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I have a number of concerns with the paper as currently written.
1) The authors write: “Besides, none of the previous studies except Pesko et al (15) that examined the associations between vaping product excise tax adoption and ENDS use has accounted for the clustering of respondents within the same localities…” This is not accurate, as citation 19 also clusters standard errors at the locality level in all specifications.
2) The authors write: "A working paper reported reduced ENDS sales, but not ENDS use prevalence or behaviours, after implementation of a vaping product excise tax policy. (19)” This is not accurate, as the cited study uses the magnitude of e-cigarette tax values, rather than an indicator variable for tax implementation. States have adopted e-cigarette taxes of different magnitudes and a number of them (such as California) have changed the magnitudes of these taxes after adoption. All of this variation is used in citation 19, contrary to the current study’s description. It's also unclear from the sentence whether citation 19 studied use and found imprecise estimates, or did not study use. It's the latter and this should be clarified. It's also unclear why the authors did not use magnitude of e-cigarette taxes themselves in the current paper, as has been commonly done in the referenced literature.
3) Authors write they use a “nationally representative sample of US young adults.” I do not beli...
3) Authors write they use a “nationally representative sample of US young adults.” I do not believe this is not accurate. The TUS-CPS sample itself may be nationally representative, but this representativeness may be lost when subgroups are explored.
4) The “vaping product excise tax policy” variable in Table 3 appears to be re-defined mid-table. Based on the discussion of the results, in column 1 it appears that this variable is an indicator equal to 1 only at the time when a state has an e-cigarette tax in place. In column 2 though, this indicator equals 1 when a state ever has an e-cigarette tax in place (even prior to it being in place). The use of the same row for a variable that changes across columns is unusual and can easily lead to the wrong interpretation.
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This article does not distinguish between characterizing flavour (menthol) bans that were implemented in Canadian provinces between 2015 and 2017 and the implementation of a national ban on menthol additives in Canada in October 2017. Although unreported, the analysis was performed exclusively on provincial characterizing flavour bans. This significant distinction should be reported to ensure that researchers and policy makers are aware of the potential impact of a characterizing flavour ban and to ensure that this policy measure is not dismissed or discounted.
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I would like to make three comments by way of a brief post-publication review.
1. The impacts of vaping tax on smoking have been completely overlooked
For a study of e-cigarette taxation to have any public health relevance, it must consider the impact of e-cigarette prices on *cigarette* demand. Cigarettes and e-cigarettes are economic substitutes. The demand for one responds to changes in the price of the other, an idea well understood in economics and quantified through the concept of cross-elasticity. The paper appears to pay no regard to the impact of vaping taxes on cigarette demand, Yet such effects might easily overwhelm any benefits from reduced e-cigarette use - in fact, impact on demand for other tobacco products and the development of informal markets are by far the most important impacts of a vaping tax. By way of example, a 2020 paper by Pesko et al.  concluded:
"Our results suggest that a proposed national e-cigarette tax of $1.65 per milliliter of vaping liquid would raise the proportion of adults who smoke cigarettes daily by approximately 1 percentage point, translating to 2.5 million extra adult daily smokers compared to the counterfactual of not having the tax."
2. The case for reducing adult vaping by taxation has not been made
The authors have based their paper on an unexamined assumption that it is a justifiable goal of policy to lower rates of adult e-cigarette use. Why should...
The authors have based their paper on an unexamined assumption that it is a justifiable goal of policy to lower rates of adult e-cigarette use. Why should this be a policy goal any more than reducing caffeine use or moderate alcohol use? The goal of public health policy is to address significant harms or self-destructive patterns of use, not to modify behaviours that the authors find distasteful. What are the harms that justify state intervention to reduce adult vaping with a tax? Further, they appear indifferent to welfare costs and the distributional impact of imposing a regressive tax burden on people who use vaping products. Tobacco control advocates should become more familiar with the idea that punitive policies impose harm on users, even though these users are supposed to be the intended beneficiaries. For example, a vaping tax harms families by drawing on the household budget of those who continue to vape.
