clock until any violation of the user fee requirement of part 1150 is
resolved. FDA is proposing this provision under its section 701(a)
authority to issue regulations for the efficient enforcement of the
FD&C Act. It would be inefficient for FDA to expend the significant
resources necessary to review an application for a product that could
not be legally marketed. It would also not be reasonable for FDA to
complete its review and issue a marketing order for a product that, if
it is put into interstate commerce, would immediately be adulterated or
misbranded and subject to FDA enforcement action. While FDA would not
refuse to accept or refuse to file an application on the basis that the
product would be adulterated for failure to pay user fees, FDA would
not complete its review of a PMTA until the applicant is in compliance
with part 1150. FDA is proposing this action, rather than refusing to
accept or refusing to file an application because noncompliance with
the requirements of part 1150 can often be resolved quickly.
---------------------------------------------------------------------------

    \15\ Currently, only the manufacturers of cigarettes, cigars,
snuff, chewing tobacco, pipe tobacco, and roll-your-own tobacco are
subject to the requirements of part 1150. See the final rule,
Requirements for the Submission of Data Needed to Calculate User
Fees for Domestic Manufacturers and Importers of Cigars and Pipe
Tobacco (81 FR 28707) (May 10, 2016), for more information.
---------------------------------------------------------------------------

    The third instance in which FDA's 180-day review period would not
run over 180 consecutive calendar days after the receipt of a complete
PMTA is where FDA is prevented from scheduling or conducting
inspections of the manufacturing sites and the sites and entities
involved with the clinical and nonclinical research (including third
parties and contract research organizations) that would prevent FDA
from completing its review of the PMTA in a timely manner. Where this
occurs, FDA may pause the 180-day review period for the number of days
necessary to complete the inspection after a delay occurs. FDA has
experienced delays in both scheduling and conducting inspections, which
results in FDA not having the information it needs to complete its
required review in 180 calendar days.
    The fourth instance in which FDA's 180-day review period may not
run over 180 consecutive calendar days after the receipt of a complete
PMTA is where FDA determines after application filing that the
applicant has not submitted an adequate EA. NEPA and regulations issued
by the Council on Environmental Quality (42 U.S.C. 4332(2); 40 CFR
parts 1500 to 1508) require FDA to assess, as an integral part of its
decision-making process, the environmental impacts of any proposed
Federal action to ascertain the environmental consequences of that
action on the quality of the human environment and to ensure that the
interested and affected public is appropriately informed. FDA has
implemented the NEPA and CEQ requirements in 21 CFR part 25. Under
Sec.  25.15(a), failure to submit an adequate EA is grounds for
refusing to file or authorize an application. Consistent with Sec.
25.15(a), FDA would refuse to authorize the marketing of a new tobacco
product where a PMTA contains an inadequate EA.
    As described in proposed Sec.  1114.27(c)(4), FDA may conduct
inspections of the applicant's manufacturing sites, and sites and
entities involved with clinical and nonclinical research (including
third parties and contract research organizations) to support FDA's
review of the PMTA. 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 and would help FDA determine under section 910(c)(2) of
the FD&C Act whether such practices conform to an applicable product
standard issued under section 907 of the FD&C Act or tobacco product
manufacturing practice requirement issued under section 906(e) of the
FD&C Act. Inspecting sites and entities involved with clinical and
nonclinical research, including their records (such as those required
to be kept under proposed 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 order. Under proposed Sec.  1114.33, failure
to grant FDA access at a reasonable time and in a reasonable manner, an
opportunity to inspect these sites and have access to, copy, and verify
all records pertinent to the application may result in the issuance of
a no marketing 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 US commercial distribution, FDA can view
the product being manufactured.

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

    Proposed Sec.  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 180 days under
Sec.  1114.9(b) or requests to withdraw an application under Sec.
1114.11;
     Third, FDA could issue a letter canceling the application
if FDA finds it mistakenly acknowledged 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 order as described in
Sec.  1114.31; or
     Sixth, FDA could issue a no marketing order as described
in Sec.  1114.33.

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

    Under section 910(c)(1)(A)(i) of the FD&C Act, FDA will issue a
marketing 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 order for a new tobacco product,
FDA must be able to determine the following:
    1. 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
marketing order withdrawal criteria in section 910(d)(1)(A) of the FD&C
Act, FDA must continue to find the product meets the APPH standard over
time. Generally, 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. Because the APPH standard
requires a balancing of product-specific potential risks and benefits,
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 potentially 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. On the
other hand, where a PMTA for the same new 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 could potentially result in the issuance of a no
marketing order because the product is not likely to have a net benefit
to the population as a whole.
    Additionally, the factors that could demonstrate 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. 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. As the tobacco
product market changes over time, the potential risks and benefits to
the population as a whole of marketing a new tobacco product might also
change. A new tobacco product that receives a marketing 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. FDA requests comment on its interpretation of the APPH
standard set forth in section 910(c) of the FD&C Act, including how it
should apply the standard over time as the tobacco product marketplace
and tobacco product use behaviors change.
    It is important to note that in order for FDA to issue a marketing
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. regarding proposed Sec.  1114.33, failure to submit sufficient
information that FDA needs to be able to make its required findings
would result in the issuance of a no marketing order.
    This proposed 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 order. The proposed rule
would create 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 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 order, FDA relies upon only valid scientific evidence to
determine whether the marketing of the new tobacco product would be
APPH. 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 also 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 it has 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 its 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 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 proposed Sec.  1114.27(b)(1)(ii)), FDA expects that PMTAs would
provide sufficient evidence to support the issuance of a marketing
order where they contain 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 its product and
the U.S. population or provides adequate justification for how the
information is relevant. FDA recognizes that this type of long-term
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 and
its label, labeling, and advertising 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 no marketing order for the
product because it would lack 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.
    2. 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 proposed 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 order under section 910(a)(1)(i)(A) of the FD&C Act. Until
such a time as 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.
    3. Based on a fair evaluation of all material facts, the proposed
labeling is not false or misleading in any particular.
    4. 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 proposed rule would be required by
proposed 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 would need to 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 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.
    Proposed Sec.  1114.31(b) describes restrictions and additional
requirements that FDA may include as part of a marketing 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. Proposed Sec.
1114.31(b)(1) reiterates this authority as part of the rule and
proposed Sec.  1114.31(b)(2) would allow FDA to include restrictions on
sales and distribution proposed by the applicant as part of its PMTA as
part of a marketing order.
    Proposed Sec.  1114.31(b)(3) would allow 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, including but 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 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 would allow FDA to ensure it can appropriately
track and monitor the impact that the use of such information. FDA
anticipates it would 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 No Marketing Order (Proposed Sec.  1114.33)

