NOT PEER REVIEWED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‐cigare...
NOT PEER REVIEWED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.
Dear Editor,
We commend Bakhturidze et al. for their study titled as ‘Smoke-Free Legislation Impact on the Hospitality Sector in the Republic of Georgia’ [1]. Their research is a new addition to the global evidence that smoke-free (SF) policies not only protect public health but also support the economic growth of the hospitality industry. The study’s results are particularly relevant given the ongoing discussions globally and tobacco industry’s claim about the negative impact of SF laws on business sectors like hospitality [2].
While the analysis presented is robust, one limitation lies in its reliance on linear regression models, particularly given the limited number of data points available. More granular analyses, such as region or city-specific data, could provide additional insights into how SF legislation impacts different areas of Georgia, revealing potential variations that may be masked in the national aggregated data. We also note an inconsistency, as the reference 11, pertaining to year 2013 was used to support the statement, “On May 1, 2018, Georgia fully implemented the FCTC SF policy…” that suggested an activity of future. The global death toll due to secondhand smoke (SHS) in 2019 was 1.3 million not 1.2 million as reported in the reference 1, citing a Global Burden of Disease study. However, a study titled “Global, regional, and national deaths, disability-adjusted life years, years lived with disability, and years of l...
Dear Editor,
We commend Bakhturidze et al. for their study titled as ‘Smoke-Free Legislation Impact on the Hospitality Sector in the Republic of Georgia’ [1]. Their research is a new addition to the global evidence that smoke-free (SF) policies not only protect public health but also support the economic growth of the hospitality industry. The study’s results are particularly relevant given the ongoing discussions globally and tobacco industry’s claim about the negative impact of SF laws on business sectors like hospitality [2].
While the analysis presented is robust, one limitation lies in its reliance on linear regression models, particularly given the limited number of data points available. More granular analyses, such as region or city-specific data, could provide additional insights into how SF legislation impacts different areas of Georgia, revealing potential variations that may be masked in the national aggregated data. We also note an inconsistency, as the reference 11, pertaining to year 2013 was used to support the statement, “On May 1, 2018, Georgia fully implemented the FCTC SF policy…” that suggested an activity of future. The global death toll due to secondhand smoke (SHS) in 2019 was 1.3 million not 1.2 million as reported in the reference 1, citing a Global Burden of Disease study. However, a study titled “Global, regional, and national deaths, disability-adjusted life years, years lived with disability, and years of life lost for the global disease burden attributable to second-hand smoke, 1990-2019: A systematic analysis for the Global Burden of Disease Study” by Zhai C et al (2023) seems to be the original source of information [3]. Correcting this discrepancy would enhance the overall rigor of the article.
Despite these minor issues, the study's contribution to global tobacco control research cannot be overstated. One of the key takeaways from the study is that Georgia’s SF legislation, enforced since 1st May 2018, did not negatively affect the hospitality sector’s economic performance. From 2018 to 2019, the number of food service establishments grew by 20%, hotels by 17%, and employment by 9%, with a 3% rise in employee wages [1]. These findings align with international studies showing that SF laws typically have a neutral or positive impact on businesses, particularly in the hospitality industry. Smoke-free environments attract more customers who prefer cleaner, healthier spaces, showing that SF policies can enhance, rather than hinder, economic growth [2, 4]. Earlier Bakhturidze et al. (2021) reported a significant reduction (91%) in air pollution levels in hospitality venues after the SF law was implemented in Georgia [5]. This dramatic reduction highlights the potential health benefits of reduced exposure to secondhand smoke (SHS) in public spaces, especially for workers and patrons. Cleaner indoor air is associated with decreased risks of respiratory and cardiovascular diseases, making SF laws essential for protecting public health [6]. The study by Bakhturidze et al., primarily focuses on economic outcomes in hospitality sector following SF implementation, but future research exploring how these improved conditions translate into long-term health benefits, such as fewer hospital visits, improved quality of life for workers, and fewer work absences due to smoke-related illnesses, would be vital.
The study also brings attention to the protection that the SF laws provide for vulnerable groups, particularly children and unborn foetuses. In Georgia, children under 14 make up about 21.3% of the 3.73 million population [7], and many of them are involuntarily exposed to SHS, especially in homes and public spaces including hotels and restaurants. A Scottish study found a 26% reduction in respiratory symptoms and decreased airway inflammation in asthmatic bar workers three months after smoke-free laws were enacted [8], and Georgia is likely to experience similar public health improvements. In addition to protecting children in public spaces, SF laws also influence smoking behaviors at home [9]. They help shift social norms around smoking, making it less acceptable in private settings. This reduces SHS exposure for non-smokers, particularly children and pregnant women, further underscoring the importance of comprehensive SF policies.
Despite Georgia’s progress with SF policies, there are challenges in other areas of tobacco control, particularly regarding taxation. Between 2020 and 2022, cigarette prices rose, but taxes were not raised in proportion, resulting in a lower tax share for the government [2]. To maintain a strong tobacco control framework, it is critical that Georgia also strengthens its taxation policies, as higher taxes on tobacco products are a proven method of reducing consumption and improving public health outcomes.
The Bakhturidze et al., in an earlier study has highlighted Georgia’s high compliance rates with SF laws, ranging from 96% to 99% in hospitality venues [5]. These impressive rates demonstrate that when SF policies are well-implemented and enforced, they can be highly effective without harming businesses. Voluntary smoke-free policies, in contrast, have been shown to be ineffective in fully protecting non-smokers, making comprehensive legislative action essential. The study reinforces the notion that only strong, enforceable SF policies can provide full protection from SHS exposure, as partial bans or designated smoking areas continue to expose individuals to harmful smoke and complicate enforcement efforts.
Georgia has made substantial progress in enforcing its SF policies since their implementation in 2018. Georgia enforces strict smoking bans in healthcare and educational facilities, requiring no-smoking signs and public reporting mechanisms [2]. The country has been able to maintain high compliance rates across the hospitality sector, showing that the policies are not only enforceable but widely accepted. Establishments are fined for not enforcing the ban,
However, there remain a few areas where smoking is still permitted, such as casinos, and enforcement of these exceptions continues to be a challenge. Growing public support, and government commitment and enforcement, for SF policies would further reinforces the success of the implementation ensuring that the progress made is sustained and that the policies reach their full potential in protecting public health.
Georgia’s experience with SF legislation mirrors that of other countries, such as Ireland, where initial resistance gave way to widespread support once the benefits became clear. Georgia’s success with high compliance rates and the positive economic outcomes of SF policies strengthens the case for maintaining and enforcing these laws not only in Georgia but globally. The findings of Bakhturidze et al. also serve as a valuable contribution to the international dialogue on SF policies, showing that economic concerns should not deter the implementation of these critical public health measures.
In conclusion, this study provides strong evidence that SF legislation is beneficial both economically and for public health. The hospitality sector in Georgia has experienced growth since the introduction of the SF law, and the reduction in SHS exposure will likely lead to lasting health improvements. We encourage continued research on the long-term impacts of SF laws and greater efforts to enhance tobacco control measures, such as taxation, in order to further reduce tobacco use and protect public health globally.
References:
1. Bakhturidze GD, Popova L, Kirpich A, Berg CJ, Eriksen MP. Smoke-free legislation impact on the hospitality sector in the Republic of Georgia. Tob Control. 2024;0:1–6. doi:10.1136/tc-2023-058513.
2. World Health Organization. WHO report on the global tobacco epidemic, 2023: protect people from tobacco smoke. Geneva: World Health Organization; 2023. Available from: https://iris.who.int/bitstream/handle/10665/372043/9789240077164-eng.pdf... accessed September 12, 2024.