3. The analysis to support the policy recommendations is wholly inadequate
The authors make over-confident policy recommendations without considering the full range of impacts of the measures they are proposing.
"Our findings suggest that adopting a vaping product excise tax policy may help reduce ENDS use and suppress the increase of ENDS use prevalence among young adults. Considering that there are still a number of US states that have not implemented vaping product excise tax policy, wider adoption of such policy across the nation would likely help mitigate ENDS use prevalence."
Without considering all the possible responses to the tax they support, they may easily be proposing tobacco control policies that do more harm than good. In fact, the most important public health impact of this policy is entirely excluded from the analysis. That is the effect of a vaping tax on smoking or other tobacco use. Given the two orders of magnitude difference in risk between smoking and vaping, only a tiny uptick in smoking would be needed to completely offset the benefits, if any, arising from reduced vaping
 Pesko MF, Courtemanche CJ, Maclean JC. The effects of traditional cigarette and e-cigarette tax rates on adult tobacco product use. J Risk Uncertain 2020;60(3):229–258. https://link.springer.com/article/10.1007/s11166-020-09330-9
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Replication attempts are one of the self-correcting mechanisms of science, and we thank the Authors for their response to our concerns and their attempt to replicate aspects of their study . Regrettably, they have failed to adequately address the central point raised in our letter of 23rd April 2021, namely that the title and conclusions of their original Article are patently invalid and have no basis in fact or evidence . Instead of strengthening their argument in support of the Article’s findings and conclusions, the Authors’ response considerably weakens them. Strikingly, the Authors reveal several new and serious issues and yet maintain that their “principle finding is unchanged”.
The Authors acknowledge that they were unable to replicate an important aspect of their original analysis, namely that a Philip Morris International (PMI) News Article  published on its website (falsely described as a “press release”) was “republished […] in 14 additional news outlets”. In their response, they note that “Our original assertion that there were 14 duplicate articles is not supported by our replication analysis”. This failure to replicate a key finding—in their own proprietary database, which several of them co-developed—is concerning. The Authors provide no explanation for the irregularity. Notably, on 20th April 2021, we were able to source these 14 articles in Tobacco Watcher since they were clearly mar...
The Authors acknowledge that they were unable to replicate an important aspect of their original analysis, namely that a Philip Morris International (PMI) News Article  published on its website (falsely described as a “press release”) was “republished […] in 14 additional news outlets”. In their response, they note that “Our original assertion that there were 14 duplicate articles is not supported by our replication analysis”. This failure to replicate a key finding—in their own proprietary database, which several of them co-developed—is concerning. The Authors provide no explanation for the irregularity. Notably, on 20th April 2021, we were able to source these 14 articles in Tobacco Watcher since they were clearly marked as “additional coverage” of the PMI News Article. Of the total, 5 of the “duplicate articles” were no longer accessible online and none of the remaining 9 mentioned IQOS at all. All of them were reporting on the EVALI outbreak and flavor ban proposals, a fact that we raised in our April letter to the Authors.
The Authors note that Tobacco Watcher is “a dynamic resource with continuous data collection and processing”. We could not find any information about the computational environment of the database, nor does there appear to be any public information about factors that can impact reproducibility and replicability. Specifically, we could not find any published information about how it collects, processes, and analyzes data, how it is version controlled and what data management plans are in place. However, a poster presentation by some of the Authors indicates that media articles are “automatically coded” using “natural language processing, trained on human-coded data” . It is therefore difficult to understand why results relating to media articles from 2019—generated from an automatic coding process—could abruptly change over the course of two months in 2021. Of course, it is entirely plausible that the 14 articles had been falsely coded, and that this error was manually addressed at some point between April 20th and June 10th, 2021. The Authors should explain if this was the case, or whether changes to the underlying Tobacco Watcher algorithms caused the change—and if so, how. They should also provide an explanation of why they remain confident in the rest of their trend analyses, given the apparent instability of Tobacco Watcher over time.