    Proposed Sec.  1114.33 describes the circumstances under which FDA
would issue a no marketing order for a new tobacco product after PMTA
review. Proposed Sec.  1114.33(a)(1) specifies that FDA would issue a
no marketing order if any of the grounds for denial listed in 910(c)(2)
of the FD&C Act apply to the application. As mentioned in the
discussion of the issuance of a marketing order, meeting the
requirements for application acceptance and filing does not mean that
an application has sufficient information to receive a marketing order.
For example, while FDA may accept and file an application that contains
the information in proposed Sec.  1114.7(k), FDA would not issue a
marketing order unless that information also makes a showing that the
marketing of a new tobacco product would be APPH. While the proposed
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 its potential health
risks or face the possibility of receiving a no marketing order.
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 may receive a no marketing order.
    Examples of when FDA would be required to issue a no marketing
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 to 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
and outside of the new tobacco product's 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 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.
    Proposed Sec.  1114.33(a) would also allow FDA to issue a no
marketing 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
order. FDA is proposing to issue a no marketing 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
proposed 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 proposed 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 order. As stated in
proposed Sec.  1114.45, the records would be required to be legible and
written in English.

    If FDA issues a no marketing 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 no marketing order, the deficiencies specified in the order might
not be an exhaustive listing of all deficiencies contained in the PMTA.

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

    Proposed Sec.  1114.35 describes the grounds and procedures for
withdrawing a marketing order for a new tobacco product. FDA would 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:
     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 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.
    FDA also interprets section 910(d)(1)(A) of the FD&C Act to provide
for the withdrawal of a marketing order where changes to the tobacco
product marketplace result in FDA finding that the marketing of a
product is no longer APPH. FDA interprets the APPH standard to require
ongoing consideration of the public health impact of the marketing of a
new tobacco product and thus what is necessary to satisfy the standard
changes with the tobacco product marketplace. 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 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 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 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. FDA requests public comments on its interpretation
of 910(d)(1)(A) of the FD&C Act. FDA requests comment on its
interpretation of the APPH standard, including how it should apply the
standard over time as the tobacco product marketplace and tobacco
product use behaviors change.
     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.
    2. Any postmarket requirement imposed by the marketing 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. FDA is proposing this requirement to allow the
withdrawal of a marketing order where an applicant fails to meet
requirements imposed by a marketing 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 may seek advice on scientific matters from any appropriate FDA
advisory committee in deciding whether to withdraw a marketing order
and may use information other than that submitted by the applicant in
deciding whether to withdraw a marketing order. Prior to withdrawing a
marketing order, FDA will notify the holder of the marketing order of
the opportunity for an informal hearing under 21 CFR part 16. If the
holder of the marketing order does not request an informal hearing or
if FDA decides to withdraw the marketing order after the informal
hearing is held, FDA will issue an order withdrawing the marketing
order. FDA will notify the public that the marketing order for the
product has been withdrawn and state the basis for the withdrawal.

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

    Proposed Sec.  1114.37 describes the grounds and procedures by
which FDA will temporarily suspend a marketing 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 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
proposed rule, FDA will notify the holder of the marketing order of the
opportunity to hold an informal hearing. If FDA determines after the
opportunity for the informal hearing that the marketing order for the
tobacco product should be temporarily suspended, the Agency will issue
an order temporarily suspending the marketing 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 order, it will proceed expeditiously to initiate order
withdrawal proceedings.

IX. Postmarket Requirements (Proposed Part 1114, Subpart D)

A. Postmarket Changes (Proposed Sec.  1114.39)

    Proposed Sec.  1114.39 describes the scope of a marketing order.
FDA issues marketing orders for the specific new tobacco product
described in the PMTA. An applicant may not make any modification to
the product that is the subject of the order, as any modification to
the tobacco product would result 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, would be required to
be reported under proposed Sec.  1114.41. Applicants seeking to make
modifications to the tobacco product may submit a standard PMTA, a
supplemental PMTA, or a request for an exemption from substantial
equivalence for the modified product, where appropriate, to FDA to seek
marketing authorization for the new tobacco product, but may not market
the new tobacco product until FDA has authorized the marketing of the
new tobacco product. 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 subject to an FDA enforcement
action.

