(a) General. The PMTA must contain sufficient information for FDA to determine whether any of the grounds for marketing denial order specified in section 910(c)(2) of the Federal Food, Drug, and Cosmetic Act apply. The application must contain the following sections:
(1) General information (as described in paragraph (c) of this section);
(2) Descriptive information (as described in paragraph (d) of this section);
(3) Product samples (as described in paragraph (e) of this section);
(4) Labeling and description of marketing plans (as described in paragraph (f) of this section);
(5) Statement of compliance with 21 CFR part 25 (as described in paragraph (g) of this section);
(6) Summary (as described in paragraph (h) of this section);
(7) Product formulation (as described in paragraph (i) of this section);
(8) Manufacturing (as described in paragraph (j) of this section);
(9) Health risk investigations (as described in paragraph (k) of this section); and
(10) The effect on the population as a whole (as described in paragraph (l) of this section);
(11) Certification statement (as described in paragraph (m) of this section).
(b) Format. (1) The application must be submitted using the form(s) that FDA provides, contain a comprehensive index (i.e., a listing of files and data associated with those files) and 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, signed a 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. As described in § 1114.49, the applicant must submit the application and all information supporting the application in an electronic format that FDA can process, read, review, and archive, unless FDA has granted a waiver.
(2) An applicant may include content in a submission by cross-reference to a tobacco product master file or a pending modified risk tobacco product application for the same tobacco product. Applicants using a master file must provide documentation of their right of reference for the master file and clearly identify the specific content being incorporated into the PMTA submission. Except as provided for in §§ 1114.15 and 1114.17, FDA will not consider content included by cross-reference to other sources of information outside of the submission.
(c) General information. The applicant must, by using the form(s) FDA provides, specify the following general information:
(1) Applicant name, address, and contact information;
(2) Authorized representative or U.S. agent (for a foreign applicant), including the name, address, and contact information;
(3) The following information to uniquely identify the product:
(i) Manufacturer;
(ii) Product name(s), including brand and subbrand (or other commercial name(s) used in commercial distribution); and
(iii) The product category, product subcategory, and product properties as provided in the following table. If the product does not have a listed product property, such as ventilation or characterizing flavor, the application must state “none” for that property.
(4) The type of PMTA (i.e., PMTA, supplemental PMTA, or resubmission);
(5) Whether the applicant requests that FDA refer the PMTA to the Tobacco Products Scientific Advisory Committee (TPSAC);
(6) Identifying information regarding any prior submissions regarding the tobacco product (e.g., submissions related to investigational tobacco products, substantial equivalence reports, PMTAs), including submission tracking numbers (STNs) where applicable;
(7) Dates and purpose of any prior meetings with FDA regarding the new tobacco product;
(8) If applicable, the dates when the tobacco product was commercially marketed in the United States;
(9) Address and the Facility Establishment Identifier (FEI) number(s), if available, of the establishment(s) involved in the manufacture of the new tobacco product;
(10) A brief statement regarding how the PMTA satisfies the content requirements of section 910(b)(1) of the Federal Food, Drug, and Cosmetic Act;
(11) A brief description of how marketing of the new tobacco product would be appropriate for the protection of the public health; and
(12) A list identifying all enclosures, labels, and labeling being submitted with the application.
(d) Descriptive information. The application must contain descriptive information in this section that outlines the major aspects of the new tobacco product, including the following items:
(1) A concise description of the new tobacco product;
(2) A statement identifying all tobacco product standards issued under section 907 of the Federal Food, Drug, and Cosmetic Act that are applicable to the new tobacco product and a brief description of how the new tobacco product fully meets any identified tobacco product standard, or if the new tobacco product deviates from a product standard, if applicable, the application must include adequate information to identify and justify those deviations;
(3) The name(s) of the product as designated on the product's label;
(4) A description of problems that were identified in prototypes that are the subject of studies in the application and previous or similar versions of the new tobacco product that were marketed, if any. If there are previous or similar versions that are the subject of studies in the application or were marketed, the application must contain a bibliography of all reports regarding the previous or similar version of the product, whether adverse or supportive; and
(5) Any restrictions on the sale, distribution, advertising, or promotion of the new tobacco product that the applicant proposes to be included as part of a marketing granted order under section 910(c)(1)(B) of the Federal Food, Drug, and Cosmetic Act to help support a showing that the marketing of the product is appropriate for the protection of the public health. If there are no proposed restrictions, the application must contain a statement to that effect.