3. Zhai C, Hu D, Yu G, Hu W, Zong Q, Yan Z, Wang Y, Wang L, Zhang T, Sun H, Cai L, Cui L, Wang F, Zou Y. Global, regional, and national deaths, disability-adjusted life years, years lived with disability, and years of life lost for the global disease burden attributable to second-hand smoke, 1990-2019: A systematic analysis for the Global Burden of Disease Study. Sci Total Environ. 2023 Mar 1;862:160677. doi: 10.1016/j.scitotenv.2022.160677. Epub 2022 Dec 5. PMID: 36481152.
4. The economics of tobacco and tobacco control Bethesda (MD): United States Department of Health and Human Services, National Institutes of Health, National Cancer Institute/Geneva: World Health Organization; 2016 (National Cancer Institute Tobacco Control Monograph 21, NIH Publication No. 16-CA-8029A).
5. Bakhturidze G, Peikrishvili N, Gvinianidze K. Impact of comprehensive smoke-free policy compliance on SHS exposure and health condition of the Georgian population. Tob Prev Cessat. 2021 Nov 26;7:70.
6. Health problems caused by secondhand smoke. In: Centers for Disease Control and Prevention/Smoking and tobacco use [website]. Atlanta (GA): Centers for Disease Control and Prevention; 2022 (https://www.cdc.gov/tobacco/ secondhand-smoke/health.html?CDC_ AA_refVal=https%3A%2F%2Fwww. cdc.gov%2Ftobacco%2Fdata_ statistics%2Ffact_ sheets%2Fsecondhand_ smoke%2Fhealth_effects%2Findex.htm, accessed 11 Sept 2024).
We value the opportunity to respond to the Special Communication by Soule et al. that reviewed our three publications [1]. We believe that continued discussion of methods and findings is both healthy and necessary to advance the science and foster more accurate understandings.
Turning to the more specific points raised in their paper, for each of the three cited studies, we provide responses to the most pertinent issues discussed.
Goldenson et al., 2020, Drug and Alcohol Dependence, 217, 108395:
We agree that experimental design and procedure are critical elements of clinical laboratory studies that should be carefully considered and evaluated. Particularly for pharmacokinetic studies of tobacco products, the product use procedure can influence nicotine uptake. In the cited publication by Goldenson et al. [2], it was noted that the controlled use procedure (i.e., 10 uniform puffs 3 s in duration for all products) enabled standardized comparisons among the seven study test products, resulting in high internal validity, whereas an ad libitum use procedure would facilitate more naturalistic use patterns and enhance external validity. Subsequent pharmacokinetic studies of JUUL products that have in fact used ad libitum use procedures [3] or both controlled and ad libitum use procedures [4, 5] consistently demonstrate that JUUL products deliver significantly lower levels of nicotine than combustible cigarettes, confirming the conclu...
We value the opportunity to respond to the Special Communication by Soule et al. that reviewed our three publications [1]. We believe that continued discussion of methods and findings is both healthy and necessary to advance the science and foster more accurate understandings.
Turning to the more specific points raised in their paper, for each of the three cited studies, we provide responses to the most pertinent issues discussed.
Goldenson et al., 2020, Drug and Alcohol Dependence, 217, 108395:
We agree that experimental design and procedure are critical elements of clinical laboratory studies that should be carefully considered and evaluated. Particularly for pharmacokinetic studies of tobacco products, the product use procedure can influence nicotine uptake. In the cited publication by Goldenson et al. [2], it was noted that the controlled use procedure (i.e., 10 uniform puffs 3 s in duration for all products) enabled standardized comparisons among the seven study test products, resulting in high internal validity, whereas an ad libitum use procedure would facilitate more naturalistic use patterns and enhance external validity. Subsequent pharmacokinetic studies of JUUL products that have in fact used ad libitum use procedures [3] or both controlled and ad libitum use procedures [4, 5] consistently demonstrate that JUUL products deliver significantly lower levels of nicotine than combustible cigarettes, confirming the conclusions of the Goldenson et al. study Soule et al. critiqued. Importantly, the findings of these Juul Labs-sponsored studies are also supported by a pharmacokinetic study conducted by two of the authors of the Soule et al. Special Communication that concluded, "cigarettes delivered more nicotine and suppressed tobacco/nicotine abstinence more effectively than JUUL" [6]. We were therefore particularly surprised that Soule et al. did not consider this broader body of literature. Together, these studies reinforce the value of conducting multiple studies with complementary designs and methodologies and support the conclusion that the abuse liability of JUUL products, and other electronic nicotine delivery systems, is lower than cigarettes.
Foxon et al., 2022, BMC Public Health, 22, 1940:
Soule et al.'s commentary on the Foxon et al. article includes misconceptions about basic aspects of the article, including the range of years analyzed, as well as how Foxon et al. *did* account for "other factors" including the FSPTCA and Tips campaign (under 'Other considerations' in the Foxon et al. article [7]). The critique that "most trained researchers would recognize that population-level data should not be used to make [such] inferences" [1], is both misguided and particularly puzzling because authors of the critique have themselves used cross-sectional, population-level time series data to make such inferences [8]. Soule et al. correctly noted that the Foxon et al. 2022 paper had been retracted by the journal, BMC Public Health. They did not note the context, that the journal retracted the paper based on methodological concerns voiced by a single unnamed member of their editorial board, and over objections from the authors and a large group of experts who stated that they "do not see a case for retraction or correction" [9]. The main concern voiced by the editorial board member was about the cut-off year between the pre- and e-cigarette eras, despite a range of possible cut-offs (we presented data assessing 2006–2011) having been explored in the paper and in subsequent correspondence with the journal supporting the findings of the paper. Soule et al. also fail to note or cite the extensive documentation we have made available on PubPeer [10] and OSF [11] that both documents the process and strongly makes the scientific case for the paper’s analysis and conclusions. Soule et al. could not have known that an updated and expanded manuscript was under review at another journal as their Special Communication was published. That updated article is now published in BMC's Harm Reduction Journal [12] and includes detailed rebuttals to the Soule et al. Special Communication. In fact, additional analyses that rebut these criticisms confirm and reinforce the original paper’s conclusions, contradicting the critique. We note that despite the data analyzed by Foxon et al. being publicly available, none of the authors of the Special Communication have published their own analysis of these data. Empirical confirmation and replication remain important foundations of scientific dialogue.
Shiffman et al., 2015, Nicotine and Tobacco Research, 17(10), 1255-1262:
We note that Soule et al. did interpret the methodology of the study correctly: the primary aim was to examine interest in flavor descriptors for e-cigarettes among nonsmoking teens compared to adults who smoke [13]. The rationale was detailed in the Introduction section of the article. In brief, potential users initially respond to the flavor descriptors, not the flavors themselves. As Soule et al. suggest, graphics could also play a role, and research on graphics would also be of interest. Nevertheless, the controversy over flavors has often focused on the flavor descriptors (e.g., see [14]). This topic was specifically addressed in the Discussion, noting that research on other aspects of marketing is an area for additional research. With respect to the populations assessed in the paper, as we fully explain in the paper, these two populations are the most important when considering the risk-benefit calculus required to optimize the public health outcomes of the availability of e-cigarettes, which requires considering potential benefits to adults who smoke and potential harm to nonsmoking youth. We certainly would welcome research on other populations, but the focus on these key groups seems appropriate. We had offered to make our research protocol and instruments available, and the editor of NTR encouraged replication, but we have received no inquiries. We reiterate: Empirical confirmation and replication remain important foundations of scientific dialogue.