B. Reporting Requirements (Proposed Sec.  1114.41)

    Proposed Sec.  1114.41 would require applicants that receive a
marketing 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 order. Proposed Sec.  1114.41 describes
the reports that FDA would require through this regulation; however,
FDA may require additional reporting in an individual applicant's
marketing order.
    Applicants would be required under proposed Sec.  1114.41 to submit
two types of reports after receiving a marketing order: Periodic
reports and adverse experience reports. Applicants would need to submit
periodic reports within 60 calendar days of the reporting date
specified in the marketing order (or potentially sooner if they choose
to use the application as the basis for a supplemental PMTA under
proposed Sec.  1114.15). FDA anticipates that the reports would be
required on an annual basis, but FDA may require in 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). Applicants would
have to submit the following information electronically together with
the appropriate form (Ref. 11) as part of each periodic report under
proposed Sec.  1114.41(a)(1):
     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 description of the changes made to the manufacturing,
facilities, or controls, if any, during the reporting period. This
description would be required to include sufficient information for FDA
to determine whether a change to the manufacturing, facilities, and
controls results in a new tobacco product or could potentially require
the marketing order to be withdrawn. This information would include a
comparison to the manufacturing, facilities, or controls described in
the PMTA, the rationale for marking 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
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
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 proposed
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 proposed Sec.  1114.7(k)(1) not previously submitted as part of
the PMTA or previous postmarket reports, as well as significant
findings from publications not previously reported. 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;
     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. This information
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 and whether the marketing order should be temporarily suspended
under section 910(d)(3) of the FD&C Act;
     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 proposed Sec.  1114.47 and 21 CFR 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, and tobacco use status.
    FDA would require 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 product continues to be APPH. The volume
of sales, demographics of purchasers, and other sales data provide
information that can help indicate trends in tobacco use behavior for
the product, such as whether nonusers are initiating tobacco product
use with the product and current tobacco product users are using the
product. These data are especially important for FDA to review because
the data inform a determination of whether the marketing of the new
tobacco product continues to be APPH. 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 higher rates of youth
initiation with the tobacco product than anticipated in the PMTA could
result in FDA finding that continued marketing of the tobacco product
is no longer APPH and the marketing order should be withdrawn under
section 910(d)(1)(A) of the FD&C Act.
     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 applicants to submit advertising because
it can indicate the potential for trends in tobacco use behavior for
the product, such as whether nonusers are likely to initiate tobacco
product use with the product and current tobacco product users are
likely to use the product (see section VII.B.6 regarding proposed Sec.
1114.7(f) for a discussion of the impact of advertising);
     A description of the implementation of all advertising and
marketing plans, including strategic creative briefs and paid media
plans (whether conducted by you, on your behalf, or at your direction)
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:
    [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;
    [cir] Targeting of specific adult audiences by age-range(s),
including young adults, ages 18-24, and other demographic or
psychographic characteristics that reflect the intended target
audience, including a list of all data sources used to target
advertising and marketing plans and media buys;
    [cir] Actions taken to restrict youth-access and limit youth-
exposure to the products' labeling, advertising, marketing, or
promotion;
    [cir] Use of owned, earned, shared, or paid media to create
labeling for, advertise, market, and/or promote the products;
    [cir] Use of partners, influencers, bloggers, or brand ambassadors
to create labeling for, advertise, market, and/or promote the products;
    [cir] Consumer engagements--whether conducted by you, on your
behalf, or at your direction--including events at which the products
are intended to be demonstrated; and
    [cir] Use of earned media or public-relations outreach to create
labeling for, advertise, market, or promote the products;
     A report or summary of the actual delivery of advertising
impressions, by channel, by product (if applicable), and by audience
demographics (e.g., age, gender, race/ethnicity, geographic location),
including a breakout by age-group (i.e., adults, ages 25+; young
adults, ages 18-24; and youth, ages 12-17 and ages 11 and under), not
previously submitted. This report or summary must be verified against
post-launch delivery-verification reports submitted to the tobacco
product company from an accredited source; and
     An overall assessment of how the marketing of the tobacco
product continues to be APPH.
    Applicants would also be required to 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 proposed Sec.  1114.41(a)(2). The serious and unexpected adverse
experience reports must be submitted to CTP's Office of Science through
the 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.
    As part of its review of a postmarket report, FDA would be able to
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 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 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 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 could be subject to
enforcement action.
    FDA notes that the proposed periodic reporting requirements in
Sec.  1114.41 apply most appropriately to new tobacco products that are
being actively manufactured, sold, distributed, or consumed. Where an
applicant temporarily ceases the introduction, or delivery for
introduction, of its new tobacco product into interstate commerce, FDA
is seeking public comment regarding whether it should include a
provision in the rule that would allow: (1) An applicant to temporarily
stop submitting periodic reports, upon notice to, and agreement by,
FDA, during the period of time in which it does not introduce, or
deliver for introduction, its new tobacco product into interstate
commerce; and (2) an applicant to resume the introduction, or delivery
for introduction, of is new tobacco product into interstate commerce,
upon notice to, and agreement by, FDA, after submitting a periodic
report to FDA meeting the requirements of Sec.  1114.41 that covers the
period in time since it last submitted a period report or received its
order if reports had yet to be submitted. In this scenario, an
applicant that fails to submit a

postmarket report and receive FDA agreement prior to resuming the
introduction, or delivery for introduction, of its new tobacco product
into interstate commerce may be marketing a product in violation of
section 902(6)(B) of the FD&C Act, rendering their product adulterated
and making it subject to enforcement action. FDA is specifically
seeking comment on factors FDA should consider in determining whether
the applicant should be allowed to temporarily cease its periodic
reporting, including whether product has ceased being manufactured,
sold, or distributed either in the United States or abroad.
    FDA is also seeking public comment regarding whether it should,
rather than creating a provision in a final rule, consider exercising
enforcement discretion regarding periodic reporting requirements on a
case-by-case basis after receiving the notice under 905(i)(3) of the
FD&C Act. Under the requirements of section 905(i)(3), an applicant
that receives a marketing order would be required to provide notice to
FDA in the event that it discontinues the manufacture, preparation,
compounding or processing for commercial distribution of the new
tobacco product.

X. Miscellaneous (Proposed Part 1114, Subpart E)

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

A. Record Retention (Proposed Sec.  1114.45)

    Consistent with the authority to require recordkeeping under
sections 909 and 910(f) of the FD&C Act, proposed Sec.  1114.45 would
require applicants receiving a marketing 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 order and
ensure that such records remain readily available to the Agency upon
request. The records would be required to be legible, written in
English, and available for inspection and copying by officers or
employees designated by the Secretary. This proposed requirement would
help 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 order in addition to the
requirements in the proposed rule.
1. Record Retention by the Applicant
    Under proposed 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 proposed 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.
     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 would also be required to 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 would also be required to 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.
2. Record Format and Availability
    The proposed rule would require 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 would have to retain the records as described in
proposed Sec.  1114.45(a)(3). Records relating to the PMTA would have
to be retained for a period of no less than 4 years from the date the
marketing order is issued. Records relating to the postmarket reports,
including both periodic reporting and adverse experience reporting
would have to 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 section 704 and 905(g) of the FD&C Act.

