On September 25, 2019, the Food and Drug Administration (FDA) published in the Federal Register a proposed rule that, when finalized, would set forth content and format requirements for premarket tobacco product applications (PMTAs) submitted pursuant to section 910 of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. § 387j. See 84 Fed. Reg. 50,566. It also addresses procedural issues related to FDA’s acceptance, filing, review, and ultimate disposition of PMTAs. Additionally, the rule would impose record retention requirements manufacturers of products subject to a PMTA order, as well as on manufacturers of grandfathered tobacco products (commercially marketed as of February 15, 2007) and products that are marketed pursuant to a substantial equivalence (SE) order or SE exemption. FDA is accepting comments submitted to the docket until November 25, 2019.
A “new tobacco product” may be marketed only after obtaining a PMTA order under FFDCA § 910(c)(1)(A)(i), 21 U.S.C. § 387j(c)(1)(A)(i), except where such product is grandfathered or covered by an SE order or SE exemption. FDA’s proposed rule would be codified at 21 C.F.R. Part 1114 and would be divided into five subsections, which are outlined below.
Subpart A – General Provisions (§§ 1114.1-.3)
In this section, FDA generally outlines the applicability of the proposed rule, including by defining terms. It also outlines what products FDA would consider to be “new,” requiring some form of premarket review. Per the statute, a new tobacco product is “any tobacco product (including those products in test markets) that was not commercially marketed in the United States as of February 15, 2007; or…any modification (including a change in design, any component, any part, or any constituent, including a smoke constituent, or in the content, delivery or form of nicotine, or any other additive or ingredient) of a tobacco product where the modified product was commercially marketed in the United States after February 15, 2007.” 21 U.S.C. § 387j(a)(1). As in the context of the proposed SE rule, FDA states that it “interprets the statutory phrase ‘as of February 15, 2007,’ as meaning that the tobacco product was commercially marketed in the United States ‘on February 15, 2007.’”
In the preamble to the proposed rule, FDA states that it believes that there are certain co-packaging situations that would require premarket review, such as co-packaging two or more tobacco products in the same container closure system (e.g., RYO kit with rolling papers inside the tin of tobacco filler). The preamble also considers, and requests comment on, proposed definitions of the terms “test marketing” and “commercial marketing” (consistent with the preamble to the proposed SE rule). FDA’s proposed definition of “test marketing” is “distributing or offering for sale…a tobacco product in the United States for the purpose of determining consumer response or other consumer reaction to the tobacco product, with or without the user knowing it is a test product, in which any of the following criteria apply: [o]ffered in a limited number of regions; [o]ffered for a limited time; [o]ffered to a chosen set of the population or demographic group.” FDA is proposing to define “commercially marketed” as “offering a tobacco product for sale to consumers in all or in parts of the United States.”
Subpart B – Premarket Tobacco Product Applications (§§ 1114.5-.17)
In this section, FDA generally outlines the content and formatting requirements for PMTAs. If a submission does not appear to contain the required content or is not properly formatted, FDA may refuse to accept the application for review. If, after initial acceptance for review, FDA determines that a PMTA does not contain sufficient required information to permit a substantive review, FDA may refuse to file the application. In the preamble, FDA states: “The main focus of the proposed rule’s content requirements is the threshold amount of information necessary for application filing, rather than every piece of information necessary to receive a marketing order both because FDA is still gaining experience in applying the authorization standard to PMTAs and because at this time, FDA believes applicants have some flexibility in the types of scientific information they can submit in order to provide sufficient health risk information to meet the standard.”
Required Content (Proposed § 1114.7(c)-(l))
General Information (§ 1114.7(c)): This section includes basic administrative information, such as:
Descriptive Information (§ 1114.7(d)): This section would include:
Product Samples (§ 1114.7(e)): The rule does not require samples as part of an initial submission, nor is failure to submit samples a basis for a refusal to accept a PMTA. Once an application has been accepted, however, FDA may require the applicant to submit samples of the finished new tobacco product, generally within 30 days of submission. In the preamble, FDA states that it generally expects to require applicants to submit product samples, and that it will detail how to submit samples and the number required.
Labeling and Marketing Plan (§ 1114.7(f)): An application must contain specimens of all proposed labeling, including labels, inserts, onserts, instructions, and other accompanying information. Such specimens must reflect the actual size and color to be used and include any required warning statements or other information.