Conclusion
As we hope our responses illustrate, critiques and exchanges regarding scientific methods can refine and advance our collective understanding of key questions. While we agree with the importance of transparency and skepticism, neither are served by outright censoring of scientific data, which is counter to principles of scientific inquiry.
Funding and Disclosures
Through Pinney Associates, Inc., Joe Gitchell, Floe Foxon, and Saul Shiffman provide consulting services on tobacco harm reduction on an exclusive basis to Juul Labs, Inc. Nicholas Goldenson is an employee of Juul Labs, Inc. The preparation of this response was funded by Juul Labs Inc., who reviewed and commented on a draft.
References
1. Soule EK, Rossheim ME, Livingston MD, LoParco CR, Tillett KK, Eissenberg T, Sussman S: Hidden flaws in e-cigarette industry-funded studies. Tob Control 2024.
2. Goldenson NI, Buchhalter AR, Augustson EM, Rubinstein ML, Henningfield JE: Abuse liability assessment of the JUUL system in four flavors relative to combustible cigarette, nicotine gum and a comparator electronic nicotine delivery system among adult smokers. Drug Alcohol Depend 2020, 217:108395.
3. Goldenson NI, Buchhalter AR, Augustson EM, Rubinstein ML, Van Hoof D, Henningfield JE: Abuse liability assessment of the JUUL system in two nicotine concentrations compared to combustible cigarette, nicotine gum and comparator electronic nicotine delivery system. Drug Alcohol Depend 2020, 217:108441.
4. Goldenson NI, Fearon IM, Buchhalter AR, Heningfield JE: An Open-Label, Randomised, Controlled, Crossover Study to Assess Nicotine Pharmacokinetics and Subjective Effects of the JUUL System with Three Nicotine Concentrations Relative to Combustible Cigarettes in Adult Smokers. Nicotine Tob Res 2021.
5. Goldenson NI, Augustson EM, Chen J, Shiffman S: Pharmacokinetic and subjective assessment of prototype JUUL2 electronic nicotine delivery system in two nicotine concentrations, JUUL system, IQOS, and combustible cigarette. Psychopharmacology (Berl) 2022, 239(3):977-988.
6. Maloney S, Eversole A, Crabtree M, Soule E, Eissenberg T, Breland A: Acute effects of JUUL and IQOS in cigarette smokers. Tob Control 2020.
7. Foxon F, Selya A, Gitchell J, Shiffman S: Population-level counterfactual trend modelling to examine the relationship between smoking prevalence and e-cigarette use among US adults. BMC Public Health 2022, 22(1):1940.
8. Rossheim ME, Livingston MD, Krall JR, Barnett TE, Thombs DL, McDonald KK, Gimm GW: Cigarette Use Before and After the 2009 Flavored Cigarette Ban. J Adolesc Health 2020, 67(3):432-437.
9. Expression of concern about the proposed retraction of Foxon et al. paper regarding the relationship between smoking prevalence and e-cigarette use among US adults. Available https://clivebates.com/documents/ExpertLetterFoxonRetractionAugust2023.pdf. 2023.
10. https://www.pubpeer.com/publications/0C19CEA0C329F1C95FC0884C7A4AE1
11. Supplemental materials for paper: Population-level counterfactual trend modelling to examine the relationship between smoking prevalence and e-cigarette use among US adults. 2023. https://doi.org/10.17605/OSF.IO/FZTNK
12. Foxon F, Selya A, Gitchell J, Shiffman S: Increased e-cigarette use prevalence is associated with decreased smoking prevalence among US adults. Harm Reduction Journal 2024, 21(1):136.
13. Shiffman S, Sembower MA, Pillitteri JL, Gerlach KK, Gitchell JG: The Impact of Flavor Descriptors on Nonsmoking Teens' and Adult Smokers' Interest in Electronic Cigarettes. Nicotine Tob Res 2015, 17(10):1255-1262.
14. American Academy of Pediatrics, American Cancer Society Cancer Action Network, American Heart Association, American Stroke Association, American Lung Association, Campaign for Tobacco-Free Kids: The Flavor Trap: How Tobacco Companies Are Luring Kids with Candy-Flavored E-cigarettes and Cigars. Available https://web.archive.org/web/20170705032610/https:/www.tobaccofreekids.or.... 2017
How can the special communication promoting the 2040 Tobacco- Free Generation goal of the European Union (1) flew in the face of the warning “we are still waiting for the European political commitment to quit tobacco.”(2)
Firstly, the communication of the goal by the Commission in 2021 remains empty words yet. Of note, the most recent directive for tobacco control, proposed by the Commission in 2012, only became applicable in 2016.
Secondly, promises only bind those who believe in them. Europe will be the only WHO region not to reach the global non-communicable diseases target by 2025,(2) Could the new goal be achievable : a) when smoking prevalence only decreased form 24% in 2010 to 19% in 2020;(3) b) when the reduction in nicotine content, a silver bullet vs young uptake, is totally ignored and when responses about measures were only obtained from 19 of 27 EU Member states,(1) questioning their implication.(1) As a French, I want to stress that in 2019, France was among the six countries globally with a smoking prevalence above 33% among people aged 15-24.(4) Its recent plan raises cigarette retail prices to €12 in 2025, and to €13 in 2026, is less than the 10% threshold for a 4% impact on sales, not to account the present high inflation rates that seriously blunt the true increase. This deliberate strategy from experts in Laffer curve accounts for the low price elasticity of a highly addictive substance in order to increase reven...
How can the special communication promoting the 2040 Tobacco- Free Generation goal of the European Union (1) flew in the face of the warning “we are still waiting for the European political commitment to quit tobacco.”(2)
Firstly, the communication of the goal by the Commission in 2021 remains empty words yet. Of note, the most recent directive for tobacco control, proposed by the Commission in 2012, only became applicable in 2016.
Secondly, promises only bind those who believe in them. Europe will be the only WHO region not to reach the global non-communicable diseases target by 2025,(2) Could the new goal be achievable : a) when smoking prevalence only decreased form 24% in 2010 to 19% in 2020;(3) b) when the reduction in nicotine content, a silver bullet vs young uptake, is totally ignored and when responses about measures were only obtained from 19 of 27 EU Member states,(1) questioning their implication.(1) As a French, I want to stress that in 2019, France was among the six countries globally with a smoking prevalence above 33% among people aged 15-24.(4) Its recent plan raises cigarette retail prices to €12 in 2025, and to €13 in 2026, is less than the 10% threshold for a 4% impact on sales, not to account the present high inflation rates that seriously blunt the true increase. This deliberate strategy from experts in Laffer curve accounts for the low price elasticity of a highly addictive substance in order to increase revenue for the budget. Previous raises were 20 cents in 2023 and 50 cents in 2024 were a win-win policy allowing producers to increase profits: Philip Morris even increased Marlboro Reds’ industrial price, the most sold brand; the retail price increasing from €11.50 to €12.50 in 2024. Concerns for “tobacco industry interference” seem naïve, at best.(1) It takes two to Tango and the industry does not appear to be the leader.
The tobacco endgame looks recalls five-year development plans of the Union of Soviet Socialist Republics. Further, health is not the priority of the Union (before the “Economic Community” and before the “Free Trade Association”), its General Secretariat has twelve Directorates-General, health being cited at the end of one about “agriculture, fisheries, social affairs. Last, "tobacco endgame" PubMed searches retrieved 10 hits for 2014 but 35 for the first semester of 2024 while Robert West recently warned: “The tobacco industry is not on the run … Globally its revenues continue to rise.”(5)
References
1. Ollila H, Ruokolainen O, Laatikainen T, Koprivnikar H and JATC-2 WP9 co-authors. Tobacco endgame goals and measures in Europe: current status and future directions. Tob Control. Published online June 17, 2024. doi:10.1136/tc-2024-058606
2. World No Tobacco Day 2021: will Europe commit to quit?. Lancet Reg Health Eur. 2021;4:100146. Published 2021 May 14. doi:10.1016/j.lanepe.2021.100146
3. OECD/European Union. Health at a Glance: Europe 2022: State of Health in the EU Cycle. OECD Publishing. 2022. Paris, https://doi.org/10.1787/507433b0-en.