B. Confidentiality (Proposed Sec.  1114.47)

    Proposed Sec.  1114.47 states that FDA would determine the public
availability of any part of any PMTA and other content related to a
PMTA as provided under this proposed 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)
(21 U.S.C. 387f(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.
    Like with drugs and devices, the intent to market a tobacco product
is often considered confidential commercial information, as premature
disclosure could result in a competitive advantage to competitors.
Therefore, FDA is proposing Sec.  1114.47(b), which would address the
confidentiality of a PMTA prior to the issuance of a marketing order.
Under the proposed

regulation and consistent with part 20, FDA would 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. Proposed Sec.
1114.47(b)(2) provides that FDA would 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 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. Proposed
Sec.  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 (which concerns the public disclosure of
advisory committee records), except information that has been shown to
fall within the exemption established for trade secrets and
confidential commercial or financial information in Sec.  20.61, or
personal privacy in Sec.  20.63.
    Proposed Sec.  1114.47(c) describes the information that FDA will
make available after issuing a marketing order consistent with the
requirements of Sec.  20.61. Under proposed Sec.  1114.47(c), FDA would
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
environmental assessment or request for categorical exclusion, and
information and data contained in postmarket reports that are not
exempted from disclosure under Sec.  20.61 for trade secrets and
confidential commercial information, or in Sec.  20.63 for personal
privacy.
    Even after receipt of a no marketing order, the intent to market
may still constitute confidential commercial information, as the
applicant may still have the goal to market the new tobacco product
that is the subject of the PMTA. Under proposed Sec.  1114.47(d), FDA
may also make certain information available after it issues a no
marketing order unless the information is otherwise exempt from
disclosure under part 20. The information that FDA may disclose would
include product category, subcategory, package size, and the basis for
the no marketing order.

C. Electronic Submission (Proposed Sec.  1114.49)

    Consistent with FDA's authority to issue regulations for the
efficient enforcement of the FD&C Act, proposed Sec.  1114.49 would
require 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 proposed 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 is proposing 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 quickly than a submission submitted on paper through
postal mail. FDA intends to provide 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). FDA intends to update this
information as needed (e.g., to accommodate changes in technology).

XI. Paperwork Reduction Act of 1995

    This proposed 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. 3501-3520). A
description of these provisions is given in the Description section of
this document with an estimate of the annual reporting and
recordkeeping. 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.
    FDA invites comments on these topics: (1) Whether the proposed
collection of information is necessary for the proper performance of
FDA's functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
    Title: Premarket Tobacco Product Applications and Recordkeeping
Requirements, OMB Control Number 0910-0768.
    Description: This proposed rule would interpret and codify
requirements related to the content and format of PMTAs, the procedure
by which FDA would review PMTAs, and the maintenance of records
regarding the legal marketing of certain tobacco products without
PMTAs. The proposed 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 proposed 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.
    FDA is proposing requirements for the content, format, submission,
and review of PMTAs, as well as other requirements related to PMTAs,
including recordkeeping requirements, and postmarket reporting. FDA is
also proposing recordkeeping requirements regarding the legal marketing
of grandfathered tobacco products and products that are exempt from the
requirements of demonstrating substantial equivalence.
    Section 910(a)(2) of the FD&C Act generally requires that a new
tobacco product be the subject of a PMTA marketing order unless FDA has
issued an order finding it to be substantially equivalent to a
predicate product or it is exempt from the requirements of
demonstrating substantial equivalence. A manufacturer may choose to
submit a PMTA under section 910(b) of the FD&C Act in an attempt to
satisfy the requirements of premarket review. Section 910(b)(1)
describes the required contents of a PMTA, which in addition

to specific items, allows FDA to require applicants to submit other
information relevant to the subject matter of the application.
    Under proposed Sec.  1114.5 an applicant may submit a PMTA to
demonstrate that a new tobacco product meets the requirements to
receive a marketing order. A new tobacco product may not be introduced
or delivered for introduction into interstate commerce under this part
until FDA has issued a marketing order for the product. Proposed Sec.
1114.7 describes the required content and format of the PMTA. The PMTA
must contain sufficient information for FDA to determine whether any of
the grounds for denial specified in section 910(c)(2) of the FD&C Act
apply. The application must contain the following sections: General
information, descriptive information, product samples as required by
FDA, a statement of compliance with 21 CFR part 25, a summary, product
formulation, manufacturing, health risk investigations, and a
certification statement.
    Proposed Sec.  1114.9 provides that FDA may request, and an
applicant may submit, an amendment to a pending PMTA. FDA generally
expects that when an applicant submits a PMTA, the submission will
include all information required by section 910(b)(1) of the FD&C Act
and proposed part 1114 to enable FDA to determine whether it should
authorize the marketing of a new tobacco product. However, FDA
recognizes that additional information may be needed to complete the
review of a PMTA and, therefore, is proposing Sec.  1114.9 to allow the
submission of amendments to a pending application.
    Proposed Sec.  1114.13 describes the steps that an applicant would
be required to take when it changes ownership of a PMTA. This proposed
section is intended to facilitate transfers of ownership and help
ensure that FDA has current information regarding the ownership of a
PMTA. An applicant may transfer ownership of its PMTA at any time,
including when FDA has yet to act on it.
    Proposed Sec.  1114.15 discusses supplemental PMTAs, which are an
alternative format for submitting a PMTA. Specifically, supplemental
PMTAs are a standardized cross-referencing format that FDA would
implement under its authority of section 701(a) of the FD&C Act to
efficiently enforce section 910 for submissions that are based on a
PMTA that FDA has previously reviewed. Applicants that have received a
marketing order would be able to submit a supplemental PMTA to seek
marketing authorization for a new tobacco product that results from a
modification or modifications to the original tobacco product that
received the marketing order. FDA is proposing to restrict the use of
supplemental PMTAs to only changes that require the submission of
limited information or revisions to ensure that FDA is able to
efficiently review the application. An applicant would also be able to
submit a supplemental PMTA for modifications made to comply with a
product standard issued under section 907 of the FD&C Act where FDA
specifies that the submission of supplemental PMTAs would be
appropriate.
    Proposed Sec.  1114.17 describes resubmissions, which are an
alternative format for submitting an application that meets the
requirements of Sec.  1114.7(b) or Sec.  1114.15 to seek a marketing
order for a tobacco product by responding to the deficiencies outlined
in a no marketing order. An applicant may submit a resubmission for the
same tobacco product that received a no marketing order or for a
different new tobacco product that results from changes necessary to
address the deficiencies outlined in a no marketing order. This
application format allows an applicant to address the deficiencies
described in a no marketing order without having to undertake the
effort of submitting a standard PMTA. The resubmission format is not
available for PMTAs that FDA refused to accept, refused to file,
cancelled, or administratively closed, or that the applicant withdrew
because FDA has not previously completed reviews of such applications
upon which it can rely, and such applications may need significant
changes to be successfully resubmitted.
    Proposed Sec.  1114.41 would require applicants that receive a
marketing order to submit postmarket reports. FDA requires such reports
as necessary to determine or facilitate a determination of whether
there may be grounds to withdraw or temporarily suspend a marketing
order. Proposed Sec.  1114.41 describes the reports that FDA would
require through this regulation; however, FDA may require additional
reporting in an individual applicant's marketing order. Applicants
would be required under proposed Sec.  1114.41 to submit two types of
reports after receiving a marketing order: Periodic reports and adverse
experience reports.
    Applicants would need to submit periodic reports within 60 calendar
days of the reporting date specified in the marketing order. FDA
anticipates that the reports would be required on an annual basis, but
FDA may require in a specific order that reports be made more or less
frequently depending upon a number of factors. Applicants would also be
required to 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 proposed Sec.
1114.41(a)(2). The serious and unexpected adverse experience reports
must be submitted to CTP's Office of Science through the HHS Safety
Reporting Portal within 15 calendar days after receiving or becoming
aware of a serious and unexpected adverse experience.
    Proposed Sec.  1114.45 would require applicants receiving a
marketing 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 order, including records related to
both the application and postmarket reports, and ensure that such
records remain readily available to the Agency upon request. Under
proposed 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.
    Proposed Sec.  1100.200 states that subpart C of part 1100 would
establish requirements for the maintenance of records by tobacco
product manufacturers who introduce a grandfathered tobacco product, or
deliver it for introduction, into interstate commerce
    Proposed Sec.  1107.3 describes that each applicant who submits an
abbreviated report under section 905(j)(1)(A)(ii) of the FD&C Act and
receives a letter acknowledging the receipt of an abbreviated report
from FDA must maintain all records to support a determination that
their exemption request meets the requirements of section
905(j)(3)(A)(i) of the FD&C Act that the modification to a product
additive described in the exemption request was a minor modification
made to a tobacco product that can be sold under the FD&C Act.
    Proposed Sec.  1114.49 would require an applicant to submit a PMTA
and all supporting and related documents to FDA in electronic format.
Under proposed 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 is proposing 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 quickly than a submission
submitted on paper through postal mail.
    FDA estimates the burden of this collection of information as
follows:

                                                     Table 21--Estimated Annual Reporting Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of
                              Activity                                  Number of      responses per     Total annual    Average burden    Total hours
                                                                       respondents       respondent       responses       per response
--------------------------------------------------------------------------------------------------------------------------------------------------------
PMTA Submission (ENDS).............................................             200             3.75              750            1,713    1,284,750 \2\
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\ This total will not be added to the total burden for this rule as its currently approved under a separate OMB control number.

                                 Table 22--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
                                                     Number of
    ``21 CFR part''; activity        Number of     responses per   Total annual   Average burden    Total hours
                                    respondents     respondent       responses     per response
----------------------------------------------------------------------------------------------------------------
1114.5 Submission of Standard                  1               1               1           1,713           1,713
 Bundled PMTAs \2\..............
Premarket Tobacco Product                     24               1              24             .50              12
 Application (PMTA) Submission
 (FDA Form 4057)................
Premarket Tobacco Product                     24              14             336            .083              28
 Application Amendment And
 General Correspondence
 Submission (FDA Form 4057a)....
1114.41 Reporting Requirements                 3               1               3              50             150
 (periodic reports).............
1114.9 Amendments...............              24               4              96             188          18,048
1114.13 Change in Ownership.....               1               1               1               1               1
1114.15 Supplemental                           2               1               2             428             856
 applications...................
1114.17 Resubmissions...........               3               1               3             565           1,695
1114.41(a)(2) Adverse Experience               3               6              18             .60              11
 Reports........................
1114.49(b) and (c) Waiver from                 1               1               1             .25             .25
 Electronic Submission..........
                                 -------------------------------------------------------------------------------
    Total.......................  ..............  ..............  ..............  ..............          22,514
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ FDA anticipates that applicants will submit bundled PMTAs, which are single submissions containing PMTAs for
  a number of similar or related products. We estimate that a bundle will contain on average between 6 and 11
  distinct products.

    FDA has based these estimates on the full analysis of economic
impacts and experience with current PMTA submissions. Table 21
describes the current estimates for OMB control number 0910-0768 which
covers the burden for ENDS products PMTA submissions. These estimates
were originally published in the Deeming Rule and recently in the
Federal Register of April 22, 2019 (84 FR 16673). FDA estimates that it
will take each respondent approximately 1,500 hours to prepare a PMTA
seeking an order from FDA allowing the marketing of a new tobacco
product. FDA also estimates that it would on average take an additional
213 hours to prepare an environmental assessment in accordance with the
requirements of Sec.  25.40, for a total of 1,713 hours per PMTA
application.
    Table 22 describes the estimated annual reporting burden per the
requirements that the proposed rule would create beyond what is covered
in the existing information collection. For this analysis, FDA assumes
that firms will submit all applications as PMTA bundles. We also
considered updated data on market consolidation that has occurred since
the Deeming Rule was published. For originally regulated products we
expect to receive one full PMTA submission for a total of 1,713 hours.
    FDA developed Form FDA 4057 for use when submitting PMTA single and
bundled submissions. FDA estimates that 24 respondents will submit PMTA
bundles using this form at .50 (30 minutes) per response. The number 24
is accounting for the bundles of ENDS products and the 1 bundle we
expect to receive yearly for originally regulated products. (200 + 1 =
201/8.5 products on average in a bundle) for a total of 12 hours.
    FDA developed FDA Form 4057a for use when firms are submitting
amendments and other general correspondence. Our estimate is 0.83 (5
minutes) per response to fill out this form. We estimate there will be
at least one amendment per application for a total of 28 hours. With
most applications being submitted toward the end of our 3-year range,
we expect fewer amendments during this period. However, FDA expects
correspondence from earlier applications to be submitted during this
period.
    FDA estimates under proposed Sec.  1114.41 that three respondents
will submit a periodic report. This number is based on the average
number of periodic report submissions expected between 2020-2022. The
preliminary regulatory impact analysis (PRIA) estimates that periodic
reports will take between 20 and 80 hours per submission. For this
estimate, we use the average of 50 per response for a total of 150
hours.
    Under proposed Sec.  1114.9 firms would prepare amendments to PMTA
bundles in response to deficiency letters. These amendments contain
additional information that we need to complete substantive review. In
the PRIA we state in our limited history reviewing PMTAs, we on average
issue four deficiency letters. Based on this, we would anticipate four
responses back per bundle. Therefore, we estimate that 24 respondents
will submit 96 amendments (24 x 4). Assuming 1,500 hours as the time to
prepare and submit a full PMTA and amendments may on average take 10
percent to 15 percent of that time (150-225). We averaged this time out
(12.5 percent of a full submission preparation time) and arrived at 188
hours per response. FDA

