¶ I enjoyed reading this paper. I appreciate the author's use of difference-in-difference (DD) methodology. There were some things I found unclear that I would like to ask the authors to comment on.

¶ First, could the authors provide greater clarity on the model for column 1 of Table 1? Is the dependent variable here a yes/no for current cigarette use? The authors write, "Adolescents reported lifetime and prior month use of cigarettes, which we combined into a count variable of days smoked in the past month (0–30)." How does lifetime cigarette use help the authors to code the current number of cigarette days? The authors later state that they show that "increasing implementation of flavoured tobacco product restrictions was associated not with a reduction in the likelihood of cigarette use, but with a decrease in the level of cigarette use among users." Do the authors mean lifetime cigarette use here, or current cigarette use? The authors estimate this equation with an "inflation model," which I am not aware of. Could the authors provide more information on this modelling technique? This is not discussed in the "Analysis" section.

¶ Second, I felt like this statement is too strong. "Our findings suggest that[...] municipalities should enact stricter tobacco-control policies when not pre-empted by state law." Municipalities need to weigh many factors in making these decisions, including the effects of population health (not just to youth tobacco use). This study provides evidence from a single state that may not be generalizable to other states without preemption policies. Other studies have found unintended negative effects of flavor policies, and these studies should be referenced to balance the discussion section.

¶ I applaud the authors for providing an early data point on the effect of these policies, but certainly more work in this space is needed before policy recommendations can be made. The authors may also wish to consider for future difference-in-difference papers whether there is evidence in support of the parallel trends assumption , which is a crucial assumption underpinning the reliability of the model.
¶ References:

¶ Friedman, Abigail S. "A difference-in-differences analysis of youth smoking and a ban on sales of flavored tobacco products in San Francisco, California." JAMA pediatrics 175, no. 8 (2021): 863-865.

¶ Xu, Yingying, Lanxin Jiang, Shivaani Prakash, and Tengjiao Chen. "The Impact of Banning Electronic Nicotine Delivery Systems on Combustible Cigarette Sales: Evidence From US State-Level Policies." Value in Health (2022).

NOT PEER REVIEWED

We would like to thank Mr. Wang for his feedback on our paper, Indicators of dependence and efforts to quit vaping and smoking among youth in Canada, England and the USA.

With regards to the ‘discrepancies’ in vaping and smoking prevalence between those reported in Table 1 and an earlier publication [1], we have previously published these same estimates [2], along with a description of the survey weighting procedures—which were modified since the first estimates were published (as outlined in a published erratum to the cited publication [3]). Briefly, since 2019, we have been able to incorporate the smoking trends from national ‘gold standard’ surveys in Canada and the US into the post-stratification sampling weights. A full description is provided in the study’s Technical Report [4], which is publicly available (see http://davidhammond.ca/projects/e-cigarettes/itc-youth-tobacco-ecig/).

Mr. Wang has also noted a change in the threshold used for a measure of frequent vaping/smoking: ≥20 days in past 30 days rather than ≥15 days, as previously reported [1]. We have adopted the convention of reporting using ≥20 days in past 30 days to align with the threshold commonly used by the US Centers for Disease Control for reporting data from the National Youth Tobacco Survey (NYTS), as well as the Population Assessment of Tobacco and Health (PATH) Study and the Monitoring the Future (MTF) survey—three of the most widely cited sources of data for youth vaping.[5,6,7]

Mr. Wang questioned whether the process for ascertaining parental consent may bias the survey responses. Ascertaining parental consent among minors is a common and required practice in most jurisdictions. To the extent that young respondents may not have provided honest responses due to concerns about confidentiality, the likely impact would be to under-report smoking and vaping status. However, the recruitment process has not changed over the course of the study; thus, this is unlikely to account for the trends over time reported in our paper. In addition, the trends in the ITC Youth Tobacco and Vaping Surveys are very similar to the trends in vaping reported by national surveillance surveys in the US,[5] Canada, [8,9,10] and England.[11]

Regarding Mr. Wang’s assertion that “when asking participants quitting plans, it is better to clarify the quitting of traditional tobacco products or quitting nicotine products”, we can confirm that questions about intentions to quit and cessation were indeed asked separately for smoking and vaping. Thus, if a youth reported smoking cigarettes and vaping e-cigarettes, they would have been asked cessation-related questions in different sections of the survey for each of cigarettes and e-cigarettes/vaping.

Finally, Mr. Wang has noted seasonal variation in smoking and vaping rates. Despite some variations in the exact survey timing, the ITC Youth Tobacco and Vaping Surveys have been conducted over a similar time period in each year. For example, across the first three waves of the survey, 64%, 79% and 74% of surveys, respectively, were conducted in the month of August. As noted above, trends in vaping prevalence over time from the ITC surveys align very closely with other national surveys over the same period. With respect to specific findings reported in our Tobacco Control manuscript, we would not expect any material differences in levels of dependence, cessation-related outcomes or vaping brands due to the minor variation in data collection periods.

We hope this additional information will provide context for interpreting the study results and feedback on the manuscript.

References
1. Hammond D, Reid JL, Rynard VL, Fong GT, Cummings KM, McNeill A, Hitchman S, et al. Prevalence of vaping and smoking among adolescents in Canada, England, and the United States: repeat national cross sectional surveys. BMJ. 2019; 365: l2219. doi: 10.1136/bmj.l2219.
2. Hammond D, Rynard V, Reid JL. Changes in prevalence of vaping among youth in the United States, Canada, and England, 2017 to 2019. JAMA Pediatr. 2020;174(8):797-800. doi: 10.1001/jamapediatrics.2020.0901.
3. Published Erratum: Prevalence of vaping and smoking among adolescents in Canada, England, and the United States: repeat national cross sectional surveys. BMJ. 2020 Jul 10;370:m2579. doi: 10.1136/bmj.m2579.
4. Hammond D, Reid JL, Rynard VL, Burkhalter R. ITC Youth Tobacco and E-Cigarette Survey:
Technical Report – Wave 3 (2019). Waterloo, ON: University of Waterloo, 2020. http://davidhammond.ca/wp-content/uploads/2020/05/2019_P01P3_W3_Technica...
5. Park-Lee E, Ren C, Sawdey MD, et al. Notes from the Field: E-Cigarette Use Among Middle and High School Students — National Youth Tobacco Survey, United States, 2021. MMWR Morb Mortal Wkly Rep 2021;70:1387–1389. DOI: http://dx.doi.org/10.15585/mmwr.mm7039a4.
6. Hyland A, Kimmel HL, Borek N, on behalf of the PATH Study team. Youth and young adult acquisition and use of cigarettes and ENDS: The latest findings from the PATH Study (2013-2019). Society for Research on Nicotine & Tobacco Annual Conference, March 2020
7. Miech R, Johnston L, O’Malley PM, Bachman JG, Patrick ME. Trends in adolescent vaping, 2017-2019. N Engl J Med. 2019;381(15):1490-1491. doi:10.1056/NEJMc1910739.
8. Government of Canada. Detailed tables for the Canadian Student Tobacco, Alcohol and Drugs Survey 2016-17. Available from https://www.Canada.ca/en/health-Canada/services/canadian-student-tobacco...
9. Government of Canada. Canadian Tobacco, Alcohol and Drugs Survey (CTADS): Summary of Results for 2017. 2017. Available from https://www.Canada.ca/en/health-Canada/services/canadian-tobacco-alcohol....
10. Statistics Canada. Canadian Tobacco and Nicotine Survey, 2019. Available from https://www150.statcan.gc.ca/n1/daily-quotidien/200305/dq200305a-eng.htm.
11. Action on Smoking and Health UK. Use of e-cigarettes among young people in Great Britain, 2021. June 2021. Available from https://ash.org.uk/wp-content/uploads/2021/07/Use-of-e-cigarettes-among-...

NOT PEER REVIEWED
We thank Mr. Clive Bates (1) and Dr. Moira Gilchrist (2) for their reconsideration of our work (3) and previous response where we corrected some errors (4). We also reiterate that all data informing our Industry Watch are publicly available at Tobacco Watcher (https://tobaccowatcher.globaltobaccocontrol.org/) for anyone to analyze. As with any analyses of observational data, there are limitations and we do not disagree with some of the limitations that Gilchrist and Bates point out in our analyses (as we addressed nearly all of these in our previous response (4)). However, we remain unchanged in our conclusion that, as the title of our initial article stated, “Philip Morris International used the e-cigarette, or vaping, product use associated lung injury (EVALI) outbreak to market IQOS heated tobacco” (3).

While statistical analysis indicated a correlation between (a) PMI’s public statements regarding EVALI and their IQOS brand of heated tobacco posted to their corporate “media center” (5) and (b) trends in news coverage of EVALI and IQOS, our primary assertion is that PMI used EVALI to market IQOS. The necessary and sufficient analysis to substantiate this assertion is reporting what PMI publicly claimed, which we did by analyzing the statement made by PMI which promoted IQOS through mentioning, contrasting or describing it along with EVALI and/or vaping.

The full text of the PMI’s public statement is available in the appendix of our original piece (the version available presently on the PMI website has been changed) and we analyze excerpts to make our case below.

PMI’s statement recounted the EVALI outbreak beginning: “Skepticism and fear around vaping has emerged following the cases of respiratory illness and deaths in the US associated with the use of e-cigarettes.” PMI then contrasted this against their IQOS heated tobacco product, writing “on April 30 2019, the FDA authorized IQOS for sale in the US, finding that marketing of the product would be ‘appropriate for the protection of public health’ [quotes used in the original release].” As we previously argued, some readers (especially novice consumers) can interpret this as implying the FDA endorses IQOS and such statements are not allowed. The Food, Drug and Cosmetic Act prohibits ‘any expressed or implied statement...that either conveys, or misleads or would mislead consumers into believing that [a tobacco] product is approved by the Food and Drug Administration’ (ACT 21 U.S.C. § 331(tt)). The same “appropriate for the protection of public health” statement also implies that IQOS is safer than vaping, a claim disallowed by the FDA.

While Bates and Gilchrist may still object to our assertions that PMI’s intent in publishing their statement was to promote IQOS using EVALI, this objection contrasts with public statements PMI executives have made that are perhaps even clearer in their intent. For example, a Wall Street Journal article began “tobacco giant Philip Morris International Inc. says vaping fears in the U.S. should give a boost to the recent launch of its IQOS smoking alternative” and cited PMI executives discussing how EVALI could be a boon for IQOS promotion just days after PMI published the materials we studied (6).

Bates and Gilchrist may similarly still object that other events (such as the failed merger talks between Altria and PMI (7)) may be responsible for news coverage of IQOS and EVALI. However, generating earned media about an issue is not a one-shot game. Any public relations expert could attest that a multi-modal strategy is required to get an issue in the news media agenda including a media statement, follow-up interviews, case studies, activations, integrations, etc.

Our assertion is that the EVALI outbreak was used by PMI as part of an overall strategy to promote IQOS - a fact we discovered in our Industry Watch piece. For example, the Irish Times reported that PM had called off merger talks with Altria, “…after it became apparent the US government crackdown on vaping could have a negative impact given Altria’s stake in Juul.” André Calantzopoulos, PMI’s chief executive, said that they had decided to focus on its launch of IQOS, which was not a vaping product (8) --thereby again leveraging EVALI to promote its new product.

We echo our previous call for the FDA to investigate the statement PMI published and subsequent news coverage for compliance and if a violation has occurred appropriate regulatory actions be taken. We call on the tobacco control community to invest in surveillance of industry speech and research on the potential impacts of industry speech that can inform additional regulations governing marketing channels such as websites, online news sources and other digital media.

NOT PEER REVIEWED
We thank Pesko for his comments and the opportunity for us to respond and clarify.

First, we appreciate Pesko’s clarification that Cotti et al. (2020) clustered standard errors to account for clustering. In the present study, we used multilevel analysis not only to account for clustering of respondents (i.e., design effects) but also to incorporate different error terms for different levels of the data hierarchy which yields more accurate Type I error rates than nonhierarchical methods where all unmodeled contextual information ends up pooled into a single error term of the model.

Second, we understand that Cotti et al. (2020) evaluated the magnitude of e-cigarette tax values, which does not contradict to our statement because our study focused on the effects of e-cigarette excise tax policies on individual e-cigarette use and prevalence rather than aggregated sales at state or county levels. We also clearly described the reason why we examined the e-cigarette excise tax policy implementation indicator rather than its magnitude in our paper’s discussion section.

Third, our study used a nationally representative sample of young adults (rather than a nationally representative sample of general adult population). While we understand Pesko’s concern that a sample’s representativeness might be lost when subgroups are explored, we believe our use of sampling weights in analysis has reduced such a concern.

Fourth, in Table 3, please note that vaping product excise tax policy indicator is a time-variant variable in Model 1. However, to present results of a standard difference-in-differences model with a binary indicator, the policy implementation status was operationalized as a time-invariant variable in Model 2, which is not unusual.

Disclosure: We did not receive any funding from the tobacco industry.

References
1. Cotti, C. D., Courtemanche, C. J., Maclean, J. C., Nesson, E. T., Pesko, M. F., & Tefft, N. (2020). The effects of e-cigarette taxes on e-cigarette prices and tobacco product sales: evidence from retail panel data. National Bureau of Economic Research. NBER Working Paper No. w26724.

NOT PEER REVIEWED
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 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.

NOT PEER REVIEWED
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. [1] 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 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

References

[1] 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

NOT PEER REVIEWED
The authors’ response published on 14 July 2021 is far from satisfactory and implausibly asserts that “Our original findings and conclusions remain plausible” [1]

The original study [2] 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 [3] 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 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 [3]. This period coincided with; the end of merger talks between Altria and PMI on 25 September [4]; also on the same day, Juul announced the departure of its CEO and new corporate practices (Juul is part-owned by Altria) [5]; a new iQOs product was launched by PMI on 26 September [6]; 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 [7].

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. [8]

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’. [9]

“White Hat Bias is bias leading to distortion of research-based information in the service of what may be perceived as righteous ends.”

References

[1]. 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...

[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...

[3]. PMI, Lung illnesses in the U.S. associated with the use of vaping products: The facts. Originally published 24 September 2019
https://www.pmi.com/media-center/news/lung-illnesses-associated-with-use...

[4]. PMI, Philip Morris International Inc. and Altria Group, Inc. End Merger Discussions, 25 September 2019.
https://www.pmi.com/media-center/press-releases/press-release-details/?n...

