NOT PEER REVIEWED
The study by Gallus et al. [1] sought to establish whether electronic cigarettes (ECs) and heated
tobacco products (HTPs) reduce or increase the probability of smoking in a cohort of Italian
participants and concluded that both EC and HTP use predict smoking initiation and relapse
among respondents. We would like to raise some concerns about the interpretation of the study
findings. The study suffers from a potentially crucial bias of the outcome being present at baseline, as
compared non-users with people who were already using products at baseline. Specifically,
smokers who were using ECs or HTPs at baseline may already represent failed attempts to quit at
baseline. Additionally, ex-smokers using these products may have already been in a trajectory to
relapse to smoking at, or even long before, baseline, and may in fact have initiated such product
use in order to avoid relapse. Still, this group may represent ex-smokers who were at higher risk
for relapsing at baseline compared to ex-smokers who did not use these products. Similarly,
never smokers who use novel nicotine products may represent individuals prone to the
engagement of an inhalational habit. Therefore, they would be more likely to initiate smoking.
The situation is very similar to assessing if people who drink beer at baseline are more likely to
drink whiskey at follow up compared to non-drinkers of beer. People who want to use alcohol
and are using alcohol at baseline, would be much more likely to use stronger liquor at follow up
compared to those who do not use alcohol. This represents a typical case of the common liability
model of addressing risk behaviors, which has been frequently misinterpreted as a “gateway”
theory. Moreover, the study design does not allow for any assessment of the motivations to use these
products. It is unclear if and how many participants were using nicotine products in an attempt to
quit (for smokers) or an attempt to prevent relapse (for ex-smokers) instead of simply
experimenting out of curiosity. Notably, while the study examined daily use through the
questionnaire, results were presented only for current users, a classification that includes both
occasional and daily users. Studies have shown that classifying daily and occasional users in the
same group can often be misleading (2-5), since frequency of use is an indirect indicator of
motivation for use (6), but also a determinant of their success as smoking substitutes (7). The study also suffers from the unpredictability of conducting surveys during COVID-19
lockdowns. Of note, there is convincing evidence that the coronavirus outbreak has had a
negative impact, inducing or exacerbating addictive behaviors as coping mechanisms. It is
possible that smokers preferred smoking – rather than alternatives – depending on their level of
distress (8,9).
Last but not least, the latest Cochrane Review finds high certainty evidence that nicotine e-cigarettes
are more effective than traditional nicotine-replacement therapy (NRT) in helping people quit
smoking (10). In conclusion, methodological issues of the study design makes it inappropriate to address the
research question.

1. Gallus S, Stival C, McKee M, Carreras G, Gorini G, Odone A, van den Brandt PA,
Pacifici R, Lugo A. Impact of electronic cigarette and heated tobacco product on
conventional smoking: an Italian prospective cohort study conducted during the COVID19 pandemic. Tob Control. 2022 Oct 7:tobaccocontrol-2022-057368. doi: 10.1136/tc2022-057368.
2. Hitchman SC, Brose LS, Brown J, Robson D, McNeill A. Associations Between ECigarette Type, Frequency of Use, and Quitting Smoking: Findings From a Longitudinal
Online Panel Survey in Great Britain. Nicotine Tob Res 2015;17:1187-94.
3. Farsalinos, K. E.; Poulas, K.; Voudris, V.; & Le Houezec, J. Prevalence and correlates of
current daily use of electronic cigarettes in the European Union: analysis of the 2014
Eurobarometer survey. 2017, Internal and emergency medicine, 12(6), 757–763.
https://doi.org/10.1007/s11739-017-1643-7
4. Farsalinos, K. E.; & Barbouni, A. Association between electronic cigarette use and
smoking cessation in the European Union in 2017: analysis of a representative sample of
13 057 Europeans from 28 countries. 2021, Tobacco control, 30(1), 71–76.
https://doi.org/10.1136/tobaccocontrol-2019-055190
5. Farsalinos, K. E.; Polosa, R.; Cibella, F.; & Niaura, R. Is e-cigarette use associated with
coronary heart disease and myocardial infarction? Insights from the 2016 and 2017
National Health Interview Surveys. 2019, Therapeutic advances in chronic disease, 10,
2040622319877741. https://doi.org/10.1177/2040622319877741.
6. Amato MS, Boyle RG, Levy D. How to define e-cigarette prevalence? Finding clues in
the use frequency distribution. Tob Control. 2016 Apr;25(e1):e24-9. doi:
10.1136/tobaccocontrol-2015-052236
7. Harlow AF, Stokes AC, Brooks DR, Benjamin EJ, Leventhal AM, McConnell RS,
Barrington-Trimis JL, Ross CS. Prospective association between e-cigarette use
frequency patterns and cigarette smoking abstinence among adult cigarette smokers in the
United States. Addiction. 2022 Dec;117(12):3129-3139. doi: 10.1111/add.16009.
8. Avena NM; Simkus J; Lewandowski A; Gold MS; Potenza MN. Substance Use
Disorders and Behavioral Addictions During the COVID-19 Pandemic and COVID-19-
Related Restrictions. Front Psychiatry. 2021;12:653674.
HTTPS://doi.org/10.3389/fpsyt.2021.653674
9. Caponnetto, P.; Inguscio, L.; Saitta, C.; Maglia, M.; Benfatto, F.; & Polosa, R. Smoking
behavior and psychological dynamics during COVID-19 social distancing and stay-athome policies: A survey. 2020, Health Psychology Research, 8(1).
https://doi.org/10.4081/hpr.2020.9124
10. Hartmann-Boyce J; Lindson N; Butler AR; McRobbie H; Bullen C; Begh R; Theodoulou
A; Notley C; Rigotti NA; Turner T; Fanshawe TR; Hajek P. Electronic cigarettes for
smoking cessation. 2022, Cochrane Database of Systematic Reviews 2022, Issue 11. Art.
No.: CD010216. DOI: 10.1002/14651858.CD010216.pub7.
https://www.cochranelibrary.com/cdsr/doi/10.1002/14651858.CD010216.pub7/...
s

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In his rapid response to our paper, Dr Pesko expresses concern with the paper’s conclusions. Our study, conducted at the US population level, demonstrated that the prolonged decline in cigarette smoking among young adults was largely unaffected by the introduction of e-cigarettes. Dr Pesko reminds us that this conclusion is contrary to findings from several quasi-experimental designs, which he feels should have primacy over our population-level analysis of time trends. We acknowledge that there are potential threats to the validity and generalizability of the findings of our study, and indeed of every study. Hence, a conclusion of causality requires that an association be robust and replicable across settings and methods. Given the significant public policy implications of any finding that e-cigarette vaping has a role in reducing cigarette smoking prevalence, we feel that presentation of transparent and easily understood population trends have an important role to play in policy discussions. In particular, to support the argument that high e-cigarette taxes cause increased smoking among youth, it would be important to have an exemplar of one or more jurisdictions that imposed a high e-cigarette tax and subsequently experienced an increase in cigarette smoking.

A substantial portion of Dr Pesko’s critique of our paper is directed towards our commentary on a paper that he co-authored, Abouk et al. (1). This commentary was incorporated at the request of a reviewer. Abouk et al. studied surveillance data for US adolescents and concluded that “there were sizable positive cigarette cross-tax effects, suggesting economic substitution between cigarettes and ENDS for youth,” or in other words, that raising taxes on e-cigarettes would drive youth tobacco consumption away from e-cigarettes and towards traditional cigarettes. Our study considered the same jurisdictions used in Abouk et al., and looked for potential exemplars with substantial populations and with high e-cigarette taxes. We then reported cigarette and e-cigarette prevalence data for these exemplars for the 18-24-year-old population (i.e. for young adults still within the age window for smoking initiation).

Table 1 of Abouk et al. outlines the 13 jurisdictions that taxed e-cigarettes between 2015 and 2019, providing average tax figures for the first two quarters of the years 2015, 2017 and 2019. Unfortunately, none of the high-quality US tobacco-use surveillance systems (including the two used by Abouk et al.) draws representative samples at the county or city levels. Thus, in three of their jurisdictions, it is not possible to present valid estimates of the change in tobacco use; simply raking the larger sample to the population distribution within the county or city does not make it representative of that jurisdiction. An additional five states did not meet the minimum population criterion of our paper (5 million), needed for reasonably tight confidence limits on the state-level population estimates. Therefore, only the following five states of the original 13 jurisdictions could be considered as possible exemplars in our paper: California, Minnesota, North Carolina, New Jersey, and Pennsylvania.

Dr Pesko’s suggestion in his critique that we should have used 2019 rather than 2017 e-cigarette tax data is problematic, because the most recent population survey with state-level estimates of tobacco use (TUS-CPS) collected two-thirds of its data in 2018. A fundamental principal of causal inference asserts that to test whether an exposure influenced an outcome, the exposure must have been in place before the outcome was assessed. (2) Accordingly, we used the 2017 e-cigarette tax data, so that the taxes were assessed prior to the prevalence estimates of 2018.

From Abouk et al. table 1, during the first two quarters of 2017, e-cigarettes taxes (per milliliter) for the five states under consideration were: Minnesota ($2.50), Pennsylvania ($1.05), California ($0.72), North Carolina ($0.05) New Jersey ($0). Pesko argues that we should have focused on the top three states as possible exemplars. However, California introduced a major increase in all tobacco taxes in the latter half of 2017 and, importantly, the tax rate on non-cigarette tobacco products was required to be equivalent to the tax imposed on cigarettes. (3) Thus, the effect of e-cigarette taxes on cigarette smoking in California is confounded by the concurrent increases in cigarette taxes. Accordingly, we concluded that there were only two possible exemplars from the Abouk et al. paper: Minnesota and Pennsylvania.

In the supplement to our paper (eTable 3) we presented data on exclusive e-cigarette vaping for each of the 24 most populous US states, for both 2014/15 and 2018/19. For Minnesota, exclusive e-cigarette vaping remained constant at 2.8% in both years, in contrast to a 2.7-fold increase in its comparable group of states. For Pennsylvania, exclusive vaping declined from 3.3% to 0.9%, in contrast to an over twofold increase in its comparable group of states. This aligns with economic theory, (4) suggesting that in each of these two states higher taxes are associated with lower demand for e-cigarettes. Thus, both of these states can be used as transparent examples of the Abouk et al. hypothesis. However, in our paper, we noted that smoking prevalence among 18-24-year-olds across all of the 24 most populous US states declined by 43% from 12.9% (95% CI: 12.2%,13.7%) in 2014/15 to 7.4% (95% CI: 6.7% to 8.1%) in 2018/19. Pesko rightly points out the wide confidence limits for individual state smoking prevalence estimates in each of these years. However, there was no discernible evidence, not even suggestive evidence, indicating that, in either of these two exemplar states, the rate of decline in cigarette smoking was slower compared to other US states.

In summary, it is important to have robust and replicable results before making conclusions that associations are causal. Before making an argument that states should refrain from increasing e-cigarette taxes because such taxes will slow down the decline in smoking initiation, it is particularly important to have transparent examples demonstrating such a cause and effect. None of the 13 jurisdictions used in the Abouk et al. study provides such a demonstration.

References
1. Abouk R, Courtemanche C, Dave D, Feng B, Friedman AS, Maclean JC, et al. Intended and unintended effects of e-cigarette taxes on youth tobacco use. J Health Econ. 2023 Jan 1;87:102720
2. Bradford Hill A. (1965). The Environment and Disease: Association or Causation?. Proceedings of the Royal Society of Medicine. 58 (5): 295–300. doi:10.1177/003591576505800503.
3. California State Board of Equalization New Tax Rate on Other Tobacco Products Effective July 1 2017 through June 30, 2018. Available at: https://www.cdtfa.ca.gov/formspubs/l502.pdf
4. International Agency for Research on Cancer (IARC). Handbooks of Cancer Prevention, Tobacco Control, Vol. 14. Effectiveness of Tax and Price Policies for Tobacco Control. Lyon, France., 2011

NOT PEER REVIEWED

Despite 20 years of sustained engagement and reductions in smoking prevalence rates globally, smoke free policy implementation remains inconsistently applied in low- and middle-income countries where there are high smoking prevalence rates and where >80% of the 1.3 billion smokers reside.1-2 Merrit’s study3 is a stark reminder that despite the forward steps of the Framework Convention on Tobacco Control,2,4-5 variations in achieving smoke free policies in specialist settings persist. Acknowledged challenges in implementing smoke free hospital policies include a lack of data, inadequate reporting, and reduced prioritisation of tobacco control at governmental level.1,3 The lack of an intersectional lens and co development with communities continues with policy development. 6

Inconsistencies in application of smoke free policies are balanced by reporting of positive implementations demonstrating improvements in some hospital systems evidenced by reductions in smoking rates and improved access to smoking cessation services underpinned by longitudinal data. 7-9

Previously, Chan 10 indicated that ‘tobacco use … threatens development in every country on every level and across many sectors — economic growth, health, education, poverty and the environment — with women and children bearing the brunt of the consequences’, - this continues today intensifying the impact of the social, structural and commercial determinants of health and need for increased pricing, incentivizing quitting and raising taxes. 11,12 The inequalities in the wider health systems will undoubtedly compound the ability of Vietnam to meet the global sustainable development goals target. 3,13

The new evidence base supports the evidence from a Cochrane system review examining the impact of no-smoking policies at the meso level in three specialist settings - hospitals, prisons and universities/ colleges. 14 An inconsistent evidence base from observational studies, with no validated biochemical measure of cotinine reported reductions in staff smoking rates in prisons and university settings post introducing smoking policies.14 However pooled data (12,485 participants) indicated a 29% reduction in active smoking rates in staff in hospitals only (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.64 to 0.78) and a 14% reduction for patients (RR 0.86, 95% CI 0.76 to 0.98)- extreme heterogeneity in pooled 11 studies. Reduced mortality rates associated with smoking-related illnesses after the introduction of a smoking ban were noted in prison settings, but inconsistent evidence exists supports an effect on reducing smoking rates (1 study, RR 0.99, 95% CI 0.84 to 1.16).

Smoking rates in prisons are 63 times higher than the general population 15 and despite successful policy implementation in some jurisdictions, smoking rates in prisons remain high, especially reported in low and middle-income countries. 16-18 Slow policy development in this specialist setting continues.

Despite the increasing number of countries with enacted legislation banning smoking in fulfilment of Article 8 of FCTC development remains unpredictable. 4,5,19 The difficulties in implementing smoke free policies in hospital settings continue to inform policy makers and practitioners. 3,20 Enforcing smoke free policies in hospital settings are critical to reducing the gap in the nexus of policy and practice to counter systemic inequity. We know that gender and ethnicity are associated with at least twice the all-cause mortality rate of never smoking; 21 therefore, the development of smoke free policies and systems-wide responses in specialist settings remain evermore critical.

References
1. Frazer K. Commentary on Wu et al.: Sustaining and advancing the global war on tobacco. Addiction. 2021 Aug;116(8):2185-6.

2. World Health Organization. The WHO framework convention on tobacco control: 10 years of implementation in the African region. World Health Organization; 2015. https://fctc.who.int/publications/m/item/the-who-framework-convention-on... [Accessed 8th October 2023]
3. Merritt JD, Yen PN, Thu-Anh N, Ngo CQ, Van Giap V, Nhung NV, Ha BT, Thuy MT, Anh NT, An NT, Marks GB. Smoking behaviour, tobacco sales and tobacco advertising at 40 ‘Smoke Free Hospitals’ in Vietnam. Tobacco Control. 2023 Sep 5.