estimates the total burden hours for preparing amendments is 18,048
hours.
    Proposed Sec.  1114.13 would allow an applicant to transfer
ownership of a PMTA to a new owner. FDA believes this will be
infrequent, so we have assigned 1 token hour acknowledging the
requirement.
    Proposed Sec.  1114.15 is an alternative format of submitting a
PMTA that meets the requirements of proposed Sec.  1114.7 that would
reduce the burden associated with the submission and review of an
application. Our estimated number of 2 respondents is based on the
number estimated for postmarket reports which is 3 bundles (which is
approximately 26 products). Not all applicants will resubmit
modifications to previously authorized products, so we estimate 2
bundles (which is approximately 17 products). FDA estimates further
that a supplemental PMTA will take 25 percent of the time it takes to
do an original submission (including EA hours) for 428 hours per
response. We estimate a total of 856 burden hours for this activity.
    Under proposed Sec.  1114.17 an applicant may submit a resubmission
for the same tobacco product that received a no marketing order or for
a different new tobacco product that results from changes necessary to
address the deficiencies outlined in a no marketing order. Based on the
PRIA, we are estimating that out of all bundles received in 2020, 2021,
and 2022, that an average of 3 bundles are authorized. If we receive 24
bundles yearly, and based on historical data, 58 percent fail at
acceptance (down to 8 bundles remaining), 17 percent fail at filing
(down to 7 bundles remaining), and 25 percent receive marketing orders
(5 left). We estimate that 50 percent will try to resubmit in a year.
Thus, this number of respondents is three (rounded up). FDA estimates
that a resubmission will take 33 percent of the time it takes to
complete an original submission (including EA hours) at 565 hours per
response for a total of 1,695 hours.
    Under proposed Sec.  1114.41(a)(2), firms would also submit adverse
experience reports for tobacco products with marketing orders. We
assume the same number of firms submitting periodic reports will submit
adverse experience reports. Currently firms may voluntarily submit
adverse experience reports using Form FDA 3800 under OMB control number
0910-0645. We have based our estimates on this information collection
which estimates that it takes 1 hour (for mandatory reporting) to
complete this form for tobacco products for a total of 18 hours.
Proposed Sec.  1114.49 would require 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. FDA does not believe we
will receive many waivers, so we have assigned one respondent to
acknowledge the option to submit a waiver. Consistent with our other
application estimates for waivers, we believe it would take .25 (15
minutes) per waiver for a total of .25.

                                                   Table 23--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Number of                       Average burden
                  ``21 CFR part'' and ``activity``                      Number of       records per      Total annual         per          Total Hours
                                                                      recordkeepers     recordkeeper       records       recordkeeping
--------------------------------------------------------------------------------------------------------------------------------------------------------
1114.45 PMTA Records...............................................               24                1               24                2               48
1100.204 Grandfathered products records............................                1                1                1                2                2
1107.3 Exemptions from Substantial Equivalence records.............                1                1                1                2                2
                                                                    ------------------------------------------------------------------------------------
    Total..........................................................  ...............  ...............  ...............  ...............               52
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.

    Table 23 describes the annual recordkeeping burden per the
requirements in this rule. FDA estimates that 26 recordkeepers will
maintain records at 2 hours per record. Additionally, the proposed
rule, if finalized, would require that firms establish and maintain
records related to SE Exemption Requests and Grandfathered products. We
expect the burden hours of this proposed rule to be negligible for SE
Exemption Requests. Firms would have already established the required
records when submitting the SE Exemption Request. Similarly, we expect
the hours of this proposed rule to be negligible for any Grandfathered
products that have already submitted Standalone Grandfathered
Submissions, because firms would have established the required records
when submitting the Standalone Grandfathered Submissions. We believe
this time is usual and customary for these firms. We estimate that it
would take 2 hours per record to establish the required records for a
total of 4 hours. Therefore, the total recordkeeping burden hours is
estimated to be 52 hours.
    The total burden for these new collections of information in this
rulemaking is 22,514 reporting hours and 52 recordkeeping hours for a
total of 22,566.
    To ensure that comments on information collection are received, OMB
recommends that written comments be faxed to the Office of Information
and Regulatory Affairs, OMB (see ADDRESSES). All comments should be
identified with the title of the information collection.
    In compliance with the Paperwork Reduction Act of 1995 (44 U.S.C.
3407(d)), the Agency has submitted the information collection
provisions of this proposed rule to OMB for review. These requirements
will not be effective until FDA obtains OMB approval. FDA will publish
a notice concerning OMB approval of these requirements in the Federal
Register.