4. GBD 2019 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;397:2337-2360. doi: 10.1016/S0140-6736(21)01169-7.
5. Burki TK. 25 organisations added to tobacco industry allies database. Lancet Oncol. 2022;23(12):1493. doi:10.1016/S1470-2045(22)00698-2
I respectfully request answers to the following questions:
1. Was public use or restricted PATH data used. This is important, since Table 2 contains a cell, n=7, that is not generally approved by NAHDAP.
2. Was the PATH cohort drawn from Waves 1 and 4, with follow-ups to age 17 years as needed from the other waves?
3. There were significant differences in youth smoking-vaping between Wave 1 (2013-14) and Wave 4 (2016-18) that might have affected the results. Was each wave analyzed separately as well as together?
4. The analysis included a variable relating to “parent(s) smoking of cigarettes, cigars, or pipes.” Did the analysis include other combustible tobacco product consumption by the subjects themselves?
5. Did the authors account for age at first smoking or vaping (public use, < 12 years and 12-14 years) or which product(s) had been used first?
Regarding the first two questions, the analyses were based on the public use data from both the PATH Study and the MCS, with links to their archives, and the PATH study sample was drawn from the original cohort, the replenishment cohort, and the shadow cohorts (see 1st and 2nd paragraphs of Methods Section). Regarding the remaining questions, please note that our stated goal was to make the MCS and PATH analytical samples as comparable as possible when testing our hypotheses using both cohorts (3rd paragraph of Methods section). As we note in the limitations section (5th paragraph of Discussion section), the MCS had relatively limited items on e-cigarette use and tobacco smoking compared to PATH. The MCS did not assess other combustible tobacco product consumption in early adolescence, nor did MCS measure the sequencing of early adolescent tobacco and e-cigarette use (noted in the limitation section). Also, MCS youth answered survey questions about ever using e-cigarettes from 2015 to 2016 (3rd paragraph of Methods section), which gave us limited variability to test for a wave x e-cigarette interaction in both datasets.
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 o...
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].
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...
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
The objective of the systematic review by Braznell et al. was “𝘵𝘰 𝘤𝘳𝘪𝘵𝘪𝘤𝘢𝘭𝘭𝘺 𝘢𝘴𝘴𝘦𝘴𝘴 𝘵𝘩𝘦 𝘮𝘦𝘵𝘩𝘰𝘥𝘰𝘭𝘰𝘨𝘪𝘤𝘢𝘭 𝘤𝘩𝘢𝘳𝘢𝘤𝘵𝘦𝘳𝘪𝘴𝘵𝘪𝘤𝘴 𝘢𝘯𝘥 𝘲𝘶𝘢𝘭𝘪𝘵𝘺 𝘰𝘧 𝘪𝘯𝘵𝘦𝘳𝘷𝘦𝘯𝘵𝘪𝘰𝘯𝘢𝘭 𝘤𝘭𝘪𝘯𝘪𝘤𝘢𝘭 𝘵𝘳𝘪𝘢𝘭𝘴 𝘪𝘯𝘷𝘦𝘴𝘵𝘪𝘨𝘢𝘵𝘪𝘯𝘨 𝘵𝘩𝘦 𝘦𝘧𝘧𝘦𝘤𝘵𝘴 𝘰𝘧 𝘩𝘦𝘢𝘵𝘦𝘥 𝘵𝘰𝘣𝘢𝘤𝘤𝘰 𝘱𝘳𝘰𝘥𝘶𝘤𝘵𝘴 (𝘏𝘛𝘗𝘴).” ¹ The review was intended to examine the quality of HTP clinical trials “𝘣𝘦𝘧𝘰𝘳𝘦 𝘤𝘰𝘯𝘴𝘶𝘮𝘦𝘳𝘴 𝘢𝘯𝘥 𝘳𝘦𝘨𝘶𝘭𝘢𝘵𝘰𝘳𝘴 𝘮𝘢𝘬𝘦 𝘪𝘮𝘱𝘰𝘳𝘵𝘢𝘯𝘵 𝘥𝘦𝘤𝘪𝘴𝘪𝘰𝘯𝘴 𝘣𝘢𝘴𝘦𝘥 𝘰𝘯 𝘵𝘩𝘦 𝘳𝘦𝘴𝘶𝘭𝘵𝘴 𝘰𝘧 𝘵𝘩𝘦𝘴𝘦 𝘴𝘵𝘶𝘥𝘪𝘦𝘴.” We have three important observations in relation to Philip Morris International’s (PMI) clinical program, which impact the interpretation of the authors’ broad-reaching conclusions.
(𝟭) 𝗥𝗲𝗴𝘂𝗹𝗮𝘁𝗼𝗿𝘆 𝗱𝗲𝗰𝗶𝘀𝗶𝗼𝗻𝘀 𝗵𝗮𝘃𝗲 𝗯𝗲𝗲𝗻 𝗺𝗮𝗱𝗲 𝗯𝗮𝘀𝗲𝗱 𝗼𝗻 𝗣𝗠𝗜’𝘀 𝗰𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝘀𝘁𝘂𝗱𝗶𝗲𝘀, 𝘄𝗵𝗶𝗰𝗵 𝘄𝗲𝗿𝗲 𝗷𝘂𝗱𝗴𝗲𝗱 𝘁𝗼 𝗯𝗲 𝗮𝘁 𝗹𝗼𝘄 𝗿𝗶𝘀𝗸 𝗼𝗳 𝗯𝗶𝗮𝘀
Whilst we will only comment on the clinical studies performed by PMI, we were pleased to see the confirmation that the study designs in our clinical assessment program were not significantly associated with a risk of bias. The authors judged that all Tobacco Heating System (marketed as IQOS) clinical studies submitted to the United States Food and Drug Administration (FDA) and other regulators were at low risk of bias when the authors excluded “blinding of participants and personnel” to the product, due to the impracticality of concealing visually distinctive products. The authors also noted that the scoring was slightly improved when compared to a similar exercise performed as part of the recent Cochrane review. ²
NOT PEER REVIEWED
The objective of the systematic review by Braznell et al. was “𝘵𝘰 𝘤𝘳𝘪𝘵𝘪𝘤𝘢𝘭𝘭𝘺 𝘢𝘴𝘴𝘦𝘴𝘴 𝘵𝘩𝘦 𝘮𝘦𝘵𝘩𝘰𝘥𝘰𝘭𝘰𝘨𝘪𝘤𝘢𝘭 𝘤𝘩𝘢𝘳𝘢𝘤𝘵𝘦𝘳𝘪𝘴𝘵𝘪𝘤𝘴 𝘢𝘯𝘥 𝘲𝘶𝘢𝘭𝘪𝘵𝘺 𝘰𝘧 𝘪𝘯𝘵𝘦𝘳𝘷𝘦𝘯𝘵𝘪𝘰𝘯𝘢𝘭 𝘤𝘭𝘪𝘯𝘪𝘤𝘢𝘭 𝘵𝘳𝘪𝘢𝘭𝘴 𝘪𝘯𝘷𝘦𝘴𝘵𝘪𝘨𝘢𝘵𝘪𝘯𝘨 𝘵𝘩𝘦 𝘦𝘧𝘧𝘦𝘤𝘵𝘴 𝘰𝘧 𝘩𝘦𝘢𝘵𝘦𝘥 𝘵𝘰𝘣𝘢𝘤𝘤𝘰 𝘱𝘳𝘰𝘥𝘶𝘤𝘵𝘴 (𝘏𝘛𝘗𝘴).” ¹ The review was intended to examine the quality of HTP clinical trials “𝘣𝘦𝘧𝘰𝘳𝘦 𝘤𝘰𝘯𝘴𝘶𝘮𝘦𝘳𝘴 𝘢𝘯𝘥 𝘳𝘦𝘨𝘶𝘭𝘢𝘵𝘰𝘳𝘴 𝘮𝘢𝘬𝘦 𝘪𝘮𝘱𝘰𝘳𝘵𝘢𝘯𝘵 𝘥𝘦𝘤𝘪𝘴𝘪𝘰𝘯𝘴 𝘣𝘢𝘴𝘦𝘥 𝘰𝘯 𝘵𝘩𝘦 𝘳𝘦𝘴𝘶𝘭𝘵𝘴 𝘰𝘧 𝘵𝘩𝘦𝘴𝘦 𝘴𝘵𝘶𝘥𝘪𝘦𝘴.” We have three important observations in relation to Philip Morris International’s (PMI) clinical program, which impact the interpretation of the authors’ broad-reaching conclusions.