4. World Health Organization (WHO). Factsheet. Tobacco. May 2020. Available at: https://www.who.int/news-room/fact-sheets/detail/tobacco (accessed October 2023).
5. Shibuya K, Ciecierski C, Guindon E, Bettcher DW, Evans DB, Murray CJ. WHO Framework Convention on Tobacco Control: development of an evidence based global public health treaty. Bmj. 2003 Jul 17;327(7407):154-7.Available from: http://www.ncbi.nlm.nih.gov/pubmed/12869461.

6. Marteau T. M., Rutter H., Marmot M. Changing behaviour: an essential component of tackling health inequalities. BMJ 2021; 372: n332. https://doi.org/10.1136/bmj.n332

7. Mattson A, Doherty K, Lyons A, Douglass A, Kerley M, Stynes S, Fitzpatrick P, Kelleher C. Evidence from a Smoking Management Service in a University Teaching Hospital in Dublin, Ireland monitored by repeat surveys, 1997-2022. Preventive Medicine Reports. 2023 Sep 13:102415. https://doi.org/10.1016/j.pmedr.2023.102415

8. Malone V, McLennan J, Hedger D. Smoke-free hospital grounds. Australian Health Review. 2020 Jan 20;44(3):405-9.

9. Fu M, Castellano Y, Feliu A, Saura J, Estrada J, Galimany-Masclans J, Moreno C, Fernández E, Martínez C. Compliance with the smoke-free policy in hospitals in Spain: the patients’ perspective. European Journal of Cancer Prevention. 2023 Jan 1;32(1):81-8.https://doi.org/10.1097/CEJ.0000000000000757

10. Chan M. Tobacco is a Deadly Threat to Global Development; 2017. https://www.who.int/news-room/commentaries/detail/tobacco-is-a-deadly-th... 30th May 2017 [Accessed 10th October 2023]

11. Hoffman SJ, Tan C. Overview of systematic reviews on the health-related effects of government tobacco control policies. BMC public health. 2015 Dec;15(1):1-1
https://doi.org/10.1186/s12889-015-2041-6

12. Tobacco Tactics. 2023 https://tobaccotactics.org/article/unsustainable-big-tobaccos-use-of-the...

13. United Nations. The Sustainable Development Goals 2016. eSocialSciences; 2016 Nov.

14. Frazer K, McHugh J, Callinan JE, Kelleher C. Impact of institutional smoking bans on reducing harms and secondhand smoke exposure. Cochrane Database of Systematic Reviews. 2016(5).https://doi.org/10.1002/14651858.CD011856.pub2

15. Plugge E, Leclerc E. Smoking bans in prisons. The Lancet Public Health. 2021 Nov 1;6(11):e781-2.

16. Semple S, Dobson R, Sweeting H, Brown A, Hunt K. The impact of implementation of a national smoke-free prisons policy on indoor air quality: results from the Tobacco in Prisons study. Tobacco control. 2020 Mar 1;29(2):234-6.

17. Tweed EJ, Mackay DF, Boyd KA, Brown A, Byrne T, Conaglen P, Craig P, Demou E, Graham L, Leyland AH, McMeekin N. Evaluation of a national smoke-free prisons policy using medication dispensing: an interrupted time-series analysis. The Lancet Public Health. 2021 Nov 1;6(11):e795-804.

18. World Health Organization. Smoking in Prisons 2022. https://www.drugsandalcohol.ie/36251/1/WHO_tobacco-use-prisons.pdf

19. Smoke Free Partnership. 2023 Smokefree Map (smokefreepartnership.eu)

20. Lyons A, Bhardwaj N, Masalkhi M, Fox P, Frazer K, McCann A, Syed S, Niranjan V, Kelleher CC, Kavanagh P, Fitzpatrick P. Specialist cancer hospital-based smoking cessation service provision in Ireland. Irish Journal of Medical Science (1971-). 2023 Sep 23:1-0.

21. Thomson B, Emberson J, Lacey B, Lewington S, Peto R, Jemal A, Islami F. Association between smoking, smoking cessation, and mortality by race, ethnicity, and sex among US adults. JAMA Network Open. 2022 Oct 3;5(10):e2231480- doi: 10.1001/jamanetworkopen.2022.31480. PMID: 36279139; PMCID: PMC9593233.

NOT PEER REVIEWED
Pichon-Riviere et al concluded that the four tobacco control interventions analyzed could successfully avert deaths and disability and significantly ease the tobacco-attributable economic burden, but are not enough, as smoking remains a leading cause of health and economic burden in Latin America (1). According to the Global Burden of Disease Project (2), regardless of the relative decrease in tobacco prevalence in the last decades, age-standardized rates of deaths and DALYs for smoking-attributable diseases remain high in Latin America, a region hard hit by the epidemic (3). Unfortunately, in most of the countries in Latin America, there are other problems related to the main strategy to reduce tobacco consumption (i.e., taxation falls short of WHO recommendations) for example cigarettes remain affordable mainly due to the commercialization of illegal tobacco products and smuggled cigarettes, an important distractor for public health authorities, as the real number of users is hidden, access for younger people is easier and health risks are surely higher (4).
In addition, as in not all countries among our region there are available pharmacological alternatives to help current smokers, cessation strategies may be adapted for novel products, and treatment recommendations for tobacco use disorder should be made within the context of a harm reduction framework wherein alternative product use may be the desired outcome (5). Also, nicotine e‐cigarettes probably do help people to stop smoking for at least six months. They probably work better than nicotine replacement therapy and nicotine‐free e‐cigarettes. They may work better than no support, or behavioral support alone, and they may not be associated with serious unwanted effects (6).
As member of the Latin-American Network for Tobacco Harm Reduction (www.reldat.org) we are actively working on reach the decision-makers to let them better understand the “harm reduction” concept for tobacco consumption, as it applies for other medical conditions.

1. Pichon-Riviere A, Bardach A, Rodríguez Cairoli F, et al. Tob Control Epub ahead of print: Health, economic and social burden of tobacco in Latin America and the expected gains of fully implementing taxes, plain packaging, advertising bans and smoke-free environments control measures: a modelling study. doi:10.1136/tc-2022-057618
2. He H, Pan Z, Wu J, et al. Health effects of tobacco at the global, regional, and national levels: results from the 2019 global burden of disease study. Nicotine & Tobacco Research 2022;24:864–70.
3. GBD. Tobacco collaborators. spatial, temporal, and demographic patterns in prevalence of smoking tobacco use and attributable disease burden in 204 countries and territories, 1990-2019: a systematic analysis from the global burden of disease study 2019. Lancet 2021;397:2337–60.
4. Ortiz-Prado E, Teran E, Cevallos-Sierra G, Villacres T, Alcivar C, Vasconez E. Anti-tobacco policy and the smuggled cigarettes, a hidden problem in Ecuador. J Public Health Emerg 2022;6:10.
5. Palmer AM, Toll BA, Carpenter MJ, et al. Reappraising Choice in Addiction: Novel Conceptualizations and Treatments for Tobacco Use Disorder. Nicotine Tob Res 2022;24(1):3-9
6. Hartmann-Boyce J, McRobbie H, Butler AR, Lindson N, Bullen C, Begh R, Theodoulou A, Notley C, Rigotti NA, Turner T, Fanshawe TR, Hajek P. Electronic cigarettes for smoking cessation. Cochrane Database of Systematic Reviews 2021, Issue 9. Art. No.: CD010216. DOI: 10.1002/14651858.CD010216.pub6. Accessed 10 May 2022.

NOT PEER REVIEWED
We acknowledge receipt of a private e-mail message from JLI regarding our paper (Yassine et al., 2022). Given the industry‘s long history of industry obfuscation, interference, and deception regarding research on tobacco products, we decided that the most transparent approach to the private e-mail that we received from an employee of a tobacco product manufacturer would be for us to report our results independently and respond to any public discussion of our work if and when it arose. Now that public discussion has arisen, we are pleased to respond to it.

We very recently analyzed the menthol and nicotine content of samples of liquid from six menthol flavor pods purchased in 2020. Three of these were liquids extracted from the pods in June 2021 for our paper and had been stored since in sealed amber glass containers at 5°C in the dark. The other three pods had been stored in their original sealed packages and were taken from the same batches as the pods analyzed in June 2021. These unopened packages were stored in the dark at room temperature over the intervening 18 months. The data from this small sample demonstrate a 24% reduction in menthol content over that period (12.01±0.46 vs 9.15±0.22 mg/ml), which helps to explain the results we reported (Yassine et al., 2022). We also found a 5% reduction in nicotine content (62.47±0.63 vs 59.52±0.49 mg/ml), as well as discoloration of the liquid in the pods that were stored at room temperature that suggests the possibility of other time-dependent changes in liquid constituents that we have not had an opportunity to evaluate comprehensively.

We acknowledge that the differences in menthol concentrations in JUUL products that were purchased across a three-year period, reported in Yassine et al., 2022, are consistent with changes in product composition that can occur during storage. A correction to the manuscript is now being published.

Our findings highlight that tobacco product manufacturers should be required to release to the public and the scientific community everything they know about their products, including product ingredients, abuse liability, potential adverse health consequences, and time- and temperature-dependent degradation of quality. For example, much of this information may be available in Premarket Tobacco Product Applications submitted to the Food and Drug Administration’s Center for Tobacco Products, and thus could be shared easily on each company’s website. This vital information should be available to all. In the meantime, our original article (Yassine et al., 2022), the industry response (Gillman, 2022), and this reply provide needed archival documentation for the scientific record.

References

Yassine A, El Hage R, El-Hellani A, Salman R, Talih S, Eissenberg T, Shihadeh A, Saliba N. Did JUUL alter the content of menthol pods in response to US FDA flavour enforcement policy? Tob Control. 2022 Nov;31(Suppl 3):s234-s237. doi: 10.1136/tc-2022-057506. PMID: 36328458; PMCID: PMC9641543.

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

We appreciate the comments from Bates and the opportunity for us to respond and clarify.

First, Bates' argument heavily relies on the assumption that e-cigarettes and combustible cigarettes are substitutes, which is theoretically possible as some consider vaping as a harm reduction alternative to combustible cigarettes. Empirically, however, there have been mixed findings about whether e-cigarettes and combustible cigarettes are substitutes (or complements). Bates cited Pesko et al. (2020) that concludes e-cigarettes and combustible cigarettes are substitutes, whereas other studies have shown that they are complements. For example, Cotti et al. (2018) found that higher cigarette excise taxes, in fact, decrease sales of both e-cigarettes and combustible cigarettes, suggesting that they are complements. Such mixed results abate Bates' argument that taxing ENDS could lead to more use of combustible cigarettes.

Second, Bates might have ignored that our study focused on young adults aged 18-24 years rather than general adults when examining the effect of vaping product tax on e-cigarette use. Although Pesko et al. (2020) suggests that e-cigarettes and combustible cigarettes are substitutes, the findings are based on the general adult population (average age: 55 years) which may not be generalizable to the young adult population. In fact, one study conducted by Abouk and Adams (2017) indicates that e-cigarettes and combustible cigarettes are not substitutes for young people. Established cigarette smokers may use e-cigarettes as a cessation tool but it is less common in young adults. In addition, even if e-cigarettes and combustible cigarettes are substitutes to some degree, the direction of substitution as well as co-use versus subsequent use should not be overlooked. Studies have shown that e-cigarettes may serve as a gateway to future combustible cigarette smoking among young people. For example, a study conducted by Hair et al. (2021) shows that youth and young adults who reported ever e-cigarette use had significantly higher odds of ever cigarette use one year later. Therefore, e-cigarette use versus combustible cigarette smoking is not simply an issue of substitution in particular among young people.

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

References:
1. Abouk, R., & Adams, S. (2017). Bans on electronic cigarette sales to minors and smoking among high school students. Journal of Health Economics, 54, 17-24.
2. Cotti, C., Nesson, E., & Tefft, N. (2018). The relationship between cigarettes and electronic cigarettes: Evidence from household panel data. Journal of Health Economics, 61, 205-219.
3. Hair, E. C., Barton, A. A., Perks, S. N., Kreslake, J., Xiao, H., Pitzer, L., ... & Vallone, D. M. (2021). Association between e-cigarette use and future combustible cigarette use: Evidence from a prospective cohort of youth and young adults, 2017–2019. Addictive Behaviors, 112, 106593.
4. Pesko, M. F., Courtemanche, C. J., & Maclean, J. C. (2020). The effects of traditional cigarette and e-cigarette tax rates on adult tobacco product use. Journal of Risk and Uncertainty, 60(3), 229-258.

NOT PEER REVIEWED
We appreciate the interest of the world’s largest transnational tobacco company, PMI,1 in our recent systematic review and would like to follow up on the points raised in Dr Baker’s rapid response.

Our review did not seek to assess the harms or benefits of HTPs. As public health researchers we are most interested in the quality of studies according to whether they give reliable evidence of the health outcomes and public health impact of HTPs. We sought to critically appraise the quality of clinical trials on HTPs and lay out for Tobacco Control readers all aspects of their design which may have implications for interpretation, especially in regard to the potential impacts of HTPs.

We decided to explore overall risk of bias when excluding the blinding of participants and personnel domain because we wanted to differentiate between studies. This is a really important domain. We excluded it because so few studies were judged to be at low risk of bias in this domain. Performance bias (which blinding if done well can guard against) remains an important source of bias that can influence study results, and one which was present in all of PMI's studies submitted to the U.S. Food and Drug Administration (FDA).1 As we explain in our risk of bias assessments, the consequences of this bias could have been minimised had the control intervention been active. Likewise, PMI’s withdrawal of its carbon-heated tobacco product from the market, which occurred after our first literature searches, does not excuse the substandard aspects of these trials, including selective reporting of study results.

We are perplexed by Dr Baker's argument that PMI’s clinical studies were designed to meet specific FDA requirements and “are not designed to assess the overall impact of HTPs on public health”. In its assessment the FDA aims to "evaluat[e] the benefit to health of individuals and of the population as a whole" (pg 8)2. As Dr Baker explains, PMI included its clinical studies as evidence on the relative risks of IQOS in its application to the FDA. While we concur no one study could wholly assess the impact of HTPs on public health, each clinical study indirectly or directly assesses this to some extent, whether it be assessing the impact of HTPs on exposure to harmful chemicals or on health outcomes. In the words of PMI's Chief Life Sciences Officer, PMI conducts "biomarker, clinical outcome and real-world evidence studies to demonstrate individual clinical and public health benefit of our smoke-free products."3

On the one hand, PMI suggests its clinical studies are appropriate evidence in establishing whether HTPs are beneficial to public health. Yet, Dr Baker's response contradictorily indicates PMI's studies were never designed to address this question and, in fact, agrees with our conclusion that they are therefore inadequate in assessing whether HTPs are beneficial to public health.

Our review found the existing HTP clinical trials provide evidence on exposure to toxicants compared to cigarettes, but fall short of what is needed to determine whether HTPs reduce the risks of tobacco-related diseases and whether they are beneficial to public health in real-world settings. This is in line with the FDA’s conclusions that PMI "has not demonstrated that, as actually used by consumers, the products sold or distributed with the proposed modified risk information will significantly reduce harm and the risk of tobacco‐related disease to individual tobacco users and benefit the health of the population as a whole, taking into account both users of tobacco products and persons who do not currently use tobacco products" (pg8, emphasis in original)1. We agree with the FDA, as quoted by Dr Baker, that subsequent studies are needed to establish the public health impact of HTPs.

