FDA's guidance on the content of a premarket tobacco application has heretofore been sparse and informal. On September 25, FDA finally issued a proposed rule to define a premarket tobacco application (PMTA). Proposed Part 1114 of the Code of Federal Regulations. 84 Fed Reg 50572.

In 2009, the Family Smoking Prevention and Tobacco Control Act (Tobacco Act) was enacted into law. The Tobacco Act gave the US Food and Drug Administration authority over the sales and marketing of tobacco products. By promulgation of the Deeming Rule, FDA has defined e-cigarettes containing nicotine and their accessories as regulated tobacco products. 81 FR 28973 (2016).

The Tobacco Act was modeled after the Medical Device Amendments providing three mechanisms for achieving marketing authorization:

  • Products on the market as of February 15, 2007 were grandfathered and could continue to be marketed if the product was not modified in any way; if marketing was restricted to adults (including print or other advertising); the product was registered with FDA; ingredients disclosed; the product met certain manufacturing standards; and warnings statements prescribed by FDA were added to labels. [E-cigarettes were not introduced until after 2007.] These products are entitled to an exemption from the regulations if truly grandfathered, involve an insignificant modification to a grandfathered product or have no public health risk. These exemptions are generally similar to those for grandfathered medical devices in 1976 or to current Class I medical devices.
  • New products could be introduced if they were substantially equivalent to the grandfathered products similar to the medical device 510(k) program. Section 905(j) of the Federal Food, Drug, and Cosmetics Act.
  • New or "modified-risk" tobacco products could also be introduced but only if approved by FDA through a premarket tobacco application (PMTA). This section was modeled after the premarket approval (PMA) applications for medical devices which in turn were modeled after the requirements for a New Drug Application (NDA). Section 910(b) of the Federal Food, Drug, and Cosmetics Act. FDA previously issued guidance on the content of a PMTA in September 2011. That guidance demonstrated that the Center for Tobacco Products was intending to borrow the predicate regulatory program for an NDA as the guide to the format and content of a PMTA. To that end, an NDA is required to have information on manufacturing, chemistry of the ingredients, toxicity of the ingredients, and clinical evidence of effectiveness -- here the clinical evidence would support reduction of risk as opposed to traditional cigarettes. The agency has now issued proposed regulations to formalize these requirements.

In the last decade, the agency has reviewed and approved two PMTAs. But, PMTAs for all new products are due by May 2020. Typically, preparation of the contents of an NDA may take years. A clinical trial itself may take more than a year. Thus, the dossier for many parts of a PMTA should be underway or, frankly, nearly complete. In part, we believe that many purveyors of new tobacco products or e-cigarettes are not familiar with the dossier required of a new drug. We have found that our experience in helping to fashion NDAs assists clients in understanding the PMTA regulations. To that end, at Baker, we have experience in reviewing and understanding the review concerns of the agency. What are the standards for demonstration of safe manufacturing? What analytical chemistry requirements are set forth in existing guidance on the drug side? What are the internationally accepted standards for toxicology studies? How does one design and report clinical trials? In short, what is FDA looking for? The PMTA should have external review before filing. We are currently engaged in such reviews.

To that end, our review of a PMTA would be composed of a review of proposed labeling and warning statements; clinical investigations; nonclinical animal studies; and information about manufacturing. These sections, reviewed in detail, are comparable to the labeling, clinical, nonclinical, and chemistry, manufacturing, and controls (CMC) sections of an NDA or, for certain components, the regulations governing manufacture for medical devices.

The proposed rule provides guidance on the sections that confirms the agency's expectations that the content will mimic an NDA. The proposed rule describes the manufacturing section to include information on the composition, constituents, container-closure, design, ingredients, and formulation of the product. The preparation of the planned content of this section could benefit from expertise in compiling the CMC or manufacturing sections of a drug or device application.

The nonclinical section includes data on genotoxicity, carcinogenicity, cardiovascular toxicity, respiratory toxicity, reproductive and developmental toxicity of the non-tobacco ingredients and constituents, including those produced during use. These studies are defined in terms of design and conduct under the drug regulations and also in guidelines issued by the International Council on Harmonization -- an international drug regulatory body. PMTA applicants should be advised therefore to not re-invent the wheel and reference these study designs.

Similarly, the clinical section and the studies can be informed by reference to the designs available for use in obtaining a PMA or NDA approval.

We are happy to help you review the new proposed regulations and the preamble to that regulation to assist you in understanding your role in a PMTA whether a tobacco manufacturer, retailer, or manufacturer of a single component for use in another manufacturer's product.

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