Additionally, FDA proposes to require PMTAs to include a description of the proposed marketing plan for the new tobacco product (if applicable). As part of this description, the PMTA must describe “the target audience, media and distribution channels, particular tactics, total dollar amount(s) of media buys and marketing and promotional activities, [and the]…timing for the activities.” The requirements of this section are far-reaching and require applicants to identify the target audience (by age range and other demographic or psychographic characteristics), insights into the target audience used to inform marketing plans, use of sponsors or influencers, and means by which youth-access or youth-exposure would be limited, among others. FDA notes that it generally expects applicants to have conducted market or consumer research to identify and gain information about its target audience. It also requests that marketing plans include any information on use of independent, third-party age and identity-verification software for internet sales and plans to distribute the product only to age-restricted locations and/or limit the quantity of product that an adult customer may purchase within a given period of time.
In the preamble FDA states that, in reviewing an applicant’s marketing plans, it “intends to consider how an applicant will target the marketing of its new tobacco product to reach its intended consumers of legal age and to assess potential effect on nonusers. FDA will also consider how the applicant intends to minimize the extent to which youth can access the product and are exposed to its marketing.” FDA further states: “[I]f the PMTA does not address youth access to the product, youth exposure to the product’s labeling, advertising, marketing, and promotion, and youth initiation, such as describing how it proposes to restrict the sale or distribution of its product to limit potential youth access to the product (e.g., selling the tobacco product in adult only establishments) or exposure to advertising (e.g., using age verification controls for digital advertising), FDA may be unable to determine that the applicant has made a showing that permitting the marketing of the new tobacco product would be APPH.” Notably, FDA states that except where used as stimuli and studies, advertising would not need to be submitted for the purposes of application filing.
Statement of Compliance with Part 25 (§ 1114.7(g)): A PMTA must contain an environmental assessment (EA) or a claim of categorical exclusion.
Summary (§ 1114.7(h)): The rule proposes to require PMTAs to include a summary of the product formulation, manufacturing, and health risk investigations sections that provides a high-level discussion of the key aspects of the application and highlights information that demonstrates why a marketing should be issued. This summary should include a concluding discussion “demonstrating how the data and information contained in the PMTA both constitute valid scientific evidence and establish that permitting the marketing of the new tobacco product would be APPH.” In particular, if a PMTA contains “information regarding another tobacco product (e.g., published literature, marketing information) with appropriate bridging studies and describes the relationship to the product that is the subject of the application, FDA will review that information to determine whether it is valid scientific evidence sufficient to demonstrate that permitting the marketing of a product would be APPH.”
Product Formulation (§ 1114.7(i)): This section implements the requirement at FDCA § 910(b)(1)(B), 21 U.S.C. § 387j(b)(1)(B), that a PMTA contain “a full statement of the components, ingredients, additives, and properties, and of the principle or principles of operation of such tobacco product.” This section states that a PMTA must describe:
Manufacturing (§ 1114.7(j)): This section implements the requirement at FDCA § 910(b)(1)(C), 21 U.S.C. § 387j(b)(1)(C), that a PMTA contain “a full description of the methods used in, and the facilities and controls used for, the manufacture, processing, and, when relevant, packing and installation of, such tobacco product.” Although FDA has not yet issued tobacco product manufacturing practice regulations pursuant to FFDCA § 906(e), 21 U.S.C. § 387f(e), FDA intends to evaluate information submitted under this section to determine whether a product will be manufactured consistently in conformance with its specifications.
This section proposes to require a listing of all facilities in which the product will be manufactured, packaged, stored or controlled. Additionally, a PMTA would be required to include a narrative description of all manufacturing, design controls, packing and storage processes, as well as a list and summary of all standard operating procedures (SOPs) and relevant forms and records for such activities. This provision is broad-reaching and encompasses production steps, process controls, managerial oversight, employee training, monitoring procedures and manufacturing controls, non-conforming product handling processes, premarket testing procedures (and all underlying methods, validation, and reports), among others.