Our review focused on clinical trials as giving the best evidence of a causal effect, but we read the two longer term observational studies Dr Baker points us to with interest. We do note that neither study is able to separate the population health effects of different cigarette alternatives or cessation interventions. We agree longer clinical and epidemiological studies are required to determine the harms or benefits of HTPs. We are pleased such studies are emerging in the literature and we look forward to reading the results of PMI's ongoing studies referenced by Dr Baker. We hope that despite the FDA’s MRTP authorisation for IQOS, PMI will remain incentivised to publish these new longer-term studies with clinical outcomes, as well as the observational study it has already completed.4

We are glad our review provided useful insight to PMI for areas of improvement. Improving future clinical research was fundamental in our desire to conduct this review. PMI's application to the FDA was a valuable source of data which have not been published in traditional academic literature. For future reviewers, the full-length reports provide a greater depth and breadth of clinical data, including data on outcomes yet to be reported in journal articles. The full reports included in the FDA application have been uploaded to PMI's data sharing website, INTERVALS.5 Unfortunately, PMI has not yet made full reports available for all its clinical studies. We encourage PMI to not only publish its study results in a timelier manner, but also to publish the full clinical study reports, which provide far greater detail and results than its journal publications.

With regards to our own funding and conflicts of interest, we accurately declared these as per Tobacco Control's policies. We note, once again, that no funders had any role or input in the design, conduct or reporting of our study.

References
1. Tobacco Tactics. Philip Morris International. 2022. Available: https://tobaccotactics.org/wiki/philip-morris-international/ [accessed 9th December 2022].
2. US Food & Drug Administration. Scientific Review of Modified Risk Tobacco Product Application (MRTPA) Under Section 911(d) of the FD&C Act -Technical Project Lead 2020. Available: https://www.fda.gov/media/139796/download [accessed 9th December 2022].
3. Insuasty, J. A letter from our Chief Life Sciences Officer. PMI Science. Available: https://www.pmiscience.com/en/about/welcome-to-pmi-science/ [accessed 9th December 2022].
4. Sponsiello-Wang Z, Langer P, Prieto L, et al. Household Surveys in the General Population and Web-Based Surveys in IQOS Users Registered at the Philip Morris International IQOS User Database: Protocols on the Use of Tobacco- and Nicotine-Containing Products in Germany, Italy, and the United Kingdom (Greater London), 2018-2020. JMIR Res Protoc. 2019; 8(5):e12061. doi: 10.2196/12061. PMID: 31094340; PMCID: PMC6532333.
5. INTERVALS. 2022. Available: https://intervals.science/homepage [accessed 9th December 2022].

NOT PEER REVIEWED

Clive Bates’ commentary on our paper repeats claims we previously addressed [1]. Here, we address seven points, the first is contextual and the remaining are raised in his letter.

1. We note the failure of the author to acknowledge Māori perspectives, in particular their support for endgame measures, concerns in relation to harm minimisation [2] as outlined in his “all in” strategy, and ethical publishing of research about Indigenous peoples. [3]

2. We reject the assertion that the basis of our modelling is “weak”. While there is uncertainty around the potential effect of denicotinisation, as this policy hasn’t been implemented, there are strong grounds to believe that it will have a profound impact on reducing smoking prevalence. This is based on both theory and logic (i.e., nicotine is the main addictive component of cigarettes and why most people smoke), and the findings of multiple randomized controlled trials (RCTs) showing that smoking very low nicotine cigarettes (VLNCs) increases cessation rates for diverse populations of people who smoke [4-7].

Our model’s estimated effect on smoking prevalence had wide uncertainty, namely a median of 85.9% reduction over 5 years with a 95% uncertainty interval of 67.1% to 96.3% that produced (appropriately) wide uncertainty in the health impacts. The derivation of this input parameter through expert knowledge elicitation (EKE) is described in the Appendix of our paper. Univariate sensitivity analyses comparing the 67.1% and 96.3% estimates (all other input parameters held at their median value) produced HALY gains ranging from 545,000 to 653,000. Our paper presents this uncertainty transparently.

3. The assertion that the effect size estimate of denicotinisation is based on one randomized trial is incorrect. The author has been informed that this assertion is false on several occasions but even so continues to repeat this claim. We used an EKE process, which is described in the Appendix of our paper. The experts considered many ‘inputs’ to their estimation, of which just one was the evidence from the multiple existing RCTs.

4. We disagree with the author’s characterisation of the EKE process as “arbitrary guesswork”. As Bates himself has noted, expert judgement can provide valuable insight in situations of uncertainty and can “provide a risk-perception ‘anchor’ … following assessment of the evidence that exists.” [8] We believe that ≥ 5 RCTs demonstrating a relationship between VLNCs and increased smoking cessation constitute a reasonable evidence base to draw upon, particularly when supported by theory/logic and other lines of evidence.[9]

Policy-making often occurs in a context of uncertainty. Denicotinisation is one such example, as we will not know its ‘real world’ impact until it has been implemented. To inform that policy making, it is astute to have estimates of the likely health impact – which requires EKE. Over time, as evidence accrues, such modelling should be updated.

5. As stated in our paper, we did not explicitly model an illicit market. Tight border security in an island nation with no land borders within 1,000 km, reduces the potential of a significant illicit tobacco market. Furthermore, the Aotearoa/New Zealand (A/NZ) Government announced new measures against tobacco smuggling in preparation for the introduction of its ‘endgame’ legislation. [10] The impact of an illicit tobacco market may be greater in other countries. In A/NZ, the illicit market is small (around 5-6% max) and has not increased greatly despite 10 years of above inflation tobacco excise increases and the introduction of plain packs – interventions which the tobacco industry routinely claims will result in an explosion in the illicit market. This suggests enforcement measures work well in the A/NZ context. Furthermore, given the widespread availability and use by people who smoke of nicotine-containing vaping products in A/NZ, seeking to replace VLNCs with illicit cigarettes is likely to be significantly less common than in jurisdictions where vaping products are not available.

6. It is possible – as Bates asserts – that we have overestimated the health gains from denicotinisation and other endgame policies because the smoking prevalence since 2020, appears to be falling more rapidly than we modelled (meaning the ‘room’ for health gains from an endgame policy is less). We discussed this in our paper.

7. Discussing the public health philosophy of denicotinisation was beyond the scope of our paper. Our focus was only on evaluating the potential health and equity impacts of four interventions included the A/NZ Smoke-free Action Plan 2025.

 
References

[1] Edwards R, Ait Ouakrim D, Wilson T, Waa A, Maddox R, Summers J, Gartner C, Lovett R, Blakely T. The case for denicotinising tobacco in Aotearoa NZ remains strong: response to online critique. November 2022 https://www.phcc.org.nz/briefing/case-denicotinising-tobacco-aotearoa-nz...

[2] Waa A, Robson B, Gifford H, Smylie J, Reading J, Henderson JA, Henderson PN, Maddox R, Lovett R, Eades S, Finlay S. Foundation for a smoke-free world and healthy Indigenous futures: an oxymoron?. Tobacco Control. 2020 Mar 1;29(2):237-40.

[3] Maddox R, Drummond A, Kennedy M, et al. Ethical publishing in ‘Indigenous’ contextsTobacco Control Published Online First: 13 February 2023. doi: 10.1136/tc-2022-057702

[4] Donny EC, Denlinger RL, Tidey JW, Koopmeiners JS, Benowitz NL, Vandrey RG, Al’Absi M, Carmella SG, Cinciripini PM, Dermody SS, Drobes DJ. Randomized trial of reduced-nicotine standards for cigarettes. New England Journal of Medicine. 2015 Oct 1;373(14):1340-9.

[5] Smith TT, Koopmeiners JS, Tessier KM, Davis EM, Conklin CA, Denlinger-Apte RL, Lane T, Murphy SE, Tidey JW, Hatsukami DK, Donny EC. Randomized trial of low-nicotine cigarettes and transdermal nicotine. American journal of preventive medicine. 2019 Oct 1;57(4):515-24.

[6] Walker N, Howe C, Bullen C, Grigg M, Glover M, McRobbie H, Laugesen M, Parag V, Whittaker R. The combined effect of very low nicotine content cigarettes, used as an adjunct to usual Quitline care (nicotine replacement therapy and behavioural support), on smoking cessation: a randomized controlled trial. Addiction. 2012 Oct;107(10):1857-67.

[7] Higgins ST, Tidey JW, Sigmon SC, Heil SH, Gaalema DE, Lee D, Hughes JR, Villanti AC, Bunn JY, Davis DR, Bergeria CL. Changes in cigarette consumption with reduced nicotine content cigarettes among smokers with psychiatric conditions or socioeconomic disadvantage: 3 randomized clinical trials. JAMA network open. 2020 Oct 1;3(10):e2019311-.

[8] Clive Bates, January 2020. Vaping is still at least 95% lower risk than smoking – debunking a feeble and empty critique. https://clivebates.com/vaping-is-sill-at-least-95-lower-risk-than-smokin...

[9] Edwards R, Johnson E, Hoek j, Waa A, Tautolo E, Ball J, Stanley J. The smokefree 2025 action plan: key findings from the ITC New Zealand (EASE) project. https://www.phcc.org.nz/briefing/smokefree-2025-action-plan-key-findings...

[10] Hon Meka WHAITIRI, May 2022. Stubbing out Tobacco smuggling. https://www.beehive.govt.nz/release/stubbing-out-tobacco-smuggling

¶ The authors make some points in their article that are reasonable: 1) the generalizability of San Francisco's flavor ban compared to other places is an open question, and 2) the original study uses the San Francisco ban effective date rather than enforcement date. The original author (Friedman), who does not accept tobacco industry funding and is a well-respected scientist in the field, had pointed to both facts in her original article. So that information isn’t new.
¶ The current authors appear to construct a straw man argument claiming that Friedman argued that she was studying the effect of San Francisco enforcing its flavor ban policy. Friedman specifically wrote in her original article that she was studying, “a binary exposure variable [that] captured whether a complete ban on flavored tobacco product sales was in effect in the respondent’s district on January 1 of the survey year.” She specifically uses effect in the above sentence, so there is no ambiguity that she is studying effective date. San Francisco’s flavor ban effective date was July 2018 (Gammon et al. 2021).
¶ The authors found new information that the San Francisco YRBSS survey was collected between November to December of 2018. Gammon et al. 2021 (Appendix Figure 1) shows that flavored e-cigarette sales declined in San Francisco between the effective date and the end of August 2018 (compensating for a 30-day look-back period for the YRBSS question wording), even though the flavor ban was not yet fully enforced. This could be due to early supply-side responses to the flavor ban (e.g., some businesses discontinuing selling flavored e-cigarettes immediately upon the law’s effective date), or demand for e-cigarettes falling due to publicity related to the flavor ban effective date. The fact that e-cigarette sales continued falling in the latter half of 2018 until full enforcement kicked in on 1/1/2019 does not by itself invalidate Friedman’s model specifically looking at effective date. Therefore, there is nothing flawed about the concept of studying the effect that the flavor ban effective date (which led to a documented decline in flavored e-cigarette sales in San Francisco between July 2018 through the end of August 2018) had on youth cigarette use measured in the San Francisco YRBSS in November to December of 2018 (compared to other locations not adopting flavor bans).
¶ The current TC paper makes many inaccurate statements that appear to undermine most of the paper.
¶ • "Thus, the San Francisco survey preceded the enforcement of its flavoured tobacco sales restriction (January 2019), making the 2019 YRBSS an inappropriate data source for evaluating the effects of the city’s flavoured tobacco sales restriction."
¶ This is not true. The decline in flavored e-cigarette sales between the July 2018 effective date to the end of August 2018 could have clearly resulted in spillover effects in the youth cigarette use marketplace. The authors provide no acknowledgement of this in their paper.
¶ • "If youth smoking rates increased similarly in Oakland following that city’s sales restriction, this would lend credence to the call for caution against flavoured tobacco sales restrictions. However, if the patterns differ, we should identify alternate explanations for the rise in San Francisco’s youth smoking prevalence."
¶ This is faulty logic. It's entirely possible that policies adopted in two separate cities could exhibit different effects (including one having an effect and the other having no effect) depending on the population's underlying preferences for tobacco products and different evasion opportunities. I don’t know if there is a reason that this could be the case or not, but that’s irrelevant. What is relevant is that the loose language as currently written is inaccurate and could lead people to conclude the wrong thing in other contexts. The authors also fail to provide statistical testing of their Oakland model as required by STROBE guidelines, nor do they acknowledge that unlike the original study their own pre-post analysis is limited by not having a counterfactual group of non-treated areas, and so there is no ability to control for trends over time.
¶ • "Since there was no ban on non-menthol cigarettes sales, we would have expected to see an increase in sales of cigarettes if youth had been switching products."
¶ • “The study actually found an overall trend of a reduction in both total tobacco sales and cigarette sales in San Francisco following the flavoured tobacco product sales restriction, further suggesting that flavoured products were not being substituted by other unflavoured tobacco products or cigarettes.”
¶ Assuming for a moment that we can observe cigarette sales sold to youth, it would be entirely possible that these cigarette sales could decline in San Francisco but decline by more in the control areas due to secular trends; therefore, suggesting the flavor ban would need to increase cigarette sales to youth is inaccurate. And of course the authors do not observe who buys these cigarettes (youth or adults), so sales data for the population as a whole does not necessarily refute youth use patterns.
¶ • “However, in order to imply causality, there cannot be ambiguous temporal precedence.”
¶ • “do not include the policy enactment and enforcement dates that are required to avoid erroneous conclusions like those in the recent analysis of the San Francisco flavoured sales restriction.”
¶ The authors state that Friedman is ambiguous about the policy timing, but this is not the case as she clearly states she is studying effective date. That is not ambiguous. The authors also state that Friedman’s study has erroneous conclusions. I do not see anything erroneous about the limited scope of her research question studying effective date.
¶ The authors also refer in their references to conversation with the CDC-Office on Smoking and Health regarding the YRBSS data collection date. This reference is incomplete per STROBE guidelines, and should include a specific individual that the authors spoke with and a date of the conversation. Since this conversation was with a government employee it is especially important that there is not the perception of the government leaking information to certain groups of scientists but not others, so full disclosure is needed here. Other researchers have tried to get effective dates for the YRBSS survey from the CDC before but have been rebuffed, creating concerns regarding inequal access to data, as well as concerns regarding if this communication between the CDC and the researchers was authorized or not.
¶ Additionally, I found the author’s discussion of the tobacco industry promoting Friedman’s study as irrelevant. This discussion has the unfortunate effect of muddying the waters of what is supposed to be a focus on the science of Freidman’s article, and could easily lead people to conclude that Friedman herself has industry funding, which is not true. None of us are impervious to industry attempts to use our research for their own gain; in fact, if we start to attack researchers whose work is used by industry, this gives industry an easy way to discredit the researchers they are most threated by (by finding a way to cite their research in industry reports and publications, etc.). How research is used after the publication process is not relevant to this debate over the merits of the science of Friedman’s original article.

