Background

With the FDA’s deadline of September 9, 2021 to finalize the review of all PMTA’s that had been submitted by Sept. 9, 2020 quickly approaching, it is not surprising that we are beginning to see actions taken by FDA against some of the more than 6.5 million products submitted last year.

On August 26, 2021 FDA released a press release announcing their denial of marketing applications by JD NOVA Group LLC, Great American Vapes, and Vapor Salon for their approximately 55,000 non-tobacco flavored e-cigarette products, claiming the applications failed to provide evidence these products “appropriately protect public health”. While FDA has issued negative actions for other applications in recent months, these are the first marketing denial orders (MDO’s) for applications that had reached the substantive scientific review phase of the application process.

In their press release, FDA made it clear that in their review of applications their focus will be primarily on the impact non-tobacco flavored e-cigarette products would have on America’s youth. Acting FDA Commissioner, Janet Woodcock, M.D., spoke on behalf of the FDA and their stance on the current review process stating: “Ensuring new tobacco products undergo an evaluation by the FDA is a critical part of our aim to reduce tobacco-related disease and death. We know that flavored tobacco products are very appealing to young people, therefore assessing the impact of potential or actual youth use is a critical factor in our decision-making about which products may be marketed.”

It seems that this falls short of definitively stating that all non-tobacco flavored e-cigarette products will be automatically denied. The Agency announced they will continue to review premarket tobacco applications for non-tobacco flavored ENDS products to determine whether there is sufficient evidence to prove a benefit to adult smokers that outweighs the product’s potential risk to youth. If applications provide evidence that meets this requirement, FDA will move forward with conducting further in-depth evaluation of the application. If the application does not provide this evidence, as in the cases of JD NOVA Group LLC, Great American Vapes, and Vapor Salon, the Agency will issue an MDO. Mitch Zeller, J.D., director of the FDA’s Center for Tobacco Products clarified “Companies who want to continue to market their flavored ENDS products must have robust and reliable evidence showing that their products’ potential benefit for adult smokers outweighs the significant known risk to youth. The burden is on the applicant to provide evidence to demonstrate that the marketing of their product meets the statutory standard of ‘appropriate for the protection of the public health.’ If this evidence is lacking or not sufficient, the FDA intends to issue a marketing denial order, which requires the product to be taken off or not introduced to market.”

Sufficient Evidence

In FDA’s recent press release, as mentioned above, they specified applications that provide “robust and reliable evidence showing that their products’ potential benefit for adult smokers outweighs the significant known risk to youth” will continue forward in the review process. To provide sufficient evidence, applications will need to thoroughly address all aspects of the FDA’s PMTA guidance document released in June, 2019: Premarket Tobacco Product Applications for Electronic Nicotine Delivery Systems: Guidance for Industry and the FDA’s recordkeeping requirements document (final rule) released in September 2020: Premarket Tobacco Product Applications and Recordkeeping Requirements. Basic requirements are to demonstrate the product’s safety through analytical testing. However, the backbone of the overall appropriate protection of public health argument will rely on human factors and perception and intent studies to demonstrate the product’s overall benefit to public health, focusing specifically on youth appeal. Areas of required research mentioned in the FDA released guidance and PMTA Recordkeeping Requirements that specifically address this include:

  • Likelihood of initiation and cessation by both users and nonusers of tobacco products (Guidance for Industry)
  • Impacts on tobacco use behavior of tobacco product users (Guidance for Industry)
  • Product user patterns (Guidance for Industry and PMTA Recordkeeping Requirements)
  • Labeling comprehension and actual use and Human Factors (Guidance for Industry and PMTA Recordkeeping Requirements)
  • Impacts on tobacco use initiation by non-users, including youth and young adults (PMTA Recordkeeping Requirements)
  • Perceptions and use intentions, and v. Human factors (PMTA Recordkeeping Requirements)
  • Impacts on tobacco use behavior of tobacco product users (PMTA Recordkeeping Requirements)

 

These research requirements can be met with sufficiently rigorous combination of focus groups, diary studies, validation (summative) testing, quantitative studies and perception and intent studies.

