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• Response to “E-cigarette manufacturers’ compliance with clinical trial reporting expectations: a case series of registered trials by Juul Labs.”
  Snigdha R Mishra
  Published on: 14 December 2022
• Trials Transparency in E-cigarette Research
  Nicholas J. DeVito
  Published on: 14 December 2022

• Published on: 14 December 2022

  Response to “E-cigarette manufacturers’ compliance with clinical trial reporting expectations: a case series of registered trials by Juul Labs.”

  • Snigdha R Mishra, Senior Vice President, Regulatory Science JUUL Labs

  NOT PEER REVIEWED

  I write on behalf of Juul Labs in response to “E-cigarette manufacturers’ compliance with clinical trial reporting expectations: a case series of registered trials by Juul Labs.” We appreciate the public health community’s interest in understanding the Company’s research. However, we want to clarify the article’s reporting on Juul Labs’ research program and publications to date, as well as our legal obligations to report the results of clinical investigations.

  First, our studies were conducted in anticipation of our submission of a Premarket Tobacco Product Application (PMTA) to the U.S. Food and Drug Administration (FDA). As such, raw data, results, and statistical code underlying our analyses of all ten registered Juul Labs studies referenced in the Tobacco Control paper have been submitted to FDA (1)

  In addition, we have been working on sharing our data in publications and posters. In fact, by the end of this month, we will have published or presented data on nine of the ten studies, in addition to having provided the clinical results to FDA. Of our ten registered studies, we have published the results of four (2, 3, 4, 5) submitted the results of an additional two studies for peer review, presented the results of two as posters (6,7) and have the results of one accepted for presentation this summer. We appreciate that the authors of the Tobacco Control paper may have drafted their article months ago, but note that there...

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  NOT PEER REVIEWED

  I write on behalf of Juul Labs in response to “E-cigarette manufacturers’ compliance with clinical trial reporting expectations: a case series of registered trials by Juul Labs.” We appreciate the public health community’s interest in understanding the Company’s research. However, we want to clarify the article’s reporting on Juul Labs’ research program and publications to date, as well as our legal obligations to report the results of clinical investigations.

  First, our studies were conducted in anticipation of our submission of a Premarket Tobacco Product Application (PMTA) to the U.S. Food and Drug Administration (FDA). As such, raw data, results, and statistical code underlying our analyses of all ten registered Juul Labs studies referenced in the Tobacco Control paper have been submitted to FDA (1)

  In addition, we have been working on sharing our data in publications and posters. In fact, by the end of this month, we will have published or presented data on nine of the ten studies, in addition to having provided the clinical results to FDA. Of our ten registered studies, we have published the results of four (2, 3, 4, 5) submitted the results of an additional two studies for peer review, presented the results of two as posters (6,7) and have the results of one accepted for presentation this summer. We appreciate that the authors of the Tobacco Control paper may have drafted their article months ago, but note that there are outdated references to publication or presentation of the five studies included by the authors in their analysis. While the article asserts that just one of the five studies that was incorrectly registered as an “applicable device clinical trial” has been published, as of this writing, results from three of the five studies have been published. (8) Across our research program, we have published a total of 17 articles (all publicly available on our science website www.juullabsscience.com) and are working on additional publications.

  Finally, although not obligated to do so (9), Juul Labs voluntarily submitted registration information for ten studies to the ClinicalTrials.gov registry. As voluntary submissions, all of the studies should have been registered as a “voluntary other trial.” Due to an administrative error at Juul Labs, six of those studies were instead registered as an “applicable device clinical trial.” These errors are in the process of being corrected and, in fact, four of the studies have been formally updated on ClinicalTrials.gov to reflect this change. (10, 11, 12, 13)

  We look forward to continuing to share results from our science and research program with the scientific and public health community as we work to advance harm reduction for adults who smoke, and to support the scientific basis for the category.
  Sincerely, Snigdha Mishra, SVP Regulatory Science