Health Risk Investigations (§ 1114.7(k)): This section implements the requirement at FDCA § 910(b)(1)(A), 21 U.S.C. § 387j(b)(1)(A), that a PMTA contain “full reports of all information, published or known to, or which should reasonably be known to, the applicant, concerning investigations which have been made to show the health risks of such tobacco product and whether such tobacco product presents less risk than other tobacco products…” The proposed rule is divided into three parts: 1) the types of investigations that would be considered investigations into the health risks of the product and whether the product presents less risk than other products; 2) the documentation an application would be required to contain to demonstrate that the application contains all published investigations; and 3) the information that would constitute a full report of an investigation.
FDA emphasizes that the proposed rule does not require a PMTA to contain each type of health risk investigation described in this section beyond what is published, known to, or should reasonably be known to, an applicant and applicants should not interpret this proposed section to be a list of investigations that they must conduct to receive a marketing order. However, if the information included in the PMTA is insufficient to show that the product would be APPH, FDA would issue a no marketing order.
For instance, FDA notes that information from nonclinical studies alone, including a product’s toxicological profile, is generally not sufficient to support a determination that permitting the marketing of the product would be APPH. Likewise, while only a “threshold” amount of abuse liability information is necessary for filing, the abuse liability of a tobacco product is an important facet of the APPH determination. Real world, actual use data may also provide outcomes relevant to the products’ abuse liability, including misuse.
In order to assess whether permitting the marketing of a proposed product would be APPH, FDA has stated that it will need to understand how youth may use or intend to use the proposed product because youth are a population of particular concern for initiating tobacco use. However, FDA does not require research to be conducted on youth. Inferences regarding youth may potentially be extrapolated from young adults, as well as derived from existing sources of data, reviews of published scientific literature, and/or bridging information obtained from other sources. In general, where there is no published information regarding the product in the above-listed categories that is known to the applicant, including information from investigations using other products that an applicant could bridge to its product, an applicant would need to conduct its own investigations and include a full report of the results in its PMTA for filing.
In the preamble, FDA provides additional guidance regarding the following:
Effect on the Population as a Whole (§ 1114.7(l)): A PMTA must analyze and discuss how the data and information in the application establish that the marketing of the new tobacco product would be APPH.
Certification Statement (§ 1114.7(m)): The application must contain a statement certified by the applicant or authorized representative.
Format (Proposed § 1114.7(b)
Under the proposed rule, a PMTA must be submitted with the appropriate form(s), contain a comprehensive index (i.e., a listing of files and data associated with those files) and a table of contents, be well-organized and legible, and be written in English. Documents that have been translated from another language into English (e.g., original study documents written in a language other than English) must be accompanied by the original language version of the document, 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.
Unless FDA has granted a waiver, PMTAs must be submitted electronically. This section also provides that a PMTA may cross reference a tobacco product master file (TPMF) or a modified risk tobacco product application for the same product (MRTPA), but FDA would not consider other consider other external cross-references (such as to a previous PMTA, SE Reports, etc.).
Amendments (§ 1114.9): The proposed rule explains that, upon request by FDA or on their own initiative, applicants may submit an amendment to a submitted PMTA (including before acceptance or filing). The effect of an amendment on the 180-day review clock depends on the significance of such amendment. For “major” amendments containing significant new data from a previously unreported study or detailed new analyses of previously submitted data, FDA would consider the applicant to have submitted a new PMTA with the review period restarting the date on which FDA receives the amendment. For minor amendments, FDA may pause the review clock from the date of FDA’s request to the date on which FDA receives a written response.
Withdrawal (§ 1114.11): The proposed rule provides that an applicant would be able to withdraw an application at any time, but such request must state, among other things, whether the withdrawal is due to a health-related concern and provide further information. Withdrawing an application would not prejudice a future submission.
Change in Ownership (§ 1114.13): Under the proposed PMTA rule, an applicant may transfer ownership of a PMTA at any time.
Supplemental PMTA (§ 1114.15): The rule proposes to permit submission of so-called supplemental PMTAs where 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. However, FDA is proposing to restrict the use of supplemental PMTAs to changes that require the submission of limited information or revisions (such alterations made to comply with a product standard). The draft rule outlines the specific content and formatting requirements for supplemental PMTAs.
Resubmissions (§ 1114.17): FDA also proposes to allow for PMTA resubmissions to address deficiencies identified in a no marketing order (such path would be unavailable to PMTAs that FDA refused to accept, refused to file, cancelled, administratively closed, or withdrawn). Generally, an applicant would make a resubmission by incorporating content in the previous PMTA by reference and then supplying new information, data, or discussions to address the deficiencies identified in the no marketing order.