(e) Samples of new tobacco products. After FDA accepts a PMTA for review, it may require the submission of samples of the new tobacco product, including its components and parts. If required, the applicant must submit samples of the finished tobacco product or its components or parts in accordance with instructions provided by FDA. FDA may also require the submission of additional samples to further aid in its review.
(f) Labeling and description of marketing plans—(1) Labeling. The application must contain specimens of all proposed labeling for the new tobacco product, including labels, inserts, onserts, instructions, and other accompanying information. The specimens of labeling must include all panels, reflect the actual size and color proposed to be used for the tobacco product, and include any warning label statements and other information required by regulation or statute, as applicable.
(2) Description of Marketing Plans. A PMTA must contain a description of the applicant's plans to market the new tobacco product, for at least the first year the product would be marketed after receiving a marketing granted order, in way that is both consistent with the applicant's discussion of the increased or decreased likelihood of changes in tobacco product use behavior, including switching, initiation, cessation, and polyuse, under § 1114.7(l), and permits FDA to determine permitting the new tobacco product to be marketed would be appropriate for the protection of public health. The description must include actions to market the product that would be taken by the applicant, on behalf of the applicant, or at the applicant's direction, and also discuss any restrictions on the sales and distribution the applicant proposes to be included in a marketing order under section 910(c)(1)(B) of the Federal Food Drug and Cosmetic Act. The description of marketing plans must contain, at minimum:
(i) A description of the specific group(s) to which the labeling, advertising, marketing, promotion, and other consumer-directed activities for the new tobacco product would be targeted (i.e., the intended audience(s));
(ii) A discussion of how the labeling, advertising, marketing, promotion, and other consumer-directed activities for the new tobacco product would be targeted to reach the intended audience(s) identified in paragraph (i) and what other group(s) would foreseeably be exposed to those materials and activities as a result;
(iii) A discussion of, for individuals below the minimum age of sale, how access to the new tobacco product would be restricted and exposure to the labeling, advertising, marketing, promotion, and other consumer-directed activities would be limited; and
(iv) A concluding summary describing how the applicant's plans for marketing the new tobacco product are consistent with the applicant's discussion of the increased or decreased likelihood of changes in tobacco product use behavior, including switching, initiation, cessation, and polyuse, under § 1114.7(l) and permits FDA to determine permitting the new tobacco product to be marketed would be appropriate for the protection of public health.
(g) Statement of compliance with 21 CFR part 25. (1) The application must contain an environmental assessment prepared in accordance with § 25.40 of this chapter, or a valid claim of categorical exclusion, if applicable. If the applicant believes that the action qualifies for an available categorical exclusion, the applicant must state under § 25.15(a) and (d) of this chapter that the action requested qualifies for a categorical exclusion, citing the particular exclusion that is claimed, and that to the applicant's knowledge, no extraordinary circumstances exist under § 25.21 of this chapter.
(h) Summary. The application must include a summary of all information contained in the application. The summary must include the following items, highlighting the effects on youth, young adults, and other relevant vulnerable populations:
(1) A summary of the product formulation section of the application;
(2) A summary of the manufacturing section of the application;
(3) A summary of the health risk investigations section of the application, including all information regarding the following items, and identify areas in which there is a lack of information, where applicable:
(i) The health risks of the tobacco product to both users and nonusers of the product and whether the tobacco product may present less health risk than other tobacco products;
(ii) The impact the product and its marketing will have on the likelihood of changes in tobacco use behavior, including cessation, switching, and polyuse, of tobacco product users;
(iii) The impact the product and its marketing will have on the likelihood of tobacco use initiation by tobacco product nonusers;
(iv) How users and nonusers perceive the risk of the tobacco product based upon its label, labeling, and advertising, to the extent that advertising has been studied;
(v) Whether users are able to understand the labeling and instructions for use, and use the product in accordance with those instructions; and
(vi) The impact of human factors on the health risks to product users and nonusers (as described in paragraph (k)(1)(v) of this section);
(4) A concluding discussion describing how the data and information contained in the PMTA both constitute valid scientific evidence and establish that permitting marketing of the new tobacco product is appropriate for the protection of the public health, as determined with respect to the risks and benefits to the population as a whole, including users and nonusers of the tobacco product. This discussion must specifically describe the effects on youth, young adults, and other relevant vulnerable populations with an emphasis on populations that are most likely to use the new tobacco product. The summary must also identify any key or pivotal studies on which an applicant is relying to establish that permitting the marketing of the new tobacco product would be APPH.