[5]. Juul Labs, Juul Labs names new leadership, outlines changes to policy and marketing, 25 September 2019
https://www.juullabs.com/juul-labs-names-new-leadership-outlines-changes...

[6]. PMI, Philip Morris International Inc. Launches IQOS 3 DUO, 26 September 2019 https://www.pmi.com/media-center/press-releases/press-release-details/?n...

[7]. 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

[8]. 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

[9]. 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/

NOT PEER REVIEWED

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 [1]

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 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.

[1] 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}

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

NOT PEER REVIEWED
The single-minded focus in this article that only multinational tobacco companies are to blame for the tobacco epidemic presents a narrow view of the problem and ultimately prevents formulation of effective interventions. It is also a uniquely western framing which does not apply to large swathes of the developing world where most tobacco users currently live.

In India for instance, home to the second largest population of tobacco users totaling nearly 270 million, industrially produced cigarettes form a small component of overall use, with hand-rolled bidis being far more widely used, and even more prevalent, comprising twice the number of smokers, is the smokeless form, khaini. Both bidis and khaini are produced by a largely unorganised sector and are not industrially made. This situation is mirrored across many countries in Asia and other parts of the developing world — where over 80% of tobacco users live and where 90% of tobacco cultivation is done.

Further, about half of the global tobacco trade is run by state-owned tobacco companies (SOTCs), and a majority of these nations are part of the FCTC protocol, yet continue to operate without focus or repercussions. The Indian state owns nearly a third of the cigarette monopoly. Despite this, it currently chairs WHO’s executive board.

Hence, to cast the tobacco crisis as industrially made and caused by multinational tobacco companies can’t be farther from the truth. While they have a share of the blame, such a construct fails to recognise the ground reality experienced by most of the world’s tobacco users, diverts attention from drawing up effective policies and shields some of the biggest contributors to the problem.

NOT PEER REVIEWED
Ruth Malone's pursuit of common ground in the tobacco control and broader public health communities is most welcome. As I emphasize in a new commentary that has received wide circulation (https://drive.google.com/file/d/1C1nk1XEZ8WhnOXtCGTqHdeqomc9HOuko/view), we must collectively climb out of our bunkers, come to the table and genuinely work together. Everyone, on all sides of the concurrent debates over tobacco harm reduction and protecting youth must stop skirting the truth when it feels inconvenient and open our minds and ears to all of the science that is before us, while discouraging and abandoning studies and pronouncements that are demonstrably biased or inadequate. We must move beyond the adversarial nature of the debate and transparently acknowledge areas of ambiguity or concern.
Combating the smoking epidemic is a social justice issue, as too little attention is now being given in many places, including the U.S., to prioritizing the importance of promoting adult smoking cessation and, for those adults addicted to smoking who cannot or are unwilling to quit nicotine -- many of whom are socially marginalized, poor, less educated, experience serious mental health conditions, or are members of the military or veterans -- helping them switch to less-hazardous, noncombustible forms of nicotine.
Regardless of ideology and policy preferences, we must at the very least tell the public as well as health care practitioners the truth about nicotine. That means that all of the major national and international messengers in this area -- NGOs and government, alike -- should do everything possible to educate the world about the continuum of risk of nicotine products, as clearly described by the U.S. Food and Drug Administration in its comprehensive plan released in July 2017, and not sweepingly demonize nicotine, which devastatingly causes widespread dependence on cigarettes but itself does not cause the illnesses suffered by the users of tobacco and is, in fact, a drug approved by the FDA as being safe and effective when used for smoking cessation.
We won’t come together if we don’t come together with openness, honesty and integrity. The time for that is now.

NOT PEER REVIEWED
I appreciated the editorial by Ruth Malone on finding "common ground" on the topic of product regulation and more broadly the role of tobacco control. I would certainly agree that the current climate in smoking harm reduction has become toxic and emotional, non-scientific, and counterproductive to achieving the public health goal of reducing premature deaths caused by using smoked tobacco (i.e., mainly cigarettes). I also agree that the cigarette companies are likely using this as a wedge to advance their own financial interests - what else would you expect? I don't think anyone interested in public health is suggesting that we dismiss the past bad actions of the cigarette manufacturers, nor accept the claims of manufacturers of alternative nicotine products. Rather, we need to heed the lessons of the past so as not to make the same mistakes going forward. The United States, the Tobacco Control Act created a framework that should incentivize manufacturers to move away from profiting from the sale of cigarettes that causes so much harm to consumers. Promoting dialogue summits would allow for participants to engage in a civil manner, educate one another about challenges and opportunities and agree to specific measurable goals and objectives. Bringing stakeholders together will not resolve all differences but it will allow serious and responsible stakeholders the opportunity to bring ideas forward and find areas of common ground that can more rapidly advance population health. As an example, issues and concerns related to adolescent use of tobacco and nicotine products should be a major topic of concern, not only by the public health and tobacco control communities but by federal, state, and local policy makers and regulators, parents and teachers, responsible retailers and distributers, and many of those associated with the manufacturing businesses. While many stakeholders share common ground in this area, the polarizing and media driven approach that has been taken over the last several years has caused what has become a war of rhetoric, with a lot of finger pointing and a failure to bring interested parties together to discuss how to collectively deal with the issue and find workable solutions to protect youth while allowing smokers to have access to cleaner alternative nicotine products. It is often said that it should be good science that drives the implementation of sound policies. However, I fear that is not happening today. Finding "common ground" will be impossible so long as there remains an unwillingness to support civil dialogue on issues of smoking harm reduction. I hope that public health/ medial organizations like WHO, ACS, FDA, CDC and others will do more to facilitating real and open dialogue on how to accelerate a reduction of smoking caused disease and death than has been the case over the past decade.

NOT PEER REVIEWED
I am writing as co-founder of Pro-Vapeo Mexico, a non-profit consumer association affiliated with the International Network of Nicotine Consumer Organisations (INNCO), explicitly mentioned in the article “Exploring the Twitter activity around the eighth meeting of the Conference of the Parties to the WHO Framework Convention on Tobacco Control”. The authors of this article explicitly recognize that “We found no evidence that the individuals affiliated with INNCO or its member organizations were themselves funded by FSFW [Foundation for a Smoke Free World] or by the TI [Tobacco Industry] directly”. While this statement is correct, it still leaves missing information that we believe it is necessary and useful, for the benefit of your readers, to fully clarify: not only has Pro Vapeo Mexico never received any funding (direct or indirect) from any industry sector (tobacco, e-cigarettes or pharmaceutical) or from INNCO or the FSFW, we are a fully independent NGO whose activities are not (and have never been) directed by the TI or the FSFW or INNCO. Our affiliation with INNCO stems from its role as an umbrella organization grouping consumer associations worldwide united in advocating for Tobacco Harm Reduction, a strategy to improve global health by providing adult smokers the option to consume nicotine without having to inhale toxic cigarette smoke.

Regrettably, the authors of the above-mentioned article claim that our twitter activity in the period 9-18 October 2018 -somehow- proves our alleged participation in a lobbying effort coordinated by the TI to disrupt the COP-8 WHO-FCTC meeting taking place at the time. This is ludicrous. Our tweets do not prove this claim, but instead reveal our effort to mobilize our community of consumers to claim our right to attend and participate in that COP WHO-FCTC meeting as a legitimate part of the civil society. We were only protesting against the unjustified exclusion from this event of INNCO and its affiliated consumer associations under the false contention that we formed a TI front. In fact, we intend to keep protesting until our right to attend and participate in COP WHO-FCTC meetings as part of the civil society is fulfilled.

NOT PEER REVIEWED
It is disappointing to see the BMJ publishing a research paper which smears consumer advocates for tobacco harm reduction by attempting to link consumer activity on social media with the tobacco industry. One can only conclude that the goal was to devalue the opinions of former smokers who have found safer nicotine products to have been beneficial to their lives.
I write as chair of the UK New Nicotine Alliance and as it is highly likely that tweets from our supporters have been included in this research, so we welcome the right to reply to the article.
The attempt to paint consumers as part of some mythical tobacco industry plot is offensive to individuals and organisations promoting tobacco harm reduction. We and our supporters, along with many other vapers, are systematically excluded from the FCTC conferences and yet have a strong stake in the outcomes of the meeting. Social media is one of the few opportunities we have to get our views across. Consumers of safer nicotine products have been acutely aware of an increasing warfare against the products which have helped them to stop smoking.
In 2018, there were clear threats being expressed by the WHO FCTC in advance of COP8 towards products that vaping consumers value highly for helping them to quit smoking. Many vapers travelled to Geneva in 2018 at their own expense, but as ‘members of the public’ were excluded from the meeting.
The article by Robertson et al was funded by Bloomberg Philanthropies: an organisation set up to distribute funds from an American multi-billionaire with antipathy to tobacco harm reduction.
In reality the article shows how successful THR consumer advocates are in dominating the Twittersphere around COP, and rightly so, because it is they are who are most affected by the outcome of COP meetings. Instead of attempting to denigrate these opinions, an altruistic approach would be to welcome the fact that consumers are engaging with the process and studying how consumer experience can help enhance public health outcomes. Sadly, this has not been considered by the authors of this report.

NOT PEER REVIEWED
It’s surprising finding oneself involuntarily part of a research study. Given no chance to contribute, perhaps I can offer privileged insight into the processes the authors seek to describe.

Analysis of tweets around the COP8 meeting show that nicotine consumer advocates were the most active, followed by public health advocates and the tobacco industry. My company – Knowledge Action Change – also tweeted, at the Geneva launch of our tobacco harm reduction report. [1] Tweeting by tobacco harm reduction advocates out-shadowed “official” FCTC messaging (and if the authors had searched #FCTCCOP8 and #COP8 as well as #COP8FCTC, they would have uncovered more).

The article asserts that tobacco industry money is behind this activity. But it is beyond this study’s narrow methodological reach to illuminate why nicotine consumer advocates tweet. My discussions with nicotine consumer advocates – the majority of whom are volunteers - demonstrate passionate interest in the policymaking that influences their lives. Having found safer alternatives to smoking, they fear that inappropriate regulation including bans will see their options disappear. They are frustrated that they are ignored by tobacco control policymakers, regulators and researchers. Barred from COP8 along with the public and press, consumer organisations are also barred from the NGO coalition Framework Convention Alliance. No other field of health policy excludes the affected. Consumers use social media to speak out, asking others to do likewise. Picking on a tiny unfunded Mexican organisation for encouraging peers to tweet misunderstands how social media works: the FCA itself recently exhorted members to tweet in the week of the postponed COP9.

Prior assumptions about tobacco industry interference dominate this article (as with much of the Bath group’s work). The authors assert that ‘vaping consumer advocacy groups’ receive industry funding, but provide no evidence for this for any national or local group cited. Net result – the article both smears and further disempowers a disenfranchised population.

Do the authors apply their ‘theory of external influence’ to their own work? The Bath group shares over $20m from the anti-nicotine and anti-tobacco harm reduction Bloomberg Philanthropies. [2] Philanthro-capitalism comes with its own strings attached. [3]

Perhaps more productive would be social science insights into the views of consumer advocates and the narratives that both drive and divide a field in which all parties ostensibly share a common outcome - an end to smoking.

1. No Fire, No Smoke: The Global State of Tobacco Harm Reduction 2018. London: Knowledge-Action-Change. https://gsthr.org/resources/item/no-fire-no-smoke-global-state-tobacco-h...
2. https://www.bath.ac.uk/announcements/major-funding-announcement-puts-bat...
3. Burning Issues: The Global State of Tobacco Harm Reduction 2020. London: Knowledge-Action-Change. https://gsthr.org/resources/item/burning-issues-global-state-tobacco-har...

NOT PEER REVIEWED
We object to the framing of Association of Vapers India (AVI), erroneously referred to as ‘Vape India’ in the paper, as a tobacco industry front group, without providing any basis for the claim except our membership of International Network of Nicotine Consumer Organisations (INNCO).

AVI was organised in August 2016, when consumers of low-risk alternatives came together to arrest the tide of state bans in India, which were being lobbied for by the Bloomberg Philanthropies network the authors belong to.[1] Though one of our directors is the current president of INNCO’s governing board, elected through a member vote in the 2020 General Assembly, he is serving in unpaid, honorary capacity.

AVI has not received funding from INNCO, nor from the Foundation for Smoke-free World (FSFW), and neither from the tobacco industry. Our work is financed through voluntary contributions, and like INNCO, the affairs are conducted by a governing board comprising unpaid consumer volunteers.

It is scurrilous to cast AVI as a tobacco industry group or anything other than a consumer-led movement that is seeking access to harm reduction avenues for India’s nearly 270 million tobacco users, among whom cancers are rising[2] even as most have meagre means to deal with the health consequences, which makes harm prevention a vital mitigation strategy. We are product agnostic and advocate access to lower-risk alternatives for both smokers and smokeless tobacco users, adhering to harm reduction and human rights principles laid out in UN drug policies and in Article 1(d) of the FCTC charter.

We find these accusations especially mischievous in light of our Indian government owning a major 28% stake in the country’s cigarette monopoly and gaining directly from the e-cigarette ban,[3] despite which it was invited to chair COP8 proceedings, whereas consumer advocates, including from AVI, who were there to seek deliberations on their right to access lower-risk alternatives, and whom the FCTC policies affect most severely, were ousted after the plenary session on the pretext of preventing industry influence, left to protest outside the venue and use social media to make ourselves heard.

We strongly oppose this unfair application of Article 5.3 of FCTC which covets tobacco-trading governments but forcefully excludes consumers and attempts to delegitimize them under the garb of the same provision.

[1] "The Union congratulates India for protecting non-smokers and ...." 11 Dec. 2019, https://theunion.org/news/the-union-congratulates-india-for-protecting-n....
[2] "Report of National Cancer Registry Programme 2020." https://www.ncdirindia.org/All_Reports/Report_2020/default.aspx.
[3] "E-cigarettes ban: As tobacco stocks surge, this is how the ...." 19 Sep. 2019, https://indianexpress.com/article/business/market/e-cigarettes-ban-tobac....

NOT PEER REVIEWED
The meta-analysis by Khouja et al. confirms the strong association in young people between e-cigarette use and subsequent smoking.[1] The critical issue is whether the relationship is causal. If there is a causal relationship, there are several factors which diminish its impact.