¶ Reference:
¶ Gammon, Doris G., Todd Rogers, Jennifer Gaber, James M. Nonnemaker, Ashley L. Feld, Lisa Henriksen, Trent O. Johnson, Terence Kelley, and Elizabeth Andersen-Rodgers . "Implementation of a comprehensive flavoured tobacco product sales restriction and retail tobacco sales." Tobacco Control (2021).

NOT PEER REVIEWED
In their response to my reply, the authors appear to not address mistakes in their analysis. It's important that any inaccurate statements be corrected for the benefit of other researchers trying to learn from this conversation. 1) The authors say in their response (and the paper) that there is no "after" period in the Friedman study. However, as reported by Gammon et al. (2022), there was an immediate decline in e-cigarette sales in San Francisco at the effective date. The authors need to explain how they can say there is no "post" period if other research clearly shows that e-cigarette sales declined starting July 2018. This is a central part of their argument and the paper unravels if there actually is a reduction in July 2018 as has been documented previously. The authors mention in their reply that they are aware of changes beginning in July 2018 ("merchant education and issuing implementing regulations"). The press may also have widely covered the effective date, which led to changes in youth's demand for e-cigarettes. Many retailers may have wished to become compliant immediately rather than wait until enforcement. All of these are valid potential mechanisms explaining why e-cigarette sales declined starting July 2018. So for the authors to say that Friedman doesn't have a "post" period is ignorant of both the literature and many valid reasons explaining why e-cigarette sales declined at the effective date. 1a) The authors state in their abstract: "We also found that 2019 YRBSS data from San Francisco, California cannot be used to evaluate the effect of the sales restriction on all flavoured tobacco products in San Francisco as the YRBSS data for this city were collected prior to enforcement of the sales restriction." This is undercut by the above finding that the policy effective date led to declines in e-cigarette sales. Additionally, for other researchers in this space, I highly recommend the use of effective date in these types of policy evaluation efforts. Only one thing can change the effective date: legislation. In contrast, any number of things can change enforcement dates including government resources and willpower to enforce the laws. Further, enforcement intensity can change over time for many reasons. For these reasons, enforcement is a messy source of variation subject to all kinds of endogeneity concerns. For this reason, the vast majority of quasi-experimental research uses effective date, and I recommend that continue. However, it's reasonable to consider alternative timing points (such as enactment date and/or enforcement date) as sensitivity analyses. 2) The authors state: "Following the sales restriction, high school youth vaping and cigarette use declined between 2017 and 2019 in Oakland. These observations of patterns are purely descriptive and observational and are not statistically significant changes." The authors cannot say that cigarette use 'declined' between 2017 and 2019 if this change is not statistically significant. 3) The authors say in their paper that they received the YRBSS survey collection date from the CDC. In their reply, they appear to acknowledge that this was false and they actually received the data from the San Francisco School District. The reference should be corrected so that people know where to go for this type of information in the future. 4) This statement is not completely accurate: "If youth smoking rates increased similarly in Oakland following that city’s sales restriction, this would lend credence to the call for caution against flavoured tobacco sales restrictions. However, if the patterns differ, we should identify alternate explanations for the rise in San Francisco’s youth smoking prevalence." It's entirely possible smoking rates could continue to fall, just by less than in control groups as a result of flavor bans. That would still be evidence that flavor bans are increasing smoking (by reducing smoking cessation). The loose language the authors use here could lead people to make the wrong conclusion in other contexts.

NOT PEER REVIEWED
These arguments by Pesko and Friedman cannot undo the central flaw in the Friedman paper. We are surprised that Pesko and Friedman continue to argue that Friedman’s analysis of the YRBSS fall data as “after” data is valid despite the Friedman paper defining the exposure variable as follows: “A binary exposure variable captured whether a complete ban on flavoured tobacco product sales was in effect in the respondent’s district on January 1 of the survey year.”[1] If Friedman had intended to treat the period immediately after July 21 2018 as the “after” period, why had she not selected July 21 of each year as the cut-off date for indicating exposure to the policy effects? It seems apparent that Friedman chose the January 1, 2019 as the cut-off for “after” data because she knew this was the enforcement date and she assumed wrongly that the YRBSS data were collected after January 1, 2019. This is evident in her own response[2] to a critique[3] of her paper as we already noted in our previous response.[4]
Friedman states that “the official/legislated effective date are used to ensure that resulting estimates capture unconfounded responses to the policy change.” Again, if this approach made sense in the specific San Francisco case, why did Friedman use January 1, 2019 in her paper? Perhaps because it simply doesn’t make sense to attribute a policy’s effects before the policy is actually implemented. Similarly, the use of enforcement date rather than effective date is not at all as unusual as Pesko claims. Pesko and Friedman’s suggestion to use effective date post hoc simply does not make any logical sense in the San Francisco case, where there was an explicit and highly publicised period of non-enforcement as well as documented non-compliance with the policy through the period of survey administration. In fact, all the existing papers on the San Francisco flavour ban,[5–8] including the Friedman paper,[1] have used the January 1, 2019 enforcement date as the cut-off date for evaluating the policy implementation effects.
Friedman rightly points out that the San Francisco Department of Public Health didn’t even begin compliance inspections until December 3rd, 2018. The YRBSS survey was already nearly complete (fielded between November 5th and December 14th, 2018) at that time. In addition, the current smoking question assesses smoking in the past 30 days, meaning that all of the survey respondents would be reporting on their smoking behaviour for a preceding period that encompasses a time before compliance checks began. When compliance checks began in December, only 17% of retailers were found to be compliant with the flavour ban, likely because they were explicitly instructed that there would be no penalties until January 1, 2019. These facts mean that youths’ retail purchase access would not have changed appreciably at that time. Her conclusion in her paper that “reducing access to flavoured electronic nicotine delivery systems may motivate youths who would otherwise vape to substitute smoking”[1] is inconsistent with the fact that e-cigarettes were still widely available in San Francisco in the fall of 2018.
Pesko and Friedman cite Gammon et al. (2021) showing reduced e-cigarette sales[5] to argue that Friedman’s analysis is still valid because the law may have led to a decrease in youth’s demand for e-cigarettes before the enforcement date. In truth, the vaping rate went from 7.1% to 16% in San Francisco between 2017 and 2019. We note that the Friedman paper omitted reporting youth vaping prevalence,[1] stating that “Recent vaping was not considered because of likely confounding. California legalised recreational marijuana use the same year San Francisco’s flavour ban went into effect; in addition, the YRBSS’s vaping questions did not distinguish vaping nicotine vs marijuana.” The decision to not control for vaping in the Friedman analysis is not justified. Friedman wrote in her response[2] to three critiques[3,9,10] of the original paper that the reason was potential misclassification of marijuana vaping due to California’s legalisation of recreational marijuana because the YRBSS questions do not specify the substance being vaped. Marijuana exclusive vapers account for only about 1% of the youth population, making this an inappropriate reason to not control for significant differential changes in vaping over time in different cities.[11–13] For example, vaping rates went down in Oakland after the flavour restriction but were up significantly in the 2018 pre-enforcement period in San Francisco. Initiation of vaping nicotine has been associated with higher rates of subsequent use of cigarettes among adolescents.[14,15] Higher rates of vaping nicotine e-cigarettes may also have been the impetus for passage of the San Francisco flavour ban, making vaping an important confounder. Taken together, these facts make uncontrolled confounders a likely explanation to cigarette use differences across locations and therefore decreases the possibility that the cigarette smoking rate went up due to an unenforced flavour ban.
Pesko and Friedman did not mention that Gammon et al. (2021) reported the predicted flavoured nicotine e-cigarette sales in San Francisco increased from 3439 units per week pre-policy (July 2015-July 2018) to 5906 units per week in the effective period (July-December 2018) and only declined after the enforcement period (January-December 2019) to 16 units per week (Table 1 in their article).[5] Clearly, flavoured e-cigarettes were still widely available in the marketplace during the effective but non-enforced period and in fact, more flavoured e-cigarettes were sold during the effective period than prior to the policy. Furthermore, Friedman also did not mention that Gammon et al. (2021) reported that cigarette sales declined post flavour ban.[5] Predicted total cigarette sales in San Francisco declined from 83424 units per week pre-policy (July 2015-July 2018) to 77370 units per week in the effective period (July-December 2018) and further declined after the enforcement period (January-December 2019) to 64220 units per week (Table 1). [5] This pattern is therefore inconsistent with Friedman’s 2021 paper conclusion that “reducing access to flavoured electronic nicotine delivery systems may motivate youths who would otherwise vape to substitute smoking” in the fall of 2018. The fact is average weekly flavoured e-cigarette sales increased while total cigarette sales decreased in San Francisco between July-December 2018 compared to pre-policy period. [5] The substitution explanation falls apart. Pesko and Friedman cannot selectively use data to have it both ways.
As we described in our paper, after Oakland implemented a convenience store flavoured tobacco sales restriction in July 2018, high school youth vaping declined from 11.2% to 8.0% (p=0.04)[16] and smoking declined from 4.4% to 2.4% (p=0.02)[17] between 2017 and 2019. Our description that vaping and cigarette use prevalence declined was accurate. Upon reviewing the YRBSS data from the CDC, the Oakland data does in fact represent a statistically significant drop in vaping and smoking rate from 2017 to 2019. Friedman objects to our use of the Oakland (neighboring city to San Francisco) data as a comparison because Oakland’s law was less comprehensive than San Francisco’s. We respectfully disagree with Friedman’s objection. The Oakland law that drastically limited youth access to flavoured tobacco products in that city certainly informs the San Francisco case. The idea that the decline in cigarette smoking prevalence after the flavour ban in Oakland was less than the decline of cigarette smoking elsewhere is disproven by the fact that there was a greater drop in current smoking rate in Oakland from 2017 to 2019 (46% decline from 4.4% to 2.4%) compared to the average decrease nationally across the United States (32% decline from 8.8% to 6.0%) based on YRBSS data.[18]
Friedman offered several post hoc explanations for why youth cigarette smoking might increase following a flavour ban. She offers no data from San Francisco to support market responses following the SF flavour ban, nor does she provide data that SF youth had switched to using flavour accessories. These scenarios also assume that flavoured tobacco products were no longer available at the time of the SF YRBSS data collection, but we know products were still largely available as of December 2018 in 83% of the retailers. It is historically inaccurate for Friedman to suggest that the outbreak of EVALI had any bearing on potentially reducing people’s willingness to buy vaping products from informal sellers in 2018 because this outbreak occurred in the fall of 2019, one year after the SF YRBSS data were collected.
Our description about receiving the YRBSS survey collection date through an inquiry from the CDC was accurate.[19] The CDC informed us that the YRBSS in San Francisco was conducted in the fall of 2018 and we used this information in our paper. We wrote to the San Francisco School District to confirm these dates as did Dr. Friedman.
Liber’s points about partial compliance rates are refuted by the availability of flavoured products during the survey administration period and are addressed by our above response. We thank him for agreeing that this case highlights the need for including more precise date of data collection identifiers in publicly available data sets. Given the significance and potential impact of these analyses for public health policy, it behooves all users of publicly available data to pay close attention to dates of data collection in relation to policy effective/enforcement dates when analyzing this information, to seek confirmation if there is any doubt, and not make assumptions about the dates. In this case the dates of the 2019 YRBSS administration ranged widely from fall of 2018 (SF) to fall of 2019 (NYC).[19]
An important benefit of flavour ban legislation is that flavoured combustible tobacco use goes down.[7] The use rates of flavoured combustible little cigars and cigarillos are similar or exceed the combustible cigarette use rate among youth in San Francisco, [11] making flavour bans an important tool in decreasing overall youth combustible tobacco rates.
The results of the 2019-2020 California Student Tobacco Survey, which was conducted after the enforcement of the flavour ban showed that the prevalence of cigarette smoking among San Francisco high schoolers was 1.6% (compared with 4.7% based on the San Francisco 2017 pre-ban YRBSS data).[11] After the enforcement of the flavour ban, we now see historically low smoking rates in San Francisco. This data from the time after the flavour ban was actually implemented by retailers further calls into question the conclusion of the Friedman paper.
References
1 Friedman AS. A Difference-in-Differences Analysis of Youth Smoking and a Ban on Sales of Flavoured Tobacco Products in San Francisco, California. JAMA Pediatr 2021;175:863–5. doi:10.1001/jamapediatrics.2021.0922
2 Friedman AS. Further Considerations on the Association Between Flavoured Tobacco Legislation and High School Student Smoking Rates—Reply. JAMA Pediatr 2021;175:1291–2. doi:10.1001/jamapediatrics.2021.3293
3 Maa J, Gardiner P. Further Considerations on the Association Between Flavoured Tobacco Legislation and High School Student Smoking Rates. JAMA Pediatr 2021;175:1289–90. doi:10.1001/jamapediatrics.2021.3284
4 Liu J, Hartman L, Tan ASL, et al. In reply: Youth tobacco use before and after flavoured tobacco sales restrictions in Oakland, California and San Francisco, California. Tob Control Published Online First: 16 March 2022. doi:10.1136/tobaccocontrol-2021-057135
5 Gammon DG, Rogers T, Gaber J, et al. Implementation of a comprehensive flavoured tobacco product sales restriction and retail tobacco sales. Tob Control Published Online First: 4 June 2021. doi:10.1136/tobaccocontrol-2021-056494
6 Guydish JR, Straus ER, Le T, et al. Menthol cigarette use in substance use disorder treatment before and after implementation of a county-wide flavoured tobacco ban. Tob Control 2021;30:616–22. doi:10.1136/tobaccocontrol-2020-056000
7 Yang Y, Lindblom EN, Salloum RG, et al. The impact of a comprehensive tobacco product flavour ban in San Francisco among young adults. Addict Behav Rep 2020;11:100273. doi:10.1016/j.abrep.2020.100273
8 Holmes LM, Lempert LK, Ling PM. Flavoured Tobacco Sales Restrictions Reduce Tobacco Product Availability and Retailer Advertising. Int J Environ Res Public Health 2022;19:3455. doi:10.3390/ijerph19063455
9 Mantey DS, Kelder SH. Further Considerations on the Association Between Flavoured Tobacco Legislation and High School Student Smoking Rates. JAMA Pediatr 2021;175:1290. doi:10.1001/jamapediatrics.2021.3287
10 Leas EC. Further Considerations on the Association Between Flavoured Tobacco Legislation and High School Student Smoking Rates. JAMA Pediatr 2021;175:1290–1. doi:10.1001/jamapediatrics.2021.3290
11 Zhu S-H, Braden K, Zhuang Y-L, et al. Results of the Statewide 2019-2020 California Student Tobacco Survey. https://www.cdph.ca.gov/Programs/CCDPHP/DCDIC/CTCB/CDPH%20Document%20Lib...
12 Zhu S-H, Zhuang Y-L, Braden K, et al. Results of the Statewide 2017-2018 California Student Tobacco Survey. https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUK...
13 Monitoring the Future (MTF) Public-Use Cross-Sectional Datasets. https://www.icpsr.umich.edu/web/NAHDAP/series/35 (accessed 1 Jul 2022).
14 Chan GCK, Stjepanović D, Lim C, et al. Gateway or common liability? A systematic review and meta-analysis of studies of adolescent e-cigarette use and future smoking initiation. Addiction 2021;116:743–56. doi:10.1111/add.15246
15 Soneji S, Barrington-Trimis JL, Wills TA, et al. Association Between Initial Use of e-Cigarettes and Subsequent Cigarette Smoking Among Adolescents and Young Adults: A Systematic Review and Meta-analysis. JAMA Pediatr 2017;171:788–97. doi:10.1001/jamapediatrics.2017.1488
16 Centers for Disease Control and Prevention. Youth Online: High School YRBS - Oakland, CA 2017 and 2019 Results Current Electronic Vapor Product Use. https://nccd.cdc.gov/Youthonline/App/Results.aspx?TT=A&OUT=0&SID=HS&QID=... (accessed 1 Jul 2022).
17 Centers for Disease Control and Prevention. Youth Online: High School YRBS - Oakland, CA 2017 and 2019 Results Current Cigarette Smoking. https://nccd.cdc.gov/Youthonline/App/Results.aspx?TT=A&OUT=0&SID=HS&QID=... (accessed 1 Jul 2022).
18 Centers for Disease Control and Prevention. Trends in the Prevalence of Tobacco Use National YRBS: 1991—2019. 2021.https://www.cdc.gov/healthyyouth/data/yrbs/factsheets/2019_tobacco_trend... (accessed 20 Jun 2022).
19 Centers for Disease Control and Prevention. Data Request and Contact Form- YRBSS. 2021.https://www.cdc.gov/healthyyouth/data/yrbs/contact.htm (accessed 1 Jul 2022).