(i) Product formulation. The application must contain a full statement of the components or parts, materials, ingredients, additives, constituents, properties, and the principle or principles of operation, of the tobacco product, including the following information:
(1) Components or parts, materials, ingredients, additives, and constituents. The applicant must provide a full statement of:
(i) Components or parts. The quantity, function, and purpose of, and, where applicable, target specification(s) of, each component or part in the product. Where the tobacco product contains software components, the applicant must provide:
(A) A description of the software or technology (e.g., Bluetooth);
(B) The purpose of the software or technology, such as monitoring where tobacco products are located, activated, or used;
(C) A description of the data collected by the software and how it will be used.
(ii) Materials. For each material in the product, include:
(A) The material name and common name(s), if applicable;
(B) The component or part of the tobacco product where the material is located;
(C) The subcomponent or subpart where the material is located, if applicable;
(D) The function of the material;
(E) The quantities (including ranges or means and acceptance limits) of the material(s) in the new tobacco product (with any specification variation, if applicable);
(F) The specification(s) (including quality/grades and suppliers) used for the new tobacco product (including any specification variations, if applicable); and
(G) Any other material properties to fully characterize the new tobacco product.
(iii) Ingredients other than tobacco. For ingredients other than tobacco in each component or part of the product, include:
(A) The International Union of Pure and Applied Chemistry (IUPAC) chemical name and common name, if applicable;
(B) The Chemical Abstracts Service (CAS) number or FDA Unique Ingredient Identifier (UNII), if applicable;
(C) The function of the ingredient;
(D) The quantity of the ingredient in the tobacco product, with the unit of measure (including ranges or means and acceptance limits) reported as mass per gram of tobacco for nonportioned tobacco products and as mass per portion for portioned tobacco products (with any specification variation, if applicable);
(E) The specification(s) (including purity or grade and supplier); and
(F) For complex purchased ingredients, each single chemical substance reported separately.
(iv) Tobacco ingredients. For tobacco ingredients in each component or part, include the following information or, if applicable, a statement that the product does not contain tobacco ingredients:
(A) The type(s) (e.g., Bright, Burley, reconstituted);
(B) The quantity with the unit of measure (including ranges or means, acceptance limits) of each tobacco ingredient in the tobacco product reported as mass per gram of tobacco for nonportioned tobacco products and as mass per portion for portioned tobacco products (with any specification variation, if applicable);
(C) The specification of tobacco used for the new tobacco product (with any specification variation, if applicable); and
(D) A description of any genetic engineering of the tobacco that impacts product characteristics.
(v) Constituents. Constituents, including HPHCs and other constituents, contained within, or emitted from (including its smoke or aerosol), the product, including any reaction product from leaching or aging, by providing:
(A) The constituent names in alphabetical order;
(B) The common name(s);
(C) The Chemical Abstract Services number;
(D) The mean quantity and variance with unit of measure;
(E) The number of samples and measurement replicates for each sample;
(F) A description of method procedure, method validation information and rationale for selecting each test method;
(G) The name and location of the testing laboratory or laboratories and documentation showing that the laboratory or laboratories is (or are) accredited by a nationally or internationally recognized external accreditation organization;
(H) Length of time between dates of manufacture and date(s) of testing;
(I) Storage conditions of the tobacco product before it was tested;
(J) Test data including test protocols, any deviation(s) from the test protocols, quantitative acceptance (pass/fail) criteria, and line data for all testing performed. Test data for combusted or inhaled products must reflect testing conducted using both intense and nonintense smoking or aerosol-generating regimens, where established; and
(K) Complete descriptions of any smoking or aerosol-generating regimens used for analytical testing that are not standardized or widely accepted by the scientific community, if applicable.
(vi) Container closure system. A description of the container closure system, including:
(A) Information describing how the container closure system protects and preserves the product from damage during transport, environmental contaminants, and potential leaching and migration of packaging constituents into the new tobacco product; and
(B) Information describing design features developed to prevent the risk of accidental exposure, if any.
