, including records
regarding each study subject's case history and exposure to tobacco
products used in the investigation, which can include, but is not
limited to case report forms, progress notes, hospital records,
clinical charts, x-rays, lab reports, and subject diaries.
    The applicant must also maintain a record of each complaint
associated with the tobacco product that has been reported to the
applicant as well as a summary and an analysis of all complaints
associated with the tobacco product reported to the applicant. The
records and analysis of complaints should reflect all reports made
about the product, including those made during clinical investigations.
FDA is requiring that records and analysis of such complaints be kept
to demonstrate whether there are any potential issues with the product
that could present health or safety issues.
    FDA received comments regarding record retention by applicants, as
discussed below.
    (Comment 133) One comment suggested that the language of the
proposed rule be amended to allow for either applicants or their third-
party representatives to retain the records required by Sec.  1114.45.
The applicant stated that this could be more efficient and save costs.
    (Response 133) FDA has amended the language of the preamble to
clarify that an applicant may utilize a third-party entity to store
records on their behalf. If an applicant uses a third-party entity to
store records, it is important to note that the applicant is still
solely responsible for ensuring that all records necessary to
facilitate a determination of whether there are or may be grounds to
withdraw or temporarily suspend the marketing granted order are readily
available to the Agency upon request. This requirement will ensure that
records are available to FDA during an inspection.
    Applicants that have stopped marketing a tobacco product may want
to retain the records for a longer period if the product might be
reintroduced in order to avoid the time and expense of having to
generate the information again. FDA may, under the terms of section
910(f) of the FD&C Act, impose additional recordkeeping and reporting
requirements as part of a marketing granted order in addition to the
requirements in the rule.
    (Comment 134) One comment expressed support for the requirement for
applicants to retain records but suggested the proposed rule should be
amended to include retention requirements for specific information that
would enable FDA to track and trace a product from the manufacturing
source to the shelf.
    (Response 134) FDA declines to make such a change because it is
outside the scope of this rulemaking. Consistent with sections 909 and
910(f) of the FD&C Act, the rule (as described in Sec.  1114.45)
requires applicants to retain all records necessary to facilitate a
determination of whether there are or may be grounds to withdraw or
temporarily suspend the marketing order as well as ensure that the
tobacco product that is the subject of the marketing order is not
adulterated or misbranded.
2. Record Format and Availability
    The rule requires the applicant to maintain records that are
legible and in the English language, and make them available for
inspection and copying by officers or employees duly designated by the
Secretary.
3. Retention Period
    Applicants must retain the records as described in Sec.
1114.45(a)(3). Records relating to the PMTA must be retained for a
period of no less than 4 years from the date the marketing granted
order is issued. Records relating to the postmarket reports, including
both periodic reporting and adverse experience reporting must be
retained for a period of at least 4 years from the date the postmarket
report was submitted or the date FDA inspects the records, whichever
occurs sooner. FDA has selected 4 years as a means to help ensure that
the records would be available for at least one biennial FDA inspection
under sections 704 and 905(g) of the FD&C Act.

B. Confidentiality (Sec.  1114.47)

    Section 1114.47 states that FDA will determine the public
availability of any part of any PMTA and other content related to a
PMTA, including all data and information submitted with or incorporated
by reference in the application, as provided under this section and
part 20 (Public Information). FOIA (5 U.S.C. 552), as well as certain
provisions of the FD&C Act, (e.g., section 301(j) (21 U.S.C. 331(j))
and section 906(c)), govern the disclosure of the existence of a
pending PMTA and the information contained in such a PMTA. Under FOIA,
the public has broad access to government documents.