Because of the Authors’ failure to replicate this important aspect of their study, there is no valid evidence to show any direct link between the PMI News Article and the increase in media coverage of IQOS and EVALI. The Authors’ invalid assumption that the PMI News Article was “republished” was presumably relied upon to support their title and conclusions and yet the evidence for this has now been shown to be nonexistent—not just by our analysis, but also by the Authors’ subsequent failure to replicate their initial finding.
Confounding Factors Ignored:
Given that the Authors have now shown that they do not have any evidence to support a direct, causal relationship between the PMI News Article and subsequent news coverage including both the terms IQOS and EVALI, potential confounders become central to the question of whether their title and conclusions are supported or not. Whilst they now concede that their evidence merely demonstrates that a causal relationship is “plausible”, they continue to ignore or dismiss other more likely explanations. Many confounding factors were laid out in our April letter—with sources beyond those emanating solely from PMI—and they provide important information about the news media environment that could credibly have caused a rise in articles mentioning IQOS and EVALI (including in particular the official press releases  by PMI and Altria on 25th September 2019—announcing that their proposed merger talks were over and that the companies would focus on launching IQOS in the U.S.— as well as a press release from the U.S. Centers for Disease Control related to EVALI). Generally, in epidemiology, sociology and other fields, there are at least three main criteria that should be met in order to establish a causal relationship: the cause occurs before the effect; the cause and the effect covary; and a lack of plausible alternative explanations . By dismissing the most plausible explanations for the increase in media coverage, and failing to provide any credible alternative evidence to explain their hypothesis, the overall analysis and conclusion presented by the Authors fails to meet these criteria for causality.
Attempt to Shift the Burden of Proof:
The Authors make logical errors in defense of their Article. They state that “PMI has not provided any verifiable disclosure about how they circulated these materials [the PMI News Article] beyond their publication and availability on internet search engines and social media”. Any perceived lack of disclosure on the part of PMI does not render the Authors’ claims any more valid. To the contrary, the burden of proof is on them to provide evidence for their assertions. In the three months since we first wrote to the Authors to express our concerns, it would have been perfectly possible for them to: (a) list which news articles actually refer to the PMI News Article and/or use the phrases ‘IQOS’ AND ‘EVALI’ (rather than ‘vaping’ and ‘illness’, which are not identical search terms); and (b) rapidly and independently verify whether any of the journalists writing about both IQOS and EVALI had seen the PMI News Article by simply asking them.
Unsubstantiated, Yet Definitive Language:
The title “Philip Morris International used the e-cigarette, or vaping, product use associated lung injury (EVALI) outbreak to market IQOS heated tobacco” is a statement purporting to be factual. However, the Authors now state that their original findings and conclusions are merely “plausible” and admit “we cannot know PMI’s intent”. Plausibility is not a statement of fact or truth. Instead, it implies that an argument is not fully formed, appears specious, superficially fair or reasonable, but in fact could be either right or wrong. As such, the title and other conclusory allegations in the Article are—by the Author’s own admission—not supported. Having ignored or discounted evidence that makes the Author’s conclusions implausible, the final paragraph of their response makes clear that in the absence of evidence, their conclusion rests solely on the Author’s distrust of the industry.
In summary, the conclusion that “Philip Morris International used the e-cigarette, or vaping, product use associated lung injury (EVALI) outbreak to market IQOS heated tobacco” can be disproven using the authors’ own tool, an analysis method that actually takes into account concomitant news events, the Authors’ acknowledgment that they failed to replicate an important aspect of their findings, and their concession that their title is merely “plausible”. The entire premise of the EVALI/IQOS Article is patently invalid and substantial revision or retraction of this paper remains urgently warranted.
 https://www.qeios.com/read/NLZDBR (see supplementary data file)
 https://www.pmi.com/media-center/news/lung-illnesses-associated-with-use... (Note: this News Article was published on 24th September 2019. The Authors response inaccurately states a publication date of 24th September 2021)
 Unlike official press releases circulated to news agencies via press services, which reach more than a hundred thousand news outlets worldwide instantly and directly (see https://services.businesswire.com/public-relations-services/press-releas...), the PMI News Article was only published on PMI.com and via our social media accounts, and as such would only have received organic traffic.
 e.g., Chambliss, Daniel & Schutt, Russell. (2018). Making Sense of the Social World: Methods of Investigation.
