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• Response to Soule et al., Hidden flaws in e-cigarette industry-funded studies, Tobacco Control, doi: 10.1136/tc-2024-058609
  Joe Gitchell, Floe Foxon, Saul Shiffman and Nicholas I. Goldenson
  Published on: 19 September 2024

• Published on: 19 September 2024

  Response to Soule et al., Hidden flaws in e-cigarette industry-funded studies, Tobacco Control, doi: 10.1136/tc-2024-058609

  • Joe Gitchell, CEO Pinney Associates, Inc.
  • Other Contributors:
    • Floe Foxon, Statistician/Data Analyst
    • Saul Shiffman, Senior Scientific Advisor
    • Nicholas I. Goldenson, Behavioral Scientist

  NOT PEER REVIEWED

  We value the opportunity to respond to the Special Communication by Soule et al. that reviewed our three publications [1]. We believe that continued discussion of methods and findings is both healthy and necessary to advance the science and foster more accurate understandings.

  Turning to the more specific points raised in their paper, for each of the three cited studies, we provide responses to the most pertinent issues discussed.

  Goldenson et al., 2020, Drug and Alcohol Dependence, 217, 108395:

  We agree that experimental design and procedure are critical elements of clinical laboratory studies that should be carefully considered and evaluated. Particularly for pharmacokinetic studies of tobacco products, the product use procedure can influence nicotine uptake. In the cited publication by Goldenson et al. [2], it was noted that the controlled use procedure (i.e., 10 uniform puffs 3 s in duration for all products) enabled standardized comparisons among the seven study test products, resulting in high internal validity, whereas an ad libitum use procedure would facilitate more naturalistic use patterns and enhance external validity. Subsequent pharmacokinetic studies of JUUL products that have in fact used ad libitum use procedures [3] or both controlled and ad libitum use procedures [4, 5] consistently demonstrate that JUUL products deliver significantly lower levels of nicotine than combustible cigarettes, confirming the conclu...

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  NOT PEER REVIEWED

  We value the opportunity to respond to the Special Communication by Soule et al. that reviewed our three publications [1]. We believe that continued discussion of methods and findings is both healthy and necessary to advance the science and foster more accurate understandings.

  Turning to the more specific points raised in their paper, for each of the three cited studies, we provide responses to the most pertinent issues discussed.

  Goldenson et al., 2020, Drug and Alcohol Dependence, 217, 108395:

  We agree that experimental design and procedure are critical elements of clinical laboratory studies that should be carefully considered and evaluated. Particularly for pharmacokinetic studies of tobacco products, the product use procedure can influence nicotine uptake. In the cited publication by Goldenson et al. [2], it was noted that the controlled use procedure (i.e., 10 uniform puffs 3 s in duration for all products) enabled standardized comparisons among the seven study test products, resulting in high internal validity, whereas an ad libitum use procedure would facilitate more naturalistic use patterns and enhance external validity. Subsequent pharmacokinetic studies of JUUL products that have in fact used ad libitum use procedures [3] or both controlled and ad libitum use procedures [4, 5] consistently demonstrate that JUUL products deliver significantly lower levels of nicotine than combustible cigarettes, confirming the conclusions of the Goldenson et al. study Soule et al. critiqued. Importantly, the findings of these Juul Labs-sponsored studies are also supported by a pharmacokinetic study conducted by two of the authors of the Soule et al. Special Communication that concluded, "cigarettes delivered more nicotine and suppressed tobacco/nicotine abstinence more effectively than JUUL" [6]. We were therefore particularly surprised that Soule et al. did not consider this broader body of literature. Together, these studies reinforce the value of conducting multiple studies with complementary designs and methodologies and support the conclusion that the abuse liability of JUUL products, and other electronic nicotine delivery systems, is lower than cigarettes.

  Foxon et al., 2022, BMC Public Health, 22, 1940:

  Soule et al.'s commentary on the Foxon et al. article includes misconceptions about basic aspects of the article, including the range of years analyzed, as well as how Foxon et al. *did* account for "other factors" including the FSPTCA and Tips campaign (under 'Other considerations' in the Foxon et al. article [7]). The critique that "most trained researchers would recognize that population-level data should not be used to make [such] inferences" [1], is both misguided and particularly puzzling because authors of the critique have themselves used cross-sectional, population-level time series data to make such inferences [8]. Soule et al. correctly noted that the Foxon et al. 2022 paper had been retracted by the journal, BMC Public Health. They did not note the context, that the journal retracted the paper based on methodological concerns voiced by a single unnamed member of their editorial board, and over objections from the authors and a large group of experts who stated that they "do not see a case for retraction or correction" [9]. The main concern voiced by the editorial board member was about the cut-off year between the pre- and e-cigarette eras, despite a range of possible cut-offs (we presented data assessing 2006–2011) having been explored in the paper and in subsequent correspondence with the journal supporting the findings of the paper. Soule et al. also fail to note or cite the extensive documentation we have made available on PubPeer [10] and OSF [11] that both documents the process and strongly makes the scientific case for the paper’s analysis and conclusions. Soule et al. could not have known that an updated and expanded manuscript was under review at another journal as their Special Communication was published. That updated article is now published in BMC's Harm Reduction Journal [12] and includes detailed rebuttals to the Soule et al. Special Communication. In fact, additional analyses that rebut these criticisms confirm and reinforce the original paper’s conclusions, contradicting the critique. We note that despite the data analyzed by Foxon et al. being publicly available, none of the authors of the Special Communication have published their own analysis of these data. Empirical confirmation and replication remain important foundations of scientific dialogue.