Subpart C – FDA Review (§§ 1114.25-.37)
This section generally concerns issues related to the FDA review process, including communication, acceptance and filing criteria, and order issuance.
Review Procedure (§ 1114.27): This provision generally describes the sequence of PMTA review following submission, i.e., acceptance review, filing review, and application review. If FDA refuses to accept or file a PMTA, it will issue a letter to the applicant noting the deficiencies (where practicable).
Acceptance Review: This would assess the facial completeness of the submission only. Under the proposed rules, FDA may refuse to accept an application where:
Examples of submissions FDA would refuse to accept include submissions lacking labeling, design parameter information, an environmental assessment, or a literature search. If FDA accepts a PMTA for further review, FDA will issue an acknowledgment letter to the applicant. After FDA accepts a PMTA for review, FDA may request product samples as described in § 1114.7(e) and will conduct a filing review to determine whether the application contains sufficient information to permit a full substantive review of the application.
Filing Review: This is an assessment of whether the application contains sufficient information required by FFDCA § 910(b)(1) and §§ 1114.7, 1114.15, or 1114.17, as applicable, to permit a substantive review of the application. Additionally, the proposed regulations state that FDA would refuse to file an application that does not contain any information regarding the following:
Additionally, FDA would refuse to file a PMTA that contains a false statement of material fact.
Application review: The proposed rule states that as part of the review process, FDA may refer the PMTA or portions thereof to the Tobacco Products Scientific Advisory Committee (TPSAC), either on its own initiative or upon applicant request. FDA may also conduct inspections of manufacturing sites or sites and entities involved in clinical and nonclinical research (including third parties and contract research organizations). Failure to grant FDA access at a reasonable time and in a reasonable manner 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.
While the rules states that FDA will complete review of a PMTA within 180 days of receipt, the review clock may be paused as described above (such as submission of minor amendments), as a result of inspection scheduling issues, or if the product would be adulterated or misbranded due to failure to report and pay user fees under 21 C.F.R. Part 1150. Additionally, the review clock may run more than 180 days if a PMTA contains an inadequate EA because FDA could not authorize the marketing of such product. Per the preamble, the 180-day clock begins when FDA receives the last piece of information necessary to complete the submission (which could include product samples submitted following acceptance review). As noted above, the 180-day clock would restart upon submission of a major amendment.
Issuance of Marketing Order or No Marketing Order (§ 1114.29, .31, .33): Generally, the regulation provides for six actions that FDA may take on a submitted PMTA. It could: 1) refuse to accept the PMTA; 2) administratively close the application via letter (for cases in which the applicant requests to withdraw an application or fails to respond to a request for amendment within 180 days); 3) issue an order canceling the application (if FDA mistakenly acknowledged such PMTA); 4) refuse to file the PMTA; 5) issue a marketing order; 6) issue a no marketing order.
In order to issue a marketing order, FDA must determine that the marketing of the product would be appropriate for the protection of the public health and none of the grounds for denial listed in FFDCA § 910(c)(2), 21 U.S.C. § 387j(c)(2), are applicable. The preamble explains that a finding that a product is APPH is a “complex determination” that FDA will make on the basis of information provided in the application and any other relevant sources of information, including reports and recommendations from TPSAC, when applicable.
FDA further explains that “[b]ecause 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.” Notably, the threshold for the APPH determination is not fixed and may change over time. The preamble explains that as the tobacco market changes, so too do the potential risks and benefits to the population as a whole of the marketing of a new tobacco product; thus, a new tobacco product might receive a marketing order under one set of market conditions but not in the context of a later set of market conditions. FDA also highlights that while an applicant may submit any type of evidence in a PMTA, FDA will only rely on valid scientific evidence to make its APPH determination.
Finally, the preamble states that while applicants do not necessarily need to conduct new studies to support an application (outside of § 1114.27(b)(1)(ii)), the agency expects that a PMTA would provide “sufficient evidence to support issuance of a marketing order … 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.” Information from nonclinical studies alone is generally insufficient to support an APPH determination. FDA also recognizes that 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.