XII. Executive Order 13132: Federalism

    We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13132. Section 4(a) of the
Executive Order requires Agencies to ``construe . . . a Federal statute
to preempt State law only where the statute contains an express
preemption provision or there is some other clear evidence that the
Congress intended preemption of State law, or where the exercise of
State authority conflicts with the exercise of Federal authority under
the Federal statute.''
    Section 916(a)(2) of the FD&C Act (21 U.S.C. 387p) is an express
preemption provision. Section 916(a)(2) provides that ``no State or
political subdivision of a State may establish or continue in effect
with respect to a tobacco product any requirement which is different
from, or in addition to, any requirement under the provisions of this
chapter

relating to . . . premarket review.'' Thus, if this proposed rule is
made final, the final rule would create requirements that fall within
the scope of section 916(a)(2) of the FD&C Act.

XIII. Consultation and Coordination With Indian Tribal Governments

    We have analyzed this proposed rule in accordance with the
principles set forth in Executive Order 13175. We have tentatively
determined that the rule does not contain policies that would have a
substantial direct effect on one or more Indian Tribes, on the
relationship between the Federal Government and Indian Tribes, or on
the distribution of power and responsibilities between the Federal
Government and Indian Tribes. The Agency solicits comments from tribal
officials on any potential impact on Indian Tribes from this proposed
action.

XIV. Analysis of Environmental Impact

    The Agency has determined under Sec.  25.30(h) that this action is
of a type that does not individually or cumulatively have a significant
effect on the human environment. No extraordinary circumstances exist
to indicate that the specific proposed action may significantly affect
the quality of the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.

XV. Preliminary Economic Analysis of Impacts

    We have examined the impacts of the proposed rule under Executive
Order 12866, Executive Order 13563, Executive Order 13771, the
Regulatory Flexibility Act (5 U.S.C. 601-612), and the Unfunded
Mandates Reform Act of 1995 (Pub. L. 104-4). Executive Orders 12866 and
13563 direct us to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages; distributive impacts; and equity). Executive Order 13771
requires that the costs associated with significant new regulations
shall, to the extent permitted by law, be offset by the elimination of
existing costs associated with at least two prior regulations.'' This
proposed rule is a significant regulatory action as defined by
Executive Order 12866.
    The Regulatory Flexibility Act requires us to analyze regulatory
options that would minimize any significant impact of a rule on small
entities. Because the proposed rule, if finalized, would generate net
benefits or negligible costs for most affected small entities, we
propose to certify that the proposed rule would not have a significant
economic impact on a substantial number of small entities.
    The Unfunded Mandates Reform Act of 1995 (section 202(a)) requires
us to prepare a written statement, which includes an assessment of
anticipated costs and benefits, before proposing ``any rule that
includes any Federal mandate that may result in the expenditure by
State, local, and tribal governments, in the aggregate, or by the
private sector, of $100,000,000 or more (adjusted annually for
inflation) in any one year.'' The current threshold after adjustment
for inflation is $154 million, using the most current (2018) Implicit
Price Deflator for the Gross Domestic Product. This proposed rule would
not result in an expenditure in any year that meets or exceeds this
amount.
    The proposed rule, if finalized, would add a requirement that
tobacco manufacturers of grandfathered tobacco products and products
that are exempt from the requirements of demonstrating substantial
equivalence maintain records to demonstrate that they can legally
market their products. For products that receive a PMTA marketing
order, the proposed rule, if finalized, would require certain
postmarket reporting, including recordkeeping, periodic reporting and
adverse experience reporting. The proposed rule also sets forth
requirements for the content and format of PMTA and the procedures we
follow to review the PMTA.
    If finalized, the proposed rule would create cost savings for firms
and for us by reducing the number of follow-on submissions for PMTAs.
The proposed rule would also create cost savings for us by reducing the
cost of review, reducing the number of deficiency letters we would
issue during substantive scientific review, and eliminating the need to
process unnecessary data. In Table 24, we present the total benefits of
the proposed rule. We estimate that average annualized benefits over 20
years would equal $5.54 million at a 7 percent discount rate and $5.44
million at a 3 percent discount rate.
    If finalized, the proposed rule would create costs for firms and
for us by increasing the number of complete PMTA submissions for deemed
and originally regulated tobacco products. Moreover, because this is
the first regulation to account for the costs of the PMTA requirements
for originally regulated products, we also include the costs to submit
and review PMTAs for these tobacco products; we already included the
costs to submit and review PMTAs for deemed tobacco products in the
final regulatory impact analysis for the Deeming Rule. Firms would
incur costs to maintain and submit postmarket reports, and we would
incur costs to review postmarket reports. Finally, firms would incur
costs to read and understand the rule and costs to maintain records for
some grandfathered products. In Table 24, we present the total costs of
the proposed rule. We estimate that average annualized costs over 20
years would equal $7.05 million at a 7 percent discount rate and $6.76
million at a 3 percent discount rate.

                                  Table 24--Summary of Benefits, Costs, and Distributional Effects of the Proposed Rule
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                                                Units
                                                                                ------------------------------------
                                     Category            Primary       Low        High                  Discount     Period              Notes
                                                        estimate    estimate    estimate      Year        rate       covered
                                                                                dollars    (percent)    (years)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Benefits..................  Annualized Monetized ($m/       $5.54       $2.57       $9.23        2017           7          20  All quantified benefits
                             year).                          5.44        2.54        9.03        2017           3          20   are cost savings.
                            Annualized Quantified....  ..........  ..........  ..........  ..........           7  ..........
                                                       ..........  ..........  ..........  ..........           3  ..........
                            Qualitative..............  ..........  ..........  ..........  ..........  ..........  ..........
--------------------------------------------------------------------------------------------------------------------------------------------------------
Costs.....................  Annualized Monetized ($m/        7.05        3.18       11.65        2017           7          20
                             year).                          6.76        3.12       11.05        2017           3          20
                            Annualized Quantified....  ..........  ..........  ..........  ..........           7  ..........
                                                       ..........  ..........  ..........  ..........           3  ..........
                            Qualitative..............  ..........  ..........  ..........  ..........  ..........  ..........
--------------------------------------------------------------------------------------------------------------------------------------------------------

Transfers.................  Federal Annualized         From:
                             Monetized ($m/year).
                            To:
                           -----------------------------------------------------------------------------------------------------------------------------
                            Other Annualized           From: Products without marketing
                             Monetized ($m/year).      orders.
                            To: Products with marketing orders.
--------------------------------------------------------------------------------------------------------------------------------------------------------
Effects...................  State, Local, or Tribal Government: None
                            Small Business: None
                            Wages: None
                            Growth: None
--------------------------------------------------------------------------------------------------------------------------------------------------------

    In line with Executive Order 13771, in Table 15 we estimate present
and annualized values of costs and cost savings over an infinite time
horizon.