However, FOIA provides certain exemptions from mandatory public
disclosure. One such provision, 5 U.S.C. 552(b)(4), exempts records
that are ``trade secrets and commercial or financial information
obtained from a person and privileged or confidential'' from the
requirement of mandatory disclosure. Part 20 of FDA's regulations sets
forth FDA's general regulations concerning public availability of FDA
records.
    FDA received several comments regarding confidentiality, as
discussed below.
    (Comment 135) One comment suggested that a public database be
established that lists the products for which a PMTA has been filed,
accepted, or is pending substantive review. The comment stated that
this is important because it would allow other state and federal
agencies to know whether a product has the ability to remain on the
shelves of stores. Similarly, another comment stated that by not making
the application process more public, FDA is not permitting adequate
participation by stakeholders other than the applicant and is contrary
to established FDA practice. The comment expressed concern that this
could result in FDA having access only to research conducted by
industry or prevent FDA from accessing research not yet published.
    (Response 135) FDA agrees that stakeholder engagement, including
with federal and state entities as well as members of the public, is
important to the effective implementation of the law and the PMTA
process generally. However, the Agency disagrees with the assertion
that a public database or other measures not included in this rule are
necessary to ensure adequate public participation or to ensure that FDA
has access to all potentially relevant information, including research
not yet published, from sources other than the applicant. As discussed
in the preamble of the proposed rule, like with drugs and devices, the
intent to market a tobacco product that is not currently marketed is
often considered confidential commercial information. This is
consistent with the recent Supreme Court decision that addressed the
legal standard for determining whether information is confidential. See
Food Mktg. Inst. v. Argus Leader Media, 139 S. Ct. 2356, 2366 (2019).
Therefore, Sec.  1114.47(b) addresses the confidentiality of a PMTA
prior to the issuance of a marketing granted order. Under the rule, FDA
will not publicly disclose the existence of a PMTA unless the applicant
has publicly disclosed or acknowledged that it has submitted the
application to FDA (as such disclosure is defined in Sec.  20.81), the
applicant has authorized FDA in writing to publicly disclose or
acknowledge the submission of the PMTA, or FDA has referred the
application to TPSAC. Section 1114.47(b)(2) provides that FDA will not
disclose the fact or contents of an FDA communication with an applicant
or regarding an application or information contained in the application
unless the applicant has publicly disclosed, acknowledged, or
authorized FDA in writing to publicly disclose or acknowledge the
existence of the FDA communication or information contained in the
application. However, if the applicant has disclosed information
contained in the application or that it received a communication from
FDA regarding the application, FDA may disclose the record of the
communication after redacting confidential commercial or trade secret
information. Section 1114.47(b)(3) provides that if FDA refers the
application to TPSAC, the PMTA will be available for public disclosure
under part 20 as described in Sec.  14.75 (21 CFR 14.75) (which
concerns the public disclosure of advisory committee records), except
information that that is exempt from public disclosure under part 20,
including trade secrets, confidential commercial information, and
personal privacy information. This is consistent with FDA's practice
for tobacco product premarket applications, as well as for premarket
applications generally.
    (Comment 136) One comment stated that section 910 of the FD&C Act
does not authorize FDA to make PMTAs publicly available as part of FDA
or TPSAC review. The comment argued that if Congress intended FDA to
have the authority to divulge the content of a PMTA, it would have
stated so in the Tobacco Control Act. Another comment argued that the
only information that should be referred to TPSAC is a limited summary
of the relevant portions of the application.
    (Response 136) As stated above, prior to the issuance of a
marketing granted order, FDA will not publicly disclose the existence
of a PMTA unless the applicant has publicly disclosed or acknowledged
that it has submitted the application to FDA, the applicant has
authorized FDA in writing to publicly disclose or acknowledge the
submission of the PMTA, or FDA has referred the application to TPSAC.
Except as described in Sec.  1114.47(b)(4) regarding referral to TPSAC,
FDA will not disclose information contained in an application unless
the applicant has publicly disclosed or acknowledged, or authorized FDA
in writing to publicly disclose or acknowledge, the existence of that
particular information.
    FDA disagrees with the assertion that it cannot make a PMTA
publicly available as part of TPSAC review because it is required to do
so under section 10(b) of the Federal Advisory Committee Act (Pub. L.
92-463, 5 U.S.C. App) and its implementing regulations. If FDA refers
the application to TPSAC, the PMTA will be available for public
disclosure under part 20 as described in Sec.  14.75 (which concerns
the public disclosure of advisory committee records), except
information that is exempt from disclosure under part 20, including
trade secrets, confidential commercial information, and personal
privacy information
    Section 1114.47(c) describes the information that FDA will make
available after issuing a marketing granted order. Under Sec.
1114.47(c), FDA can make available data previously disclosed to the
public, protocols for a test or study, information and data in the
application that demonstrate the new tobacco product is appropriate for
the protection of the public health, any correspondence between FDA and
the applicant, the EA or request for categorical exclusion, and
information and data contained in postmarket reports, so long as the
information listed above is not exempted from disclosure under part 20.
    Even after receipt of a marketing denial order for an application
for a product that is not currently marketed, the intent to market may
still constitute confidential commercial information, as the applicant
may still have the intent to market the new tobacco product that is the
subject of the PMTA and it is the type of information that is
customarily and actually treated as private by its owner. Under Sec.
1114.47(d), FDA may also make certain information available after it
issues a marketing denial order unless the information is otherwise
exempt from disclosure under part 20. The information that FDA may
disclose includes product category, subcategory, package size, and the
basis for the marketing denial order. FDA notes that where an applicant
receives a marketing denial order for, or FDA refuses to accept or
file, a PMTA for a new tobacco product that is currently on the market
as a result of FDA's compliance policy for deemed tobacco products on
the market as of August 8, 2016, FDA may disclose additional
identifying information about the product to help ensure that it is
taken off of the market. Where a product is marketed, basic identifying
information regarding the