(vii) Statement of tobacco blending, reconstitution, or manipulation. Information regarding tobacco blending, reconstitution, or manipulation, where applicable.
(2) Other properties. The applicant must provide a full description of the additional properties of the tobacco product that includes:
(i) Product dimensions and construction. The product dimensions and the overall construction of the product using a diagram or schematic drawing that clearly depicts the finished tobacco product and its components with dimensions, operating parameters, and materials.
(ii) Design parameters and test data. (A) All final design parameters of the product, specifying nominal values or the explicit range of values as well as the design tolerance (where appropriate), including, but not limited to, the parameters specified in tables 1 to 22 of this paragraph as applicable. If a design parameter specified in tables 1 to 22 does not apply to the tobacco product, applicants must explain why the required design parameter does not apply or how an alternative design parameter would satisfy the required design parameter. If the product has additional design parameters that are not specified in tables 1 to 22, the application must contain a description of the design specifications as well as test data and processes to demonstrate that the design parameters and their associated processes are adequately controlled; and
(B) A quantitative description of the performance criteria, including test protocols, line data, and a summary of the results, for each applicable intermediate and final design parameter and manufacturing step, that includes, but is not limited to the test data specified in tables 1 to 22 of this paragraph for the product category as applicable. If the test data specified in the applicable table does not apply to the tobacco product, applicants must explain why the test data does not apply or how alternative test data would satisfy this requirement. Where tobacco cut size or particle size is a required design parameter for a product category or subcategory and the target specifications and range limits are not available, the following alternative information may be submitted in place of this information: a description of the tobacco cutting process (including a complete description of the milling, cutting, and sifting process; the control parameters of the miller or cutter; and any sift specifications), or the measured particle size distribution;
(iii) Function. How the product is intended to function.
(iv) Product pH and nicotine formulation. The pH of the product and the formulation of nicotine in the product, if applicable, including the form (e.g., unprotonated nicotine, nicotine salts) and quantity.
(v) Fermentation process. For smokeless tobacco products and tobacco products that contain fermented tobacco (including naturally fermented tobacco), information on the fermentation process, including the following:
(A) Description of the fermentation process;
(B) Composition of the inoculum (starter culture) with genus and species name(s) and concentration(s) (if applicable);
(C) Any step(s) taken to reduce endogenous microbes (e.g., cleaning of product contact surfaces);
(D) Specifications and test data for pH, temperature, moisture content, and water activity;
(E) Frequency of aeration or turning (if applicable);
(F) Duration of fermentation;
(G) Added ingredients;
(H) Method used to stabilize or stop fermentation (e.g., heat treatment) (if applicable), including parameters of the method (e.g., length of treatment, temperature) and method validation data; and
(I) Storage conditions of the fermented tobacco prior to further processing or packaging and duration of storage (if applicable).
(vi) Heat treatment process. For tobacco products that are heat treated, the application must contain the following information regarding the heat treatment process:
(A) Description of the heat treatment process;
(B) Type of heat treatment;
(C) Conditions of heat treatment, including time, temperature, and moisture; and
(D) Method validation data, including microbial loads (including bacteria, spores, yeast, and fungi) and TSNAs before and after heat treatment.
(vii) Shelf life and stability information. With the exception of applications for roll-your-own tobacco products and cigarettes that are not HTPs, the application must contain information on the stability of the tobacco product over the shelf life and including the following:
(A) The length of the shelf life, a description of how the shelf life is determined, and a description of how shelf life is indicated on the tobacco product, if applicable;
(B) Stability data assessed at the beginning (zero time), middle, and end of the expected shelf life. If a tobacco product does not have a defined shelf life, provide stability data over a specified amount of time and a justification for why that time period is appropriate. Stability testing must be performed for the microbial and chemical endpoints as follows: Microbial content data, including total aerobic microbial count and total yeast and mold count; water activity; tobacco-specific nitrosamines (TSNAs) yields (total TSNAs, N′-nitrosonor-nicotine (NNN), 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone) (NNK)); and preservatives content.