(𝟭) 𝗥𝗲𝗴𝘂𝗹𝗮𝘁𝗼𝗿𝘆 𝗱𝗲𝗰𝗶𝘀𝗶𝗼𝗻𝘀 𝗵𝗮𝘃𝗲 𝗯𝗲𝗲𝗻 𝗺𝗮𝗱𝗲 𝗯𝗮𝘀𝗲𝗱 𝗼𝗻 𝗣𝗠𝗜’𝘀 𝗰𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝘀𝘁𝘂𝗱𝗶𝗲𝘀, 𝘄𝗵𝗶𝗰𝗵 𝘄𝗲𝗿𝗲 𝗷𝘂𝗱𝗴𝗲𝗱 𝘁𝗼 𝗯𝗲 𝗮𝘁 𝗹𝗼𝘄 𝗿𝗶𝘀𝗸 𝗼𝗳 𝗯𝗶𝗮𝘀
Whilst we will only comment on the clinical studies performed by PMI, we were pleased to see the confirmation that the study designs in our clinical assessment program were not significantly associated with a risk of bias. The authors judged that all Tobacco Heating System (marketed as IQOS) clinical studies submitted to the United States Food and Drug Administration (FDA) and other regulators were at low risk of bias when the authors excluded “blinding of participants and personnel” to the product, due to the impracticality of concealing visually distinctive products. The authors also noted that the scoring was slightly improved when compared to a similar exercise performed as part of the recent Cochrane review. ²
We agree that regulatory decisions should be based on a critical scientific review of the evidence available, taking into consideration the quality and source of the data. The U.S. FDA performed a rigorous multi-year review of the totality of evidence for IQOS which resulted in the granting of Modified Risk Tobacco Product orders with exposure modification claims for the product. They concluded “𝘵𝘩𝘢𝘵 𝘢 𝘮𝘦𝘢𝘴𝘶𝘳𝘢𝘣𝘭𝘦 𝘢𝘯𝘥 𝘴𝘶𝘣𝘴𝘵𝘢𝘯𝘵𝘪𝘢𝘭 𝘳𝘦𝘥𝘶𝘤𝘵𝘪𝘰𝘯 𝘪𝘯 𝘮𝘰𝘳𝘣𝘪𝘥𝘪𝘵𝘺 𝘰𝘳 𝘮𝘰𝘳𝘵𝘢𝘭𝘪𝘵𝘺 𝘢𝘮𝘰𝘯𝘨 𝘪𝘯𝘥𝘪𝘷𝘪𝘥𝘶𝘢𝘭 𝘵𝘰𝘣𝘢𝘤𝘤𝘰 𝘶𝘴𝘦𝘳𝘴 𝘪𝘴 𝘳𝘦𝘢𝘴𝘰𝘯𝘢𝘣𝘭𝘺 𝘭𝘪𝘬𝘦𝘭𝘺 𝘪𝘯 𝘴𝘶𝘣𝘴𝘦𝘲𝘶𝘦𝘯𝘵 𝘴𝘵𝘶𝘥𝘪𝘦𝘴, 𝘢𝘯𝘥 𝘪𝘴𝘴𝘶𝘢𝘯𝘤𝘦 𝘰𝘧 𝘢𝘯 𝘰𝘳𝘥𝘦𝘳 𝘪𝘴 𝘦𝘹𝘱𝘦𝘤𝘵𝘦𝘥 𝘵𝘰 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.” ³
(𝟮) 𝗖𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝘀𝘁𝘂𝗱𝗶𝗲𝘀 𝗶𝗻 𝗴𝗲𝗻𝗲𝗿𝗮𝗹, 𝗯𝘂𝘁 𝘀𝗽𝗲𝗰𝗶𝗳𝗶𝗰𝗮𝗹𝗹𝘆 𝗣𝗠𝗜’𝘀 𝗰𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝘀𝘁𝘂𝗱𝗶𝗲𝘀, 𝘀𝗵𝗼𝘂𝗹𝗱 𝗻𝗼𝘁 𝗯𝗲 𝗲𝘃𝗮𝗹𝘂𝗮𝘁𝗲𝗱 𝗮𝗴𝗮𝗶𝗻𝘀𝘁 𝗽𝗼𝘀𝘁 𝗵𝗼𝗰 𝗼𝗯𝗷𝗲𝗰𝘁𝗶𝘃𝗲𝘀
Braznell et al. fail to acknowledge that almost all of PMI’s clinical studies were specifically designed to deliver the pre-market scientific evidence that regulatory agencies need to authorize modified risk tobacco products (see FDA’s “Modified Risk Tobacco Product Applications. Guidance for Industry” ). ⁴
This means that the study duration, study populations, study endpoints, and analyses are selected to answer very specific research questions and are not designed to assess the overall impact of HTPs on public health by themselves. Some studies were of short duration (e.g., pharmacokinetic/ pharmacodynamic studies); some were performed in confinement because they were designed to provide evidence on the impacts of confirmed complete switching, and some with ambulatory study phases to better evaluate the impacts with a closer representation of real-world use. The ultimate real-world use studies are being conducted in the post-market setting.
It is inappropriate to assess the quality of a diverse set of studies—studies that were specifically designed to answer a range of different scientific questions—against a broad post hoc scientific objective that none of the studies were intended or designed to address by themselves. It is, therefore, misguided for Braznell et al. to conclude that “many characteristics of the reported clinical trials, such as short duration, confined settings, and choice of comparator and participants, are not representative of real-world use and fail to adequately investigate whether HTPs reduce harm and are beneficial to public health.” What the authors describe as “inadequacies” are, in fact, crucial elements of the individual study design.
As a follow-up to these pre-market studies, in 2022, PMI initiated three new clinical studies on IQOS—a 3-year chronic obstructive pulmonary disease (COPD) study (NCT05569005) ⁵, a 1-year cardiovascular disease study (NCT05566678) ⁶, and a cross-sectional study to assess reduced exposure, inflammation, and oxidative stress two years after switching compared to continued smoking (NCT05385055) ⁷—which will examine longer-term switching and clinically relevant health changes in adult smokers who have switched to IQOS. These studies should be reassuring for those who have expressed concern that the assessment of HTPs relies on short-term studies in the absence of long-term epidemiological studies. The authors may perhaps be unaware of more recent epidemiological studies in the published literature (by both PMI and independent researchers), which have assessed the potential impact of HTPs and other smoke-free alternatives in the real world. Choi et al., 2021 ⁸ looked 5.16 million South Korean adult men and concluded that smokers switching to smoke-free products were associated with a lower cardiovascular disease risk than those continuing to smoke cigarettes, although higher than cessation (no smoke-free product use). Van der Plas et al., 2022 ⁹ observed a significant reduction in the number of hospitalizations for COPD and a non-significant reduction in hospitalizations for COPD plus lower respiratory tract infections as well as ischemic heart disease following the introduction of HTPs in a time-trend analysis of the Japanese Medical Data Center (JMDC) database.
