FDA recently revised its draft guidance on the “Use of Investigational Tobacco Products.” This draft guidance was originally issued in September 2015; however, after receiving numerous comments, FDA decided to revise the guidance to clarify certain information. FDA also regards the revision to be in furtherance of its commitments under the Agency’s comprehensive plan for tobacco and nicotine regulation. One of these commitments was to develop new guidance and regulations to improve transparency and efficiency in the tobacco product regulatory review process. This revised, draft guidance sets out to accomplish the Agency’s stated goals by providing tobacco product manufacturers, researchers, and institutional review boards the types of information the agency intends to consider in making enforcement decisions regarding the use of investigational tobacco products, with an increased emphasis on human subject protection.

By way of background, under section 910(g) of the Federal Food, Drug, and Cosmetic Act, FDA has the authority to issue regulations to exempt tobacco products intended for investigational use from the requirements of Chapter IX of the Act, including premarket submission requirements. To date, FDA has not issued such regulations, but the Agency recognizes that researchers may seek to study tobacco products that do not have marketing authorization or that do not comply with an applicable tobacco product standard for the purpose of supporting premarket applications, other submissions, or for general knowledge (e.g., studying tobacco products with special characteristics such as low nicotine content, evaluating use on certain populations, etc.). Until such regulations are finalized and issued, FDA states that it intends to evaluate specific uses of investigational tobacco products on a case-by-case basis, and in accordance with potential human subject protection concerns or other impacts on public health. The draft guidance makes certain clarifications to FDA’s position, including the following points:

• FDA includes more information specific to studies seeking to assess modified tobacco products that are already legally on the market. In the revised guidance, FDA reiterates its recommendation that sponsors meet with FDA before making a submission, especially for products with minor modifications that are already legally marketed because FDA generally expects those submissions to require less information. FDA encourages sponsors to submit information that is limited to the modification(s), and FDA requests the product information to be provided in tabular format.
• In the revised draft guidance, FDA appears to acknowledge the difficulty in distinguishing the risks associated with the use of an investigational tobacco product from use of the study subject’s own, typically-used product. FDA adds that, while it intends to consider each protocol on its own merits, some of the issues FDA would consider include:
  • assessing whether the trial participants currently are nicotine users,
  • the risk to trial participants in light of the route of administration of the investigational product, and
  • the adequacy of the study settings, including monitoring and stopping criteria.

FDA reminds sponsors to also consider the risk implications for non-users who may be exposed to the investigational tobacco product, such as friends, family, and colleagues.

• FDA also provides additional guidance around nonclinical laboratory investigations in the revised guidance, which are defined as in vivo or in vitro experiments in which investigational tobacco products are studied prospectively in test systems under laboratory conditions. Notably, in the revised guidance, FDA does not recommend that investigators engaging in nonclinical laboratory investigations correspond with FDA in all situations. This is in direct contrast with the earlier version of the guidance, in which FDA explicitly recommended that persons who intend to study investigational tobacco products meet with CTP to discuss research plans, including the conduct of nonclinical laboratory studies and clinical investigations. In the revised version of the guidance, FDA does, however, continue to advise investigators to take measures to ensure the reliability and validity of nonclinical laboratory studies, including following good laboratory practices as specified in 21 CFR part 58 (Good Laboratory Practice for Nonclinical Laboratory Studies). FDA also acknowledges that sponsors of nonclinical studies can always decide to meet with FDA early in the development process to discuss what, if any, animal testing is appropriate, as well as the suitability and acceptability of non-animal tests for a particular product.
• FDA also gives additional direction around document retention. According to FDA, sponsors, CROs, sponsor-investigators, and clinical investigators should maintain documentation to permit evaluation of the conduct of a clinical investigation (especially with regards to assessing the quality and integrity of the study data and protection of human subjects). The revised draft guidance recommends that records be maintained and available for inspection upon request for either: (1) a period of at least 4 years after the date on which the investigation is terminated or completed, or (2) the date that the records are no longer considered necessary for supporting marketing of a product, whichever is later. This reflects a longer retention period than what was specified in the 2015 version of the guidance (2 years).
• With regards to supporting data, we notice a change in the way FDA describes the information. The old version of the guidance advised sponsors to provide “[a]ny information about the investigational tobacco product, both favorable and unfavorable, known or reasonably obtainable by the sponsor, such as results of product testing, nonclinical laboratory studies, and clinical investigations, and information on marketed tobacco products similar to the investigational tobacco product.” The new version, on the other hand, advises sponsors to provide, “[a]ny known or reasonably known information, both favorable and unfavorable, about the investigational tobacco product, such as results of product testing, nonclinical laboratory studies, and clinical investigations, and information on marketed tobacco products similar to the investigational tobacco product (if available).” Thus, FDA appears to be emphasizing that sponsors should provide data or information that may be “reasonably known,” as opposed to “reasonably obtainable,” yet adds the acknowledgment that certain information may not be readily available. It will be interesting to see how FDA decides to apply this guidance in marketing submissions, and what, if any, significance the revised language has with respect to FDA’s review criteria.

Stakeholders can comment on any guidance at any time. However, comments should be submitted by April 22, 2019 to ensure that the Agency considers the information before it begins work on the final version of the guidance.