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The authors’ response published on 14 July 2021 is far from satisfactory and implausibly asserts that “Our original findings and conclusions remain plausible” 
The original study  uses a media analysis to make a claim that a statement made by the tobacco company Philip Morris International (PMI) about an outbreak of lung disease in the US  was a marketing ploy for its heated tobacco product, iQOS. At the time, the lung injury outbreak was falsely attributed by many to nicotine vaping. Heated tobacco products are an alternative to nicotine vaping for smokers looking for a low-risk alternative to smoking.
I will now list some of the problems with this claim.
1. The research findings do not support the headline claim
The study title contains a strong and unqualified assertion of cynical opportunism on the part of the company. The new formulation that findings "remain plausible" does not justify the confidence in the assertion made in the title. "Plausible" is a reasonable basis for choosing a hypothesis to investigate, but a far from sufficient basis for drawing an aggressive conclusion. The authors do not seem to dispute the technical or factual accuracy of the statement about iQOS and EVALI made by PMI. Their allegation is about malign motives and, as such, it should be a cause for caution and a high standard of evidence.
2. No specific articles were provided to substantiate the...
2. No specific articles were provided to substantiate the claim
The headline finding is not, however, even remotely plausible. The company has made it clear that it made its iQOS-EVALI statement available passively for information purposes. If it had generated even one story among 384 the authors say that matched their keyword search in the 30 days after publication, the authors could have produced it. If they had a good case and wanted to avoid a retraction, they could have looked through these results (or to save time, articles published in the two weeks after PMI's statement) and shown at least some articles clearly derive from the statement. Though searching only with Google, I have been unable to identify a single article. That doesn't mean there aren't any, but it's not me making the allegations. The authors are making the allegations and the burden of evidence is with them. They should now respond with examples of articles that support their critique and publish the list of 384 articles captured in their search as a supplementary file that is open to anyone to examine
3. Confounding by other news is a fatal problem for this study
The problem of confounding by other news related to the company, product and sector at around the same time is overwhelming. PMI published its iQOS-EVALI statement on 24 September 2019 . This period coincided with; the end of merger talks between Altria and PMI on 25 September ; also on the same day, Juul announced the departure of its CEO and new corporate practices (Juul is part-owned by Altria) ; a new iQOs product was launched by PMI on 26 September ; there was an ongoing controversy with high news value developments on a lung injury outbreak in the United States, which was at the time often falsely attributed to nicotine vaping. For example, a significant CDC press release on 27 September .
4. Many news media will have covered several issues at once
The timing in question was a crisis period for products and companies making low-risk alternatives to cigarettes. It will have generated many news pieces that would have covered specific stories but also rounded up the other news. For example, Reuters reported both the PMI-Altria merger news and Juul restructuring in the same piece on 25 September 2019 with references to both lung injures and to iQOS, but without any reference to PMI's 24 September 2019 statement. 
5. The study method has no credible approach to confounding
Much of the response seems to be devoted to discussing sloppy though trivial errors in the original paper. This is a distraction from addressing the fundamental flaw, on which the response has relatively little to say. Without some sort of strategy to address confounding by other news and thereby to isolate from the signal (of PMI cynical opportunism) from the cacophonous noise of the news flow at the time, the authors have no basis for their claim. On top of this, the failure to produce a single article that appears to be derived in whole or even in part from the allegedly cynical communication suggests the authors have nothing.
6. Failure to put findings to the company
There is no sign here that the authors contacted the company or made any efforts to verify their story or check for alternative explanations. Why not? Why is it acceptable to avoid this most basic of journalistic practices simply because the authors are writing in an academic journal and about an organisation they do not like?
Just because the object of this research is the tobacco industry, it doesn't mean scientific standards or research and investigative ethics should be jettisoned. Precisely because the target of this research is a tobacco company, it makes a good test of scientific integrity and ‘white hat bias’. 