  References

  1. See 21 U.S.C. § 387j(b)(1)(A) (requiring that manufacturers submit in a PMTA “full reports of all information, published or known to, or which should reasonably be known to, the applicant, concerning investigations which have been made to show the health risks of such tobacco product and whether such tobacco product presents less risk than other tobacco products.”)
  2. Jay, et. al. Five-Day Changes in Biomarkers of Exposure Among Adult Smokers After Completely Switching From Combustible Cigarettes to a Nicotine-Salt Pod System. Nicotine & Tobacco Research 2019. https://doi.org/10.1093/ntr/ntz206
  3. Goldenson, et. al. Abuse liability assessment of the JUUL system in two nicotine concentrations compared to combustible cigarette, nicotine gum, and comparator electronic nicotine delivery system. Drug and Alcohol Dependence 2020. https://doi.org/10.1016/j.drugalcdep.2020.108441
  4. Goldenson, et. al. Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparative electronic nicotine delivery system among adult smokers. Nicotine & Tobacco Research 2020 https://doi.org/10.1016/j.drugalcdep.2020.108395
  5. Oldham, et al. Room air constituent concentrations from use of electronic nicotine delivery systems and cigrettes using different ventilation conditions. Scientific Reports 2021 https://doi.org/10.1038/s41598-021-80963-9
  6. https://www.juullabsscience.com/wp-content/uploads/sites/8/2020/09/CPDD-... ;
  7. https://www.juullabsscience.com/wp-content/uploads/sites/8/2020/09/Chara...
  8. See supra notes 3-5.
  9. Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) and implementing regulations issued by the National Institutes of Health (NIH) do not require registration of clinical trials involving tobacco products, as defined under the Federal Food, Drug, and Cosmetic Act (FDCA). See 42 USC 282(j); 42 CFR Part 11.
  10. https://clinicaltrials.gov/ct2/show/NCT03596034?term=Juul&recrs=e&draw=2...
  11. https://clinicaltrials.gov/ct2/show/NCT03605641?term=Juul&recrs=e&draw=5...
  12. https://clinicaltrials.gov/ct2/show/NCT03700112?term=juul&cntry=NZ&draw=...
  13. https://clinicaltrials.gov/ct2/show/NCT03719391?term=Juul&draw=3&rank=10

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  Conflict of Interest:
  Senior Vice Preseident, JUUL Labs

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• Published on: 14 December 2022

  Trials Transparency in E-cigarette Research

  • Nicholas J. DeVito, Doctoral Student University of Oxford

  NOT PEER REVIEWED

  On behalf of my co-authors, we thank Dr. Mishra for taking the time to comment on our paper examining reporting of trials registered by Juul Labs Inc.

  We do not doubt that Juul has submitted the results from all of these studies to the FDA as part of their Premarket Tobacco Product Application (PMTA). Unfortunately, this step does not ensure the full results of these trials will be made available to the public, clinicians, and other key stakeholders.

  We also acknowledge and appreciate that since conducting our analysis in August 2020, two additional studies, of the five we examined, have appeared in the peer reviewed literature (published in December 2020 and January 2021)[1,2] and additional results may become available through other methods. We understand that these publications may contain additional outcome reporting compared to the posters we assessed. We welcome any and all additional results disclosures from Juul Labs. That said, we believe the risk of outcome reporting bias remains and is, unfortunately, not addressed in Juul’s comment despite being a major facet of our paper. The one publication that was available as of our analysis date excluded 4 of the 19 prespecified secondary outcomes without comment and another 5 outcomes had clear issues in their reporting compared to the registered outcomes. While we have not conducted a detailed assessment of the two new publications, it is apparent that journal publication does no...

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  NOT PEER REVIEWED

  On behalf of my co-authors, we thank Dr. Mishra for taking the time to comment on our paper examining reporting of trials registered by Juul Labs Inc.

  We do not doubt that Juul has submitted the results from all of these studies to the FDA as part of their Premarket Tobacco Product Application (PMTA). Unfortunately, this step does not ensure the full results of these trials will be made available to the public, clinicians, and other key stakeholders.

  We also acknowledge and appreciate that since conducting our analysis in August 2020, two additional studies, of the five we examined, have appeared in the peer reviewed literature (published in December 2020 and January 2021)[1,2] and additional results may become available through other methods. We understand that these publications may contain additional outcome reporting compared to the posters we assessed. We welcome any and all additional results disclosures from Juul Labs. That said, we believe the risk of outcome reporting bias remains and is, unfortunately, not addressed in Juul’s comment despite being a major facet of our paper. The one publication that was available as of our analysis date excluded 4 of the 19 prespecified secondary outcomes without comment and another 5 outcomes had clear issues in their reporting compared to the registered outcomes. While we have not conducted a detailed assessment of the two new publications, it is apparent that journal publication does not necessarily guarantee the full reporting of all specified outcomes. This unfortunately holds true throughout the reporting of clinical research. [3, 4]

  Additionally, we showed that for the conference posters identified by our searches there was a clear risk of unreported outcomes for these short-format publications. Potentially making some studies only available as posters or abstracts risks further outcome reporting issues or delays.