(𝟯) 𝗔𝗿𝗲𝗮𝘀 𝗳𝗼𝗿 𝗶𝗺𝗽𝗿𝗼𝘃𝗲𝗺𝗲𝗻𝘁 𝗲𝘅𝗶𝘀𝘁 𝗳𝗼𝗿 𝗮𝗹𝗹 𝗽𝗮𝗿𝘁𝗶𝗲𝘀
We recognize that our reporting on clinicaltrials.gov may not meet the expectations of today; however, at the time the clinical program was initiated, publishing smoking cessation studies was common; however, publishing tobacco and tobacco harm reduction studies in this database was not common; in fact, we were among the first to report these types of studies there and did so to increase our scientific transparency. The authors accurately reflect incomplete reporting on a small number of our clinical studies, including studies on a carbon-heated tobacco product. However, in 2021, we took a decision not to proceed with commercialization ¹⁰, meaning that, according to the authors’ exclusion criteria, this study should not have been part of their analysis. Additionally, we have two studies that have been completed. Although the data for the endpoints have been posted on clinicaltrials.gov and therefore are in the public domain, the study publications with additional secondary and exploratory endpoints have just been or are in the process of being published. Whilst we are actively working on publishing these studies, we acknowledge that this delay in publication is not ideal and must be improved in the future. We recognize the importance of publishing the results of our studies in peer-reviewed journals but also note that we often face significant challenges in achieving timely publication because a number of journals (including Tobacco Control) refuse to accept or even review such publications based purely on affiliation and not the quality of the research.
Constructive criticism of our research is always welcome, but we reject the suggestion that PMI’s clinical studies “ 𝘸𝘦𝘳𝘦 𝘴𝘶𝘣𝘴𝘵𝘢𝘯𝘥𝘢𝘳𝘥 𝘪𝘯 𝘮𝘢𝘯𝘺 𝘳𝘦𝘴𝘱𝘦𝘤𝘵𝘴.” As mentioned above, the FDA conducted a substantive review of our studies, including inspection visits at our facilities and at some of our clinical research partners. FDA noted that their inspections of two U.S. clinical sites “𝘳𝘦𝘷𝘦𝘢𝘭𝘦𝘥 𝘯𝘰 𝘮𝘢𝘫𝘰𝘳 𝘉𝘐𝘔𝘖 [𝘉𝘪𝘰𝘳𝘦𝘴𝘦𝘢𝘳𝘤𝘩 𝘔𝘰𝘯𝘪𝘵𝘰𝘳𝘪𝘯𝘨] 𝘪𝘴𝘴𝘶𝘦𝘴 𝘰𝘳 𝘤𝘭𝘪𝘯𝘪𝘤𝘢𝘭𝘭𝘺-𝘴𝘪𝘨𝘯𝘪𝘧𝘪𝘤𝘢𝘯𝘵 𝘱𝘳𝘰𝘵𝘰𝘤𝘰𝘭 𝘥𝘦𝘷𝘪𝘢𝘵𝘪𝘰𝘯𝘴 𝘵𝘩𝘢𝘵 𝘸𝘰𝘶𝘭𝘥 𝘤𝘰𝘮𝘱𝘳𝘰𝘮𝘪𝘴𝘦 𝘥𝘢𝘵𝘢 𝘷𝘢𝘭𝘪𝘥𝘪𝘵𝘺 𝘢𝘯𝘥 𝘪𝘯𝘵𝘦𝘨𝘳𝘪𝘵𝘺.” In addition, the results of the authors’ own review confirm the appropriate design and conduct of our studies (i.e., low risk of bias). Therefore, the authors’ non-scientific statement that their failure to find significant differences in the risks of bias between the trials from different affiliations should only be interpreted as “𝘢𝘣𝘴𝘦𝘯𝘤𝘦 𝘰𝘧 𝘦𝘷𝘪𝘥𝘦𝘯𝘤𝘦, 𝘯𝘰𝘵 𝘦𝘷𝘪𝘥𝘦𝘯𝘤𝘦 𝘰𝘧 𝘢𝘣𝘴𝘦𝘯𝘤𝘦” is pure speculation and has no basis in fact in regard to PMI’s studies.
In the spirit of constructive criticism, we note that whilst the authors were investigating the possibility of bias in PMI’s studies, it is possible that their own bias may be affecting their interpretation of results. When disclosing their competing interests, they fail to note that their own affiliation with, and funding from, Bloomberg Philanthropies’ “𝘚𝘛𝘖𝘗: 𝘚𝘵𝘰𝘱𝘱𝘪𝘯𝘨 𝘛𝘰𝘣𝘢𝘤𝘤𝘰 𝘖𝘳𝘨𝘢𝘯𝘪𝘻𝘢𝘵𝘪𝘰𝘯𝘴 𝘢𝘯𝘥 𝘗𝘳𝘰𝘥𝘶𝘤𝘵𝘴” could create a risk of bias. In fact, that potential for bias is plain since the lead author has previously written that “𝘵𝘩𝘦𝘳𝘦 𝘪𝘴 𝘭𝘪𝘵𝘵𝘭𝘦 𝘳𝘰𝘭𝘦 𝘧𝘰𝘳 𝘩𝘦𝘢𝘵𝘦𝘥 𝘵𝘰𝘣𝘢𝘤𝘤𝘰 𝘱𝘳𝘰𝘥𝘶𝘤𝘵𝘴 𝘢𝘵 𝘦𝘪𝘵𝘩𝘦𝘳 𝘪𝘯𝘥𝘪𝘷𝘪𝘥𝘶𝘢𝘭 𝘰𝘳 𝘱𝘰𝘱𝘶𝘭𝘢𝘵𝘪𝘰𝘯 𝘭𝘦𝘷𝘦𝘭” and that “𝘩𝘦𝘢𝘵𝘦𝘥 𝘵𝘰𝘣𝘢𝘤𝘤𝘰 𝘱𝘳𝘰𝘥𝘶𝘤𝘵𝘴 𝘩𝘢𝘷𝘦 𝘯𝘰 𝘱𝘶𝘣𝘭𝘪𝘤 𝘩𝘦𝘢𝘭𝘵𝘩 𝘳𝘰𝘭𝘦.” ¹¹ This potential conflict was not made clear to readers. The reference by Bero ¹² used by the authors in their introduction states that “𝘤𝘰𝘯𝘴𝘪𝘥𝘦𝘳𝘢𝘵𝘪𝘰𝘯 𝘴𝘩𝘰𝘶𝘭𝘥 𝘣𝘦 𝘨𝘪𝘷𝘦𝘯 𝘵𝘰 𝘢𝘧𝘧𝘪𝘭𝘪𝘢𝘵𝘪𝘰𝘯 𝘰𝘳 𝘪𝘯𝘵𝘦𝘳𝘦𝘴𝘵 𝘨𝘳𝘰𝘶𝘱 𝘣𝘪𝘢𝘴.” Bero notes that “[𝘢]𝘯 𝘪𝘯𝘵𝘦𝘳𝘦𝘴𝘵 𝘨𝘳𝘰𝘶𝘱 𝘪𝘴 𝘢𝘯 𝘰𝘳𝘨𝘢𝘯𝘪𝘻𝘦𝘥 𝘨𝘳𝘰𝘶𝘱 𝘸𝘪𝘵𝘩 𝘢 𝘯𝘢𝘳𝘳𝘰𝘸𝘭𝘺 𝘥𝘦𝘧𝘪𝘯𝘦𝘥 𝘷𝘪𝘦𝘸𝘱𝘰𝘪𝘯𝘵, 𝘸𝘩𝘪𝘤𝘩 𝘱𝘳𝘰𝘵𝘦𝘤𝘵𝘴 𝘪𝘵𝘴 𝘱𝘰𝘴𝘪𝘵𝘪𝘰𝘯 𝘰𝘳 𝘱𝘳𝘰𝘧𝘪𝘵𝘴. 𝘛𝘩𝘦𝘴𝘦 𝘨𝘳𝘰𝘶𝘱𝘴 𝘢𝘳𝘦 𝘯𝘰𝘵 𝘦𝘹𝘤𝘭𝘶𝘴𝘪𝘷𝘦𝘭𝘺 𝘣𝘶𝘴𝘪𝘯𝘦𝘴𝘴 𝘨𝘳𝘰𝘶𝘱𝘴 𝘣𝘶𝘵 𝘤𝘢𝘯 𝘪𝘯𝘤𝘭𝘶𝘥𝘦 𝘢𝘭𝘭 𝘬𝘪𝘯𝘥𝘴 𝘰𝘧 𝘰𝘳𝘨𝘢𝘯𝘪𝘻𝘢𝘵𝘪𝘰𝘯𝘴 𝘵𝘩𝘢𝘵 𝘮𝘢𝘺 𝘢𝘵𝘵𝘦𝘮𝘱𝘵 𝘵𝘰 𝘪𝘯𝘧𝘭𝘶𝘦𝘯𝘤𝘦 𝘨𝘰𝘷𝘦𝘳𝘯𝘮𝘦𝘯𝘵𝘴. 𝘐𝘯𝘵𝘦𝘳𝘦𝘴𝘵 𝘨𝘳𝘰𝘶𝘱𝘴 𝘤𝘢𝘯 𝘣𝘦 𝘦𝘹𝘱𝘦𝘤𝘵𝘦𝘥 𝘵𝘰 𝘤𝘰𝘯𝘴𝘵𝘳𝘶𝘤𝘵 𝘵𝘩𝘦 𝘦𝘷𝘪𝘥𝘦𝘯𝘤𝘦 𝘢𝘣𝘰𝘶𝘵 𝘢 𝘩𝘦𝘢𝘭𝘵𝘩 𝘳𝘪𝘴𝘬 𝘵𝘰 𝘴𝘶𝘱𝘱𝘰𝘳𝘵 𝘵𝘩𝘦𝘪𝘳 𝘱𝘳𝘦𝘥𝘦𝘧𝘪𝘯𝘦𝘥 𝘱𝘰𝘭𝘪𝘤𝘺 𝘱𝘰𝘴𝘪𝘵𝘪𝘰𝘯.” We encourage the authors to transparently disclose that their own funding from, and affiliation with, “𝘚𝘛𝘖𝘗: 𝘚𝘵𝘰𝘱𝘱𝘪𝘯𝘨 𝘛𝘰𝘣𝘢𝘤𝘤𝘰 𝘖𝘳𝘨𝘢𝘯𝘪𝘻𝘢𝘵𝘪𝘰𝘯𝘴 𝘢𝘯𝘥 𝘗𝘳𝘰𝘥𝘶𝘤𝘵𝘴”—an interest group that actively campaigns against HTPs, the tobacco industry, and PMI—presents a potential conflict of interest.
(𝟰) 𝗖𝗼𝗻𝗰𝗹𝘂𝘀𝗶𝗼𝗻