“White Hat Bias is bias leading to distortion of research-based information in the service of what may be perceived as righteous ends.”
. Ayers JW, Leas EC, Dredze M, Zhu SH, Cohen JE. Our original findings and conclusions remain plausible, Authors' response. Tobacco Control. 14 July 2021. https://tobaccocontrol.bmj.com/content/early/2021/04/15/tobaccocontrol-2...
. Ayers JW, Leas EC, Dredze M, Caputi TL, Zhu SH, Cohen JE. Philip Morris International used the e-cigarette, or vaping, product use associated lung injury (EVALI) outbreak to market IQOS heated tobacco. Tob Control 2021 https://tobaccocontrol.bmj.com/content/early/2021/04/15/tobaccocontrol-2...
. PMI, Lung illnesses in the U.S. associated with the use of vaping products: The facts. Originally published 24 September 2019
. PMI, Philip Morris International Inc. and Altria Group, Inc. End Merger Discussions, 25 September 2019.
. Juul Labs, Juul Labs names new leadership, outlines changes to policy and marketing, 25 September 2019
. PMI, Philip Morris International Inc. Launches IQOS 3 DUO, 26 September 2019 https://www.pmi.com/media-center/press-releases/press-release-details/?n...
. CDC, THC Products May Play a Role in Outbreak of Lung Injury Associated with E-cigarette Use, or Vaping, 27 September 2019. https://www.cdc.gov/media/releases/2019/p0927-thc-vaping.html
. Reuters, Juul boss exits in vaping crisis as Philip Morris, Altria axe merger talks, 25 September 2019. https://www.reuters.com/article/us-altria-m-a-philipmorris-idUSKBN1WA1DY
. The concept originates with: Cope MB, Allison DB. White Hat Bias: Examples of its Presence in Obesity Research and a Call for Renewed Commitment to Faithfulness in Research Reporting. Int J Obes (Lond) 2010;34(1):84. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2815336/
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We thank Dr. Moira Gilchrist (1) for her careful attention to our work (2). Gilchrist argues our principal findings were erroneous and any change in news coverage of IQOS and the e-cigarette, or vaping, product use associated lung injury (EVALI) outbreak were confounded by other Philip Morris International (PMI) media materials and not those specifically discussing EVALI and IQOS (3) which we attributed our findings to. However, a deeper inspection of this argument suggests our original findings and conclusions remain plausible.
Tobacco Watcher is a dynamic resource with continuous data collection and processing. Thus, the results of analyses on the platform can vary over time. On June 10, 2021 we replicated our analysis. After correcting an error that the PMI’s materials on EVALI and IQOS (3) was initially published on 24 September 2021 (not 25 September) the principal finding is unchanged. News coverage mentioning both “IQOS” and EVALI (i.e., including the terms ‘vaping’ and ‘illness’) reached an all-time high immediately after PMI published materials about EVALI and IQOS on their website. Thirty days prior to PMI posting this material (August 25th through September 23rd) 2.0 news stories per day matched our search compared to 12.8 for the 30 days after their publication (September 24th through October 23rd), with 384 news reports matching our keyword search for the latter period. Our original assertion that there were 14 duplicate articl...
Tobacco Watcher is a dynamic resource with continuous data collection and processing. Thus, the results of analyses on the platform can vary over time. On June 10, 2021 we replicated our analysis. After correcting an error that the PMI’s materials on EVALI and IQOS (3) was initially published on 24 September 2021 (not 25 September) the principal finding is unchanged. News coverage mentioning both “IQOS” and EVALI (i.e., including the terms ‘vaping’ and ‘illness’) reached an all-time high immediately after PMI published materials about EVALI and IQOS on their website. Thirty days prior to PMI posting this material (August 25th through September 23rd) 2.0 news stories per day matched our search compared to 12.8 for the 30 days after their publication (September 24th through October 23rd), with 384 news reports matching our keyword search for the latter period. Our original assertion that there were 14 duplicate articles is not supported by our replication analysis.