Firstly, most of the studies used ‘ever smoking’ as the outcome. Ever smoking is a poor marker for smoking-related harm as most smoking by vapers who later smoke is experimental and infrequent and few progress to established smoking (100+ lifetime cigarettes). Shahab et al. found that only 2.7% of youth who tried e-cigarettes first progressed to established smoking. Only established smoking is linked to significant smoking-related death and disease.[2]

Secondly, the absolute number of non-smokers who progress from vaping to smoking is small as smoking precedes vaping in the vast majority of cases (70-85%).[3] If there is a gateway from vaping to smoking, this only affects a minority of young vapers.

Thirdly, the authors use Bradford Hill’s dose-response and specificity criteria to assess whether the association between vaping and subsequent smoking is likely to be causal.

They acknowledge that the dose-response criterion is mostly based on nicotine dependence, indicating that that nicotine dependent vapers are more likely to progress to smoking. However, nicotine dependence in non-smoking vapers is rare, less than 4% in the 2018 National Youth Tobacco Survey (NYTS).[4]

They point out that studies with ‘negative control outcomes’ would reduce specificity but do not cite any studies to demonstrate this. A number of studies have found that vaping also predicts other risky behaviors such as alcohol, marijuana and other substance use.[5,6] There is no biologically plausible mechanism for e-cigarette use being a causal factor for these other behaviours. We think that, like smoking, these associations are best explained by a common liability.[7]

Finally, the recent study by Shahab et al. using NYTS data found that nicotine vaping appears to be protective against future smoking.[2] Teens who vaped first were significantly less likely to subsequently become established smokers than 1) those who smoked first and 2) a matched group of non-vapers.

Their findings suggest that, if there is a gateway from vaping to smoking it is very small and is outweighed by a much larger effect of diverting youth away from cigarette smoking.

References

1. Khouja JN, Suddell SF, Peters SE, et al. Is e-cigarette use in non-smoking young adults associated with later smoking? A systematic review and meta-analysis. Tobacco control 2020 doi: 10.1136/tobaccocontrol-2019-055433 [published Online First: 2020/03/12]
2. Shahab L, Beard E, Brown J. Association of initial e-cigarette and other tobacco product use with subsequent cigarette smoking in adolescents: a cross-sectional, matched control study. Tobacco control 2020 doi: 10.1136/tobaccocontrol-2019-055283
3. Berry KM, Reynolds LM, Collins JM, et al. E-cigarette initiation and associated changes in smoking cessation and reduction: the Population Assessment of Tobacco and Health Study, 2013-2015. Tobacco control 2018;28(1):42-49. doi: 10.1136/tobaccocontrol-2017-054108
4. West R, Brown J, Jarvis M. Epidemic of youth nicotine addiction? What does the National Youth Tobacco Survey reveal about high school ecigarette use in the USA? 2019 [Available from: https://www.qeios.com/read/article/391 accessed 24 February 2020.
5. Park E, Livingston JA, Wang W, et al. Adolescent E-cigarette use trajectories and subsequent alcohol and marijuana use. Addictive behaviors 2020;103:106213. doi: 10.1016/j.addbeh.2019.106213 [published Online First: 2019/12/22]
6. Rigsby DC, Keim SA, Adesman A. Electronic Vapor Product Usage and Substance Use Risk Behaviors Among U.S. High School Students. J Child Adolesc Psychopharmacol 2019;29(7):545-53. doi: 10.1089/cap.2019.0047 [published Online First: 2019/07/26]
7. Vanyukov MM, Tarter RE, Kirillova GP, et al. Common liability to addiction and "gateway hypothesis": theoretical, empirical and evolutionary perspective. Drug and alcohol dependence 2012;123 Suppl 1:S3-17. doi: 10.1016/j.drugalcdep.2011.12.018 [published Online First: 2012/01/21]

NOT PEER REVIEWED
This is a well written original research about the burning issue of tobacco manufacturer lobbying. These manufacturing industries have developed strategies to undercut minimum price laws. By increasing tobacco taxes an effective policy has been designed to decrease tobacco use. In Pakistan currently, 209 million people smoke and about 83 billion cigarettes are smoked per year. As Pakistan has not ratified any anti-smoking policies, there should be great effort made to raise excise duties and taxes on tobacco companies to reduce the demand for cigarettes. In 2017 the local price of cigarettes was about 75 rupees of which half was excise duties [1].
With this expansion of taxes, there will be responses of reducing tobacco consumption, but the cigarette manufacturing industries developed specific promotions and lobbies to encourage their consumers to purchase lower taxed or lower priced tobacco products. It is the responsibility of health authorities to regulate the prices and promotion of such hazardous products [2]. According to WHO, “MPOWER” was the slogan in 2015, according to which M= monitor tobacco usage, P= Protect people from tobacco smoke, O= offering help to quit tobacco use, W= warning about its hazards, E= enforce to ban its advertisement, R = Raise tobacco taxes [3].
For smoke free Pakistan and all over the world four key factors should be instruments: Education, legislation, quitting support and financial policies.

1. Bate R. Large cigarette tax hikes, illicit producers, and organized crime: Lessons from Pakistan. AEI Paper & Studies. 2018 Jun 1:1.
2. Apollonio DE, Glantz SA. Tobacco industry promotions and pricing after tax increases: An analysis of internal industry documents.
3. World Health Organization. WHO report on the global tobacco epidemic 2015: raising taxes on tobacco. World Health Organization; 2015 Jul 31.

NOT PEER REVIEWED
Mr. Clive Bates’ response to our article, the Foundation for a Smoke-Free World and healthy Indigenous futures: an oxymoron?, indicates the need to clarify several issues. In this response, we emphasise two key issues:
1. Organisations claiming to serve the good of the public, but who receive direct or third-party funding from the tobacco industry, are faced with serious conflicts of interest (COI); and
2. harm reduction is only part of a comprehensive approach to reducing commercial tobacco use.

As Indigenous peoples, we have an inherent responsibility to protect the health and wellbeing of Indigenous peoples now and for our future generations. The tobacco industry poses, and has posed in the past, a significant threat to our health and wellbeing. Therefore, we are deeply concerned about the Philip Morris-funded Foundation focusing on Indigenous peoples.

Philip Morris International, the Philip Morris Funded-Foundation and the Centre for Research Excellence: Indigenous Sovereignty and Smoking
Mr. Bates states that “There is no credible analysis (anywhere) of the actual, rather than the imagined, relationship between PMI and the Foundation for a Smokefree World”. This is incorrect 1-5. Researchers in journals such as The Lancet and Tobacco Control have analyzed key documents from the Foundation, including tax returns and bylaws that highlighted numerous relationship issues and conflicts of interest 1-5.

Addressing conflicts of interest is fundamentally important for ethical practice. Conflicts of interest are commonly described in ethical principles, including specific Indigenous codes 6-8. The Tri-Council Policy Statement describes a COI as:
“when activities or situations place an individual or institution in a real, potential or perceived conflict between the duties or responsibilities related to research, and personal, institutional or other interest. These interests include, but are not limited to, business, commercial or financial interests pertaining to the institution and/or the individual, their family members, friends, or their former, current or prospective professional associates.” 6, page 93

A clear COI is created when the tobacco industry’s role is purported to support health research, while also profiting from the sale and promotion of tobacco products–all while smoking continues to be identified as the single greatest avoidable cause of death and disease worldwide 9 10. In other words, there is a COI when health professionals accept funding from the tobacco industry 9 10. This COI was also identified in the United Nations General Assembly, when they recognised the “fundamental conflict of interest between the tobacco industry and public health” 11, page 5. The Foundation was launched with a 12-year funding commitment from PMI of $1 billion 12. There has been financial dependence on PMI as well as conflicting commercial and business interests 2-4 12. Further, analysis of the Foundation’s tax return indicated that the Foundation remains solely funded by PMI. 3 The Foundation and subsequently the Centre have received PMI funding. As Yach and Bettcher stated in an earlier time, “tobacco is at the centre of the contradictions... …It is where the goals of a set of multinationals are clearly in conflict with public health and welfare.” 13, page 6

The COI, actual and perceived, and the inherent conflict of duty can manifest in additional ways:

1) the PMI-funded Foundation’s harm reduction role serves PMI’s agenda of moving into the Alternative Nicotine Devices market, while PMI continues to promote and sell tobacco 14. Therefore, the Foundation serves PMI’s Alternative Nicotine Devices market aspirations 14-16.

2) The Foundation serves a public relations role for PMI. The PMI-funded Foundation’s mission of progressing toward ending smoking through health, science, and technology for smoking cessation and tobacco harm reduction tools, supports PMI’s corporate responsibility agenda. Therefore, it could be argued that the Foundation contributes a veneer of credibility to PMI. This veneer provides public relations opportunities for PMI to frame themselves as “good” global corporate citizens 17-19. Further, Legg et al. 3 provide additional analysis of the relationship between PMI and the Foundation, highlighting that the Foundation’s expenditure on public relations was more than their expenditures on research, challenging the Foundation’s purported image as a “scientific body” and supporting the growing consensus that they serve as a PMI public relations function 3 20.

As Mr. Bates highlights, the tobacco industry continues to directly and indirectly fund foundations, centers, and researchers. Funding foundations, centers, and researchers can be used in its effort to gain credibility 3 21. The tobacco industry has marketed global corporate responsibility with attractive research funding and courted prominent scientists. This has included epidemiologists including Dr. Ernst Wynder, an early proponent of tobacco harm reduction 17, and Dr. Alvan R. Feinstein, editor of the Journal of Clinical Epidemiology 18. Feinstein critiqued the “atmosphere [in which a tobacco industry] consultant’s stature, credibility, and integrity become instantly impugned and tarnished by the depravity of associating with the tobacco ‘bad guy’” 18. However, Feinstein failed to declare that he, too, was a tobacco industry consultant 22-24. The Foundation’s director has also previously detailed such industry strategies as “buying scientists” to serve commercial objectives and undermine effective tobacco control 25. In 2007, Yach and Bettcher stated, “As the vector of the tobacco epidemic, the tobacco industry's actions fall far outside of the boundaries of global corporate responsibility” 13, page 207.

The tobacco industry has a long and productive history of colluding in covering up, denying, confusing, and questioning the science on smoking and smoking-related morbidity and mortality 26. Given the long and comprehensive history of the tobacco industry using public relations firms and scientists in its manipulation of research 27 28, the connections between the Foundation and bodies with long-standing tobacco industry links continues to raise significant concerns about the legitimacy of the PMI-funded Foundation, the Centre, and their research messages.

3) the Foundation and its protagonists create divisions both real and perceived. For example, the Foundation and its protagonists can frame institutions and various peoples as “for” or “against” harm reduction in a binary fashion, but in fact there are many aspects and diverse views on harm reduction 29-32. The arguments about who to trust and who researchers should accept funding from can dilute the health sectors’ efforts, sow confusion and doubt, and generate opportunities to promote the tobacco industry agenda 16 33. As outlined, this echoes a common colonisation tool - divide and conquer. 10 34 This credibility dilemma over who the public should engage with, believe, and trust creates a false dichotomy of “us vs. them”. In reality, views lie on a diverse continuum. Such divisions, real or perceived, do not help progress constructive debate about reducing tobacco use or tobacco related harms, and disrupt knowledge production processes in public health and medicine. 28 Indigenous processes are about inclusivity and our right to the enjoyment of the highest attainable standard of health. 35 We want to have fora that promote that standard, where different perspectives can be heard and discussed free from externally imposed agendas. 32 35

Harm reduction and a comprehensive approach to reducing tobacco use among Indigenous peoples
The World Health Organization (WHO) Framework Convention on Tobacco Control (FCTC) 32, and others 29-31, have outlined the need for a comprehensive and multifaceted systems approach to reducing commercial tobacco use, including preventing tobacco uptake. 29-32 A comprehensive systems approach emphasises that there is no single solution to addressing smoking disparities; by definition, the solutions are complex. 9 30-32 In addition, the FCTC guiding principles recognize the particular needs and challenges experienced by Indigenous peoples, and the importance of facilitating Indigenous participation in developing, implementing, and evaluating tobacco control. 32 Indigenous peoples should be able to engage in tobacco reduction debates, including about forms of harm reduction, free from external or tobacco industry agendas. 32 35 While Mr. Bates states, “There is a far more imaginative way to see the Centre, the Foundation and PMI”, our interests are clear. We are interested in reducing tobacco use, and consequently tobacco-related death and disease. We are interested in improving our health and wellbeing. “For the tobacco epidemic, the vector is not a virus, bacterium, or other microorganism – it is an industry and its business strategy.” 36, page 71

Conclusion
There is a need for evidence-based debate to reduce tobacco-related death and disease, and we encourage constructive debate that strengthens and advances tobacco control programs and policies. But this science must be ethical and independent from the tobacco industry. 2 5 25 27 28 32 37 We must reinforce the calls from WHO, the public health community, and Indigenous peoples to reject collaborations with the Foundation 3 10 20 32 38. We encourage centers and researchers not to accept Foundation funds, and we urge the Foundation to return its funding to PMI. Tobacco-related death and disease is completely preventable 9, and the “health and well-being of Indigenous peoples is too critical, the promise of future Indigenous generations too important.” 10, page 3 