There are legitimate concerns about bringing any new nicotine or tobacco product to the market, but these concerns should be considered against the backdrop of the science that is known about smoking. People who smoke and regulators will best be served by informing them of the relative risks of such products compared to continuing to smoke. This requires an unbiased review of the existing science whilst continuing to study the impact on individual and public health. Such actions will help and inform those who currently smoke to transition away from cigarettes and non-smokers not to start to use any nicotine or tobacco product.
(𝟱) 𝗥𝗲𝗳𝗲𝗿𝗲𝗻𝗰𝗲
1.) Braznell S, Van Den Akker A, Metcalfe C, et alCritical appraisal of interventional clinical trials assessing heated tobacco products: a systematic review. Tobacco Control Published Online First: 08 November 2022. doi: 10.1136/tc-2022-057522
2.) Tattan-Birch_H, Hartmann-Boyce_J, Kock_L, Simonavicius_E, Brose_L, Jackson_S, Shahab_L, Brown_J. Heated tobacco products for smoking cessation and reducing smoking prevalence. Cochrane Database of Systematic Reviews 2022, Issue 1. Art. No.: CD013790. https://doi.org/10.1002/14651858.CD013790.pub2
3.) Food and Drug Administration (2020) Scientific Review of Modified Risk Tobacco Product Application (MRTPA) STNs MR0000059 - MR0000061, MR0000133 -Technical Project Lead Document (https://www.fda.gov/media/139796/download)
4.) Food and Drug Administration (FDA) (2012): Modified Risk Tobacco Product Applications. Guidance for Industry (https://www.fda.gov/media/83300/download).
5.) NCT05569005 (https://www.clinicaltrials.gov/ct2/show/NCT05569005?spons=Philip+Morris&...)
6.) NCT05566678 (https://www.clinicaltrials.gov/ct2/show/NCT05566678?spons=Philip+Morris&...)
7.) NCT05385055 (https://www.clinicaltrials.gov/ct2/show/NCT05385055?spons=Philip+Morris&...)
8.) Choi, S., Lee, K., Park, S.M., (2021) Combined associations of changes in noncombustible nicotine or tobacco product ad combustible cigarette use habits with subsequent short-term cardiovascular disease risk among South Korean men. Circulation, 144: 1521-1538. doi: 10.1161/CIRCULATIONAHA.121.054967
9.) van der Plas A, Antunes M, Romero-Kauss A, Hankins M and Heremans A (2022) Ischemic Heart Disease and Chronic Obstructive Pulmonary Disease Hospitalizations in Japan Before and After the Introduction of a Heated Tobacco Product. Front. Public Health 10:909459. doi: 10.3389/fpubh.2022.909459
10.) Philip Morris International 2021 Annual Report (p42) published on 24.03.2022
11.) Gilmore A B, Braznell S. US regulator adds to confusion around heated tobacco products BMJ 2020; 370 :m3528 doi: 10.1136/bmj.m3528
12.) Bero LA. Tobacco industry manipulation of research. Public Health Rep 2005;120:200–8. doi: 10.1177/003335490512000215
We thank Cummings and colleagues for their interest in and comments on our umbrella review published recently in Tobacco Control.[1] The authors criticize us for not including the latest studies. Yet, for an umbrella review, those studies need to be in a published review to be included, as we indicated in our methods and limitations. Generally, given the lengthy review and publication processes, any review will not be inclusive of all studies in a field that has as high a publication breadth and intensity as tobacco regulatory science. In addition, the authors mentioned that our meta-analysis was not available in PROSPERO pre-registration. This is because the review registration was completed in the very early stages of the review. We have updated this information in PROSPERO now to include the meta-analysis. The issue of overlap was addressed in our limitations, as we had to screen over 3,000 studies included in our selected reviews. However, given the importance of this issue for the meta-analysis, we performed a new meta-analysis that included the individual studies in each domain instead of using the odds ratio reported by the review to eliminate the effect of including the same study more than one time on our results. We confirm that the results of the new meta-analysis, which includes each study only once, are similar to the original meta-analysis (Supplement A: https://www.publichealth.me...