We recognize that for any observational data analysis there are alternative explanations. However, Gilchrist’s alternative explanations are debatable. First, she argues the materials published by PMI on EVALI and IQOS (3) were not a “press release” and therefore could not have engendered a change in media coverage. We now refer to the materials published by PMI on EVALI and IQOS as a “public statement” published on PMI’s website. Yet, PMI has not provided any verifiable disclosure about how they circulated these materials beyond their publication and availability on internet search engines and social media, a concern we raised in our study (2). Regardless, PMI’s public statement was potentially consumed and amplified by other media makers. Second, she assumes the increase in news coverage was due to a PMI publication entitled “Philip Morris International Inc. and Altria Group, Inc. End Merger Discussions” (4) which does not mention EVALI. While a sizable percentage of the news articles we studied mention the merger, their inclusion of IQOS and EVALI suggests the possibility of additional source material for these stories. It is plausible that information from the published materials we studied tying IQOS and EVALI and the larger merger story were discussed in tandem.
There were factual errors in our report that we missed during the copy edit of our piece: the date of PMI’s materials being published was misstated (25 versus 24 September), the date of another reference was misstated, and references were misordered. Additionally, the date we submitted our piece was misstated due to a production system issue created by a delay in submitting the revised version. Last, in light of PMI stating that the 25 September publication was not a press release, the article has been amended accordingly. We have provided Tobacco Control with an errata to correct these errors. However, the principal conclusion of our work was unaffected by any error.
While we can measure the potential spillover effect of published claims, we cannot know PMI’s intent. It is paramount that the earned media strategies of the tobacco industry come under closer inspection. The tobacco industry has used varied tactics to sow misimpressions that favor them and their products, a fact well documented in both the scientific literature and courts of law (5); earned media campaigns may be yet another.
1. Gilchrist M. Study alleging Philip Morris International used the EVALI outbreak to market IQOS requires substantial methodological revision and further peer review, or retraction. Tob Control Rapid Response.
2. Ayers JW, Leas EC, Dredze M, et al. Tob Control. Epub ahead of print: doi:10.1136/ tobaccocontrol-2021-056661.
3. Philip Morris International. Lung illnesses associated with use of vaping products in the US. Available: https://www.pmi.com/media-center/news/lung-illnesses-associated-with-use... [Accessed 10 Mar 2021].
4. Philip Morris International. Philip Morris International Inc. and Altria Group, Inc. End Merger Discussions. https://philipmorrisinternational.gcs-web.com/static-files/78a6afb3-107d... Accessed 11 June 2021.
5. Ong EK, Glantz SA. Constructing "sound science" and "good epidemiology": tobacco, lawyers, and public relations firms. Am J Public Health. 2001;91.
A review of this study has been published by the target of its criticism, the tobacco company Philip Morris International (PMI), via the post-publication review server Qeios 
The main finding of this study, and the allegation raised in its title, is that PMI cynically used an outbreak of lung injuries in the United States (initially but incorrectly attributed to nicotine vaping) to promote its heated tobacco product, iQOS. Heated tobacco products are one alternative to vaping for those looking for a safer alternative to smoking. On 24th September 2019, PMI published an information notice about its products in response to the lung injury outbreak. The authors assert that PMI was trying to gain commercial publicity from a health crisis: a serious allegation. But the allegation appears to be based on a major error by the authors.
The study used a "fully automated media analysis engine" to count stories that mention iQOS around that time, showing that there were considerably more than usual. On this basis, the authors concluded that PMI's unethical promotional gambit had worked. However, the day after PMI allegedly disreputably sought publicity for iQOS, the company also issued a press release disclosing that merger negotiations with the American tobacco company, Altria, had ceased. PMI and Altria have a joint marketing agreement for iQOS in the United States. The end of merger talks would be big news in the business pre...