(C) Stability testing details for each microbial and chemical endpoint, including: The mean quantity and variance with unit of measures; the number of samples and measurement replicates for each sample; the methods used, including any deviation(s) from the methods, associated reference(s), and full validations reports for each method; the testing laboratory or laboratories and documentation showing that the laboratory or laboratories is (or are) accredited by a nationally or internationally recognized external accreditation organization; length of time between date of tobacco product manufacture and date(s) of testing; storage conditions of the tobacco product before it was tested; a statement that the testing was performed on a tobacco product in the same container closure system in which the tobacco product is intended to be marketed; and full test data (including quantitative acceptance (pass/fail) criteria, complete data sets, and a summary for the results) for all stability testing performed.
(viii) Product and packaging design risks and misuse hazards. A review and assessment of reasonably foreseeable risks associated with the design of the tobacco product and its package that may occur during normal use of the tobacco product or during any foreseeable misuse of the product, including user error, which may cause illness, injury, or death not normally associated with the use of the tobacco product. The review and assessment must identify the measures taken to reduce or eliminate each risk associated with the design of the tobacco product and package.
(3) Principles of operation. The applicant must provide a full statement of the principle or principles of operation of the tobacco product, including full narrative descriptions of:
(i) The way in which a typical consumer will use the new tobacco product, including a description of how a consumer operates the product, how long a single unit of product is expected to last (e.g., total length of time of use to consume a unit, number of use sessions expected per unit), and, where applicable, how a consumer can change the product design and add or subtract ingredients;
(ii) A justification for an applicant's determination of what constitutes a single unit of product as described in the PMTA; and
(iii) Whether the product incorporates a heating source, and if so, a description of the heating source.
(4) Product testing and analysis information. Each analysis required in this paragraph must be performed on test samples that reflect the finished tobacco product composition and design, and must be conducted using a sufficient sample size and number of replicates to substantiate the results of the type of testing conducted. Additionally, the applicant must provide the following information:
(i) The name and location of the testing laboratory or laboratories and documentation showing that the laboratory or laboratories is (or are) accredited by a nationally or internationally recognized external accreditation organization;
(ii) The length of time between dates of manufacture and date(s) of testing;
(iii) The storage conditions of the tobacco product before it was tested;
(iv) The number of samples and measurement replicates for each sample;
(v) A description of method procedure, method validation information and rationale for selecting each test method, including relevant voluntary testing standards, test protocols, quantitative acceptance criteria, line data, and a summary of the results;
(vi) Reports of product formulation testing that include test protocols, quantitative acceptance criteria, line data, and a summary of the results, for each applicable design parameter; and
(vii) Complete descriptions of any smoking or aerosol-generating regimens used for analytical testing that are not standardized or widely accepted by the scientific community, if applicable.
(j) Manufacturing. The application must contain a full description of the methods used in, and the facilities and controls used for, the design (including design validation and design verification, to assess whether the tobacco product, as manufactured, performs in accordance with design specifications), manufacture, packing, and storage of the tobacco product in sufficient detail to demonstrate whether the product meets manufacturing specifications, can be manufactured in a manner consistent with the information submitted in the application, and conforms to the requirements of any regulations issued under section 906(e) of the Federal Food, Drug, and Cosmetic Act, including:
(1) A list of all manufacturing, packaging, storage, and control facilities for the product, including the facility name, address, and FEI number, if applicable, and a contact name and telephone number for a representative from each facility;
(2) A narrative description, accompanied by a list and summary, of all standard operating procedures (SOPs) and examples of relevant forms and records for the following categories of information for all manufacturing, design controls, packing, and storage for the tobacco product:
(i) Manufacturing and production process activities at each establishment, including a description of each establishment, all production steps, and process controls, process specifications with relevant acceptance criteria, and monitoring and acceptance activities;
(ii) Managerial oversight and employee training related to the manufacture, processing, packing, and installation of the tobacco product, as applicable;
(iii) Monitoring procedures and manufacturing controls for product design, product characteristics, and changes in products, specifications, methods, processes, or procedures, including a hazard analysis that details the correlation of the product design attributes with public health risk, as well as any mitigation strategies implemented;
(iv) Activities related to identifying and monitoring suppliers and the products supplied (including, for example, purchase controls and product acceptance activities);
(v) Handling of complaints, nonconforming products and processes, and corrective and preventative actions;
(vi) Testing procedures carried out before the product is released to market, including:
(A) A list and summary of any standards used for all testing methods;
(B) Validation and verification activities for all test methods used to ensure that the tobacco product meets specifications;
(C) Documentation of accreditation information for all testing laboratories;
(D) Complete description of smoking or aerosol-generating regimes used for analytical testing, if any; and
(E) Tobacco product specifications (including any physical, chemical, and biological specifications) and acceptance criteria for those specifications;
(F) Reports of release testing performed on finished products to demonstrate conformity with established specifications, including test protocols, line data, and a summary of the results for each applicable testing.
