§1114.27. Review procedure. — Inbound Citations

(a) Refuse to accept the application as described in § 1114.27(a);

(d) Refuse to file the application as described in § 1114.27(b);

(1) 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) 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) 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) 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) 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) 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.