  Shiffman et al., 2015, Nicotine and Tobacco Research, 17(10), 1255-1262:

  We note that Soule et al. did interpret the methodology of the study correctly: the primary aim was to examine interest in flavor descriptors for e-cigarettes among nonsmoking teens compared to adults who smoke [13]. The rationale was detailed in the Introduction section of the article. In brief, potential users initially respond to the flavor descriptors, not the flavors themselves. As Soule et al. suggest, graphics could also play a role, and research on graphics would also be of interest. Nevertheless, the controversy over flavors has often focused on the flavor descriptors (e.g., see [14]). This topic was specifically addressed in the Discussion, noting that research on other aspects of marketing is an area for additional research. With respect to the populations assessed in the paper, as we fully explain in the paper, these two populations are the most important when considering the risk-benefit calculus required to optimize the public health outcomes of the availability of e-cigarettes, which requires considering potential benefits to adults who smoke and potential harm to nonsmoking youth. We certainly would welcome research on other populations, but the focus on these key groups seems appropriate. We had offered to make our research protocol and instruments available, and the editor of NTR encouraged replication, but we have received no inquiries. We reiterate: Empirical confirmation and replication remain important foundations of scientific dialogue.

  Conclusion

  As we hope our responses illustrate, critiques and exchanges regarding scientific methods can refine and advance our collective understanding of key questions. While we agree with the importance of transparency and skepticism, neither are served by outright censoring of scientific data, which is counter to principles of scientific inquiry.

  Funding and Disclosures

  Through Pinney Associates, Inc., Joe Gitchell, Floe Foxon, and Saul Shiffman provide consulting services on tobacco harm reduction on an exclusive basis to Juul Labs, Inc. Nicholas Goldenson is an employee of Juul Labs, Inc. The preparation of this response was funded by Juul Labs Inc., who reviewed and commented on a draft.

  References

  1. Soule EK, Rossheim ME, Livingston MD, LoParco CR, Tillett KK, Eissenberg T, Sussman S: Hidden flaws in e-cigarette industry-funded studies. Tob Control 2024.
  2. Goldenson NI, Buchhalter AR, Augustson EM, Rubinstein ML, Henningfield JE: Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers. Drug Alcohol Depend 2020, 217:108395.
  3. Goldenson NI, Buchhalter AR, Augustson EM, Rubinstein ML, Van Hoof D, Henningfield JE: Abuse liability assessment of the JUUL system in two nicotine concentrations compared to combustible cigarette, nicotine gum and comparator electronic nicotine delivery system. Drug Alcohol Depend 2020, 217:108441.
  4. Goldenson NI, Fearon IM, Buchhalter AR, Heningfield JE: An Open-Label, Randomised, Controlled, Crossover Study to Assess Nicotine Pharmacokinetics and Subjective Effects of the JUUL System with Three Nicotine Concentrations Relative to Combustible Cigarettes in Adult Smokers. Nicotine Tob Res 2021.
  5. Goldenson NI, Augustson EM, Chen J, Shiffman S: Pharmacokinetic and subjective assessment of prototype JUUL2 electronic nicotine delivery system in two nicotine concentrations, JUUL system, IQOS, and combustible cigarette. Psychopharmacology (Berl) 2022, 239(3):977-988.
  6. Maloney S, Eversole A, Crabtree M, Soule E, Eissenberg T, Breland A: Acute effects of JUUL and IQOS in cigarette smokers. Tob Control 2020.
  7. Foxon F, Selya A, Gitchell J, Shiffman S: Population-level counterfactual trend modelling to examine the relationship between smoking prevalence and e-cigarette use among US adults. BMC Public Health 2022, 22(1):1940.
  8. Rossheim ME, Livingston MD, Krall JR, Barnett TE, Thombs DL, McDonald KK, Gimm GW: Cigarette Use Before and After the 2009 Flavored Cigarette Ban. J Adolesc Health 2020, 67(3):432-437.
  9. Expression of concern about the proposed retraction of Foxon et al. paper regarding the relationship between smoking prevalence and e-cigarette use among US adults. Available https://clivebates.com/documents/ExpertLetterFoxonRetractionAugust2023.pdf. 2023.
  10. https://www.pubpeer.com/publications/0C19CEA0C329F1C95FC0884C7A4AE1
  11. Supplemental materials for paper: Population-level counterfactual trend modelling to examine the relationship between smoking prevalence and e-cigarette use among US adults. 2023. https://doi.org/10.17605/OSF.IO/FZTNK
  12. Foxon F, Selya A, Gitchell J, Shiffman S: Increased e-cigarette use prevalence is associated with decreased smoking prevalence among US adults. Harm Reduction Journal 2024, 21(1):136.
  13. Shiffman S, Sembower MA, Pillitteri JL, Gerlach KK, Gitchell JG: The Impact of Flavor Descriptors on Nonsmoking Teens' and Adult Smokers' Interest in Electronic Cigarettes. Nicotine Tob Res 2015, 17(10):1255-1262.
  14. American Academy of Pediatrics, American Cancer Society Cancer Action Network, American Heart Association, American Stroke Association, American Lung Association, Campaign for Tobacco-Free Kids: The Flavor Trap: How Tobacco Companies Are Luring Kids with Candy-Flavored E-cigarettes and Cigars. Available https://web.archive.org/web/20170705032610/https:/www.tobaccofreekids.or.... 2017

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  Conflict of Interest:
  Through Pinney Associates, Joe Gitchell, Floe Foxon, and Saul Shiffman provide consulting services on tobacco harm reduction on an exclusive basis to Juul Labs, Inc. Nicholas Goldenson is an employee of Juul Labs, Inc. The preparation of this response was funded by Juul Labs Inc., who reviewed and commented on a draft.

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