(k) Health risk investigations—(1) Study types. The application must contain full reports of all information, both favorable and unfavorable, published or known to, or which should reasonably be known to, the applicant concerning investigations, including nonclinical and human subject studies regarding the following topics. If no substantive information exists regarding the topics specified in § 1114.27(b)(1)(ii), including information from published literature or that may be bridged from an investigation of another tobacco product, an applicant may need to conduct its own investigation(s) to ensure substantive information is included in the PMTA to meet the application filing requirements.
(i) Health risks of the product. The potential health risks of the tobacco product to users and nonusers, including potential exposures and information regarding risks to youth, young adults, and other relevant vulnerable populations, and whether the product may present different risks than other tobacco products, including:
(A) The health effects of the constituents, including HPHCs, at the quantitative levels delivered to both users and nonusers under the range of conditions under which the product might be used;
(B) The toxicological profile of the new tobacco product related to the route of administration, including the genotoxicity, carcinogenicity, reproductive toxicity, immunotoxicity, acute toxicity, and repeat dose (chronic) toxicity of the new tobacco product relative to other tobacco products. The toxicological profile also includes information on the toxicity of the ingredients, additives, and HPHCs, relative to the route of administration and the range of potential levels of exposure resulting from the use of, or exposure to, the new tobacco product, including studies which discuss the toxicological effects of any leachables and extractables that can appear from the container closure system and the ingredient mixture, such as additive or synergistic effects;
(C) The pharmacological profile of the new tobacco product, including the pharmacokinetics, pharamacodynamics, metabolism, and elimination profile, of any of the ingredients, additives, and HPHCs for the range of potential levels of exposure resulting from the use of, or exposure to, the new tobacco product relative to other tobacco products. The applicant must specify whether the studies were conducted in vitro, in vivo, ex vivo, or in silico; and
(D) The health risks of the tobacco product compared to other tobacco products on the market, never using tobacco products, quitting tobacco product use, and using the tobacco product in conjunction with other tobacco products.
(ii) Impacts on tobacco use behavior of tobacco product users. How the product and its label, labeling, and advertising, to the extent that advertising has been studied, will affect the tobacco use behavior of tobacco product users, specifically considering youth, young adults, and other relevant vulnerable populations, including:
(A) The abuse liability of the tobacco product;
(B) How users actually use the product, including use topography, product use frequency, use trends over time, and how such use affects the health risks of the product to individual users;
(C) The likelihood that users will use the product in conjunction with other tobacco products;
(D) The likelihood that current tobacco product users will start using the product;
(E) The likelihood that current tobacco users who adopt the product will switch to or switch back to other tobacco products that may present increased risks to individual health; and
(F) The likelihood that current tobacco users who may have otherwise quit using tobacco products will instead start or continue to use the product.
(iii) Impacts on tobacco use initiation by nonusers, including youth, young adults, and other relevant vulnerable populations. The impact of the tobacco product and its label, labeling, or advertising, to the extent that advertising has been studied, on tobacco use initiation by nonusers, including:
(A) The likelihood that consumers who have never used tobacco products, particularly youth, young adults, and other relevant vulnerable populations, will initiate use of the tobacco product;
(B) The likelihood that nonusers of tobacco products who adopt the tobacco product will switch to other tobacco products that may present higher levels of individual health risk; and
(C) The likelihood that former users of tobacco products will re-initiate use with the tobacco product.
(iv) Perceptions and use intentions. The impact of the product and its label, labeling, and advertising, to the extent that advertising has been studied, on individuals:
(A) Perception of the product;
(B) Use intentions; and
(C) Ability to understand the labeling and instructions for use and use the product in accordance with those instructions.
(v) Human factors. The impact of human factors on product risk, including discussion of use conditions, use environments, use related hazards, estimated use error risk, potential unintended uses, risk controls to ensure that harms and unintended consequences are minimized, and adverse experiences related to such uses.