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

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
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
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.

The paper by Asfar et al (1) had a noble objective, which was to inform ENDS health risk communications by updating the 2018 evidence review by the US. National Academies of Sciences, Engineering and Medicine (NASEM) (2). The need for improved risk communications about ENDS is reinforced by a recent study which found that only 17.4% of US smokers believe that nicotine vaping is safer than smoking (3). While ENDS use is not safe, the evidence from toxicant exposure studies does show that ENDS use is far safer than smoking cigarettes and may benefit public health by assisting those who smoke to quit smoking (4, 5).
An important limitation of the umbrella review method utilized by the authors is that it does not directly attempt to systematically characterize new research. This is a concern because the marketplace of ENDS products used by consumers has evolved since the 2018 NASEM report (4, 5). Furthermore, the authors have included some meta-analyses of selected reviews for some domains, but these meta-analyses were not in the Prospero pre-registration (6), nor explained in the paper. It’s thus unclear how or why certain reviews were selected for meta-analysis, and also whether the comparators are the same for these reviews. More importantly, these meta-analyses risk single studies contributing multiple times to the same pooled estimate. The authors noted this as a limitation commenting inaccurately that ‘it was impossible to identify articles that were included in multiple reviews’. In our view this serious methodological flaw merits removal of all pooled estimates from their analyses. Additionally in several places, association is conflated with causality (e.g. “ENDS use impedes smoking cessation”) when based on observational data. The classification of evidence is also not transparent, cannot be found in the source the authors cited, and in places does not follow from the evidence presented (e.g. gateway evidence classified as high when based on observational studies).
The review also excludes research reviews supported by ENDS manufacturers. While we recognize and agree with the authors’ concerns about possible bias in industry publishing, we also believe that the exclusion of such research without any analysis of the scientific merits of the research itself precludes a comprehensive assessment of the scientific literature regarding the health risks of ENDS. Also, excluding industry publications necessarily eliminates from consideration evidence that the Center for Tobacco Products may be asked to consider when it is reviewing product applications for product marketing authorizations and modified risk claims.
The paper falls short, as well, in addressing the risk communication implications of the findings since the authors’ recommendations often do not match the evidence of what is known and not known about the risks of using ENDS. A careful analysis of suggested risk messages contained in supplementary material to the paper finds messages that do not appear to be supported by the evidence reviewed in the paper. For example, the suggested risk messages that "nicotine in vapes can harm memory, concentration, and learning in young people," "vaping nicotine can harm learning ability in young people," and "exposure to nicotine during adolescence can interfere with brain development" do not appear to be derived from a comprehensive review of scientific evidence. The evidence of nicotine having adverse effects on brain development or learning in adolescents comes primarily from rodent studies where dosing of nicotine is not necessarily analogous to exposure from ENDS.
For most of the topics reviewed, the umbrella review reveals that the health risks of ENDS remain unsettled at this time. Whilst biomarker exposure data clearly indicate reduced risk compared to tobacco cigarettes (4), we would suggest restraint is needed in communicating absolute risk information to the public (7). Also we would go one step further in noting that whatever the health risks of ENDS may be, they are going to be most observable in those persons using ENDS on a persistent basis for months or years at a minimum. For example, the health risks of cigarette smoking do not reliably emerge until after smokers exceed 10 pack-years or more of exposure (87). Few studies of ENDS health risks have actually focused on the likely higher risk group of persistent ENDS users (4).
We also take issue with the paper’s main conclusion that direct comparison between the harms of cigarettes and ENDS should be avoided (1). In fact, such comparisons are likely unavoidable and necessary since the group most likely to use ENDS on a persistent basis are those who have a history of cigarette use. Moreover, ENDS were originally developed as a cessation aid and evaluations of cessation aids almost always incorporate evidence on the relative harms compared to continuing to smoke. We do recognize that accounting for a person’s smoking history complicates evaluations of the health risks of ENDS, but dismissing such comparisons simply ignores the fact that ENDS are existing or potential cigarette substitutes for many smokers (4, 5). A recent review of biomarker studies found that compared to smoking, using ENDS leads to a substantial reduction in biomarkers of toxicant exposure associated with cigarette smoking, while also acknowledging that the degree of any residual risk from smoking remains unclear because of the lack of comparisons between long-term former smokers, and with those who have never smoked or used ENDS (4).
Communicating health risk information about ENDS has to have some context to be meaningful to consumers. A common misconception about tobacco use is that the most dangerous component of the product is nicotine (9-14). However, while nicotine can be addictive, it is the other toxicants in tobacco, especially burned tobacco, that are the true culprits of tobacco-related diseases (2, 4). Thus, when communicating information about the health risks of tobacco products, it makes sense to provide consumers with information about the relative health dangers from burned compared to unburned tobacco products. The example risk messages included in the supplementary materials to the paper appear to be developed with a goal of discouraging anyone from using a vaping product rather than to inform potential users about risks.
Public health authorities can reduce the risk of misinforming or confusing the public by acknowledging when evidence is incomplete or based on statistical association rather than clear evidence of causality, and by updating any statements or recommendations quickly when plausibly causal evidence becomes available (7).

 
References
1. Asfar T, Jebai R, Li W, et al. Risk and safety profile of electronic nicotine delivery systems (ENDS): an umbrella review to inform ENDS health communication strategies. Tob Control Epub ahead of print: [please include Day Month Year]. doi:10.1136/ tobaccocontrol-2022-057495
2. National Academies of Sciences, Engineering, and Medicine; Health and Medicine Division; Board on Population Health and Public Health Practice; Committee on the Review of the Health Effects of Electronic Nicotine Delivery Systems. Public Health Consequences of E-Cigarettes. Eaton DL, Kwan LY, Stratton K, editors. Washington (DC): National Academies Press (US); 2018 Jan 23.
3. Kim S, Shiffman S, Sembower MA. US adult smokers' perceived relative risk on ENDS and its effects on their transitions between cigarettes and ENDS. BMC Public Health. 2022 Sep 19;22(1):1771. doi: 10.1186/s12889-022-14168-8.
4. McNeill, A, Simonavičius, E, Brose, LS, Taylor, E, East, K, Zuikova, E, Calder, R and Robson, D (2022). Nicotine vaping in England: an evidence update including health risks and perceptions, September 2022. A report commissioned by the Office for Health Improvement and Disparities. London: Office for Health Improvement and Disparities.
5. Balfour DJK, Benowitz NL, Colby SM, Hatsukami DK, Lando HA, Leischow SJ, Lerman C, Mermelstein RJ, Niaura R, Perkins KA, Pomerleau OF, Rigotti NA, Swan GE, Warner KE, West R. Balancing Consideration of the Risks and Benefits of E-Cigarettes. Am J Public Health. 2021 Sep;111(9):1661-1672.
6. Rime Jebai, Wei Li, Oluwole Olusanya Joshua, Beck Graefe, Celia Rubio. Systematic Review of Reviews on the Harmful Effects of Electronic Nicotine Delivery Systems: Building Evidence for Health Communication Messaging. PROSPERO 2021 CRD42021241630 Available from: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021241630
7. United States Surgeon General. Confronting Health Misinformation: The U.S. Surgeon General’ s Advisory on Building a Healthy Information Environment [Internet]. 2021 [cited 2022 Aug 9]. Available from: https://www.hhs.gov/sites/default/files/surgeon-general-misinformation-a...
8. Doll R, Peto R, Boreham J, Sutherland I. Mortality from cancer in relation to smoking: 50 years observations on British doctors. Br J Cancer. 2005 Feb 14;92(3):426-9. doi: 10.1038/sj.bjc.6602359.
9. O’Brien EK, Nguyen AB, Persoskie A, Hoffman AC. U.S. adults’ addiction and harm beliefs about nicotine and low nicotine cigarettes. Prev Med. 2017;96:94-100.
10. Steinberg MB, Bover-Manderski MT, Wackowski OA, Singh B, Strasser AA, Delnevo CD. Nicotine Risk Misperception Among US Physicians. J Gen Intern Med. 2021, 36(12):3888-3890.
11. Elton-Marshall T, Driezen P, Fong GT, et al. Adult perceptions of the relative harm of tobacco products and subsequent tobacco product use: Longitudinal findings from waves 1 and 2 of the population assessment of tobacco and health (PATH) study. Addict Behav. doi:10.1016/j.addbeh.2020.106337.
12. Parker MA, Villanti AC, Quisenberry AJ, Stanton CA, et al. Tobacco Product Harm Perceptions and New Use. Pediatrics. 2018 Dec;142(6):e20181505. doi: 10.1542/peds.2018-1505.
13. Yong HH, Gravely S, Borland R, Gartner C, et al. Perceptions of the Harmfulness of Nicotine Replacement Therapy and Nicotine Vaping Products as Compared to Cigarettes Influence Their Use as an Aid for Smoking Cessation? Findings from the ITC Four Country Smoking and Vaping Surveys. Nicotine Tob Res. 2022 Aug 6;24(9):1413-1421. doi: 10.1093/ntr/ntac087.
14. National Cancer Institute. Health Information National Trends Survey. HINTS 5 cycle 3, 2019. Available at: https://hints.cancer.gov/view-questions-topics/question-details.aspx?PK_...

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 appreciate the authors’ concern about industry “astroturfing.” We believe astroturf activities undermine the genuine consumer movement that INNCO and its members represent. But the conclusions that the authors draw from their research are attenuated and inaccurate. In particular, we object strenuously to the authors’ conclusion that because INNCO has received funding from the Foundation for a Smoke-Free World (the Foundation), we are a tobacco front group.

INNCO was formed in 2016, a year before the Foundation was established. All of INNCO’s members are autonomous, independent consumer organisations, and with rare exception are run by volunteers on a shoe-string budget. These organisations joined forces to create INNCO, and they nominate and elect INNCO’s Governing Board members, who serve without compensation.

INNCO only accepts funding from sources where our independence as an organisation run by and for consumers is assured. INNCO operated for more than two years with only volunteer efforts and no funding. (Funding from the Foundation was received in December of 2018, which is after the period this paper covers.)

As the authors note, INNCO was formed in large part to ensure the consumer voice is heard on international platforms. However, we question the authors’ intent in casting our desire to engage as legitimate stakeholders as nefarious.

While the authors have cited numerous references on the motivations of the tobacco industry, they appear to not understand the tobacco harm reduction consumer space, relying solely on the previous work of their own organisation to draw inferences. Consumer advocates are passionate about alternatives that have helped them wean off smoking, and are committed to ensuring continued access for these potentially life-saving products.

Consumers are aligned with FCTC’s goals of mitigating tobacco-related death and disease, although our approach differs in that we reject prohibitionism and stigmatisation in favour of pragmatic, humane and ultimately more effective policies that recognise human rights and the agency of users to become proactive participants in improving their health. INNCO thus brings a unique, ear-to-the-ground perspective to tobacco control efforts, and should be welcomed as FCTC observers.

By encouraging governments, policymakers and others to view consumers and consumer groups as fronts for the tobacco industry, the authors deplatform and disenfranchise an already unfairly marginalised group. We urge the authors to consider the ethical implications of nudging decisionmakers to dismiss the consumer voice. This disregard of the most profoundly affected stakeholders occurs in no other health or policy arena.

NOT PEER REVIEWED
Freedom of speech is a fundamental right in a free society. There is no justification to either interfere with the right of stakeholders to participate in the public debate regarding tobacco harm reduction policy, or to malign those that exercise that right. Given that the outcome of these policy discussions will affect the lives of more than one billion people on the planet who smoke, everyone must be free to advance arguments for and against any policy, and each argument must be scrutinized and evaluated on its evidence base and merits. Unfortunately, the recent paper in Tobacco Control—Exploring the Twitter activity around the eighth meeting of the Conference of the Parties to the WHO Framework Convention on Tobacco Control—missed the opportunity to do this.
Instead of engaging in a discussion on the key issues and arguments put forth in the public discussion around the eighth meeting of the Conference of the Parties (COP8), the authors employ diversionary ad hominem tactics. They mischaracterize Philip Morris International’s (PMI’s) legitimate participation in the public debate on the role that products with the potential to reduce the risk of harm compared to smoking can play in global public health policy. Using phrases like ‘tobacco industry actors’ and ‘front groups’ the authors falsely imply that any person or organization who publicly supports tobacco harm reduction are paid to do so by the tobacco industry, and specifically PMI.
We fundamentally disagree with the authors’ approach. However, if they wish to pursue it in a robust way, we invite them to address an obvious inconsistency, and lack of rigor, in their present publication: the failure to explore the funding or linkages of individuals or organizations they deemed not to have tobacco industry links. By excluding this analysis, the authors have ignored the potential bias of almost one third of the Twitter accounts that they say engaged in the debate around COP8, including many who have links to their own funders (Bloomberg Philanthropies’ STOP: Stopping Tobacco Organizations and Products), and who have their own agendas (1-4) . Completing this analysis would be a useful way to shift from ad hominem attacks and move forward to a robust, science-based debate about tobacco harm reduction in the context of the next Conference of the Parties (COP9).
The importance of tobacco harm reduction policy to hundreds of millions of the world’s population means that it deserves a reasoned, fact-based dialogue between all parties, with science and consumers at the centre of discussion. It is legitimate to disagree, but ad hominem attacks have nothing to do with the argument at hand and simply serve to undermine progress. Dismissing views that differ from one’s own, or—worse still—attempting to intimidate dissenters into silence, will not move the debate forward. Emotions should not be allowed to dictate what and who does and does not get heard—truth and accuracy should be the only considerations.
For more than a decade, PMI has been at the forefront of researching, developing and scientifically assessing products that have the potential to reduce the risk of harm compared to smoking for adults who would otherwise continue to smoke. We are convinced that such products can contribute to improving public health. We are confident in the robustness of our scientific findings and the arguments in favor of tobacco harm reduction. We are proud of our scientists who have developed products that have the potential to reduce the risks of harm compared to smoking for those adults who do not quit. These products are precisely the ones which can make the policy of tobacco harm reduction work. We are open to discuss our strategies, actions and achievements with everyone who has a role to play in shaping public policy to reach better outcomes for men and women who smoke. If the authors of the recent paper—or anyone else—would like to engage in a factual discussion on the issues that really matter, we are ready and willing to debate with them.
(1) https://www.who.int/tobacco/about/partners/bloomberg/en/ (accessed 20 Nov 2020)
(2) https://www.fctc.org/about-us/ (accessed 23 Nov 2020)
(3) https://untobaccocontrol.org/kh/article-53/bloomberg-philanthropies-sele... (accessed 23 Nov 2020)
(4) https://www.tobaccofreekids.org/what-we-do/global/bloomberg (accessed 20 Nov 2020)

NOT PEER REVIEWED

When doing scientific research, following the scientific method, you have a hypothesis (question) that you are going to investigate - in this case: Does xxx consumer organisation have any direct ties to tobacco companies that influence their advocacy?