  In Footnote 9 of the comment, Dr. Mishra states that “Section 801 of the Food and Drug Administration Amendments Act of 2007 (FDAAA) and implementing regulations issued by the National Institutes of Health (NIH) do not require registration of clinical trials involving tobacco products”

  The Final Rule is entirely silent on the specific coverage status of tobacco products. Searching the Final Rule document for the word “Tobacco” reveals 0 results.[5] Another Final Rule issued well after the Sottera decision, 21 CFR 201, 801, and 1100, and an FDA guidance document both make clear that under certain circumstances tobacco products can be considered covered under the FDAAA.[6, 7]

  To quote the FDA Guidance:

  “If an ENDS product is marketed for tobacco cessation or for any other therapeutic purpose, the product is a drug or device, rather than a tobacco product, under the authorities of FDA’s Center for Drug Evaluation and Research or Center for Devices and Radiological Health, and appropriate approval must be sought to market a product as a drug or device.” (Page 9)

  And 21 CFR 201, 801, and 1100:

  “Whether the product, as used in the study, is subject to regulation as a drug depends on whether the product is being investigated for any of the purposes described in § 1100.5(a) or (b) of this rule. To determine if a product made or derived from tobacco is being investigated for one of these purposes, FDA generally would review the protocol for the study, including the proposed methods and measures. In the Agency’s experience, the proposed methods and measures for a study can provide insight into the purposes for which a product is being investigated.” (Page 2213)

  We also note that the FDAAA Final Rule requires trials of drugs and devices to report regardless of whether or not they plan to seek any approvals with the FDA [5]:

  “The final rule maintains the proposal to require the submission of results information for applicable clinical trials of unapproved, unlicensed, or uncleared products, regardless of whether FDA approval, licensure, or clearance is or will be sought or obtained.” (Page 64995)

  We discuss the relevant legal frameworks, and their unfortunate ambiguity, in more depth in the manuscript.

  Our determination of potential FDAAA coverage was based on public registration information directly provided by Juul and matched to official published criteria for determining FDAAA coverage. As stated in their comment, Juul Labs have now updated many of their registrations to no longer match these criteria. However the registered trials we assessed contained outcomes related to the uptake and pharmacokinetics of nicotine in the body, a key feature of addiction, and measures directly relevant to smoking cessation like product use, dependency, urge to smoke, and aspects of withdrawal. It is, however, ultimately up to the FDA to make official determinations about which trials are covered under the FDAAA based on their assessment of the purpose and outcomes of a given study.

  Regardless of the exact regulatory status of these trials, a matter we hope the FDA will offer further clarity on, we strongly encourage Juul Labs to consider amending their existing registrations with the results of these trials. ClinicalTrials.gov offers a rapid, public, open source repository for trial results that enhances their availability, transparency, and discoverability and should not preclude subsequent peer reviewed publications.[8] It is clear from their response that Juul Labs understands the importance of trial registration and reporting to the public and scientific community, and we welcome this recognition. ClinicalTrials.gov allows for full results to be reported, without space limitations or delays associated with journal publication, and with a clear public link to all prespecified outcomes and other registered details. While the FDAAA compels this type of reporting, there is no limitation on voluntary submission of results if trials are not covered under the law. We strongly believe it is in the public interest that all outcomes for all trials that form PMTA applications should be fully and publicly reported in a timely manner. Currently this does not appear to be the case even if it may have improved since our evaluation.

  Whether compelled to report by legal requirements or not, we hope Juul will consider setting a strong precedent for transparency in tobacco-industry e-cigarette research by adhering to global ethical standards [9] and reporting their full trial results for these, and future, trials to ClinicalTrials.gov and assuage any doubts about selective reporting of results or outcomes.

  References:
  1. https://doi.org/10.1016/j.drugalcdep.2020.108395

  2. https://doi.org/10.1038/s41598-021-80963-9

  3. https://doi.org/10.1186/s12916-015-0520-3

  4. https://doi.org/10.1186/s13063-019-3173-2

  5. https://www.govinfo.gov/content/pkg/FR-2016-09-21/pdf/2016-22129.pdf

  6. https://www.govinfo.gov/content/pkg/FR-2017-01-09/pdf/2016-31950.pdf

  7. https://www.fda.gov/media/127853/download

  8. http://www.icmje.org/recommendations/browse/publishing-and-editorial-iss...

  9. https://doi.org/10.1371/journal.pmed.1001819

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  Conflict of Interest:
  None declared.

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