product is not a trade secret or confidential commercial information.
    (Comment 137) One comment states that the final rule should be
amended to state that all aspects of the PMTA, including all data and
information submitted with or incorporated by reference into the
application, are confidential information under Sec.  1114.47.
    (Response 137) As explained elsewhere in this section, FDA will
determine the public availability of any information contained in a
PMTA under Sec.  1114.47 and part 20. This includes the data and
information in the application submitted in both full text and
incorporated by cross-reference. FDA has amended the language in this
section, to clarify what information would be confidential under the
rule and part 20.
    (Comment 138) One comment stated that the final rule should be
amended to state that all data and information received in an ITP
submission prior to a PMTA being filed with the Agency is also
confidential. Furthermore, the comment stated that FDA should update
part 20 to describe the legal standard for FOIA exemption 4 established
by the Supreme Court in Food Mktg. Inst. v. Argus Leader Media.
    (Response 138) This rulemaking addresses the general process by
which PMTAs are submitted and reviewed. Any comments concerning the
investigational tobacco product submission process or FDA's public
information regulations under part 20 are outside the scope of this
rule.
    (Comment 139) One comment stated that FDA should publicly disclose
the existence of PMTAs for which the applicant has previously submitted
a MRTPA or submits an MRTPA concurrently with the PMTA.
    (Response 139) FDA has amended Sec.  1114.47 to state that it will
disclose the existence of a PMTA for a new tobacco product for which an
MRTPA has been made available for public comment under section 911(e)
of the FD&C Act. Once FDA makes an MRTPA for the new tobacco product
publicly available, the intent to market the new tobacco product would
no longer be confidential commercial information. Further, as stated
previously, the contents of a PMTA that is referred to TPSAC (either as
a standalone application or concurrently with an MRTPA) will be
available for public disclosure under part 20 as described in Sec.
14.75 (which concerns the public disclosure of advisory committee
records), including withholding information that is trade secrets,
confidential commercial information, or personal privacy information.
    (Comment 140) One comment stated that it is important for FDA to
publicly disclose all data and information submitted to demonstrate the
marketing of a product would be APPH, marketing plans, and postmarket
reporting for each new tobacco product that is authorized by FDA. The
comment stated that marketing plans concern the sale and distribution
of tobacco products, which under section 916 of the FD&C Act (21 U.S.C.
387p) may also be subject to state and local regulation, even if such
regulations are different or stricter than Federal regulations. The
comment further stated that the public health interest in disclosure
outweighs other interests and should result in marketing plans and
postmarket reporting being disclosed to the public.
    (Response 140) As described in this section, FDA may make
information publicly available after the issuance of a marketing
granted order consistent with Sec.  1114.47(c) and part 20. FDA is
unable to make any information in an application, including
descriptions of marketing plans, publicly available to the extent that
it constitutes trade secrets or confidential commercial information
unless it is disclosed publicly or authorized to be disclosed publicly
by the applicant.

C. Electronic Submission (Sec.  1114.49)

    Consistent with FDA's authority to issue regulations for the
efficient enforcement of the FD&C Act, Sec.  1114.49 requires an
applicant to submit a PMTA and all supporting and related documents to
FDA in electronic format that FDA can process, review, and archive
unless an applicant requests, and FDA grants, a waiver from this
requirement. Reasons that an applicant might request a waiver would
include that the applicant has no access to email or a computer. Under
Sec.  1114.49(c), an applicant that has a waiver would submit a paper
submission to the address that FDA provides in the letter granting the
waiver.
    FDA received one comment regarding the proposed electronic
submission provision, as discussed below.
    (Comment 141) One comment stated that while the submission of
electronic documents may be a preferred delivery mechanism, it should
not be a requirement that an applicant submit a PMTA and all supporting
and related documents in electronic format.
    (Response 141) FDA declines to take this recommendation. FDA is
implementing Sec.  1114.49 based on FDA's general experience with
electronic submissions, which FDA has found help facilitate premarket
reviews because electronic submissions typically enable FDA to receive,
access, search, and review a submission more efficiently than a paper
submission. FDA has provided technical specifications on its website
for submitting information in an electronic format that FDA can review,
process, and archive (e.g., method of transmission, media, file
formats, preparation, organization of files, accompanying metadata)
(https://www.fda.gov/tobacco-products/manufacturing/electronic-submissions-tobacco-products) and update this information as needed to
accommodate changes in technology. As previously discussed, applicants
who have limited access to email or a computer may apply for a waiver
from the electronic submission requirement, which if granted by FDA,
would allow an applicant to submit a paper submission to the address
that FDA provides.