After you have chosen your method, you then gather your evidence, make an objective analysis and state your findings and make a conclusion.

Your method SHOULD be thorough and your research should be objective in order to maintain the integrity of your research (and yourself). The evidence will either prove/disprove your original hypothesis.

Instead, the authors have chosen to not only demonise the participation of consumers in the narrative of their own health, one has lobbied false claims about tobacco industry connections that do not exist.

It is very concerning that the authors find it necessary to disenfranchise the very people who are fighting for their right to make informed choices about their health. It defies logic, and the principles of fairness and decency.

It perhaps would have been more helpful to all concerned if the authors had done due diligence beyond looking at a website that does not have verified information, to cast aspersions on consumer advocacy organisations.

It definitely would be more productive to welcome the voices of the people for whom felt impassioned enough to get involved in consumer advocacy to help smokers not only have the choices they need switch to less harmful alternative, but to be informed consumers of safer nicotine products.

NOT PEER REVIEWED
Thank you for the opportunity to clarify and correct some of the recent statements about our research article, ‘Exploring the Twitter activity around the eighth meeting of the Conference of the Parties to the WHO Framework Convention on Tobacco Control’.

Mr Sarangapani, Director of the Association of Vapers India (AVI), is incorrect in claiming that our article makes “false allegations” and “unsubstantiated claims”, and that it frames AVI as a tobacco industry (TI) front group. We categorise his organisation as a ‘next generation product (NGP) advocate’ and we state that AVI is a member of the International Network of Nicotine Consumer Organisations (INNCO). We also report that INNCO has received funding from the Foundation for a Smoke-Free World (FSFW),[1] which is an organisation that continues to be funded solely by Philip Morris International.[2] Thus, AVI is a member of an organisation that receives indirect funds from Philip Morris International, via the FSFW. Those statements are factual and substantiated; readers can locate further details and references to the FSFW’s grantees and tax returns via our Tobacco Tactics pages, as referenced in our article. In his letter, Mr Sarangapani points out that the Founder-Director of AVI is the current President of INNCO’s Governing Board; however, our research article makes no mention of that fact. We clearly state that: “We found no evidence that the individuals affiliated with INNCO or its member organisations were themselves funded by FSFW or by the TI directly” (p4). I acknowledge that on page 5 of the article, we have referred to AVI by their Twitter handle (vapeindia), as opposed to the organisation’s full name.

Mr Cullip’s interpretation of our article as a “smear” against vaping consumer advocates is an inaccurate representation of our research. As set out in our research objectives (p2), we examined the main themes and sentiment of tweets about WHO FCTC COP8, identified and classified the most active tweeters, explored how people who tweeted about COP8 engaged with one another and, lastly, explored the presence of TI links among the most active tweeters. Our article makes no statements that denigrate vapers’ opinions. Rather, we conclude there was an extensive online presence by Philip Morris International (PMI) executives, and by organisations and individuals funded directly and indirectly by PMI (e.g. Consumer Choice Center, Foundation for a Smoke-Free World, INNCO, Knowledge-Action-Change). We conclude that our findings are consistent with PMI’s 2014 corporate affairs strategy, which was leaked as part of an exposé by Reuters.[3] Far from being a “mythical tobacco industry plot” as Mr Cullip claims, PMI’s corporate affairs strategy described engaging tobacco harm reduction advocates to “amplify and leverage the debate on harm reduction” around events such as the WHO FCTC COP.[3]

Dr Gilchrist’s letter contains several inaccurate assertions. Our research does not “malign” either the individuals or the organisations that participated in the Twitter debate during COP8. We do not use the term “front group” in relation to any of the organisations supporting tobacco harm reduction referred to in our article. Nor do we imply that “any person or organisation who publicly supports tobacco harm reduction are paid to do so by the industry”. Our research article presents a factual account of the most common topics and sentiment of tweets that used #COP8FCTC, the categories of individuals and organisations tweeting, and their networks and patterns of engagement with one another. Around one-fifth of the most active tweeters were either tobacco companies, third-party organisations that have received direct tobacco industry funding, or employees of those organisations. We refer (accurately) to those tweeters as ‘tobacco industry actors’; we provide a detailed definition of our inclusion criteria and provide references to evidence tobacco industry funding. The only specific criticism Dr Gilchrist makes about our study is that we did not explore links between the most active tweeters and non-tobacco industry sources of funding. Given the irreconcilable conflict between the tobacco industry’s interests and tobacco control policy interests, and given tobacco companies’ repeated attempts to influence policy via third parties and intermediaries,[4] our focus on documenting tobacco industry involvement in FCTC debates is justified. Unlike tobacco companies, public health advocacy groups do not stand to generate or lose billions of dollars in profit as a result of decisions made at WHO FCTC COP. Neither do they have a history of obfuscating their funding sources.

Professor Stimson’s letter incorrectly states that we claim tobacco industry money is behind all the activity on Twitter by harm reduction advocates; in fact, on page 4 we state: “…for 23 of the 50 NGP [next generation product] advocates, we found no publicly available evidence of any link with the TI”. Professor Stimson is correct that we state: “…vaping consumer advocacy groups that receive TI funding are emerging and attempting to influence the WHO.” He insinuates this claim is unsubstantiated, yet we provide clear evidence that factasia.org and INNCO, each of whom describe themselves as a vaping consumer advocacy organisation, receive funding from PMI (directly and indirectly, respectively).[1,5] We do not claim TI links with national vaping advocacy groups and, as already noted, we state: “We found no evidence that the individuals affiliated with INNCO or its members organisations were themselves funded by FSFW or by the TI directly” (p4). As Professor Stimson points out, our article includes a paragraph where we report that a member of INNCO, ProVapeo Mexico, encouraged vapers to tweet during COP8. Professor Stimson interprets our research as “picking on” that organisation, yet we make no criticism of ProVapeo Mexico’s activities. Our article documents only the facts about the number of tweets using #COP8FCTC that appear to have been posted as a result of ProVapeo Mexico’s appeal.

In response to Julie Woessner’s letter, at no point does our article state that INNCO is a tobacco front group. As I note above, our article documents substantial activity on Twitter during COP8 both by PMI, and by organisations (and people affiliated with those organisations) that have received money from PMI either directly, or indirectly via the FSFW. We believe this activity is consistent with proposed actions laid out in PMI’s leaked 2014 corporate affairs strategy, which included plans to: “Establish the concept of harm reduction as legitimate public policy in tobacco regulation”, “Identify and engage non-traditional 3rd party stakeholders/allies (e-cigarette manufacturers and retailers, adult consumers of RRP products, tobacco harm reduction advocates…” and “Amplify and leverage the debate on harm reduction around global events (eg, COP6)”.[3] We believe our findings raise important questions about PMI’s claims of transformation, as the activity we have documented appears part of a long-standing corporate affairs plan. Our article presents the facts that some harm reduction-related organisations receive PMI (or FSFW) funds. We do not cast those funded organisations as “nefarious”.

Our research aims to increase transparency in tobacco control policy-making. Making known any links between tobacco companies and individuals and organisations that participate in tobacco control policy debates, even if those links are indirect and occur through intermediaries, is in the public interest and consistent with the principles of WHO FCTC Article 5.3.[6] Vapers who belong to INNCO-affiliated organisations are also entitled to know the network (or “umbrella organization”) to which their organisation belongs receives tobacco industry funding via the FSFW. It is encouraging therefore to observe that following our publication, INNCO appears to have added a statement declaring its FSFW funding onto its homepage (that development appears to have occurred between 1 and 16 November 2020).[7,8]

We are transparent about our research funders. The researchers working on this paper were funded by Bloomberg Philanthropies through the STOP initiative, and by Cancer Research UK; neither funder, nor any of the STOP partners, had any role in the research conceptualisation, study design, data collection, analysis, decision to publish, or preparation of the manuscript.

Lindsay Robertson, MPH, PhD
Conflict of Interest: None declared

References

[1] Tobacco Control Research Group (TCRG). International Network of Nicotine Consumer Organisations (INNCO). https://tobaccotactics.org/wiki/international-network-of-nicotine-consum... (accessed 23 November 2020).
[2] Tobacco Control Research Group (TCRG). Foundation for a Smoke-Free World. https://tobaccotactics.org/wiki/foundation-for-a-smoke-free-world/ (accessed 23 November 2020).
[3] Philip Morris International (author unknown). 10 Year Corporate Affairs Objectives and Strategies (p.5). 2014. https://assets.documentcloud.org/documents/4333395/10-Year-Corporate-Aff... (accessed 23 November 2020).
[4] Ulucanlar S, Fooks GJ, Gilmore AB. The policy dystopia model: an interpretive analysis of tobacco industry political activity. PLoS Medicine 2016; 13(9): doi.org/10.1371/journal.pmed.1002125.
[5] Factasia.org. Our Supporters. 2020. https://web.archive.org/web/20200302113900/https://www.factasia.org/our-... (accessed 2 March 2020).
[6] World Health Organization (WHO). Guidelines for implementation of Article 5.3 of the WHO Framework Convention on Tobacco Control. Available at: https://www.who.int/fctc/guidelines/article_5_3.pdf?ua=1 (accessed 20 August 2020).
[7] International Network of Nicotine Consumer Organisations. Home page. https://web.archive.org/web/20201101140032/https://innco.org/ (accessed 1 November 2020).
[8] International Network of Nicotine Consumer Organisations (INNCO). Home page. https://web.archive.org/web/20201116161303/https://innco.org/ (accessed 16 November 2020).

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
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
We thank Tobacco Control for the opportunity to respond to the comment above. Our study was obviously not looking into the harms of secondhand aerosol from e-cigarettes (SHA). Our paper departs from previous compelling research on the harms of SHA and assesses the prevalence and duration of such exposure among e-cigarette non-users, i.e., bystanders who are potentially exposed to the aerosols emitted by e-cigarette users.

Firstly, it is clear that we conducted the study on the basis of knowledge that bystanders were involuntarily exposed to potentially hazardous SHA in many places. We have clearly mentioned the growing evidence that supports our assertion about the potential harms of SHA in the Introduction and Discussion sections of the paper. SHA contains many toxicants, including nicotine, particulate matter and carcinogens (e.g., volatile organic compounds, polycyclic aromatic hydrocarbons, formaldehyde, acetaldehyde and tobacco specific nitrosamines-TSNAs). As mentioned, this evidence comes from previous scientific research (please, foresee the references 11 to 14 of our paper). Of special interest, fine particulate matter (PM2.5) concentration increased during e-cigarette use sessions with human volunteers in settings such as a room[1–3], during vapers’ conventions[4,5], and in vape shops and their neighbouring businesses[6]. Some TSNAs, such as N-nitrosonornicotine and nicotine-derived nitrosamine ketone, which are carcinogenic[7], have been identified in e-cigarette aerosol (reference 12 of our paper). Airborne nicotine concentration was found to increase after e-cigarette use in an experimental study in a room[1], in an observational study conducted in users’ and non-users’ homes (reference 13 of our paper), and in a study of vapers’ conventions[8]. Also, nicotine in SHA was found to be systematically absorbed by bystanders at levels comparable to secondhand tobacco smoke (references 10 and 42 of our paper), which is worrisome. Additionally, SHA may cause reduced lung function and asthma exacerbations among non-users exposed to it (references 15 and 16). Unfortunately, we are unable to review the study conducted by the California Department of Public Health that was mentioned in the comment, as the source is a blogsite without any specific reference to the scientific publication. Personal blogsites tend to be subjective and are dominantly used to express the bloggers’ personal views, even when these blogsites are maintained by academics. It is worth mentioning, our work was published in a peer-reviewed journal, developed by a team of researchers devoted to public health, and, importantly, who have no conflict of interests.

Secondly, the evidence available at the time of the writing of our paper shows that e-cigarette use and seeing e-cigarette use may renormalise tobacco smoking, induce relapse to smoking among former smokers and trigger initiation of e-cigarette use among non-smokers, particularly young people, by decreasing the harm perception of e-cigarettes (references 17 to 21, and 57). This means the concern around SHA is not only about the air quality but also the social norm it might shape.

In conclusion, based on the evidence mentioned, we wanted to know to what extent e-cigarette exposure was perceived among the general population in European countries; consequently, our study estimates the prevalence of passive exposure to SHA from e-cigarettes. Perhaps the “fear” (we prefer to say “concern”) should exist for selling or using products that may harm the health of people who use them and bystanders who are involuntarily exposed to their aerosols. Based on our results, current evidence, and arguments previously discussed[9], we continue to believe that governments should include e-cigarettes use in smoke-free laws.

References mentioned in this response:

1 Schober W, Szendrei K, Matzen W, et al. Use of electronic cigarettes (e-cigarettes) impairs indoor air quality and increases FeNO levels of e-cigarette consumers. Int J Hyg Environ Health 2014;217:628–37. doi:10.1016/j.ijheh.2013.11.003
2 van Drooge BL, Marco E, Perez N, et al. Influence of electronic cigarette vaping on the composition of indoor organic pollutants, particles, and exhaled breath of bystanders. Environ Sci Pollut Res 2019;26:4654–66. doi:10.1007/s11356-018-3975-x
3 Volesky KD, Maki A, Scherf C, et al. The influence of three e-cigarette models on indoor fine and ultrafine particulate matter concentrations under real-world conditions. Environ Pollut 2018;243:882–9. doi:10.1016/j.envpol.2018.08.069
4 Chen R, Aherrera A, Isichei C, et al. Assessment of indoor air quality at an electronic cigarette (Vaping) convention. J Expo Sci Environ Epidemiol 2018;28:522–9. doi:10.1038/s41370-017-0005-x
5 Soule EK, Maloney SF, Spindle TR, et al. Electronic cigarette use and indoor air quality in a natural setting. Tob Control 2017;26:109–12. doi:10.1136/tobaccocontrol-2015-052772
6 Li L, Nguyen C, Lin Y, et al. Impacts of electronic cigarettes usage on air quality of vape shops and their nearby areas. Sci Total Environ 2021;760:143423. doi:10.1016/j.scitotenv.2020.143423
7 Hecht SS. Biochemistry, Biology, and Carcinogenicity of Tobacco-Specific N -Nitrosamines. Chem Res Toxicol 1998;11:559–603. doi:10.1021/tx980005y
8 Johnson JM, Naeher LP, Yu X, et al. A biomonitoring assessment of secondhand exposures to electronic cigarette emissions. Int J Hyg Environ Health 2019;222:816–23. doi:10.1016/j.ijheh.2019.04.013
9 Wilson N, Hoek J, Thomson G, et al. Should e-cigarette use be included in indoor smoking bans? Bull World Health Organ 2017;95:540–1. doi:10.2471/BLT.16.186536

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Recent work from Ilies et al. (1) is very informative toward understanding the degree to which heated tobacco products might confer less health risk than combusted cigarettes. This publication extends well beyond the existing HTP emissions evidence base, much of which was not conducted by independent groups. The authors should be commended for leveraging strong methodology, and for their comprehensive evaluation of toxicants generated by these products.