Industry Impact

With the FDA’s court-ordered action deadline quickly approaching, the industry is going to see significantly more MDO’s issued over the next few days and weeks, specifically for applications that did not provide robust, substantial evidence their non-tobacco flavored products’ benefit to adult smokers outweighs their product’s potential risk to youth. Weak applications missing large sections of required information, such as environmental assessment studies, with no plan to address the gaps will also likely be issued MDO’s for these products.

 

If an application thoroughly addressed all points listed above through perception and intent studies that satisfies the published guidance, then it has already made a strong case that those products are marketed to current traditional tobacco users and are not designed to attract “new” or “underaged” users. In this case, along with other sufficient data and evidence provided in the application, a strong argument can be made that the product in question would likely be appropriate for the protection of public health. In this case, the Agency may determine that an application warrants a full review. If that review is performed, the next action from the Agency will likely be to issue a deficiency letter not a product withdrawal order, giving the applicant time to respond with additional information and evidence to further argue their case. In this case, if additional data to support an appropriate protection for public health determination is required for non-tobacco flavored products based on the danger of youth uptake, such as a randomized controlled trial or longitudinal cohort study. These types of studies would likely be requested as a part of an ongoing surveillance program, provided the initial study was sound and indicated a positive population health outcome if the product is allowed to remain on the market.

Next Steps

For applications that did not provide thorough perception and intent studies or were missing large sections of required information, an MDO for those products is likely and could be expected as early as this week. Companies who believe their applications do not meet these requirements will need to adjust their strategy, and quickly, to keep their products on the market.

The first step will be for companies to use a reputable manufacturer to transition their products from traditional tobacco-sourced nicotine over to synthetically derived or “tobacco free nicotine”, commonly referred to as “TFN”. The FDA currently has legal jurisdiction over tobacco-derived nicotine products, but this does not include synthetically derived nicotine products, making any ENDS products that use tobacco-free nicotine a legal grey area for enforcement (for now). This will allow these products to remain on the market for the immediate future. However, this is only a short-term strategy. While tobacco-free nicotine is a legal grey-area on a federal level, this will not keep states and counties from banning these products, making the long-term viability of these products unlikely.

For this reason, brands will need to immediately begin work in the background to “reboot” their current PMTA application to address areas of missing or weak information and then resubmit the application. Applications will need to undergo a gap analysis to identify areas of concern and create a multi-step correction plan, inclusive of a clinical and longitudinal studies which is now clearly required for perception and intent studies, to address those areas of concern and provide “robust and reliable evidence” showing that their products’ potential benefit for adult smokers outweighs the significant known risk to youth. Once those changes and additions have been built into the application, the application can then be resubmitted for review.

Finally, brands that do not currently include tobacco flavors in their present assortment should diversify their assortment to include those profiles. Through their recent marketing denial orders and press releases, it has become clear the Agency will be scrutinizing non-tobacco flavored products more closely than tobacco flavored products in relation to their potential negative impact on public health, specifically youth. Brands that diversify to include tobacco flavored products could be providing themselves an added safety-net to ensure the long-term viability of their brand in an uncertain marketplace.

Final Thoughts

In the following days and weeks, the ENDS industry is going to see significant action taken by the Agency on all pending PMTA’s submitted by the September 9, 2020 deadline. It is likely the majority of the applications that included non-tobacco flavored products will receive MDO rulings, as it is likely they did not fully provide substantial and robust evidence proving their benefit to adult traditional tobacco users outweighs their potential risk to youth users. Companies worried about their current applications will need to quickly adjust their PMTA strategies to include short term solutions, such as TFN, as well as prepare for an application “reboot” to include any weak or missing information, such as longitudinal studies, to properly address the appropriate protection of public health argument. Lastly, to make those strategic adjustments properly, brands will need to partner with an organization that fully understands

 

both short-term and long-term strategies in the ENDS industry and can quickly and easily adapt to changes in industry guidance. If you are looking for a partner to help you take on these regulatory challenges, contact us today to discuss your application. Our regulatory team will work with you to create a correction plan that addresses your unique application and manufacturing needs.