XII. Paperwork Reduction Act of 1995

    This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3521). The title,
description, and respondent description of the information collection
provisions are shown in the following paragraphs with an estimate of
the annual reporting and recordkeeping burden. Included in the estimate
is the time for reviewing instructions, searching existing data
sources, gathering and maintaining the data needed, and completing and
reviewing each collection of information.
    Title: Premarket Tobacco Product Applications and Recordkeeping
Requirements, OMB Control Number 0910-0879.
    Description: This rule interprets and codifies requirements related
to the content and format of PMTAs, the procedure by which FDA reviews
PMTAs, and the maintenance of records regarding the legal marketing of
certain tobacco products without PMTAs. The rule also addresses issues
such as the procedures of retention of records related to the PMTA,
confidentiality of application information, electronic submission of
the PMTA and amendments, and postmarket reporting requirements.
    Description of Respondents: This rule applies to tobacco product
manufacturers. Manufacturer is defined here as any person, including
any repacker or relabeler, who: (1) Manufactures, fabricates,
assembles, processes, or labels a tobacco product or (2) imports a
finished tobacco product

for sale or distribution in the United States.
    As required by section 3506(c)(2)(B) of the Paperwork Reduction Act
of 1995 (PRA), FDA provided an opportunity for public comment on the
information collection requirements of the proposed rule that published
in the Federal Register of September 25, 2019 (84 FR 50566). In
response to this rule FDA received two PRA-related comments:
    (Comment 142) One comment made specific comments requesting changes
to elements in Form 4057.
    (Response 142) FDA has considered these comments and agrees that
many updates are necessary. The list below details the updates we have
made to the form in response to the comments.
     FDA has harmonized, as appropriate, terms used within the
PMTA and other FDA forms.
     FDA has revised the form by adding fields for address and
contact information for manufacturer information to provide for the
situation where the manufacturer is different from the Applicant.
     FDA agrees that the form does not collect organization
information for certain parties. FDA has revised the form by providing
fields to enter organization information for certain parties, e.g., the
authorized representative. Additionally, FDA has revised the form by
providing additional fields to describe the alternate point of contact.
     FDA has revised section III which now contains additional
fields to identify cross-referenced submissions (ITP, SE, and MRTPA)
and formal meetings held with FDA that pertain to the PMTA. For
example, the applicant can now input in the revised form document
keywords, document filenames, and submission dates for cross-referenced
content. For formal meetings with FDA, the applicant can now input in
the revised form the new tobacco product name. These fields would also
help ensure FDA identify the cross-referenced content or related
submission.
     Section III of the revised form also contains new fields
(e.g., ``document keyword'' and ``document filename'') that allow the
submitter to adequately describe the content they are cross-
referencing. Section III now allows the applicant to indicate if the
cross-referenced content is relevant to a specific product or to all
bundled products in the application. Across all product categories, the
subcategory of ``co-package'' has been removed. However, co-packaged
items can be grouped within the same submission and the unique
identification of this co-packaged product would include the specific
items needed to identify each product within the co-package.
     In section IV, FDA has added a ``Submission Table of
Contents'' with fields for ``filename,'' ``title,'' ``table of contents
category,'' and ``keyword'' in order that FDA can easily identify the
application contents listed in section IV.
    (Comment 143) One comment made specific comments requesting changes
to elements in Form FDA 4057a.
    (Response 143) FDA has considered these comments and agrees that
many updates are necessary. The list below details the updates we have
made to the form in response to the comments.
     FDA has combined sections I and IV to only ask for current
owner's information once. The current owner's information is now only
required in section I of the revised form.
     FDA now allows the manufacturer's address and contact
information to be provided (if a different entity from the applicant)
contact information is to be provided.
     FDA has revised the form to allow the organization's name
to be provided (where an organization is an alternate point of
contact). Additionally, FDA added a field so that organizational
affiliation of the authorized representative information can be
provided.
     For a change in authorized representative FDA agrees that
``Replace'' is the appropriate step and has added this as an option in
section I, subsection C of the form.
     The form has been edited to allow the submitter to
indicate the purpose of the amendment (i.e., whether it was for a
single new tobacco product or for a bundled/grouped submission).
     Section III of the form has been revised to allow the
submitter to indicate the addition, updating or removal of cross-
referenced content, related submissions, and meetings with FDA. Section
III now allows the submitter to describe the cross-referenced content,
related submissions, and meetings, and to indicate the purpose of the
cross-referenced content, related submissions, and meetings.
Additionally, section III allows the submitter to indicate whether the
submitter intends to ``add,'' ``update'' or ``remove'' referenced
content, related submissions, and meetings.
     Section III of the revised form now contains a
``submission summary'' field which allows the applicant to be used to
describe the subject of the amendment.