While the methodology and results of this publication appear sound, there are a number of inaccurate claims that warrant criticism in the second paragraph of the Introduction section:

• The second paragraph discusses nicotine vaping products (e-cigarettes), however citation #2 (Centers for Disease Control and Prevention (CDC). Use of cigarettes and other tobacco products among students aged 13-15 years--worldwide, 1999-2005. MMWR Morb Mortal Wkly Rep 2006;55:553) utilize data from 1999 through 2005, which mostly spans a time frame prior to the invention of the first e-cigarette in 2004 (2), and certainly spans a timeframe prior to their widespread marketing in the United States. The citation follows the sentence “However, the death toll provoked by their [e-cigarettes] consumption has increased significantly, reaching 650,000 annually, and it is likely to rise over the coming year…” This citation is clearly inapplicable to the unfounded claim being made about deaths attributable to e-cigarette use.

• Citation #3 also supports claims about e-cigarette use, however the cited paper (Sinha DN, Kumar A, Bhartiya D, et al. Smokeless tobacco use among adolescents in global perspective. Nicotine Tob Res 2017;19:1395–6) references non-combusted tobacco products in general, as opposed to the many publications which have looked explicitly at e-cigarette use in a more comprehensive fashion. After reading the Sinha et al. research letter, I am not sure that e-cigarettes were considered at all.

• Citation #4 (US Department of Commerce CB. National cancer Institute and centers for disease control and prevention Co-Sponsored tobacco use supplement to the current population survey 2007) does not provide a direct link to any supporting data/publication. It appears the authors are generally referring to the 2006-2007 Tobacco Use Supplement to the Current Population Survey (CPS-TUS), which was conducted in April 2006, August 2006, and January 2007 (3). The first report of an e-cigarette being imported to the United States is from August 2006 (https://rulings.cbp.gov/ruling/M85579), and the 2006-2007 CPS-TUS did not include any survey items related to e-cigarettes. As such, there is no data from the 2006-2007 CPS-TUS that supports the claim “[e-cigarettes] are highly addictive and can cause serious health problems”.

• The claim “More than 30 carcinogenic compounds in high concentrations were identified, leading to severe health hazards such as oral, pharyngeal, oesophageal and pancreatic cancers” is unfounded, as there is no longitudinal data linking e-cigarettes and cancer to date, nor am I aware of evidence that over 30 carcinogenic compounds in “high concentrations” have been identified in any studies of e-cigarette emissions. Additionally, the provided citation (citation #5: Hatsukami D, Zeller M, Gupta P, et al. Smokeless tobacco and public health: a global perspective 2014) does not talk about e-cigarettes even once.

• Citation #6 (Gupta R, Gupta S, Sharma S, et al. Risk of coronary heart disease among smokeless tobacco users: results of systematic review and meta-analysis of global data. Nicotine and Tobacco Research 2019;21:25–31) also does not pertain to e-cigarettes at all, and the accompanying claim “Cardiovascular death risks and stillbirths were also shown to increase up to four times, signalling real concerns regarding human health safety” is baseless with respect to the epidemiological literature on e-cigarettes.

While these concerns do not directly impact the study results or conclusions, e-cigarettes have become a polarizing topic in the tobacco control community and beyond. As such, claims about e-cigarettes must be made with the utmost care, based on rigorous scientific evidence and sound, balanced interpretations of relevant findings. This publication will be read and cited many times over as heated tobacco products continue to proliferate in tobacco markets across the globe, making it that much more important to address these misleading, and at times, blatantly false claims.

References:
1. Ilies BD, Moosakutty SP, Kharbatia NM, et al. Identification of volatile constituents released from IQOS heat-not-burn tobacco HeatSticks
using a direct sampling method. Tobacco Control. Published Online First: 26 May 2020. doi: 10.1136/tobaccocontrol-2019-055521

2. Henningfield JE & Zaatari GS. Electronic nicotine delivery systems: emerging science foundation for policy. Tobacco Control
2010;19:89e90. doi:10.1136/tc.2009.035279

3. US Department of Commerce, Census Bureau (2006-2007). National Cancer Institute and Food and Drug Administration co-sponsored
Tobacco Use Supplement to the Current Population Survey. 2006-2007. https://cancercontrol.cancer.gov/brp/tcrb/tus-cps/

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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.

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It should be noted that the Aspire Cleito coils used in this study have a manufacturer stated operating power range of between 55 and 75 watts. This is noted both on the box and laser etched into the side of the coil housing proper. it should be noted that the first data points in the graph ( to demonstrate the presence of CO in both liquid samples are in excess of the stated power range of the element.

"Strawnana" at 80 watts
"Black Ice" at 100 watts

This leads me to question the normalizing curve for the black ice sample as there are no data points in the graph (Figure 2) within the manufacturer noted operating range for that coil.

Furthermore, while this statement " ...though the bulk liquid temperature is controlled by boiling limits of the e-liquid component" would be accurate were the coil to be completely submerged in liquid, the mechanics of coil design will confound that principle. The resistance coils in electronic cigarettes are not, by design, submerged in liquid, they are in contact with a liquid saturated wick. Any heat energy applied to the coil whether in magnitude or duration, that exceeds the supply of liquid saturating the wick will result in a temperature spike which could cause the temperature to spike causing thermal degradation of what liquid does remain, and the singeing of the cotton wick.

It can be expected that where combustion occurs, carbon compounds will be present.

I would be interested in seeing the data sets to better understand exactly how far out of operating range CO began to manifest in the study.

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I hope that Tobacco Control will offer a right of reply to the target of this one-sided criticism. In the meantime, let me put a few points to the authors:

1. There is no credible analysis (anywhere) of the actual, rather than the imagined, relationship between PMI and the Foundation for a Smokefree World (FSFW - ‘the Foundation’) that suggests PMI exerts material control over the Foundation. Its basic legal documents suggest otherwise. Nor have the authors explained why the Foundation's goal of ending smoking within a generation is somehow a bad thing or insincere.

2. Nor is there a credible assessment of the relationship between the Foundation and the new Centre for Research Excellence: Indigenous Sovereignty and Smoking (the Centre) that is the subject of criticism in this paper. There are two degrees of separation between the Centre and PMI, and the philosophy of the Foundation is to support centres of excellence and to leave them to get on with their work. The Centre has an excellent (Māori) leader and is quite capable of asserting its independence. How it would somehow do the bidding of PMI is not explained by the authors.

3. The authors dismiss the Centre’s focus on ‘harm reduction’ and instead emphasise: “the need to shift attention away from individuals to the true source of the problem: commercial tobacco and the companies that sell and promote it.”. While I share the sentiment about individual smoking cessation, I believe their proposed alternative problem-definition is overly simplistic and that it will not serve smokers of any ethnicity well. The appropriate approach is to take a ‘system view’, in which the system includes individuals, community, tobacco industry and supply chain, technology and innovation, information, regulation, taxation and enforcement - and to recognise this system is undergoing a significant disruption. A focus on ‘harm reduction’ should not be misunderstood as an individualist perspective. It requires careful engineering of incentives through ‘risk-proportionate’ policies that bear down hard on the cigarette trade but encourage smokers to switch to lower risk products. It is not an alternative to conventional MPOWER techniques, but a way of widening and improving the responses available to smokers.

4. No analysis is provided of the Centre's mission or work programme and how this will, somehow, harm the interests of indigenous people. No consideration is given to the implications of NOT having the Centre, of NOT doing its work and NOT producing its intellectual property. What is gained by NOT trying to reduce the smoking-related harms among indigenous people? Why is it better for this money to be spent elsewhere or returned to PMI's shareholders than spent on improving the life-chances of New Zealand’s indigenous populations?

5. Instead of dispassionate analysis of the Centre's work programme and the Foundation's aims, an array of irrelevant arguments and innuendo about the original funder is deployed in an effort to discredit the Centre and its work. It amounts to a superficial analysis of business motivations and the incentives of tobacco firms and fails to grasp how these have been fundamentally changed by the ongoing technology disruption created by new forms of non-combustible products. Yet, that is precisely why such a centre has such an important role in the rapidly evolving environment.

6. Indigenous people's smoking rates in New Zealand remain far higher than the European origin population (daily smoking prevalence was 31.2% among Māoris compared to 13.5% among the European population in 2018). Clearly, the standard tobacco control playbook has not been a conspicuous success in this population, yet Māoris suffer a disproportionate burden from the key tobacco policy: tobacco taxes set at a high level. Māoris account for 26% of national expenditure on tobacco, but only account for 15% of the adult population and around 70% of their expenditure is tax (approximately $NZ 700m). The harm reduction approach should also be seen as a way to mitigate the economic inequities that arise from tobacco use and tobacco taxation - there are large savings to smokers who switch from smoking to vaping.

7. Given the relative failure of conventional tobacco control in reducing smoking prevalence in indigenous populations, surely it makes sense to try new approaches - including the 'harm reduction' approach that aims help smokers switch from combustible to non-combustible nicotine products. For many, this will be an easier transition than complete cessation because it involves giving up less (i.e. it does not involve giving up nicotine, sensory impacts, behavioural ritual etc) but for almost the same health gain.

8. There is some support for this in New Zealand’s parliament. A joint House of Representatives Māori Affairs and Health Committee inquiry noted in December 2018 that New Zealand was off-track to meet the Aotearoa 2025 goal and that regularising the market for vaping products should be recognised as part of the policy response:

"We recommend that legislation be enacted to recognise and regulate vaping and e-cigarettes as a pathway to help smokers to quit".

9. Emotive rhetoric about a 'new colonisation' may help to fire up activists but it adds little of practical value to the debate. Nicotine is one of several drugs in widespread and longstanding use in most societies. As a drug, nicotine is relatively benign and does not cause intoxication, overdose, violence, accidents, sexual vulnerability, job losses, family breakdown etc. We now have an opportunity to address its ‘dirty’ delivery system, the inhalation of tobacco smoke, and so to reduce the great harm that arises from how nicotine is administered. How does a Centre trying to reduce smoking-related harm among indigenous people colonise anyone?

10. There is a far more imaginative way to see the Centre, the Foundation and PMI. This is how I see it: due to a major technology disruption in the consumer nicotine marketplace, some tobacco companies are now repositioning themselves in a way that will be beneficial for public health despite their ongoing participation in the cigarette business. A valuable by-product of that has been the release of $1 billion to support research and programmes that reduce smoking and related harms and facilitate a transition from combustible nicotine products to non-combustible. Committed public health advocates and academics should at least keep an open mind about this, while others seize the opportunity to do good and reduce harm with these funds, especially in disadvantaged communities. In this case, the Centre and its leadership have done exactly that and, in my view, they should be given time and some encouragement to prove their worth to indigenous communities.

Note: I have no relationship with the Centre, the Foundation or PMI, and I do not speak on their behalf or at their behest. The views stated here are my own. I have been a public health advocate for tobacco harm reduction since 1998.

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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.

NOT PEER REVIEWED
PMI finally responded to my paper in Tobacco Control1 showing that the data submitted in their MRTP application to the FDA to market IQOS with reduced risk claims did not actually support claims of reduced risks.

Specifically, PMI’s MRTP application included their 3-month study of 24 non-cancer biomarkers of potential harm (which PMI calls “clinical risk endpoints,” CRE) in humans using IQOS compared to conventional cigarettes. These biomarkers include measures of inflammation, oxidative stress, lipids, blood pressure, and lung function. (PMI did separate studies of biomarkers of exposure, several of which are carcinogens.) While PMI’s application emphasizes that these biomarkers generally changed in positive directions, my examination of the data revealed no statistically detectable difference between IQOS and conventional cigarettes for 23 of the 24 BOPH in Americans and 10 of 13 in Japanese. Moreover, it is likely that the few significant differences were false positives. Thus, despite delivering lower levels of some toxicants, PMI’s own data failed to show consistently lower risks of harm in humans using IQOS compared to conventional cigarettes.

Their undated response, “The Difference between IQOS and Continued Smoking,”2 presents two arguments:

• The original study submitted to FDA was “NOT DESIGNED to serve as the sole pivotal evidence with regards to CRE’s and to show statistically significant changes in the CREs.”
• PMI has a new, larger study 6-month human study comparing IQOS with conventional cigarettes that concluded that IQOS is less risky than conventional cigarettes.3

With regard to the first point, one is left with the question of why PMI submitted and represented data in the original MRTP application, when it now admits that the study was not designed to provide key evidence. They did not question the specific conclusions that I drew in my paper.

The new 6-month study differs from the study presented in the original MRTP application in several important ways.

First, it is much larger (984 people in the new study compared to 79 in the US study and 112 in the Japanese study cited in the MRTP application). Making the study larger increases statistical power and makes it more likely to declare a difference statistically significant. This is a good thing.

Second, and of greater concern, the new study only considers 6 of the 24 non-cancer biomarkers in the earlier study, leaving the question of why PMI did not measure the other 18. (The 2 other biomarkers in the new study are biomarkers of exposure [CO and NNAL], which were not included in the earlier study and are not at issue in my paper.) Most of the things that they leave out are determined from blood tests, but they had to draw blood to measure the biomarkers they do report. The others are more detailed measures of lung function than the one reported in the new study and easily measured measures of blood pressure.

PMI should be expanding, not dropping, clinical endpoints because of evidence that IQOS is different from cigarettes.4,5 Indeed, the data they presented in the MRTP application suggested that IQOS may be causing liver damage not observed in cigarettes.6

Given the millions of dollars PMI’s application represents, cost does not justify dropping these routine clinical measures. Their detailed presentation on the new study3 does not address this question.

Third, PMI uses an arcane, little-used statistical method, the Hailperin-Rüger method, that was developed to confirm earlier studies.7 (Neither I nor two biostatistics colleagues have seen this used in any recent clinical trials. A PubMed search with the keyword “Hailperin-Rüger” conducted on December 19, 2018, resulted in just one study.8 The basic argument of the Hailperin-Rüger method is that it is overly cautious to require that all observed changes be statistically significant in order to confirm that a therapy works, and that if some lesser number of the variables change significantly, that should be good enough for a global test. The number of significant changes is specified in advance and the probability of a chance finding is adjusted.

PMI decided that if 5 of the 8 biomarkers (6 clinical risk and 2 exposure) changed in the direction of less risk, that would be enough to conclude that IQOS was less risky than conventional cigarettes. They do not provide a clear explanation of why they used 5, other than it was “more than half.”

PMI justified using Hailperin-Rüger because “the probability of finding five significant tests (p<0.05) by chance alone is extremely low (0.006%).” This is a misleading statement because this low probability would only be the case a chance finding if none of the five variables actually changed. The probabilities are much higher when there are real changes.

So, in the new study, PMI went from considering changes in 24 clinical risk biomarkers in the original study to 8 in the new study to only requiring 5 to be statistically significant.

