Statement:
- The views expressed in this article are solely those of the interviewee and do not represent the position of 2Firsts.
- This article does not constitute any legal, investment, or business advice.
U.S. Food and Drug Administration (FDA) recently published 13 memos outlining its review policy for Premarket Tobacco Product Applications (PMTA) for non-tobacco flavored e-cigarettes. These documents clarify FDA's approach and criteria for assessing e-cigarette products. To further explore these developments, 2Firsts spoke with Dr. Jessica Zdinak, Chief Research Officer and CEO of Applied Research and Analysis Company (ARAC).
In the interview, Dr. Jessica Zdinak discussed views on emerging age-gating technologies, and the challenges FDA faces in the PMTA process based on her extensive experience in both government and industry settings. She noted that while age-gating technology can help reduce underage access to e-cigarettes, it cannot replace the need for robust scientific research. Manufacturers, she emphasized, must continue to invest in evidence-based studies to assess the effectiveness of age-gating and its role in reducing tobacco use among unintended audiences.
Key points from Dr. Jessica Zdinak include:
- FDA's "fatal flaw" review process, which aimed to handle the large volume of applications with limited resources, was reasonable and scientifically sensible but should have been more readily communicated.
- All PMTA applications for non-tobacco flavored e-cigarettes must still include robust research to demonstrate switching, specifically randomized controlled studies or cohort studies.
- While age-gating technology can help mitigate risks, it is not a substitute for a comprehensive scientific assessment of its public health benefits.
- FDA has made its review requirements clearer through memos and other communications. Manufacturers should take the initiative to meet these standards in order to increase their chances of a successful application.
Here is the full content of this interview:
2Firsts: How do you evaluate the fatal flaw review process of FDA's internal substantiative review process for non-tobacco flavor products dating back to July 2021? Could you give us more detailed background for this?
Dr. Jessica Zdinak: The way I understand the memos referencing FDA's review is that they had to create a strategy "in real time" to handle the vast number of applications submitted at one time (or even day) for review. It seems several factors were considered in this strategy: 1) where the application was in the review process, 2) the timing of application submission, 3) the likelihood candidate product specific Switching data was included in the application, and 4) a randomization of applications into a review order. I believe that the internal memos were the only way that the FDA CTP could move forward with any type of review process given the number of applications that were submitted at the same time, and the fact that CTP was such a young center within the FDA. This belief also comes from my experience working in and with the federal government for several years, as I know how long it takes to get anything done. There are so many boxes to check and agreement among people, what might seem like a simple decision in private industry, actually requires months or years of within the public sector/government.
Furthermore, at the time when some of these memos were released, the federal government, and other public health and tobacco control groups were becoming aware of increasing youth use of flavored ENDS products. It seems that because of this, the FDA CTP established a "threshold" for scientific reviewers to determine whether sufficient evidence was present in an application. Sufficient evidence was then further defined as "reliable and robust" in the form of experimental-based designs or longitudinal cohort studies. As behavioral science experts, we at ARAC know that these are the top two methods for demonstrating the added benefit of flavors to public health, in comparison to tobacco-flavored ENDS. These types of study designs allow the FDA to make a direct comparison between flavors and tobacco ENDS, and an indirect comparison with the risk to public health. In this instance, this risk was predominantly being driven by the increasing rates of flavored ENDS use among youth. As research psychologists, we have been trained in the scientific understanding that to adequately assess the effect of a variable on an outcome and to establish a causal relationship, a randomized study must be conducted. However, Longitudinal Cohort Studies can also establish clear evidence of strong correlational relationships when a multitude of variables are accounted for in the analysis and/or model.
We are unable to comment on these memos from a manufacturer's perspective, as we are an independent third-party research institute and we are mostly unaffected by FDA's positions within these memos. Our focus is on providing manufacturers with what we believe to be the most appropriate scientific approach to address FDA's needs. Our experience and success within the U.S. FDA regulatory environment gives us great confidence that this scientific background and experience are well-aligned with what FDA was, and is, looking for, regardless of the "fatal flaw" process or not.
2Firsts: If non-tobacco products have already applied for PMTA with age-gated technology, do they still need the RCT or longitudinal study for non-tobacco flavor products for the PMTA process?
Dr. Jessica Zdinak: Yes, I believe that all applicants attempting to obtain authorization of non-tobacco flavored ENDS products will need these studies. For one, the past can't be rewritten overnight. The increase in youth use of flavored ENDS that occurred several years ago will not be forgotten for a while. There are many who were affected by this, including parents, school systems, teachers, health care providers, public health or tobacco control groups, etc. We've recently seen in 2024 NYTS data some promising results that showed a significant decline in youth use of flavored ENDS. That doesn't mean, however, that there will be less of a focus on protecting youth from using these products.
Furthermore, age-gating technology may be a way to reduce youth access, but I think it is yet to be determined whether it reduces youth use. We've seen a variety of different age-gated technologies, and the industry can't assume that because one of these technologies is incorporated into their product, that they now don't have to demonstrate a risk-benefit ratio within their application. I can imagine the FDA will be interested in assessing the likelihood that the technology can be "broken," or the extensiveness of the technology at preventing product purchase, first-time product use, versus each-time product use, etc. From the regulator's perspective, it's probably difficult to understand why manufacturers would spend tens of millions of dollars on product development/innovation, technology, software systems, and on other scientific research for a PMTA, but not spend an additional ~$1M on a study that they continuously ask for to demonstrate the "benefit" to public health. The age-gated technology could likely be a mechanism to reduce the "risk" side of the equation, but a company will still need to assess the level of "benefit" it has to the smoking population through a robust, generalizable, and well-designed switching study.
A motto I use a lot in my own life is "When I know better, I do better," and I think this applies here. Prior to the "fatal flaw" becoming public, I can understand why companies would not have known precisely what the FDA was looking for, and I can understand and sympathize with their frustration at not having the chance to give the FDA these studies. But now the industry knows better, and most manufacturers ARE doing better, but it's still challenging for others to be convinced these studies are needed when so many applications are still pending "review" and determination by FDA. I'm hoping the flood gates will open soon and long awaited decisions will be made by the agency. I don't think it will be until then that manufacturers and industry representatives will proceed out of the current "freeze or flight" psychological state.
ARAC BIO
Applied Research and Analysis Company (ARAC) is a leading U.S. based behavioral science research firm that designs, executes, and presents scientifically-sound, yet customizable studies to support manufacturers, regulatory agencies, and industry consultants. Their expertise includes consumer-focused research services in product development and innovation and regulatory science supporting marketing authorization applications, with SUCCESS in U.S. product authorizations and applications.
ARAC specializes in MODULE 5 & 6 studies including: label/claim development and comprehension, human factors/usability testing, and clinical/behavioral studies, such as randomized experimental longitudinal, actual use, TPPI, and post-market surveillance systems.
"Most Outstanding Service to Industry" 2024 Golden Leaf award-winning fully staffed IN-HOUSE psychologists, behavioral scientists, statisticians, survey methodologists, and medical monitoring offer tailored research solutions with unparalleled integrity and an exceptional client experience. (Source: ARAC)
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