                                                           Table 15--E.O. 13771 Summary Table
                                             [In $ millions 2016 dollars, over an infinite time horizon] \a\
--------------------------------------------------------------------------------------------------------------------------------------------------------
                                                              Primary       Lower bound     Upper bound       Primary       Lower bound     Upper bound
                                                           estimate (7%)       (7%)            (7%)        estimate (3%)       (3%)            (3%)
--------------------------------------------------------------------------------------------------------------------------------------------------------
Present Value of Costs..................................         $104.04          $47.84         $170.31         $214.04         $101.20         $349.33
Present Value of Cost Savings...........................           83.18           38.76          138.98          177.26           82.15          296.89
Present Value of Net Costs..............................           20.86          (0.23)           44.29           36.78         (14.19)           91.71
Annualized Costs........................................            3.03            1.39            4.96            6.23            2.95           10.17
Annualized Cost Savings.................................            2.42            1.13            4.05            5.16            2.39            8.65
Annualized Net Costs....................................            0.61          (0.01)            1.29            1.07          (0.41)            2.67
--------------------------------------------------------------------------------------------------------------------------------------------------------
\a\ Only the primary estimates (mean) sum in simulation results.

    We have developed a comprehensive Preliminary Economic Analysis of
Impacts that assesses the impacts of the proposed rule. The full
analysis of economic impacts is available in the docket for this
proposed rule (Ref. 118) and at https://www.fda.gov/about-fda/reports/economic-impact-analyses-fda-regulations.

XVI. Proposed Effectivre Date

    FDA proposes that any final rule that issues based on this proposal
become effective 30 days after the final rule publishes in the Federal
Register.

XVII. References

    The following references marked with an asterisk (*) are on display
at the Dockets Management Staff and are available for viewing by
interested persons between 9 a.m. and 4 p.m., Monday through Friday;
they also are available electronically at https://www.regulations.gov.
References without asterisks are not on public display at https://www.regulations.gov because they have copyright restriction. Some may
be available at the website address, if listed. References without
asterisks are available for viewing only at the Dockets Management
Staff (see ADDRESSES). FDA has verified the website addresses, as of
the date this document publishes in the Federal Register, but websites
are subject to change over time.

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Specific N-Nitrosamines,'' Critical Reviews in Toxicology, 26:2,
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3. Brunnemann, K.D., J.C. Scott, and D. Hoffman. ``N-
Nitrosomorpholine and Other Volatile N-Nitrosamines in Snuff
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4. *Institute of Food Technologists, ``Evaluation and Definition of
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5. Gale, N., G. Errington, and K. McAdam, ``Effects of Product
Format on Nicotine and TSNA Extraction from Snus Pouches,''
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Williamsburg, VA, September 15-18, 2013, available at: https://www.researchgate.net/publication/299854728_Effects_of_Product_Format_on_Nicotine_and_TSNA_Extraction_from_Snus_Pouches.
6. *Form FDA 4057.
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behaviours,'' Cochrane Database of Systematic Review, 10, 2011,
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11. *FDA Form 4057a.
12. *HHS, ``Preventing Tobacco Use Among Youth and Young Adults,'' A
Report of the Surgeon General, 2012, available at: https://www.hhs.gov/surgeongeneral/reports-and-publications/tobacco/index.html.
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Preventive Medicine, 29:313-320, 1999, available at: https://www.sciencedirect.com/science/article/pii/S0091743599905546?via%3Dihub.
16. *Beiner, L. and Siegel, M., ``The Role of Tobacco Advertising
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Media in Promoting and Reducing Tobacco Use, Tobacco Control
Monograph No. 14, National Institutes of Health, National Cancer
Institute, NIH Pub No. 02-5086 (2001), available at https://cancercontrol.cancer.gov/brp/tcrb/monographs/14/m14.pdf.
17. Wakefield, M., et al., ``Role of the media influencing
trajectories of youth smoking,'' Society for the Study of Addiction,
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18. Feighery, E., et al., ``Seeing, wanting, owning: the
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suceptibility in your people,'' Tobacco Control, 7:123-128, 1998,
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19. Pierce, J.P, et al., ``Receptivity to Tobacco Advertising and
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Tobacco Use: Assessing the Evidence for Causality,'' Pediatrics,
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21. Agaku, I.T. and Ayo, O., ``The Effect of Exposure to Pro-Tobacco
Advertising on Experimentation With Emerging Tobacco Products Among
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22. Fischer, P., et al., ``Brand Logo Recognition by Children Aged 3
to 6 Years,'' JAMA, 266(22):3145-3148, 1991, available at: https://jamanetwork.com/journals/jama/fullarticle/393811.
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Camel Cigarettes to Children,'' JAMA, 266(22), 1991, available at:
https://jamanetwork.com/journals/jama/fullarticle/393814.
24. Arnett, J.J., ``Adolescents' responses to cigarette
advertisements: links between exposure, liking, and appeal of
smoking,'' Tobacco Control, 7:129-133, 1998, available at: https://tobaccocontrol.bmj.com/content/7/2/129.
25. *HHS, ``E-Cigarette Use Among Youth and Young Adults,'' A Report
of the Surgeon General; 2016, available at: https://e-cigarettes.surgeongeneral.gov/documents/2016_sgr_full_report_non-508.pdf.
26. *Centers for Disease Control and Prevention, ``Tobacco Use Among
Middle and High School Students--United States,'' 2011-2015,
Morbidity and Mortality Weekly Report, 65(14):361-367, 2016,
available at: https://www.cdc.gov/mmwr/volumes/65/wr/mm6514a1.htm.
27. Mantey D.S., Cooper, M.R., Clendennen S.L., et al., ``E-
Cigarette marketing exposure is associated with e-cigarette use
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