Investigational Tobacco Product (ITP) Applications - Considerations for Future Premarket Application Planning

FDA Center for Tobacco Products (CTP) began receiving premarket applications soon after the 2009 Tobacco Control Act (TCA) was signed. While these applications were called "premarket" they were mostly Substantial Equivalence (SE) Reports for products currently-marketed in the U.S.

A quick history on applications submitted to CTP since 2009:

SE Reports submitted by March 2011 to CTP were called provisional SE Reports. These reports compared provisional tobacco products to pre-existing tobacco products (a tobacco product that was commercially marketed in the U.S. as of February 15, 2007). These SE Reports were mostly comparisons of incremental changes to tobacco blends, design parameters and ingredient amounts to pre-existing tobacco products. The statutory requirement to meet for the comparison was "no different questions of public health" between the pre-existing product and the provisional. During CTP scientific review over the next several years these products were allowed to remain on the market.

In August 2016 FDA extended its tobacco product authority to other categories of tobacco products including electronic nicotine delivery systems (ENDS). With this action any tobacco product not currently-marketed as of August 8, 2016 had to be removed from the market and proceed through the premarket tobacco product application (PMTA) process before being reintroduced. The statutory requirement for a PMTA is "appropriate for the protection of public health". Notwithstanding the current litigation involving these applications, currently-marketed products could remain on the market until September 2020 when PMTAs were to be submitted for any of these "deemed" products.

Since the beginning of the regulatory framework instituted at CTP, most nicotine and tobacco products in the U.S. have been allowed to remain on the market under FDA enforcement discretion while their applications were in administrative and science review. From 2009 to 2023 very few products have undergone a truly premarket review process at CTP and been successfully brought to market, with the exception of some New Product SE Reports and PMI's IQOS heat-not-burned PMTAs and MRTPA. As previous-generation nicotine and tobacco products exit the market over time, I believe building truly premarket application processes will be important to success in the future. In addition to preparing for pre-submission meetings with CTP and developing robust science and evidence plans, a key component of that market authorization journey will be submitting ITP applications to CTP in advance of PMTA submissions. Use of Investigational Tobacco Products - Guidance for Industry and Investigators

ITPs are not required to be submitted but can provide CTP with a preview of clinical and non-clinical investigations a product manufacturer proposes to conduct for a new tobacco product. This could include research with human participants evaluating consumer perception or clinical testing. To be sure, there are several limitations and contradictions contained within the draft guidance, mainly that guidance proposes a one-size-fits-all approach to a wide variety of research that is already governed by other best practices to ensure participant safety. In its current draft form, the ITP guidance reads more like a notification process with FDA having enforcement discretion. The lack of a predefined submission structure can present challenges but flexibility and creativity is a requirement when building applications for CTP. The draft guidance does contain some generally prescriptive recommendations for assembly.

• Administrative Information: Identifies the submission name, brand, sub-brand and proposed use of an ITP in a clinical investigation including case report forms. Also may include certain chemistry and manufacturing information.

• Study Protocols: Protocol titles, design and setting and a description of the study population. This would also include a statistical analysis plan that includes statistical methods.

• Packaging and Labeling: Copies of all packaging and labeling provided to clinical investigators or study subjects.

Possible actions post-Scientific Review of the ITP:

1. ‘No Concerns’ letter indicating no human subject protection issues were identified. This is sent when the submission includes a new protocol, a response to a previous ‘Concerns’ letter, or a revised protocol with significant protocol changes AND human subject protection issues are not identified during the review.

2. No letter is sent. For unsolicited protocol revisions, annual reports, and study updates when there are not significant changes to the protocol and no human subject protection issues or other items needing FDA comment, then no letter is sent to the sponsor.

3. ‘Concerns’ letter indicating human subject protection issues were identified. This is sent when the scientific reviewers identify issues that need to be resolved due to the risk posed to human subjects who may be enrolled in the study.