References
1. Chapman S. Tobacco giant wants to eliminate smoking: British Medical Journal Publishing Group, 2017.
2. Daube M, Moodie R, McKee M. Towards a smoke-free world? Philip Morris International’s new Foundation is not credible. The Lancet 2017;390(10104):1722-24.
3. Legg T, Peeters S, Chamberlain P, et al. The Philip Morris-funded Foundation for a Smoke-Free World: tax return sheds light on funding activities. The Lancet doi: 10.1016/S0140-6736(19)31347-9
4. van der Eijk Y, Bero LA, Malone RE. Philip Morris International-funded ‘Foundation for a Smoke-Free World’: analysing its claims of independence. Tobacco Control 2018 doi: 10.1136/tobaccocontrol-2018-054278
5. J. Liberman. The new Philip Morris-funded Foundation for a Smoke-Free World: independent or not?, McCabe Centre for Law & Cancer, 30 January 2018, accessed June 2019 2018 [
6. Canadian Tri-Council. Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS2): Ottawa, ON: Canadian Institutes of Health Research, Natural Sciences and …, 2010.
7. Hudson M, Milne M, Reynolds P, et al. Te ara tika. Guidelines for Māori research ethics: a framework for researchers and ethics committee members 2010
8. Ermine W, Sinclair R, Jeffery B. The ethics of research involving Indigenous peoples: Indigenous Peoples' Health Research Centre Saskatoon, Saskatchewan 2004.
9. Health UDo, Services H. The health consequences of smoking—50 years of progress: a report of the Surgeon General: Atlanta, GA: US Department of Health and Human Services, Centers for Disease …, 2014.
10. Waa A, Robson B, Gifford H, et al. Foundation for a Smoke-Free World and healthy Indigenous futures: an oxymoron? Tobacco Control 2019:tobaccocontrol-2018-054792. doi: 10.1136/tobaccocontrol-2018-054792
11. Political Declaration of the High-level Meeting of the General Assembly on the Prevention and Control of Non-communicable Diseases, A/RES/66/2 (24 January 2012), para. 38; 2012.
12. Foundation for a Smoke-Free World. Media advisory: Foundation forming to eliminate smoking worldwide, 2017.
13. Yach D, Bettcher D. Globalisation of tobacco industry influence and new global responses. Tobacco Control 2000;9(2):206-16. doi: 10.1136/tc.9.2.206
14. Philip Morris International. Philip Morris International, 2018 Annual Report, 2018.
15. Foundation for a Smoke-Free World. Our Vision: Foundation for a Smoke-Free World; 2018 [Available from: https://www.smokefreeworld.org/our-vision accessed 18 September 2018.
16. Foundation for a Smoke-Free World. Strategic Plan 2019-2021 The Foundation for a Smoke-Free World: Foundation for a Smoke-Free World, 2018.
17. Fields N, Chapman S. Chasing Ernst L Wynder: 40 years of Philip Morris’ efforts to influence a leading scientist. Journal of Epidemiology & Community Health 2003;57(8):571-78.
18. Mukherjee A, Ekanayake E. Epistemic communities and the global alliance against tobacco marketing. Thunderbird International Business Review 2009;51(3):207-18.
19. Malone RE. On tobacco industry cultural appropriation. Tobacco Control 2009;18(6):425-26. doi: 10.1136/tc.2009.034488
20. Global Center for Good Governance in Tobacco Control. An open letter to the Director General and Executive Board of the World Health Organization, 2019.
21. Smith KE, Fooks G, Collin J, et al. “Working the system”—British American tobacco's influence on the European union treaty and its implications for policy: an analysis of internal tobacco industry documents. PLoS Medicine 2010;7(1):e1000202.
22. Nixon L, Mejia P, Cheyne A, et al. Big Soda’s long shadow: news coverage of local proposals to tax sugar-sweetened beverages in Richmond, El Monte and Telluride. Critical Public Health 2015;25(3):333-47.
23. Etter JF. Secondhand smoke in Geneva, 1996–2006: changes in exposure, opinions, and workplace smoking bans in the absence of national legislation. International journal of occupational and environmental health 2009;15(2):159-65.
24. Dockrell M. Eye and heart at mortal war: coronaries and controversy in a smoke-free Scotland. Expert review of pharmacoeconomics & outcomes research 2009;9(1):23-27.
25. Yach D, Bialous SA. Junking science to promote tobacco. American journal of public health 2001;91(11):1745-48.
26. Francey N, Chapman S. “Operation Berkshire”: the international tobacco companies' conspiracy. BMJ: British Medical Journal 2000;321(7257):371.
27. Bero LA. Tobacco industry manipulation of research. Public health reports 2005;120(2):200.
28. Brandt AM. Inventing conflicts of interest: a history of tobacco industry tactics. American journal of public health 2012;102(1):63-71.
29. Carson KV, Brinn MP, Labiszewski NA, et al. Interventions for tobacco use prevention in Indigenous youth. Cochrane Database of Systematic Reviews 2012(8)
30. Chamberlain C, Perlen S, Brennan S, et al. Evidence for a comprehensive approach to Aboriginal tobacco control to maintain the decline in smoking: an overview of reviews among Indigenous peoples. Systematic reviews 2017;6(1):135.
31. Minichiello A, Lefkowitz AR, Firestone M, et al. Effective strategies to reduce commercial tobacco use in Indigenous communities globally: a systematic review. BMC Public Health 2015;16(1):21.
32. World Health Organization. WHO Framework Convention on Tobacco Control. Geneva: WHO Document Production Services, 2003:44.
33. Friedman LC, Cheyne A, D G, et al. Tobacco Industry Use of Personal Responsibility Rhetoric in Public Relations and Litigation: Disguising Freedom to Blame as Freedom of Choice. American Journal of Public Health 2015;105(2):250-60.
34. Banerjee SB. The Practice of Stakeholder Colonialism: National Interest and Colonial Discourses in the Management of Indigenous Stakeholders. In: Prasad A, ed. Postcolonial Theory and Organization Analysis: A Critical Engagement. New York: Palgrave Macmillan 2003:255-82.
35. UN General Assembly. United Nations Declaration on the Rights of Indigenous peoples. UN Wash 2007;12:1-18.
36. Leung CM-K, Leung AKC, Hon K-LE, et al. Fighting tobacco smoking--a difficult but not impossible battle. International journal of environmental research and public health 2009;6(1):69-83. doi: 10.3390/ijerph6010069 [published Online First: 2009/01/05]
37. Cohen JE, Zeller M, Eissenberg T, et al. Criteria for evaluating tobacco control research funding programs and their application to models that include financial support from the tobacco industry. Tobacco control 2009;18(3):228-34.
38. World Health Organization. WHO Statement on Philip Morris funded Foundation for a Smoke-Free World: WHO Geneva, 2017.

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We read with interest a recent publication by Li, et. al, entitled Association of smoking and electronic cigarette use with wheezing and related respiratory problems in adults: cross-sectional results from the Population Assessment of Tobacco and Health (PATH) study, wave 2. The primary finding, reported in the abstract, was that risk of wheezing and related respiratory symptoms was significantly increased in current exclusive e-cigarette users compared to never users, with an adjusted odds ratio of 1.67 (1.23, 2.15). We think the report is misleading for several reasons.

First, the main multivariable analysis (Table 2) did not adequately adjust for important confounders that impact wheeze, most importantly, cigarette smoking history. In most analyses of medical outcomes in adults, pack-years of smoking has a strong relation to smoking-related diseases, over-and-above current smoking status. Since three quarters of vapers in the main model were ex-smokers, cigarette smoking history is almost certainly contributing to the size and significance of the main reported finding. Other combustible tobacco use and current marijuana smoking would also be expected to exacerbate cough and wheeze. Our bet is that large numbers of e-cigarette users also use marijuana.

The authors partially addressed smoking history with a secondary analysis (Table 3), in which they stratified by former smoking status. In that analysis, vaping was not significantly associated with any respiratory symptom among persons with no previous cigarette smoking history. The secondary analysis strongly suggests that if a measure capturing extent of former smoking was entered as a covariate in the main model, the primary reported finding of an association between e-cigarette use and pulmonary symptoms would have been null.

Second, the analyses did not adjust for conditions that exacerbate wheeze (chronic obstructive pulmonary disease, congestive heart failure and certain cardiac medications), another potential source of residual confounding. These conditions may also cause declining health, prompting the person to quit smoking or switch from smoking to vaping, adding to a cross sectional association through reverse causality.

While addressing this last issue requires longitudinal data, we believe adding former smoking status and marijuana smoking to the main analysis should be done. The inclusion of these covariates would provide a less biased estimate of the cross-sectional association between vaping and respiratory symptoms and perhaps reach entirely different conclusions. We hope the authors will publish updated results in their response to this comment.

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We would like to clear up some misconceptions in Dr. Glantz’s reply to our recent article (1). First, our analytic approach did not assume linearity as the title of Dr. Glantz’s response implies. On the contrary, we applied a log linear form, which not only better fit the data, but also incorporates non-linearities. Additionally, we also conducted and provided results using a linear form in the supplementary material, which yielded similar results.

In his reply to our paper, Dr. Glantz claims that we should have started the vaping period in 2009 rather than in 2014 or 2013. However, we feel this criticism is wrong since we provided extensive data in the paper showing that vaping among youth was minimal until at least 2013.
Consequently, we focused on when vaping became more widespread and, by most accounts, became a concern. Further, we conducted analyses that considered changes in trend for other years and obtained qualitatively similar results when the transition was specified as dating back to 2013 or 2012. We also conducted analyses which allowed for changes in trend in both 2009 and 2014 and found no change in trend from 2009 onward, whereas the change in trend from 2014 onward continued to hold. We understand that Dr. Glantz and colleagues in another paper (2) used 2009 as a base year for vaping. However, we feel this choice was a poor one since virtually no students were using e-cigarettes in 2009, and hence vaping would not be a factor influencing adolescent smoking.

Dr. Glantz also criticizes our study by pointing out several years during the vaping period when smoking prevalence did not decline. While it is true that smoking did not decline in some years during the vaping period, exceptions do not prove the rule. Indeed, the point of statistical analysis is to distinguish salient trends. Our aim was to provide straightforward analyses of the trends in cigarette smoking replicated across six different surveys. We estimated equations which allowed for long-term trends and changes in trend, and corrected for autocorrelation in the error terms where tests indicated a problem. Across six separate surveys, we obtained remarkably consistent results showing that the downward trend in smoking rates were greatly accelerated since vaping became more widespread.

In his criticism of our study Dr. Glantz focused particular attention on our results from the NYTS. We began our analysis of these data in 2011 because data became publicly available on an annual basis beginning in that year. Further, these data show that, while high school smoking rates fell from 15.8% to 12.7% between 2011 and 2013, representing a 20% drop in that three-year period, smoking rates declined to 9.8% in 2014 representing a 25% decline in just one year. Smoking prevalence further declined to 7.6% in 2017, representing a 40% drop since 2013. Nonetheless, the NYTS data provides the weakest indication of the change in trend during the vaping period due to the limited ability to detect pre-vaping trends.

Since our study was completed, more recent data have been published on youth and young adult smoking and vaping. In particular, the just released Monitoring the Future data indicate that last 30 day prevalence of smoking by 12th graders fell from 9.7% in 2017 to 7.6% in 2018, a 22% drop in just one year. In addition, NHIS data indicate that smoking prevalence for 18-24 year olds (both genders) fell from 13.1% in 2016 to 10.4% in 2017, a 21% drop in one year. These new data are consistent with the trends we describe in our paper.

Finally, we disagree in three ways with Dr. Glantz’s criticism that our paper only narrowly focused on cigarette use while ignoring total tobacco product use, including e-cigarettes. First, our decision to focus on the associations between e-cigarettes and cigarettes was based on concerns that e-cigarette use leads to increased smoking (3). Second, we think it is inappropriate to combine e-cigarettes and cigarettes in the same category of health risk, since virtually all scholarly evidence reviews have concluded that e-cigarettes are likely substantially less harmful than cigarettes and other combustible tobacco products, including the NASEM (3), PHE (4), and RCP (5) reports. Third, despite FDA’s legal classification of e-cigarettes as tobacco products, a strong argument can be made that e-cigarettes are not tobacco products at all, but rather a specific type of nicotine delivery product, just as nicotine patches, gum, and lozenges are also nicotine delivery products. No one would classify nicotine patches, gum, and lozenges as tobacco products. Indeed, classifying e-cigarettes as tobacco is the reason that Dr. Glantz can make his final claim that total tobacco use has risen with the introduction of e-cigarettes. While this conclusion is true under the classification scheme that Dr. Glantz uses, it is irrelevant to the arguments we made. Our arguments hinge on whether the increase in vaping is offset by a greater decrease in smoking (and other tobacco use) than would be expected in a world without e-cigarettes. We have never suggested better than one for one substitution, and would agree that vaping has substantially increased.

The data presented by Dr. Glantz on e-cigarette use are based on any last 30 day use. An important advance in our study over prior analyses, including the earlier study by Dr. Glantz and colleagues (2), was that we also considered measures of more established use, such as having smoked 100 cigarettes, daily smoking and smoking half a pack a day. These are more valid measures of regular smoking and are thus more directly related to public health impacts. Our study found that the conclusions about trends in vaping and smoking were robust across different measures of smoking. Indeed, we considered the ratio of daily to last 30 day smoking as an indicator of transitions from experimental to more regular cigarette smoking. We again found more rapidly declining rates during the period after vaping became more widespread.

It will be important to carefully monitor trends in the use of cigarettes, e-cigarettes and other nicotine delivery products to inform the kinds of policies that are likely to yield beneficial health outcomes for the population.

References
(1) Levy DT, Warner KE, Cummings KM, et al., Examining the relationship of vaping to smoking initiation among US youth and young adults: a reality check. Tob Control. 2018 Nov 20. pii: tobaccocontrol-2018-054446. doi: 10.1136/tobaccocontrol-2018-054446. [Epub ahead of print]

(2) Dutra L, Glantz S. E-cigarettes and national adolescent cigarette use: 2004-2014. Pediatrics. 2017 Feb;139(2). pii: e20162450. doi: 10.1542/peds.2016-2450.

(3) National Academy of Sciences Engineering and Medicine. Public health consequences of e-cigarettes. Washington, DC: The National Academies Press, 2018.

(4) Public Health England. E-cigarettes and vaping: policy, regulation and guidance. London: PHE;2018.

(5) Royal College of Physicians. Nicotine without smoke: Tobacco harm reduction. London: RCP;2016.

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David Levy and colleagues’ paper “Examining the relationship of vaping to smoking initiation among US youth and young adults: a reality check” used data from all the surveys over time that measured youth and young adult e-cigarette use and smoking and concluded there was a substantial increase in youth vaping prevalence beginning in about 2014. Time trend analyses showed that the decline in past 30-day smoking prevalence accelerated by two to four times after 2014. Indicators of more established smoking rates, including the proportion of daily smokers among past 30-day smokers, also decreased more rapidly as vaping became more prevalent.

The inverse relationship between vaping and smoking was robust across different data sets for both youth and young adults and for current and more established smoking. While trying electronic cigarettes may causally increase smoking among some youth, the aggregate effect at the population level appears to be negligible given the reduction in smoking initiation during the period of vaping's ascendance.

The good news is that Levy and colleagues are finally accepting the overwhelming evidence that kids who start with e-cigarettes are more likely to end up smoking cigarettes, the so-called “gateway effect.”

Now they have fallen back to arguing that the gateway effect is not big enough to overcome the benefits of e-cigs as substitutes for cigarettes.

The approach they used, interrupted time series analysis, estimates the declining trend in cigarette use over time, then tests whether this trend changes (in this case, they generally tested for a slope change) after the advent of e-cigarettes.