FDA would issue a no marketing order where a PMTA does not contain sufficient information regarding:
In addition, FDA may issue a no marketing order if the applicant does not permit inspection of facilities and records. A no marketing order will, where practicable, describe the PMTA’s deficiencies.
Once a marketing order has been issued, FDA may determine that such order must be withdrawn or suspended. FDA may withdraw a marketing order if it determines that any of the grounds at FFDCA § 910(d)(1), 21 U.S.C. § 387j(d)(1), are met, if the PMTA holder fails to meet a post-market requirement imposed by the marketing order, or where changes to the tobacco product marketplace result in FDA finding that the marketing of a product is no longer APPH. FDA provides the following example: 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.
A marketing order may also be temporarily suspended if the continued distribution would result in serious, adverse health consequences or death greater than ordinarily caused by marketed tobacco products. Prior to withdrawing or suspending a marketing order, a PMTA holder is entitled to an informal hearing pursuant to 21 C.F.R. Part 16.
Subpart D – Postmarket Requirements (§§ 1114.39-.41)
This Subpart describes the requirements imposed on PMTA holders following issuance of a marketing order by FDA. Under the proposed rule, an applicant may not make any modifications to a product that is the subject of an order without submitting a new PMTA, supplemental PMTA, or request for SE exemption and receiving authorization to market such modified product. 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 in a periodic report.
The proposed rule also imposes substantial post-market reporting requirements on applicants that receive a marketing order. These provisions would require applicants to submit periodic and adverse experience reports.
Periodic Reports: The proposed rule would require the submission of period reports annually within 60 calendar days of the reporting dates specified in the marketing order and would continue for the life of the order. Generally, such reports would be required to contain:
Serious and unexpected adverse experience reports: The proposed rule requires such reports to be filed with FDA within 15 calendar days after the report is received by the applicant.
FDA is seeking comment regarding whether the requirement to submit post-marketing reports should be suspended if an applicant temporarily ceases the introduction of its new product into interstate commerce, and then reinstated if the product is reintroduced to commerce by the applicant.
Subpart E – Miscellaneous (§§ 1114.45-.49)
The final sections of the proposed rule deal with record retention following receipt of a marketing order, confidentiality of submissions, and the requirement of electronic submission.
Generally, the proposed rule would require an applicant to retain all documents submitted to FDA, whether as part of the initial application or as part of post-market reports, as well as information that was not submitted to FDA but that demonstrate: 1) conformance with good laboratory practices or 2) whether investigators had financial conflicts of interest. FDA also proposes to require retention of data necessary to substantiate study results and 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. Records would generally be required to be maintained for four (4) years from date of the marketing order, or, in the case of post-market reports, the date of submission or date of FDA inspection, whichever occurs sooner.
The proposed confidentiality provisions generally state that FDA will not publicly disclose the existence of a PMTA except where the PMTA has been referred to TPSAC or where the applicant has already publicly disclosed or acknowledged, or authorized FDA in writing to publicly disclose or acknowledge, the existence of the application. Following issuance of a marketing order, certain information would generally be available for public disclosure upon request or at the agency’s initiative (except where covered by certain provisions of 21 C.F.R. Part 20, e.g., trade secret or confidential commercial information), such as data previously disclosed, protocols for tests or studies, information or data submitted to demonstrate the product is APPH, correspondence, the EA or categorical exclusion claimed, and information or data submitted in post-market reports. Because the existence of a PMTA may remain confidential commercial information following issuance of a no marketing order, the breadth of information that may be disclosed following such order is much narrower, and extends only to information related to product category and subcategory, package size, product quantity, characterizing flavor, and the basis for the order.
Finally, the proposed rule would require all submissions to be made electronically except where a waiver from such requirement is obtained.
Record Retention for Grandfathered Products, SE Reports,
Requests for an SE Exemption (§§ 1100.200-.204; Part 1107)
Separate from the
requirements pertaining to PMTAs, the proposed rule provides that FDA would
require certain records to be maintained for a period of four (4) years from
the date of grandfather determination, cessation of marketing, or
acknowledgement letter (in the case of SE exemptions), as applicable. The
information that would be required to be maintained is specific to the
 Non-grandfathered deemed tobacco products (e.g., vapor products) that were on the market on August 8, 2016, are currently marketed under FDA’s enforcement discretion policy.