(2) Literature search. The applicant must conduct a literature search for each type of information described in paragraph (k)(1) of this section, and the application must contain a description of the literature search performed, including the databases searched and the date searched, search terms, reasons for inclusion or exclusion of documents, and the strategy for study quality assessment. The application must also contain a bibliography of all published studies and articles referenced in the application. If a literature search was performed and resulted in no information found, the application must contain a statement to that effect.
(3) Study reports. The full report of each study included in the application must describe the specific product studied and include the following items, where applicable and to the extent reasonably available. For applicable items not contained in the full report of an investigation, the applicant must contain a description of the actions taken to obtain the information and why the document is not reasonably available.
(i) Full copies of any published articles and other reference materials;
(ii) Documentation of all actions taken to ensure the reliability of the study. For all studies, to the extent reasonably available or obtainable, the application must contain a certification that investigators do not have, or documentation fully disclosing, any financial conflicts of interest, such as the financial arrangements specified in the Financial Disclosure by Clinical Investigators regulation in part 54 of this chapter. Additionally, for nonclinical laboratory studies, the application must contain, for each study, documentation of all actions taken to ensure the reliability of the study, e.g., documentation of whether the study was conducted in accordance with good laboratory practices, such as those specified in part 58 of this chapter;
(iii) Copies of all versions of protocols and amendments that were used in the study;
(iv) Copies of all versions of investigator instructions, if any were produced in addition to the protocol;
(v) The statistical analysis plan, including a detailed description of the statistical analyses used (including all variables, confounders, and subgroup analyses), the scientific rationale for the choice of sample sizes, and any amendments to the plan;
(vi) Line data, including data definition files that include the names of the variables, codes, and formats in each dataset, and copies of programs and any necessary macro-programs used to create derived datasets, and the results included in the study reports;
(vii) A list of sites and clinical investigators that conducted the study, including contact information and physical address(es);
(viii) The location of all source data. If the site where the study was conducted has not maintained all of the source data, indicate where the data are located;
(ix) The format of the records and data (e.g., electronic or hard copy);
(x) A list of all sites that had early termination and the reason for early termination, if applicable;
(xi) A list of contractors who participated in the study, the role of each contractor, and the initiation and termination dates of the participation of each contractor;
(xii) A signed full report of all findings;
(xiii) For human subject studies:
(A) All versions of study materials (e.g., consent forms, questionnaires, stimuli) used;
(B) All versions of case report forms used; and
(C) Individual case report forms related to participant deaths, other serious and unexpected adverse experiences, withdrawals, and participant discontinuation where the study participant was exposed to the tobacco product that is the subject of the PMTA or similar products; and
(xiv) For tobacco product perception and use intention studies that use advertising as stimuli, a statement describing whether the advertising used is representative of advertising that the applicant intends to use in marketing the product. If the advertising is not representative of the advertising an applicant intends to use in marketing the product, the applicant must describe whether the study results are still relevant to the likely impact of the advertising on tobacco product perceptions and use intentions.
(l) The effect on the population as a whole. The application must contain an analysis and discussion of how the data and information contained in the application establish that permitting the tobacco product to be marketed would be appropriate for the protection of public health determined with respect to the population as a whole, including users and nonusers of the tobacco product. The analysis and discussion must integrate all of the information in the application regarding the product and its likely effects on health, and tobacco use behavior, including tobacco use cessation and initiation, to provide an overall assessment of the likely effect that the marketing of the tobacco product may have on overall tobacco-related morbidity and mortality.
(m) Certification statement. The application must contain the following certification, with the appropriate information inserted (as indicated by parenthetical italicized text), signed by an authorized representative of the applicant:
“I (name of responsible official) on behalf of the applicant, (applicant name), hereby certify that the applicant will maintain all records to substantiate the accuracy of this application for the period of time required in 21 CFR 1114.45 and ensure that such records remain readily available to FDA upon request. I certify that this information and the accompanying submission are true and correct, that no material fact has been omitted, and that I am authorized to submit this on the applicant's behalf. I understand that under section 1001 of title 18 of the United States Code anyone who knowingly and willfully makes a materially false, fictitious, or fraudulent statement or representation in any matter within the jurisdiction of the executive, legislative, or judicial branch of the Government of the United States is subject to criminal penalties.”