Interrupted time series is a well-established method for analyzing changes in trends. Indeed Lauren Dutra and I (1) used interrupted time series to do a similar analysis of the effect that the advent of e-cigarettes had on cigarette smoking among youth using the National Youth Tobacco Survey from 2004 to 2014. Based on data over that time, we found that the advent of e-cigarettes (using a start date of 2009 for e-cigs) did not affect the declining trend in cigarette smoking, but led to an increase in total tobacco product use (Figure 1 in our paper).
Lauren and I also used individual-level data (something Levy and colleagues did not consider in their analysis) and found that about one-third of the kids using e-cigarettes had risk profiles that made them unlikely to start using nicotine with conventional cigarettes. Thus, e-cigarettes are expanding the tobacco market.

Levy and colleagues expand the time period of analysis up to 2016 or 2017 (depending on the data source). This is an important addition because, as they note, e-cigarette use has continued to grow since 2014 (their Figure 1).

I have several concerns about the analysis and interpretation of the data that Levy and colleagues present.

The assumption in interrupted time series analysis as they (and we) do it is that the underlying trend is linear (a straight line). The figures in the supplementary file suggest that many of the time histories are curved. Failing to account for this curvature can distort the results and also make the results highly sensitive to the break year (i.e., where the line bends) in the analysis.

A related concern because of the curvature in the data is that the break year they use in their analysis is 2014. They justify this by arguing that 2014 is when e-cigarette use took off. But, if you look at their Figure 1, you could also argue for using 2009 as the break year because that is where the data they have on e-cig use extrapolated back to zero. While e-cig use was lower before 2014, an increasing effect of e-cigs would be captured in the slope change in an interrupted time series model (assuming that the linear assumption is met).

The specific shape of the data curve is especially important in most recent years where e-cigarette use has increased so much among youth and young adults. This fact, combined with the gateway effect, would lead one to predict that historical drops in cigarette smoking would stop or even reverse. Indeed, looking at the detailed data in the supplementary figures shows this in several (but not all) cases:

• The Monitoring the Future (MTF) data showed increases in 10th grade 30 day and daily cigarette smoking (Supplementary Figures 1 and 8) and essentially flat 12th grade smoking between 2016 and 2017 (Supplementary Figure 2).

• The National Youth Tobacco Survey showed flat 30 day cigarette smoking from 2014 to 2017 (Supplementary Figure 3), the first time that there was not a drop in cigarette smoking since NYTS started in 2004. (I also do not understand why Levy and colleagues did not use the NYTS back to 2004; they started in 2011.)

• The National Health Interview Survey showed flat young adult smoking prevalence from 2015 to 2016 for both males and females (Supplementary Figures 13 and 14).
Another important omission in Levy and colleagues’ paper is that they only present data on cigarette smoking rather than total tobacco product use. This is an exceptionally important variable because if e-cigarettes are increasing nicotine use among youth, that is a bad thing.
And that is what Lauren Dutra and I found through 2014 (figure above). The rapid increase in e -cigarette use after 2014 in Levy’s Figure 1 reinforces this concern.

New data for 2018 released by the CDC in the November 16, 2018 MMWR (2) reinforces how serious this problem is. They documented continuing increases in e-cigarette use through 2018 (figure in MMWR) and, more important, increases in any tobacco use.

That is the real reality.

REFERENCES

(1) Dutra L, Glantz S. E-cigarettes and National Adolescent Cigarette Use: 2004-2014. Pediatrics. 2017 Feb;139(2). pii: e20162450. doi: 10.1542/peds.2016-2450.
(2) Cullen KA, Ambrose BK, Gentzke AS, Apelberg BJ, Jamal A, King BA. Notes from the Field: Use of Electronic Cigarettes and Any Tobacco Product Among Middle and High School Students — United States, 2011–2018. MMWR Morb Mortal Wkly Rep 2018;67:1276–1277. DOI: http://dx.doi.org/10.15585/mmwr.mm6745a5

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More than 1,000 participants were exposed to IQOS in our clinical studies. The authors of the letter “Possible hepatotoxicity of IQOS" based their analysis on approximatively 10% of the data instead of examining the data as a whole. For example, for the five-day exposure studies in confinement, they stated that the percentage of participants with elevated bilirubin in IQOS arm was more than three times higher than that observed in the smoking abstinence (SA) arm in the European study (8.8% [7 participants] in IQOS arm, 2.6% [1 participant] in SA arm). However, they missed reporting that this percentage was lower in the IQOS arm than in the cigarette smoking (CC) arm in the Japanese study (10% [8 participants] in IQOS arm, 15% [6 participants] in CC arm). They also stated that the mean increase in alanine aminotransferase (ALT) was higher with IQOS than with CC or SA in the Japanese study but did not report that in the European study, the mean increase in ALT was lower in the IQOS arm than in the CC or SA arm.
Similarly, for the 90-day exposure studies in an ambulatory setting, they mentioned that the percentage of participants with increased ALT levels after 60 days of exposure was higher within the IQOS arm (6.3% [5 participants] in IQOS arm, 0% in CC arm, 2.6% [1 participant] in SA arm) in the U.S. study. However they omitted to mention that in the Japanese study, this percentage was lower in IQOS arm compared with CC or SA arms after 30 days of exposure (1.3% [1 participant] in IQOS arm, 4.8% [2 participants] in CC arm, 7.5% [3 participants] in SA arm).
Taken together, the changes reported by the authors concern a small number of participants across all arms and most likely represent normal fluctuations of these parameters.
Finally, the grade 2 ALT increase in IQOS arm that was mentioned in the letter corresponds to a participant with an isolated increase at Day 30, which is explained by the use of concomitant medication. This information was also part of the publicly available information but was not taken into account by the authors.
In conclusion, the data submitted to the FDA as well as the data gathered in the context of our post-market safety surveillance system, based on pharmaceutical industry best practices, show unquestionably that there is no increased risk of developing hepatotoxicity after switching to IQOS.

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The potential presence of formaldehyde cyanohydrin in the polylactic acid (PLA) filter of Marlboro Heatstick when heated was reported by Davis and al. PLA is a biodegradable thermoplastic derived from renewable resources such as corn starch. This tentative identification is based on the GC-MS analysis of the headspace of a heated piece of PLA, and the subsequent compound identification by mass spectra matching (acceptance criteria >85%) with the spectra library of the National Institute of Standard and Technology (NIST). However, this was not confirmed by injecting a purchased analytical grade reference standard, in order to unambiguously prove the presence of formaldehyde cyanohydrin. Therefore, we decided to repeat the experiment using headspace injection gas chromatography coupled to high resolution mass spectrometry under similar conditions as described in the publication. Our headspace GC-HR-MS analyses showed four peaks, at retention times of 16.38, 16.47, 17.14, and 18.58 min, in good agreement with the reported data reported (figure 4).

From the analysis of reference standards, we have confirmed the presence of both e-caprolactone (CAS# 502-44-3) and (S,S)-lactide (CAS# 4511-42-6) eluting at 16.47 and 17.14 min, respectively. We identified triacetin (CAS# 102-76-1) at 18.58 min, based on the reference standard, instead of 1,2-diacetin (their EI mass spectra are very similar).
However, we have demonstrated unambiguously the absence of formaldehyde cyanohydrin by injecting the reference standard (Sigma, CAS# 107-16-4, ref. 50640). The formaldehyde cyanohydrin is eluting at 11.53 min and does not correspond to the peak eluting just before e-caprolactone that the authors tentatively identified as formaldehyde cyanohydrin (17.97 min under their conditions). This peak has been confirmed, using the purchased reference standard (NatureWorks, CAS # 13076-19-2), to be meso-lactide, the third isomers of lactide. The experimental details are available on PMIScience.com (https://www.pmiscience.com/library/publication/analysis-of-polylactic-ac...).
It is well known among analytical chemists that unit mass matching with a single data base is insufficient to prove the identity of a compound. Therefore, we typically use commercially available reference standards to verify our findings. This is important to us, as we are focused on developing reduced risk alternatives to combustible cigarettes. In this context, it is key that our science is always verified to the highest possible standards.

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Coleman et al’s important report [1] on transitions in the vaping and smoking status of a nationally representative cohort of American 18+ adults who use electronic cigarettes (EC) from the PATH study provides rich data that can greatly advance our understanding of the natural history of EC use and their potential in harm reduction.

However, we were struck by the absence of emphasis in the report of what is perhaps its most important finding. If we examine the report’s data and consider the net impact of vaping on the critical goals of having vapers stopping smoking and vaping non-smokers not starting to smoke, the findings are very disturbing and should strong reason for pause among those advocating e-cigarettes as a game-changing way of stopping smoking.

At Wave 2, 12 months on from Wave 1, of the cohort of 2036 dual users (EC + smoking) only 104 (5.1%) had transitioned to using only EC and another 143 (7%) had quit both EC and smoking for a combined total of 247 or 12.1%. Of the 896 exclusive EC users at Wave 1, 277 (30.9%) had stopped vaping at Wave 2. Together, 524 out of the 2932 EC users (17.9%) followed from Wave 1 might be considered to have had positive outcomes at Wave 2.

The other side of the coin however, shows that of the 2036 dual users at Wave 1, 886 (43.5%) relapsed to using cigarettes exclusively. In addition, among the 896 exclusive EC users from Wave 1, 109 (12.2%) had stopped vaping and were now smoking, with another 121 having resumed smoking as well as using EC (i.e. became dual users). Importantly, 502 of 896 (56%) exclusive e-cigarette users were those who had never been established smokers prior to using e-cigarettes. Alarmingly, of these 502 adults, 120 (23.9%) progressed from using only e-cigarettes to either dual use (54 or 10.8%) or smoking only (66 or 13.2%).

Taken together, 886 dual users in Wave 1 relapsed to become exclusive cigarette smokers in Wave 2, and 230 exclusive vapers in Wave 1 took up cigarette smoking in Wave 2 (dual use or exclusively cigarettes). Undoubtedly, these should be considered as negative outcomes.

The table below shows that for every person vaping at Wave 1 who benefited across 12 months by quitting smoking, there are 2.1 who either relapsed to or took-up smoking. Most disturbingly, in this adult cohort nearly one in four of those who had never been established smokers took up smoking after first using EC. Concern about putative gateway effects of ECs to smoking have been dominated by concerns about youth. These data showing transitions from EC to smoking in nearly a quarter of exclusive adult EC users with no histories of established smoking should widen this debate to consider adult gateway effects too.

By far the largest proportion of those with negative outcomes are those dual users who relapsed to smoking (886 or 43.5% of dual users). As the authors note in their discussion, many of these were infrequent EC users, possibly involved in transitory experimentation at Wave 1. If we add the 902 who were still dual using at Wave 2, then 1788 of 2036 dual users (87.8%) in this sample might be said to have been held in smoking (dual using or exclusive smoking) 12 months later compared to 12.1% dual users who may have benefitted by using ECs.

We would expect commercial interests in both the tobacco and EC industries would be more than delighted with these findings. However, from a public health harm reduction perspective these results argue against EC being an effective harm reduction strategy, and point to their far stronger potential to both recruit smokers and hold many smokers in smoking.

A table summarizing the above data can be found here: https://ses.library.usyd.edu.au/bitstream/2123/18240/3/Missing%20Elephan...

Reference
1. Coleman B et al Transitions in electronic cigarette use among adults in the Population Assessment of Tobacco and Health (PATH) Study, Waves 1 and 2 (2013-2105). Tobacco Control 2018; doi:10.1136/tobaccocontrol-2017-054174

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The reporting of the results of this study is far from complete, which is concerning given the highly politicised controversy that surrounds this product. I hope the authors should respond to this comment by publishing supplementary material with all the data they collected in a an accessible form such a CSV file and summarised in tables in a supplementary memo.

In particular, the authors should provide all data on the following:
+ Vaping and JUUL current use (used in past 30-days) prevalence stratified by age, clearly differentiating between 18 and over and under-18s
+ Frequency of use of vaping products and JUUL within the 30 days among current (past-30 days) users, ideally using the same frequency breakdown used in the National Youth Tobacco Survey
+ Breakdown of vaping status by smoking status and frequency of vaping and JUUL use - to help determine the extent to which regular JUUL use is concentrated among smokers
+ Smoking prevalence and frequency

There is a rare opportunity to gain insights into a live controversy, yet the reporting of the survey is so incomplete it is difficult to draw any serious conclusions from it about the overall effect. For example, JUUL maybe displacing other vaping products used by youth as it is in the market overall. JUUL may be functioning as an alternative to smoking in both adolescents and adults and contributing to achieving smoke-free public health objectives.

The Truth Initiative is proud of its advocacy for young people, but as far as presentation and interpretation of data are concerned, such activist commitment amounts to a competing interest. For that reason, everyone, including Truth, is served by full disclosure of the survey data in an appropriate and accessible form and answers to key data questions that would help understand the JUUL phenomenon.

NOT PEER REVIEWED
In the article Potential deaths averted in USA by replacing cigarettes with e-cigarettes (1), a Status Quo model is performed, which suggests that this change will avoid premature deaths of millions. Although the statement is interesting, it´s necessary to mention that, the quantity of cigarettes consumed wasn´t considered. In addition, it´s important to recognize that a controversy still exists about the use of these devices and their toxicity.

Believing that e-cigarettes are an alternative against the use of cigarettes is tempting, but we have to be cautious. One of the major risk factors for cancer is an excessive consumption of cigarettes. In Müezzinler A et al (2), a dose response between the number of cigarettes consumed and mortality of any cause was seen. Therefore, it is not only if you smoke, it is also important how much you smoke. Nevertheless, since this outcome was not assessed, we assume that risk was uniform. In addition, they classify as “never smokers” any persons with less of forty years that smoke cigarettes. Is possible that a person of thirty-eight years who smoke twenty cigarettes per day for twenty years could be classified like a “never smoker”? We doubt it.

Currently, the use of e-cigarettes is controversial. As Chen J et al states in their study (3), we should carefully interpret this idea of a substitution. There is a great quantity of information about the risks of conventional cigarettes in estimation models like MCDA (Multi Criteria Decision Analysis); in comparison of the e-cigarettes that are “new” products, with less users and long-term information. Therefore, the possible consequences would be less precise and suggest a lower risk. Besides this, the authors found that the use of e-cigarettes expose the users to 9 from the 12 significant hazards identified in the conventional cigarettes, which are more related to neoplastic and respiratory effects. In addition, the virulence increase of the methicillin-resistant Staphylococcus aureus (MRSA) strains exposed to the vapor of e-cigarettes has also been described in rat models of pneumonia (4). Do we want to promote their use, although we don´t truly know the potential hidden risks of these devices?
As noted above, future research about e-cigarettes as an alternative to cigarettes has to consider the known risks about this topic. Therefore, it would provide a valuable conclusion about this global health problem instead of a dangerous illusion.