The study used a "fully automated media analysis engine" to count stories that mention iQOS around that time, showing that there were considerably more than usual. On this basis, the authors concluded that PMI's unethical promotional gambit had worked. However, the day after PMI allegedly disreputably sought publicity for iQOS, the company also issued a press release disclosing that merger negotiations with the American tobacco company, Altria, had ceased. PMI and Altria have a joint marketing agreement for iQOS in the United States. The end of merger talks would be big news in the business press and would likely include a discussion of consequences for iQOS.
So, an analysis that tries to measure media interest in PMI and iQOS for cynical publicity purposes at that time would be heavily confounded by other unrelated but newsworthy developments concerning the same company and product. A check of the press releases by the company should have raised the alarm. PMI also states that it did not seek any publicity for its safety notice about iQOS, which PMI says the authors:
"falsely describe as a “press release”, despite it never being published through a press release distribution service"
Now that it has been pointed out, it is quite clear that a serious error has been made here that undermines the foundations of the study and renders the allegation made in the title baseless. The simple way to deal with this is to acknowledge the error, retract the article, apologise, and resolve to be more careful in future. That should take a couple of hours, not several months and there would be no shame in it. That this has not happened is troubling.
 Moira Gilchrist (PMI) Review of: Philip Morris International used the e-cigarette, or vaping, product use associated lung injury (EVALI) outbreak to market IQOS heated tobacco. Qeios. [https://www.qeios.com/read/NLZDBR}
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...
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
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-... ;
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.
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...
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. 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 :
“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. 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  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.
A brief review of this ‘Industry Watch’ article alleging heated tobacco product advertising through an earned media approach highlights significant methodological errors that are serious enough to invalidate the article’s conclusions, including its title. The authors allege that Philip Morris International (PMI) used the e-cigarette, or vaping, product use associated lung injury (EVALI) outbreak to promote IQOS in September 2019 and the weeks that followed. Using the authors’ own tool (TobaccoWatcher.org), we replicated their search strategy and revealed several fundamental and concerning errors in the authors’ analysis.
They report a rise in news stories mentioning IQOS on and after 25th September 2019, and falsely attribute this rise to an article published on our website on 24th September 2019, which they also falsely describe as a “press release”, despite it never being published through a press release distribution service. Our analysis shows that the authors failed to consider several confounding and unrelated events that caused the rise in news coverage of both IQOS and EVALI during the time period in question and which can be found by replicating the authors’ search strategy in TobaccoWatcher.org.
For example, on 25th September 2019, Philip Morris International (PMI) issued a single press release via Business Wire (1) entitled “Philip Morris International Inc. and Altria Group, Inc. End Merger Discussions” (PMI/Altria Annou...
For example, on 25th September 2019, Philip Morris International (PMI) issued a single press release via Business Wire (1) entitled “Philip Morris International Inc. and Altria Group, Inc. End Merger Discussions” (PMI/Altria Announcement). The release noted that “the companies have agreed to focus on launching IQOS in the U.S.” PMI is listed on the New York Stock Exchange and is therefore subject to the rules of the NYSE and the Securities and Exchange Commission, including requirements for the disclosure of material events such as the PMI/Altria Announcement. We estimate that during a date range similar to that used by the authors, of the total number of stories retrieved using the authors’ search terms, >85% were reporting on the above noted PMI/Altria Announcement. The authors failed to mention this and other confounders in their discussion.
The authors state that “the original PMI press release (sic) was republished (including editing or revisions to make the republication consistent with the publisher’s format) in 14 additional news outlets.” We performed a full text review of the 14 articles mentioned and of those that were still accessible, none mentioned IQOS. The authors’ conclusion that “PMI capitalised on EVALI by using an earned news media strategy to market their IQOS brand of heated tobacco for free across scores of news outlets that reached millions of readers. This marks the first known case where a tobacco company used the EVALI outbreak to promote tobacco products” is therefore completely unsupported by their own data.
These facts, and other errors detected in this article, were communicated to the authors on 23rd April 2021. In summary, we believe that the article is unreliable, and that urgent substantial revision or retraction is warranted to prevent other studies citing the currently published inaccuracies.
(1) https://philipmorrisinternational.gcs-web.com/static-files/78a6afb3-107d... Accessed 5th May 2021