That is a pretty major drop in the level of evidence PMI now suggests is sufficient to demonstrate that IQOS is less risky than cigarettes.

In the new study 5 of the changes were statistically significant, so PMI concluded that, overall, IQOS was better. Had they picked 6 in their plan, the overall results would not have been significant, even under the Hailperin-Rüger method’s relaxed standards.

There are other problems with using the Hailperin-Rüger method. First, it is designed to confirm results of earlier studies. The earlier study did not convincingly show that IQOS was better than conventional cigarettes. Second, the usual way that Hailperin-Rüger is used is when you have several measures of the same thing. (For example, the one paper8 located in PubMed that used Hailperin-Rüger assessed 10 different measures of neurological function and pre-specified that if 5 of the 10 were statistically significant, the global test would be considered statistically significant.) The idea is that requiring all of them to change significantly is being too stringent a requirement to identify a change in lung function. In this case, PMI mixed apples and oranges by applying the text to a set of 6 clinical variables and 2 exposure that were measuring different underlying physiological processes.

PMI also used a one-tail test that assumes that one only need worry above improvements in the biomarkers without any concern for the possibility that they might worsen the biomarkers. (As noted above, PMI presented – but did not emphasize – other evidence in their MRTP application showing that IQOS caused problems not observed in cigarettes.6) I tell my students that, with rare exceptions, one should always do two-tail tests. Two-tail tests require larger differences to reach statistical significance, so by using a one-tail test, PMI made it easier to conclude changes were statistically significant. In this case the overall conclusion would have been the same with a two-tail test, so this bias did not make any practical difference, but they should have not used a one-tail test.

PMI’s use of a one-tailed test was especially hypocritical since back in the early 1990’s the tobacco companies sued the US EPA for using a one-tail test in their risk assessment that concluded that secondhand smoke caused lung cancer.9 EPA used a one-tail test because they said it was inconceivable that secondhand smoke exposure would protect against lung cancer (the other tail). The irony there was that EPA would have reached the same conclusion using a two-tailed test.

All this raises the question of whether PMI manipulated the experimental design and analysis to get the desired conclusion, as they have done in the past.10

The law requires the MRTP applicant PMI to demonstrate, among other things, that IQOS, as it is actually used by consumers, will “significantly reduce harm and the risk of tobacco-related disease to individual tobacco users.” Neither the original 3 month study nor the newer 6 month study meet this standard.

The bottom line: FDA and other regulatory agencies should not rely on PMI’s new study to support a conclusion that IQOS is less risky than conventional cigarettes.

As slightly reformatted version of this post has been submitted to the IQOS MRTP docket at FDA with tracking number 1k2-978f-eqmr. A PDF of the comment is available here.

References

1. Glantz S. PMI’s Own in vivo Clinical Data on Biomarkers of Potential Harm in Americans Show that IQOS is Not Detectably Different from Conventional Cigarettes. Tob Control. 2018;27(Suppl 1):s9-s12. doi: 10.1136/tobaccocontrol-2018-054413. Epub 052018 Aug 054421.
2. Baker G, Harris C, Hankins M, et al. The Difference between IQOS and Continued Smoking. 2018; https://www.pmiscience.com/resources/docs/default-source/news-documents/.... Accessed 19 Dec 2018.
3. PMI Research & Development. Study Results Overview: ZRHR-ERS-09 US (Evaluation of Biological and Functional Changes in Healthy Smokers After Switching to THS 2.2 for 26 Weeks. In PMI IQOS MRTP June 8, 2018 Amendment: Additional Information and Data from a Recently Completed Clinical Study (.zip – 1.3 GB) (added November 29, 2018). 2018; https://digitalmedia.hhs.gov/tobacco/static/mrtpa/PMP/June%208%2C%202018.... Accessed 18 Dec 2018.
4. Glantz S. Heated tobacco products: The example of IQOS. Tobacco Control. 2018;27(Suppl 1):s1-s6; DOI: 10.1136/tobaccocontrol-2018-054601.
5. St. Helen G, Jacob P, Nardone N, Benowitz N. IQOS: Examination of Philip Morris International’s claim of reduced exposure. Tob Control. 2018;27(Suppl 1):s30-s36. doi: 10.1136/tobaccocontrol-2018-054321. Epub 052018 Aug 054329.
6. Chun L, Moazed F, Matthay M, Calfee C, Gotts J. Possible Hepatotoxicity of IQOS. Tob Control. 2018;27(Suppl 1):s39-s40. doi: 10.1136/tobaccocontrol-2018-054320. Epub 052018 Aug 054321.
7. Koch GG, Gansky SA. Statistical Considerations for Multiplicity in Confirmatory Protocols. Drug Information Journal. 1996;30(2):523-534.
8. Schellenberg R, Todorova A, Wedekind W, Schober F, Dimpfel W. Pathophysiology and psychopharmacology of dementia--a new study design. 2. Cyclandelate treatment--a placebo-controlled double-blind clinical trial. Neuropsychobiology. 1997;35(3):132-142.
9. Schachtman NA. EPA Post Hoc Statistical Tests – One Tail vs Two. 2012; http://schachtmanlaw.com/epa-post-hoc-statistical-tests-one-tail-vs-two/. Accessed 19 Dec 2018.
10. Wertz MS, Kyriss T, Paranjape S, Glantz SA. The toxic effects of cigarette additives. Philip Morris' project mix reconsidered: an analysis of documents released through litigation. PLoS medicine. 2011;8(12):e1001145.

NOT PEER REVIEWED
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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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.

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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, based on existing literature [1] and high resolution mass spectra, is highly likely 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.
[1] Arrieta MP, Parres-Garcia F, Lopez-Martinez J et al. Pirólisis de residuo de bioplásticos : Productos obtenidos del ácido poliláctico (PLA). Dyna Ingenieria e Industria, 2012 ; 87(4):395-399. doi:10.6036/4673

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In view of the rising prevalence of adolescent smoking worldwide, it makes a lot of sense to strictly limit cigarette sales only to alcohol licensed premises, particularly, in countries where there are minimum age requirements for buying alcohol. In a previous letter (1) to Lancet Global Health we had argued in favor of the same as we believe that restricting sale of cigarettes or other tobacco products will bring about a decrease in consumption by adolescents.

Smoking addictions are usually acquired during adolescence and this usually happens due to an apparently unregulated sale of tobacco products. Regulation is difficult when the number of tobacco selling establishments far exceeds the managing capacity of local administration. In India, adolescents have unrestricted access to tobacco products as small vendors, whose only source of income is by selling tobacco products, tend not to compromise on any business opportunity.

Although there is a positive association between alcohol and smoking, as the authors have pointed out “tobacco sales are not financially important for the majority of alcohol-licensed tobacco retailers”, so it is a win-win situation for preventing initiation of cigarette smoking by adolescents as alcohol vendors will have no incentive to bypass regulations by selling tobacco products to those who do not qualify as per legal age restrictions. In India, smoking and consumption of alcohol are also social taboos and this particular factor in itself might deter adolescents from buying tobacco products. We feel that limiting sale of tobacco products to alcohol-licensed premises will surely prevent initiation of cigarette by adolescents.

References:
1. Barua MP, Mishra V, Kumar S. Reducing adolescent smoking in India. Lancet Glob Health. 2017 Mar;5(3): e266. doi: 10.1016/S2214-109X(17)30036-0. PubMed PMID: 28193389

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This paper’s core findings are quite helpful: (1) Tax/price increases for non-cigarette tobacco products can effectively reduce their use; and (2) Tax/price increases for non-cigarette tobacco products could prompt some users to increase their cigarette smoking if comparable tax/price increases for cigarettes are not done at the same time. But the paper’s related analysis is incomplete, producing misleading conclusions, largely because the paper focuses on cigarettes versus non-cigarette tobacco products without also considering the more important distinction for health-directed tobacco tax strategies between smoked tobacco products and non-combustible tobacco products.

In its abstract, the paper concludes that the “positive substitutability between cigarettes and non-cigarette tobacco products suggest that tax and price increases need to be simultaneous and comparable across all tobacco products.” But the paper does not appear to consider that the only substitutions that could significantly increase public health harms would be if the tax increases prompted some non-combusted tobacco product users to move to more-harmful smoking or prompted some smokers who would otherwise do so not to move to less-harmful non-combusted tobacco products. As a result, the paper fails to acknowledge that significant tax/price increases for only combusted tobacco products would not prompt any harm-increasing substitution and would directly secure desirable public health gains by directly reducing smoking. It would be foolish for the public health community to reject or not support such a tax increase because it did not also increase taxes on non-combustible tobacco products. But the paper suggests otherwise.

A tobacco tax increase on cigarettes and all other combustibles would secure even larger public health gains if it also used different sized tax increases on different combustible products in order to raise the prices of all smoked tobacco products to the same level as cigarettes (typically the most highly taxed tobacco products), thereby making it more likely that cigarette smokers would respond to the tax increases by cutting back their smoking or quitting altogether, rather than by switching to less-taxed and less-expensive smoked tobacco products, such as little cigars or RYO. But the paper does not consider this option, and its support for comparable tax increases for all tobacco products argues against it.

A tax increase for combusted tobacco products could secure even larger public health gains if it also increased non-combustible tobacco product taxes and prices. But only if the increases to the combusted and non-combusted tobacco product taxes did not make the non-combustibles significantly more expensive relative to cigarettes and other smoked tobacco products, either relatively or in real terms, that they dampened moves from smoking to e-cigarettes or other non-combustibles or prompted some non-combustible users to increase their smoking. But that, also, is not discussed in the paper.

Instead, the main text of the paper talks about taxes to produce equal price increases for each type of tobacco product and concludes by offering the overly broad and potentially misleading recommendation that countries with tobacco-diverse markets “should raise taxes on non-cigarette tobacco products to prevent premature death.”

Perhaps all the additional policy analysis suggested here is too much to expect from a study with the rather simple stated objective of just systematically reviewing the price elasticity of demand of non-cigarette tobacco products. But the paper goes well beyond providing that information and also encourages tax increases for non-cigarette tobacco products, either on their own or along with comparable increases for cigarettes. Given that the paper has decided to make policy recommendations, it should do so more thoughtfully, with more explanation and more detailed guidance.

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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.

NOT PEER REVIEWED Elias and Ling conclude that ‘Regulatory bodies should consider toxin exposure, and new products’ actual use, abuse potential and population health effects before endorsing them as safer’. We agree, and that is exactly what Public Health England and the Royal College of Physicians have done [1-4].

1. Britton, J. and Bogdanovica, I. Electronic cigarettes. A report commissioned by Public Health England. Public Health England, 2014. https://www.gov.uk/government/uploads/system/uploads/attachment_data/fil...
2. Bauld, L., Angus, K., and de Andrade, M. E-cigarette uptake and marketing. A report commissioned by Public Health England. Public Health England, 2014. https://www.gov.uk/government/uploads/system/uploads/attachment_data/fil...
3. McNeill, A., Brose, L., Calder, R., Hitchman, S.C., McRobbie, H., and Hajek, P. E-cigarettes: an evidence update. A report commissioned by Public Health England. Public Health England, 2015. https://www.gov.uk/government/uploads/system/uploads/attachment_data/fil...
4. Tobacco Advisory Group of the Royal College of Physicians. Nicotine without smoke - tobacco harm reduction. Royal College of Physicians, 2016. Available from: https://www.rcplondon.ac.uk/projects/outputs/nicotine-without-smoke-toba...

NOT PEER REVIEWED Martin Jarvis is right to describe the Hunter Committee era as “a sorry tale” that by and large is well told by Elias and Ling, but his assertion that “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” is way over the top, as is his criticism of “the editorial processes and decision-making of Tobacco Control”.

In a paper that runs to a little over five pages of text, there are very brief references to current policies on the first page, then further brief references towards the end, suggesting that there are lessons to be drawn from the earlier episodes.

The paper might indeed have expanded further on the industry-friendly record of the Hunter Committee, noting that after his term as Chairman of the Committee ended, Lord Hunter became a consultant for Imperial Tobacco, while a civil servant who worked on smoking and serviced the Hunter Committee went on to work for Gallahers. It might also have included more emphasis on the way tobacco substitutes dominated public discourse on tobacco policy issues during the 1970s (1), although in fairness to the authors they appear to have been misled by the re-writing of history evident in some of the material they cite, particularly from industry actors.

But this would simply have added more weight to the conclusion that during the 1970s discussion, debate and massive promotion of tobacco substitutes by tobacco companies succeeded in hijacking the tobacco public policy and media agenda, and diverted the government of the day from evidence-based approaches recommended by health authorities to reduce smoking. Elias and Ling have good reason to suggest that there are similarities between then and now.

In passing, Jarvis’s summary that the novel products of the day failed “because consumers rejected them” omits much. One important reason for the failure of tobacco substitutes was that industry rhetoric and hype to the contrary, there was ultimately justifiable concern, with concomitant media coverage, that “all the generally available brands contained 75 per cent tobacco, and were no more than additions to the low and low-to-middle tar range” (1). Indeed, it would have been quite possible for smokers switching to part-substitute brands to find themselves moving to higher tar products.

But before this message hit, there had been a mountain of industry-generated publicity promoting the notion that “safer” and (as inevitably reported) “safe” new brands were on the way. This approach was supported with public relations ploys such as an Imperial Tobacco press conference about part-substitute cigarettes the day after the launch of the 1977 Royal College of Physicians’ “Smoking Or Health” report. Not surprisingly, the tobacco trade press was quick to congratulate the company concerned on its success in diluting the impact of the College report.

1. Daube M. The politics of smoking: thoughts on the Labour record. Community Medicine. 1979; 1, 306-314

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Euromonitor International is a privately held, independent provider of strategic market research with no agenda other than to present the most realistic illicit trade data impartially and within its wider industry context. Subscribers to Euromonitor’s Passport Tobacco database are varied and include tobacco control/ public health groups, academia, retailers, manufacturers of raw materials as well as tobacco brand owners and banks/ consultancies, amongst others.

These same stakeholders are approached by Euromonitor for comment on industry trends, including those of illicit sales. Euromonitor’s stated sources for illicit cigarettes sales thus include trade press, customs offices, interviews with manufacturers and retailers, government and academic organisations. This is reconciled against local knowledge of the market and illicit trade’s wider context – eg national economic performance, trends in taxation, unit prices and duty paid sales, porosity of borders, law enforcement efforts, and so on. There is no reliance on any one source.

By its very nature, illicit trade in tobacco products is a contentious area and one that is difficult to quantify – there are often wide discrepancies between various sources on illicit trade, reflecting vested interests in either deflating or inflating figures. In these circumstances, Euromonitor strives to present the most widely accepted and realistic estimate of the illicit market, based on a holistic view of the wider national context and the factors that contribute towards it (as described above) – no single source or figure is taken as definitive and all figures undergo this wider review. Furthermore, this wider context is discussed at length in the attendant analysis in each country report where the trends behind the figures are laid out.

Given Euromonitor’s exhaustive geographic coverage of this dataset – at 100 markets researched in-field for illicit trade, there is no other source like it – as well as our annual revisiting of this dataset, it is inevitable that some changes between editions will be necessary. Euromonitor is transparent about its reasons for change and welcomes any discussion on what can be a opaque area - we are always happy to engage with all concerned stakeholders and review their own sources, on a country-by-country basis, should they exist.

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.