References:
1. Levy D, Borland R, Lindblom E, Goniewicz M, Meza R, Holford T, et al. Potential deaths averted in USA by replacing cigarettes with e-cigarettes. Tob Control. 2017 Oct 2. pii: tobaccocontrol-2017-053759.
2. Müezzinler A, Mons U, Gellert C, Schöttker B, Jansen E, Kee F, et al. Smoking and All-cause Mortality in Older Adults: Results From the CHANCES Consortium. Am J Prev Med. 2015 Nov;49(5):e53-e63.
3. Chen J, Bullen C, Dirks K. A Comparative Health Risk Assessment of Electronic Cigarettes and Conventional Cigarettes. Int J Environ Res Public Health. 2017 Apr 5;14(4).11.
4. Hwang J, Lyes M, Sladewski K, Enany S, McEachern E, Mathew D, et al. Electronic cigarette inhalation alters innate immunity and airway cytokines while increasing the virulence of colonizing bacteria. J Mol Med (Berl). 2016 Jun;94(6):667-79.

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Feliu et al’s conclusion “in the European Union countries with the higher scores in the Tobacco Control Scale, which indicates higher tobacco control efforts, have lower prevalence of smokers, higher quit ratios and higher relative decreases in their prevalence rates of smokers.” deserved comment.

First, it seems a tautology. Tobacco control policies are robustly evidence based. Accordingly, more efforts, less smokers.

Second, a PubMed search with “"tobacco control scale" only retrieved 27 articles since 2006 and no validation published yet. Obviously, the Scale poorly correlated with smoking rate: r2 being .58 in 2002/3, .15 in 2006/7 and .06 in 2010/11.(From table 3 in 2; n= 11 European countries).

Third, why make simple stuff complex? This surrogate is complex to calculate and its items are subjective because issuing a decree is useless if no implementation were enforced. In contrast, the smoking rate and its evolution are simple and reliable! How France can be ranked 4th among 28 countries with a 57/100 score (1) while smoking prevalence has been plateauing for so long at more than 30%? In France, from 2004 to 2017 no relevant increase in tobacco taxes, no implementation of the legal smoking ban in cafés or of the ban of sale to minors despite sting operations by NGO showing evidence of serious breaches.(3)

Fourth, claiming “the European Union should continue implementing comprehensive tobacco control policies in Europe.”(1) is optimistic, at best. The European Union is the chimney of rich countries: smoking prevalence in Italy, France and Germany is almost twice that in Australia and 1.5 fold that in the US. Almost no tobacco control in the European Union but Finland! The Scale is a smokescreen for tricky politicians cherry picking the weakest measures without even providing tools for implementation or monitoring.

Last, I am not aware that a critical assessment of the Eurobarometer method is available, and the limitations of such surveys cannot be overlooked. This deserves scrutiny as other data from the European Union on such a topic are a cause for concern: eg. the European School Project on Alcohol and other Drugs estimates smoking prevalence only on a declarative basis, roughly 10% of the data are missing despite only recruiting those attending school and only 80 % of the students said that they thought that their classmates had answered the questions honestly.(4)

1 Feliu A, Filippidis FT, Joossens L et al. Impact of tobacco control policies on smoking prevalence and quit ratios in 27 European Union countries from 2006 to 2014. Online Feb 22.

2 Kuipers MA, Monshouwer K, van Laar M, Kunst AE. Tobacco control and socioeconomic inequalities in adolescent smoking in Europe. Am J Prev Med 2015;49:e64-e72.

3 Braillon A, Mereau AS, Dubois G. [Tobacco control in France: effects of public policy on mortality]. Presse Med 2012;41:679-81.

4 Hibell B, Molinaro S, Siciliano V, Kraus L. The 2013 ESPAD validity study. European Monitoring Centre for Drugs and Drug Addiction. Publications Office of the European Union. Luxembourg. 2015.

NOT PEER REVIEWED
The paper by Filippidis et al [1] provides data re-confirming the well-known fact that most ex-smokers attempt to quit without using any form of assistance, whether pharmaceutical, professional or via e-cigarettes. Moreover, the proportion of ex-smokers trying to quit unaided increased substantially in Europe between 2012-17 (ex-smokers using no assistance increased from 73.9% to 80.7%), a period where e-cigarette use accelerated in some nations.

Regrettably however, this study does not permit any comparison of success rates by method, as no data are reported on which method of cessation (assisted v unassisted) was used by ex-smokers on their last, final (and so successful) quit attempt.

The authors report that those “who successfully quit reported much lower use of cessation assistance compared with smokers who had tried to quit without success” and suggest that this might reflect indication bias, whereby those who find it harder to quit self-select to use assistance, leaving the low hanging fruit of non- or less addicted smokers to fall off the smoking tree using their own determination.

While this will be true for some, there are many former heavy smokers who quit without assistance. This argument also borrows assumptions from the discredited hardening hypothesis [2], which holds, in the face of evidence to the contrary, that as smoking prevalence falls the concentration of hardened, more deeply addicted smokers increases.

If our concern is (as it should be) to better understand the means of quitting that produce the largest net volume of ex-smokers across whole populations, studying the methods these former smokers used when they succeeded is critical. Yet the “inverse impact law of smoking cessation [3] shows that unassisted cessation, which undisputedly delivers more ex-smokers than any other method, is hugely neglected in smoking cessation research [4].

It is almost as if researchers want to turn away from learning more about the most successful route that has always delivered the largest number of successful quits. [5]

Rather than seeing the increase in unassisted quitting as something to be highlighted as a positive, motivating celebration of agency that could be megaphoned in campaigns to smokers imbued with pessimistic messages about how hard quitting is going to be, the authors conclude that their findings ”highlight the need for approaches to ensure that smokers get support”.

In 40 years of tobacco control, I cannot ever recall attending a meeting or conference on cessation where those whose living depended on them selling smoking cessation aids or providing professional cessation services did not reach similar conclusions. Yet 40 years on, the same cracked record is being played: we need to convince more smokers that they should not try foolishly to quit alone and that they need our help!

Analysis at the level of the success of quit “attempts” often shows that head-to-head, unassisted cessation attempts are less successful than those using assistance. But many so-called cessation attempts are empty gestures akin to those who attempt to get fit by buying an exercise bike, use it once or twice and then consign it to the corner. West and Sohal’s work on catastrophe theory noted that many who were not planning to quit at time 1, had succeeded at time 2. They suggested that “smokers have varying levels of motivational “tension” to stop and then “triggers” in the environment result in a switch in motivational state. If that switch involves immediate renunciation of cigarettes, this can signal a more complete transformation than if it involves a plan to quit at some future point.” [6]

The importance of continually stimulating the motivational tension to stop smoking and providing both informational and policy triggers for quitting cannot be over-emphasised.

It is long overdue that we gave far more attention to the net contribution of unassisted cessation at the population level. [7 ] Many smokers have little interest in being helped to quit. In this, they are very aware of many friends and acquaintances who quit alone when they were sufficiently motivated to do so. Over 40 years of professional hand-wringing, research and campaigning about how to undermine unaided quitting and sell more drugs and clinic appointments have thankfully done little to erode this.

References

1. Filippidis FT, Mons U, Jiminez-Ruiz C, Vardavas CI. Changes in smoking cessation assistance in the European Union between 2012 and 2017: pharmacotherapy versus counselling versus e-cigarettes. Tobacco Control http://dx.doi.org/10.1136/tobaccocontrol-2017-054117

2. Cohen JE, McDonald PW, Selby P. Softening up on the hardening hypothesis. Tobacco Control ttp://dx.doi.org/10.1136/tobaccocontrol-2011-050381

3. Chapman S. The Inverse Impact Law of Smoking Cessation. Lancet 2009; 373(9665):701-3.

4. Chapman S, Mackenzie R. The global research neglect of unassisted smoking cessation: causes and consequences. PLoS Medicine 2010; 7(2): e1000216. doi:10.1371/journal.pmed.1000216.

5. Smith A, Chapman S. Quitting unassisted: the 50 year neglect of a major health phenomenon. JAMA 2014;311(2):137-138. doi:10.1001/jama.2013.282618.

3. West R, Sohal T. “Catastrophic” pathways to smoking cessation: findings from national survey. BMJ. 2006 Feb 25; 332(7539): 458–460.
doi:  10.1136/bmj.38723.573866.AE
4. Smith A, Carter SM, Chapman S, Dunlop S, Freeman B. Why do smokers try to quit without medication or counseling? A qualitative study with ex-smokers. BMJ Open 5:e007301 doi:10.1136/bmjopen-2014-007301

I am grateful to Bashash et al. for raising some important methodological and policy-related issues. Responding to their specific points:

(1) Very high formaldehyde concentrations may arise in aerosols when atomisers generate excessive heat[1]. Under these circumstances recommended safety limits for formaldehyde may indeed be exceeded and this compound contributes most to the cancer potency summation.

(2) Goodson et al. [2] provide a framework for assessing whether low dose compounds that are not necessarily individual carcinogens may become involved in carcinogenesis when acting in concert. Although discussed under "Strengths and limitations" synergystic phenomena were not accommodated in the cancer potency model as it is not yet possible to predict the mechanism and magnitude of such interactions in tobacco or e-cigarette aerosols. Under the Goodson et al. model adverse effects reflect adventitious synergystic combinations. These may be statistically more likely in tobacco smoke where the number of different compounds greatly exceeds those of simpler aerosols, however this effect is expected to be minor compared with the exceptionally high carcinogenic potencies of some well-established carcinogens in tobacco smoke.

(3) Lifetime cancer risk is linearly dependent on the daily volume of vapour inhaled (equation 7) and the effect on risk of increased consumption after switching to heat not burn (HnB) products is directly related to the change in number of sticks. Any implication that HnB products pose acceptable risks was certainly not intended: the adjective 'safe' should never be used to encourage the use of HnB products, nor indeed any VNP with the possible exception of medicinal devices.

(4) Neither emissions nor biomarkers are suitable for accurate determination of absolute risks; long-term clinical evidence is needed for reliable estimates. In the meantime the emissions data used in the paper suggest that the relative lifetime cancer risk from HnB devices may be up to 50 times less than that of combustible cigarettes. The risk is still large - about 10,000 times greater than inhaling an equivalent volume of ambient air. In contrast the modelling suggests that many e-cigarettes pose cancer risks within a factor of 10 of a nicotine inhaler that has been approved for use by the public. E-cigarettes, if used as the manufacturer intended, appear to offer significantly lower risk alternatives to HnB for the smoker intent on using these novel products as aids to quitting to avoid cancer. The relative risks of other diseases are yet to be quantified.

References
[1] Farsalinos KE, Voudris V, Spyrou A, Poulas K. E-cigarettes emit very high formaldehyde levels only in conditions that are aversive to users: A replication study under verified realistic use conditions. Food and Chemical Toxicology. 2017;109:90-4.
[2] Goodson WH, Lowe L, Carpenter DO, Gilbertson M, A. MA, Lopez de Cerain Salsamendi A, et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis. 2015;36 (Suppl 1):S254-S96.

NOT PEER REVIEWED
We thank Dr. Jarvis for his appreciation of our historical scholarship but disagree that our conclusion, “the promotion of tobacco harm reduction may serve the interests of tobacco companies more effectively than the public,” is an attack.

Our paper is about how policy affects ideas and vice versa. The ideas guiding the product modification program led to bad outcomes. That these ideas have been reanimated merits critical assessment. Voluntary agreements led to industry influence over the ISCSH’s recommendations, which in turn undermined public health. We point out that some of the same premises that led the ISCSH astray are popular again. Jarvis claims that current UK harm reduction policy has nothing to do with the product modification program, and everything to do with the influence of the late Michael Russell. Russell’s impressive scholarship – and oft-quoted statement, “people smoke for the nicotine, but die from the tar” – is indeed hugely influential among proponents of tobacco harm reduction. Jarvis posits that Russell’s work serves as a “paradigm shift” on which the UK’s current embrace of long-term nicotine maintenance and tobacco harm reduction actually rests, and which severs any link between the failures of product modification and widespread fears of a redux today.

Yet Russell’s work represents more a variation in theme than it does revolution in content. Russell’s policy recommendations operate from the same premises as the ISCSH. While Russell criticized the ISCSH for its discount of compensation, (which he believed medium- high- nicotine cigarettes could help remedy) the same foundations appear in his recommendations: reduced toxicity is reduced risk, (1) collaboration with the tobacco industry doesn’t influence outcomes, (2) nicotine addiction is inevitable, (3) and products must be popular to curtail use. (4)

We caution that enthusiasm for the tantalizing fantasy of reduced risk products and tobacco industry resources may lead us to readopt the premises promoted by the tobacco industry for decades.

In their response, Drs. Britton and O’Connor implore public health to promote evidence-based tobacco harm reduction. We could not agree more.

1. The Lancet. Nicotine Use After the Year 2000. Lancet. 1991; 337: 1191-2.
2. Russell M. Conversation with Michael AH Russell. Addiction (Abingdon, England). 2004; 99: 9-19.
3. Jarvis M and Russell M. Comment on the Hunter Committee's second report. British medical journal. 1980; 280: 994.
4. Russell M. The future of nicotine replacement. British Journal of Addiction. 1991; 86: 653-8.

NOT PEER REVIEWED
Elias & Ling throw useful light on the slow-motion disaster that was the series of voluntary agreements begun in the 1970s between government and the tobacco industry in the UK, overseen by the Independent Scientific Committee on Smoking and Health (ISCSH). These had as their aim to address the issue of tobacco product modification to reduce the health risks of smoking. Industry produced new smoking materials with the aim of reducing the biological activity of the tar fraction of smoke from cigarettes, and agreed to a programme of gradual tar yield reduction across the years. The novel products failed because consumers rejected them (there were too few users even to recruit for trials to examine their potential benefits), and the reductions in machine-smoked tar yields were achieved largely through increasing filter ventilation. The material cited shows that the low tar programme fiasco was characterized by undue influence from tobacco industry and a complete lack of understanding of the dynamics of smoking behaviour on the part of the scientific experts charged by government with supervision of the programme.
This is a sorry tale from the early days of tobacco control, and Elias & Ling tell it well. So far so good. But in framing and interpreting their material they go well beyond the data they cite, and draw quite unwarranted conclusions about what they see as the deficiencies of the current UK harm reduction policy. Indeed, taken as a whole, their paper reads more as an attack on current UK policy than as a scholarly contribution to the history of tobacco control. Current policy, which had its beginnings some 20 years or more later, is painted as being an outgrowth of the low tar programme and as being similarly tainted with industry influence. It reflects no credit on the editorial processes and decision making of Tobacco Control that authors were permitted to get away with such unsupported conclusions in their published paper.
The idea that reduction in tar yield of cigarettes could be an effective way of reducing the health risks of smoking goes back to the 1960s at least. It was supported by many distinguished epidemiologists, including Doll, Peto, and Wynder. See for example this 1979 statement by Ernst Wynder: ““One of the things that has always appealed to me about science is that if I find something that makes biological sense, then I feel reassured. Thirty years ago, when we had a 40mg tar cigarette, if you smoked 30 cigarettes a day you were exposed to about 1200 mg tar a day. Today’s cigarettes have 20 mg tar, so you are exposed to 600 mg daily. If there’s one thing everybody can agree on, it is that all tobacco-related cancers are dose related.” (1)
What was lacking in this formulation was an understanding that the risk from products is not simply determined by their composition, but resides in the interaction between the user and the product – as Michael Russell pointed out, if tar yield was everything, the most dangerous product would be the large Cuban cigar (1).
Russell was an outspoken critic of the ISCSH’s record. In a 1980 comment on the committee’s second report (2) he noted “Most of all it [the report] is remarkable for the stunning naivety of its implicit model of smoking behaviour”. He pointed out that: “Lower risk cigarettes are equated with cigarettes with lower tar and nicotine yields. If people smoked cigarettes in the same way that smoking machines do, this would indeed be the case. But there is much evidence that they do not….The tendency for smokers to regulate their smoke intake has been ignored by the Hunter Committee”.
Russell was not a member of the ISCSH (indeed, the membership of the committee was heavily tilted towards epidemiology and toxicology, and included no behavioural science expertise). It is in Russell’s insights and policy prescriptions that we can see the real intellectual underpinnings of UK policy on harm reduction in recent years.
Russell had a number of key insights, the most fundamental of which is that people smoke for nicotine (3). This coupled with the observation that the harms of smoking come not from the drug people are seeking, but from contaminants of the delivery system used to obtain it, led to his dictum “People smoke for the nicotine, but die from the tar”. As early as the mid-1970s he began to advocate an approach to tobacco harm reduction that was based on an appreciation of nicotine’s role (4, 5). He was the first to expose the fallacy of low tar cigarettes (6) and the first to explore the potential of non-combustible nicotine products for harm reduction (7-9). His 1991 paper in the British Journal of Addiction (10) and editorial in The Lancet (11) set out a vision for a transformed nicotine market: “If a strategy were adopted to sanction and encourage the use of purified nicotine products as substitutes for smoking, and at the same time impose stringent regulations on permissible constituents of cigarette smoke …….. the virtual elimination of smoking could become a more realistic health promotion target” (11). This represents a paradigm shift from the failed approach adopted in the 1970s. How it, or something springing from it, became a part of UK tobacco control policy in recent years, is a story for others to tell. But it did not happen through tobacco industry influence.
References
1. Gori GB, Bock FG. Banbury Report 3: A Safe Cigarette? Cold Spring Harbor Laboratory; 1980.
2. Jarvis MJ, Russell MAH. Comment on the Hunter Committee's second report. British Medical Journal. 1980;5; 280(6219):994-5.
3. Russell MA. Cigarette smoking: natural history of a dependence disorder. Br-J-Med-Psychol. 1971;44(1):1-16.
4. Russell MA. Realistic goals for smoking and health. A case for safer smoking. Lancet. 1974;16; 1(851):254-8.
5. Russell MA. Low-tar medium-nicotine cigarettes: a new approach to safer smoking. Br-Med-J. 1976;12; 1(6023):1430-3.
6. Russell MAH, Jarvis M, Iyer R, Feyerabend C. Relation of nicotine yield of cigarettes to blood nicotine concentrations in smokers. British Medical Journal. 1980;280(6219):972-6.
7. Russell MAH, Jarvis MJ, Feyerabend C. A new age for snuff? Lancet. 1980;1; 1(8166):474-5.
8. Russell MAH, Jarvis MJ, Devitt G, Feyerabend C. Nicotine intake by snuff users. Br Med J. 1981;26; 283(6295):814-7.
9. Russell MAH, Jarvis MJ, West RJ, Feyerabend C. Buccal absorption of nicotine from smokeless tobacco sachets. Lancet. 1985;2(8468):1370.
10. Russell MAH. The future of nicotine replacement. Br-J-Addict. 1991;86(5):653-8.
11. Russell MAH. Nicotine use after the year 2000. The Lancet. 1991;337:1191-2.

NOT PEER REVIEWED The results provided by Stephens [1] may suggest to readers that since the concentrations of carcinogens are lower in vapourised nicotine products (VNPs), the risks of cancer are smaller compared to conventional cigarettes. The article uses the linear non-threshold model for risk assessment (a uniform cancer risk per unit dose from higher to lower doses), which is also used by most regulatory agencies. This model is considered to have a high degree of uncertainty; nevertheless, it implies that any dose of carcinogens increases the risk of cancer. Accordingly, the primary conclusion of Stephens and other’s[2] findings of the presence of carcinogens, particularly in heat-not-burn cigarettes (HNB) is that HNB poses a significant risk of cancer. In addition:
1) The article highlights a summation approach of overall cancer risk for each product, yet the individual concentrations of human carcinogens (for example, formaldehyde [3]) are still at risk level.
2) The assessment of carcinogenesis of low-level exposure to a mixture of chemicals is challenging [4]. Stephens’s summation model assumes that the effect of chemicals is independent. Even if we assume that for an individual chemical a lower concentration lowers carcinogenicity, we cannot rule out the potential effects of interactions among chemicals.
3) The analysis relies on holding consumption constant. However, manufacturer studies have suggested that consumption increases after a switch to HNB devices [5]. For non-smokers or occasional smokers to whom HNBs are introduced as a safe product, any additional burden of toxicants increases the risk of cancer.
4) The conclusion concentrates on reduced risk of VNPs compared to the most harmful product (i.e tobacco smoke) and should also calculate elevated risk of using VNPs compared to background concentration.

In summary, smoking imposes exposure to a variety of toxicants with known and/or unknown health effect regardless of name, shape and means of use. These findings suggest that HNB cigarettes should be subject to the same regulations as tobacco cigarettes. The tobacco control community should communicate the absolute risks associated with these products. In particular, there is an urgent need for tobacco control policy actors to understand the potential absolute harms of heat-not-burn (HNB) cigarettes that PMI is pushing as ‘less harmful alternatives to smoking’ in their declared movement toward a smoke-free world (https://www.pmi.com/sustainability).

References:

[1] Stephens WE. Comparing the cancer potencies of emissions from vapourised nicotine products including e-cigarettes with those of tobacco smoke. Tobacco Control 2017.
[2] Auer R, Concha-Lozano N, Jacot-Sadowski I, et al. Heat-not-burn tobacco cigarettes: Smoke by any other name. JAMA Internal Medicine 2017.
[3] Cogliano VJ, Grosse Y, Baan RA, et al. Meeting report: summary of IARC monographs on formaldehyde, 2-butoxyethanol, and 1-tert-butoxy-2-propanol. Environmental health perspectives 2005:1205-1208.
[4] Goodson III WH, Lowe L, Carpenter DO, et al. Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead. Carcinogenesis 2015;36(Suppl_1):S254-S296.
[5] Lüdicke F, Baker G, Magnette J, et al. Reduced Exposure to Harmful and Potentially Harmful Smoke Constituents With the Tobacco Heating System 2.1. Nicotine & Tobacco Research 2017;19(2):168-175.

NOT PEER REVIEWED In his critique, Stan Glantz, PhD interprets and presents our study as doing something we explicitly warned readers it was not intended to do. He argues that “the model is based on a series of assumptions that are inconsistent with empirical evidence.” However, we explicitly state and he reiterates, that the model is not meant to be predictive. In our previous work (Addiction 2017: NTR 2017), we presented a framework to help better understand the effects of e-cigarettes and argued that we need better information before we rush to judgement about the actual impact of e-cigarette use.

Our goal in writing this paper was simply to show that e-cigarettes could help us reach a real smoking and tobacco control endgame. In the US, we have made great progress applying traditional policies, such as tax increases, smoke-free air laws and media campaigns. However, SimSmoke models for the US and other countries indicate that traditional tobacco control policies can only get us partially to the endgame. We think that we can achieve more. Many countries have complied fully or near fully with the FCTC and still have unacceptably high rates of smoking prevalence. The point of our paper is to show that strategies shifting smokers to e-cigarettes can play a role in achieving the endgame.

While Glantz recognizes that we provide a “pessimistic” as well as an “optimistic” scenario, he dwells on the optimistic scenario. Many in the public health community seem to think that supporting a thoughtful e-cigarette based harm reduction strategy could have horrible public health consequences. We included a pessimistic scenario with major differences from the optimistic scenario to incorporate the concerns of those most skeptical of e-cigarettes as a harm reduction tool. One of the main findings of this study was to show that even if a strategy that secured large shifts away from smoking sharply increased e-cigarette use among those who would otherwise quit all tobacco use and otherwise nonsmoking youth – and even if e-cigarettes also turned out to be much more harmful than currently available research indicates – an aggressive switching strategy would still secure large net public health benefits. Again, we are not claiming that we know the answer, but we are asking that tobacco control advocates keep an open mind towards strategies encouraging cigarette smokers to switch to e-cigarettes.

Glantz has indicated that he believes that there are alternative ways to achieve endgame goals in regard to smoking without prompting any large shifts from smoking to e-cigarettes. We would encourage Glantz to publish his ideas and estimates of a set of policies that could possibly move us to such an endgame without prompting shifts to e-cigarette use. Cigarette tax increases, graphic health warnings on cigarettes, more aggressive anti-smoking public education campaigns, and even much more novel and aggressive strategies such as minimizing nicotine levels or banning menthol will all directly reduce smoking. But they will also likely move many smokers to e-cigarette use. Among other things, our study shows that securing large smoking declines through such measures will secure large public health gains even if they do so primarily by shifting smokers first to e-cigarettes.

It is interesting that Glantz has ended with a quote from our article, “tobacco industry documents reveal an industry strategy of ‘divide and conquer’ focused primarily on fostering divisions within the tobacco control community regarding modified risk products.” It is important that we in tobacco control do not stray into pointless, divisive stances. We have made great progress in reducing cigarette use, but much more can be done, and we’ll get there faster if we work together.

NOT PEER REVIEWED
The paper, “Potential deaths averted in USA by replacing cigarettes with e-cigarettes” by David Levy et al. published in Tobacco Control on October 2, 2017, attracted a moderate amount of attention with its conclusion that “Compared with the Status Quo, replacement of cigarette by e-cigarette use over a 10-year period yields 6.6 million fewer premature deaths with 86.7 million fewer life years lost in the Optimistic Scenario. … Our projections show that a strategy of replacing cigarette smoking with vaping would yield substantial life year gains, …”

This is a pretty impressive result until you consider that the Optimistic Scenario is based on a series of assumptions that are of which are inconsistent with empirical evidence to date:

Cigarette smoking prevalence drops from 17% to 5% in 10 years (from 19.3% to 4.6% in men and from $14.1% to 4.6% in women between 2016 and 2026).
The existence of e-cigarettes does not, on average, depress quitting cigarettes.
There is no relapse from e-cigarette use to cigarette smoking.
No youth who initiate with e-cigarettes progress to cigarette use.
No dual use of cigarettes and e-cigarettes.
The evidence free claim that e-cigarettes are 5% as dangerous as cigarettes.

(These assumptions were not clearly stated in the main paper; we figured them out based on the appendix and by examining the Excel spreadsheet of the model that the authors shared with us in response to an email. Their Pessimistic Scenario is based on similar assumptions, albeit with a higher e-cig risk.)

It is important to recognize that the authors don’t even pretend that their estimates are based on reality. In their Discussion they state: “Unlike previous models of e-cigarette use, our model was not developed to predict future e-cigarette and cigarette use based on past trends. Rather the aim was to examine a hypothetical endgame strategy of reducing cigarette use through switching to e-cigarettes. ”

I used their model to investigate the lives saved if cigarette use dropped along the same trajectory that the authors assumed because of increased smokefree laws, anti-smoking media, higher taxes and achieving smokefree movies without anyone even using an e-cigarette. Doing so (without e-cigarettes) would have saved even more lives – 7.0 million fewer lives lost and 91.4 million fewer life years lost.

The centrality of the first assumption is demonstrated by the fact that, using the Levy et al model (which they provided me as a spreadsheet) requires that e-cigarettes be more dangerous than cigarettes (about 120-130% more dangerous) to end up having a net negative population health impact. This is because they assume huge drops in smoking cigarettes.

In other words, all that this paper shows is that if a lot fewer people smoke, there will be a lot fewer premature deaths from smoking. It contributes absolutely nothing to the discussion of the efficacy of e-cigarettes for harm reduction.

It would be like someone asking what would happen to melting ice sheets if we were to be able to bring greenhouse gasses back to pre-industrial levels in 10 years. The calculation is possible but the results would not contribute anything to public policy because, like the Levy paper, the assumptions are discordant with reality.

Finally, in the Conclusion of their paper Levy et al state that “tobacco industry documents reveal an industry strategy of ‘divide and conquer’ focused primarily on fostering divisions within the tobacco control community regarding modified risk products. Indeed, the tobacco control community has had divided approaches to e-cigarettes, and in the process may have lost focus on cigarettes, the most deadly form of nicotine delivery ... Most important, an e-cigarette substitution strategy provides the justification to redouble efforts to target cigarette use, as called for by the WHO Framework Convention for Tobacco Control.” The authors are, of course, welcome to their opinion. But nothing in this paper provides an empirical support for this argument.

NOT PEER REVIEWED The United Kingdom government is now recommending e-cigarettes as important tools in helping individuals to quit smoking (http://www.bbc.co.uk/news/health-41339790). It is widely acknowledged that, for many, smoking tobacco is detrimental to health. However, it is perhaps less widely appreciated that we have only a limited understanding of why smoking tobacco is bad for our health. Why, for example, might you be 40 times more likely of succumbing to lung cancer if you are a persistent heavy smoker? What is it in tobacco or in the act of smoking which is damaging to health? These are the enigmas of smoking tobacco which have remained largely unanswered. We are interested in the myriad ways that humans are exposed to aluminium in everyday life (http://pubs.rsc.org/en/content/articlepdf/2013/em/c3em00374d). Intriguingly one such way is smoking tobacco and the main reason for this is the presence of significant amounts of aluminium in tobacco (http://www.amjmed.com/article/S0002-9343(05)00710-2/pdf).When tobacco is smoked its components form an aerosol which is taken down into the lung before it is eventually expired. Anyone who has set up a ‘smoking machine’ to investigate this will no doubt have been impressed by the efficiency with which a surrogate lung fluid transforms the black smoke coming out of the cigarette into the white wispy vapour which is eventually expired. The surrogate lung fluid, on the other hand, changes from a clear solution to one which is tinged with yellow. We found that a significant amount of aluminium (ca 50(micro)g/L), presumably originating from the tobacco, was retained by the surrogate lung fluid and we speculated that this aluminium could contribute towards tobacco-related illnesses.
The arrival of e-cigarettes encouraged us to repeat our previous experiments. In the first instance we measured the aluminium content of many commercially-available e-liquids. Their aluminium content ranged from 26(micro)g/L for pure propylene glycol (the usual vehicle for e-liquids) to 147(micro)g/L (<0.2ppm) for a Virginian e-liquid with high nicotine content. Nevertheless even the higher figure is considerably lower than the aluminium content of tobacco (ca 2.0ppm) and so we were not expecting e-cigarettes to be a significant source of aluminium to lung fluids. However, we were to be surprised! When a 0.5mL volume of e-liquid was ‘smoked’ to completion through 50mL of a surrogate lung fluid the aluminium content of the lung fluid varied between 2000 and 9000(micro)g/L which equated to between 100 and 500(micro)g of aluminium per 0.5mL of e-liquid. Further experiments where the branded e-liquid was replaced with propylene glycol (which contains only 26(micro)g/L aluminium) produced results up to 13000(micro)g/L aluminium in the surrogate lung fluid, equivalent to approximately 700(micro)g of aluminium per 0.5mL of propylene glycol vehicle.
Smoking e-cigarettes is potentially much more hazardous with respect to potential toxicity due to aluminium than smoking tobacco. The source of the aluminium is the e-cigarette itself and not the e-liquid though the latter may contribute towards the dissolution of aluminium from various components of the e-cigarette.
We do not know if some of the health-related effects of smoking tobacco are attributable to aluminium in tobacco. However, if they are then such will not be addressed by smoking e-cigarettes.

NOT PEER REVIEWED
Background
E-cigarette is a delusive name for what the product actually is; an electronic vaporization device. Basic parts of an e-cigarette include: a tank containing the liquid to be vaporized, some sort of heating element, a battery to power the device, and a mouth piece. The liquid, often referred to as e-liquid, usually contains a base (for production of thick vapor) and flavor. E-liquid may or may not contain nicotine. The heating element converts the e-liquid into aerosol, which is then inhaled by the user. While many models resemble a conventional cigarette, others look nothing alike. Colloquially referred to vaporizers, such models have become more common in the recent years.
In the western world e cigarettes proposed as a tobacco control strategy for possible nicotine reduction and stressed on policy appraisals of harm and safety on regulation of other ingredients of the products. The related conflicts and controversies of e cigarettes as a contemporary tobacco control are discussed (1).
E-cigarettes began to appear in the Indian market around 2010. Today, E-cigarettes pose a complex challenge for the tobacco stricken country. According to Global Adult Tobacco Survey (GATS) 2010, 34.6% of the Indian adults were current tobacco users with 14% of adults indulging in current tobacco smoking (5.7% current cigarette smokers, 9.2% current bidi smokers) (2). Global Youth Tobacco Survey (GYTS) 2009 estimated current tobacco use among Indian students at 14.6%, with 4.4% students reported to be current cigarette smokers (3). Alarmingly, the survey revealed that 56.2% of students who bought cigarettes in a store were not refused purchase because of their age. Allowing e-cigarettes to remain unregulated in such a setting is assumed by many to be be a recipe for disaster. However, a blanket ban without considering any potential health benefits also not without its cons. The smoking community is likely to feel further marginalized, deprived of what is perceived as an alternative with lower risk profile. (4–6)

E cigarettes in India
Initially, E-cigarettes were available only in a select smoke shops in metropolitan cities. They were generic, low quality models mostly imported from China, where the production had first begun in 2003. Over the years, a wide variety e-cigarettes and vaporizers have become available in many shops across urban areas. It isn’t uncommon to see a couple of low end models stocked in the neighborhood smoke shop.
Internet are rife with e-cigarette listings as well. The price ranges anywhere from 200 INR (~ 3 USD) for disposable models to 10,000 INR (~150 USD) for rechargeable imported ones. The price of entry level models doesn’t pose a significant barrier for adults or for students. A google search yielded more than 20 websites within first 5 pages of results, catering to sale of e-cigarettes and vaporizers, as well as related paraphernalia (7). These are not including the major online marketplaces like Amazon.in and Flipkart.com that too contain a number of listings for e-cigarettes. They can also be easily imported from other countries.
When ITC, the major tobacco player in India, released its first e-cigarette products (under ION brand) in 2014, it did so without seeking any prior approval (8). Earlier during the same year, India’s national carrier, Air India faced an inquiry for advertisement and sale of e-cigarettes to airline customers (9).
Legal Status in India
Under Poisons act, 1919, Nicotine is classified as a poisonous substance. In the form of Tobacco products, its sale is regulated under Cigarette and Other Tobacco Products Act (COTPA, 2003). Sale of Nicotine gums as a method of cessation is regulated under Drugs & Cosmetics Act, 1940. Since COTPA deals exclusively with Tobacco Products, and D&C Act doesn’t explicitly mention electronic Nicotine delivery devices, there exists an unregulated gray space for both the sale and advertisement of e-cigarettes in India.
Several State governments (Punjab, Chandigarh, Karnataka, Kerala and Maharashtra) have since issued a ban against the sale/intent of sale of e-cigarettes (10,11). Impact of these bans remains questionable despite the initial conviction receiving considerable media coverage (11). This is in part due to extensive availability of vaping products in online marketplaces.
When marketed as only flavor delivery devices, containing no nicotine whatsoever, there exists no regulation for manufacture/sale/possession/advertisement of e-cigarettes. This is often used by manufacturers/sellers to circumvent the rudimentary regulations that do exist to restrict sale of nicotine containing products, while offering an end-product with unknown risk profile and no health benefits. Popular online marketplaces like Amazon and Flipkart are flooded with such products.

The Dilemma
A balanced approach into this matter is warranted. COTPA should be appropriately revised to include e-cigarettes. Increasing delay is likely to lead to establishment of a more robust supply chain and consumer base. Furthermore, relevant inquiries must be made to assess the public and individual health impact of e-cigarettes in India.
As of now, it would be imprudent to classify it as anything more than a nicotine and/or delivery product. If anything, such a clean starting position allows us to adequately examine what this product means to different populations, and how closely do these images correlate with the reality.
References

1. Malone RE. Tob Control 2017;26:e1–e2
2.Global Adult Tobacco Survey (GATS) India: 2009-2010. [Last accessed on 20117 Mar 29]. available from: http://www.searo.who.int/LinkFiles/Regional_Tobacco_Surveillance_System_.... published by IIPS, Mumbai and funded by the Ministry of Health and Family Welfare, GOI 2010 .
3. Gajalakshmi V, Kanimozhi CV. A Survey of 24,000 Students Aged 13–15 Years in India: Global Youth Tobacco Survey 2006 and 2009. Tobacco Use Insights. 2010;3:23–3.
4. Berg CJ, Stratton E, Schauer GL, Lewis M, Wang Y, Windle M, et al. Perceived Harm, Addictiveness, and Social Acceptability of Tobacco Products and Marijuana Among Young Adults: Marijuana, Hookah, and Electronic Cigarettes Win. Subst Use Misuse [Internet]. 2015 Jan;50(1):79–89. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4302728&tool=p...
5. Brose LS, Brown J, Hitchman SC, McNeill A. Perceived relative harm of electronic cigarettes over time and impact on subsequent use. A survey with 1-year and 2-year follow-ups. Drug Alcohol Depend. 2015 Dec;157:106–11.
6. Tomashefski A. The perceived effects of electronic cigarettes on health by adult users: A state of the science systematic literature review. J Am Assoc Nurse Pract. 2016 Sep;28(9):510–5.
7.Google.Lovelites.in, littlegoa.com, vapeadda.com, vapourindia.com, litejoy.co.in, ecigindia.com, purevapors.in, evolvevapors.com, smokefree.in, planetion.in, indiabongs.com, evapeshop.in, esutta.com, ivape.in, vapecircle.com, tygrtygr.in, greenvapo.com, indianvapegarage.in, ecigarettecart.com, vape.co.in, vapin.in, epuff.in, ivapeindia.com, beyondvapeindia.com
[Retrieved 2017 Apr 1]
8.http://www.business-standard.com/article/companies/itcs-e-cigarettes-lik... Business Standard. 2014. [Retrieved 2017 Apr 1]
9.http://timesofindia.indiatimes.com/india/E-cigarette-sale-on-Air-India-f... Times of India. 2014 [Retrieved 2017 Apr 1]

10.http://www.thehindu.com/news/cities/bangalore/State-Govt-bans-e-cigarett... The Hindu. 2016. [Retrieved 2017 Apr 1]
11.http://indianexpress.com/article/india/india-news-india/kerala-govt-deci... Indian Express. 2016. [Retrieved 2017 Apr 1]
12. http://www.tribuneindia.com/news/chandigarh/community/e-cigarette-seller... Tribune India. 2016. [Retrieved 2017 Apr 1]

NOT PEER REVIEWED
The editors of this journal, Tobacco Control, argue in their blog that debate about published articles should be concentrated on their rapid reaction facility. It is possible that they are making a constructive invitation to their critics to join a debating platform they might otherwise be wary of. However, the blog has been widely read as disparagement of other forms of engagement, notably social media and blogs. It is possible that the editors do not fully appreciate why people use blogs and social media to respond to papers they find problematic, and not Tobacco Control's rapid response feature. Here are several reasons:

1. Trust

Critics may consider, rightly or wrongly, that Tobacco Control has a track record of publishing papers that have dubious scientific merit, overconfident conclusions and policy recommendations that cannot be supported by the paper - almost always reinforcing a particular (abstinence-only) perspective. Critics may be concerned that their work will be treated unfairly or sidelined, or that they will be judged or ridiculed. They may distrust the editors, believe the journal is not impartial, or hold it in low esteem.

2. Conflict of interest and incentives

Not everyone is content to have their reactions edited or approved by the same people whose work they are criticising. Once a journal has published an article that is open to criticism, it develops a conflict of interest between its own reputation and the pursuit of truth. Editors have personal and professional incentives not to look foolish or be shown up for the failure of peer review or editorial quality control. Critics may suspect that in the moderation process, editorial judgements of criticisms will be pedantic and be more concerned with the reputation of authors and the journal and be less concerned with an accurate reflection of the views of critics.

3. Style and expression

Many people prefer to communicate in their own style and not adopt the convoluted and opaque vernacular of science journal writing. They may have different types of knowledge and experience and wish to communicate in their own way. They may wish to adopt a more journalistic style or write in a way that encourages understanding. They may wish to be funny, satirical and engaging as well as rigorous. It may be a false perception that their voice is unwelcome, but it is not a surprising one. They may have their own audience which follows their commentaries, and they may wish to write for that audience.

4. Substantive reactions

Critics may wish to write at greater length and with more sophistication than a rapid response allows for, but not submit a paper for publication and wait months and spend many hours responding to poorly conceived or tactically obstructive questions from reviewers. They may not wish to have their work locked behind a paywall. They may wish to include graphics or formatting. In my own case, I wrote a comprehensive critique on my blog of the ['tobacco endgame' proposals published in 2013. There is no way I could spend months writing that up for publication in Tobacco Control, and the end result would have been a pale imitation of the original had I done so.

5. Responsiveness

Critics may be responding to 'moral panics' or media frenzies created by over-hyped science published in the journal. In this case, they need to respond rapidly and have the means to compose and publish according to their own timetable. They may wish to provide an initial reaction and then update it or add in other reactions. The "within 7-14 days" response time promised for publishing 'rapid reactions' is not consistent with the way news is consumed and commentary produced in the present era.

Other concerns include the following:

1. Wrong criteria for assessing the value of challenge

The dismissal of media other than the one preferred by and controlled by the journal's editors is disappointing. Surely, in public health, it should be the 'public' that decides where the debate is held? If criticism or insight is serious and thoughtful, then academics or editors should engage, because that's where the discussion is taking place. The journal has applied the wrong criteria by picking what sort of platform it is prepared to engage on. The decision should be based on the quality and seriousness of the criticism, not where it is produced or who produces it.

2. Self-limiting access to knowledge and insight

There is much high quality and readable analysis that is at least as valuable in intellectual depth, insight and accessibility as much formal publishing in this field [1] below. There are also trenchant and valid criticisms about motivation, ethics, intellectual quality, framing, inexperience etc on many other blogs that are well worth engaging with for anyone who wishes to - often these are opinion-formers. It is a mistake to believe that the real debate takes place in journals and everything else is just ignorant noise - it is a place to look for different insights. A bigger mistake is to disengage from 21st-century ways of communicating and sharing public knowledge. In other fields, this type of discourse is flourishing.

3. Where is the driven curiosity?

This is a critical field in which hundreds of millions of lives are at stake, and the pursuit of insight and the right thing to do should be relentless. I find it inexplicable that anyone involved should wish to shut themselves off from any form of engagement that that offers any useful insight. Where is the hunger for knowledge, the curiosity, the willingness to understand the views of people who are often the subject of study and often know far more than those doing the studying? Why would editors not want to be exposed to the feelings and adverse reactions to the research that is published in this journal? Why would they not engage more, instead of withdrawing?

Personally, I am committed challenging poor quality papers in whatever forum I can. I will continue to blog about them and expand my use of PubMed Commons, a neutral space for informed criticism. If Tobacco Control's rapid response platform provides a richer exchange, then I will try that.

[1] See for example:

Mike Siegal http://tobaccoanalysis.blogspot.com

Brad Rodu http://rodutobaccotruth.blogspot.com

Carl V. Phillips https://antithrlies.com

Chis Snowdon http://velvetgloveironfist.blogspot.com

Konstantinos Farsalinos http://www.ecigarette-research.org

Jaques Le Houeze http://jlhamzer.over-blog.com

My own: Counterfactual http://www.clivebates.com