We thank Cummings and colleagues for their interest in and comments on our umbrella review published recently in Tobacco Control.[1] The authors criticize us for not including the latest studies. Yet, for an umbrella review, those studies need to be in a published review to be included, as we indicated in our methods and limitations. Generally, given the lengthy review and publication processes, any review will not be inclusive of all studies in a field that has as high a publication breadth and intensity as tobacco regulatory science. In addition, the authors mentioned that our meta-analysis was not available in PROSPERO pre-registration. This is because the review registration was completed in the very early stages of the review. We have updated this information in PROSPERO now to include the meta-analysis. The issue of overlap was addressed in our limitations, as we had to screen over 3,000 studies included in our selected reviews. However, given the importance of this issue for the meta-analysis, we performed a new meta-analysis that included the individual studies in each domain instead of using the odds ratio reported by the review to eliminate the effect of including the same study more than one time on our results. We confirm that the results of the new meta-analysis, which includes each study only once, are similar to the original meta-analysis (Supplement A: https://www.publichealth.med.miami.edu/_assets/pdf/meta-analysis.pdf).
The authors also accuse us of not being transparent about our adopted classification of evidence strategy, while a careful check of the reference we provided shows it (Morton et al. Page 131 (Box 4-2).[2] This classification is also adopted by the National Academies of Sciences.[3] Our assessment of the gateway effect as high evidence is consistent with this classification (National Academies of Sciences, Engineering, and Medicine 2018; Page 5, Box S-2: High evidence (including conclusive and substantial) (Supplement B: https://www.publichealth.med.miami.edu/_assets/pdf/level-of-evidence.pdf).[3] Generally, we object to the authors’ characterization that observational studies cannot imply causality. In fact, carefully designed observational studies led to most of what we know about major risks to health, such as smoking, hypertension, diabetes, and high cholesterol levels.[4-7]
We excluded research supported by the tobacco industry, given the ample evidence of the industry's fraudulent scientific behavior, which prompts objective scientists to question the extent to which industry-sponsored authors report methods and results accurately.[8, 9] We note that our stance regarding industry-supported publications is also consistent with the policy of Tobacco Control. Contrary to the commentary’s critique, the message about nicotine’s effect on the developing brain is supported by evidence from human and animal studies and endorsed by the CDC as well as major credible public health bodies.[10-13]
The authors state that comparing ENDS to cigarette smoking is needed, given their potential to help addicted smokers quit. Alas, an accurate comparison of these products is currently not feasible. Unlike cigarettes, which were suspected of causing lung cancer as far back as the late 19th century and for which we have more than a half-century of robust evidence of the health effects, we have much more modest literature on ENDS health effects, spanning less than two decades.[14] Also, unlike today’s combustible cigarette, a rather standardized tobacco use method with a standardized pattern of use and standardized assessment tools, ENDS are not standardized. The heterogeneity of ENDS products, their use patterns, and still nascent long-term ENDS exposure assessment tools make accurate comparisons impossible. In fact, even the same product, manufactured by the same maker, can have variability in its liquid content and ingredient proportions.[15] While the commentary criticized our review based on the acknowledged lack of long-term data about ENDS effects on health, they make an unsubstantiated claim that the group most likely to use ENDS on a persistent basis are smokers.
To navigate the complexity of ENDS, we adopted a consumer rights stand that recognizes that every consumer needs to be aware of the potential risks and benefits of the products they are using. So, although the evidence is inconclusive about the real-world effects of ENDS in helping smokers quit, and the fact that the FDA has not yet approved any of them as a cessation device, we have created some messages to support this based on evidence from randomized clinical trials.[16] We agree that it will take more time before robust scientific evidence about the long-term effects of ENDS accumulates, but this lack of knowledge should not be an excuse for failing to alert users of potential adverse health consequences of ENDS use. The public has a right to know whether any novel product that was being used by a significant proportion of the population contains known toxicants, despite lacking robust evidence of long-term effects on health. Why should ENDS be any different?
References
1. Asfar, T., et al., Risk and safety profile of electronic nicotine delivery systems (ENDS): an umbrella review to inform ENDS health communication strategies. Tobacco Control, 2022: p. tobaccocontrol-2022-057495.
2. Morton, S., et al., Finding what works in health care: standards for systematic reviews. 2011.
3. National Academies of Sciences, E., Medicine., Public health consequences of e-cigarettes. 2018.
4. Mahmood, S.S., et al., The Framingham Heart Study and the epidemiology of cardiovascular disease: a historical perspective. The lancet, 2014. 383(9921): p. 999-1008.
5. Doll, R., et al., Mortality in relation to smoking: 50 years' observations on male British doctors. Bmj, 2004. 328(7455): p. 1519.
6. Kannel, W.B. and D.L. McGee, Diabetes and cardiovascular disease: the Framingham study. Jama, 1979. 241(19): p. 2035-2038.
7. Castelli, W.P., et al., Incidence of coronary heart disease and lipoprotein cholesterol levels: the Framingham Study. Jama, 1986. 256(20): p. 2835-2838.
8. Kessler, G., Amended Final Opinion. USA v. Philip Morris, 2006.
9. Pisinger, C., N. Godtfredsen, and A.M. Bender, A conflict of interest is strongly associated with tobacco industry-favourable results, indicating no harm of e-cigarettes. Prev Med, 2019. 119: p. 124-131.
10. Centers for Disease Control and Prevention. It’s not like you can buy a new brain. 2019 [cited 2022 November 29th]; Available from: https://www.cdc.gov/tobacco/basic_information/e-cigarettes/Quick-Facts-o...
11. Goriounova, N.A. and H.D. Mansvelder, Short-and long-term consequences of nicotine exposure during adolescence for prefrontal cortex neuronal network function. Cold Spring Harbor perspectives in medicine, 2012. 2(12): p. a012120.
12. England, L.J., et al., Nicotine and the developing human: a neglected element in the electronic cigarette debate. American journal of preventive medicine, 2015. 49(2): p. 286-293.
13. Surgeon General, U., E-Cigarette Use Among Youth and Young Adults. A Report of the Surgeon General. 2016, Retrieved from Atlanta, GA: https://ecigarettes. surgeongeneral. gov ….
14. Proctor, R.N., The history of the discovery of the cigarette–lung cancer link: evidentiary traditions, corporate denial, global toll. Tobacco control, 2012. 21(2): p. 87-91.
15. Yassine, A., et al., Did JUUL alter the content of menthol pods in response to US FDA flavour enforcement policy? Tobacco control, 2022. 31(Suppl 3): p. s234-s237.
16. Hajek, P., et al., A Randomized Trial of E-Cigarettes versus Nicotine-Replacement Therapy. N Engl J Med, 2019. 380(7): p. 629-637.
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Show MorePichon-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‐cigare...
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Dear Editor,
Show MoreWe commend Bakhturidze et al. for their study titled as ‘Smoke-Free Legislation Impact on the Hospitality Sector in the Republic of Georgia’ [1]. Their research is a new addition to the global evidence that smoke-free (SF) policies not only protect public health but also support the economic growth of the hospitality industry. The study’s results are particularly relevant given the ongoing discussions globally and tobacco industry’s claim about the negative impact of SF laws on business sectors like hospitality [2].
While the analysis presented is robust, one limitation lies in its reliance on linear regression models, particularly given the limited number of data points available. More granular analyses, such as region or city-specific data, could provide additional insights into how SF legislation impacts different areas of Georgia, revealing potential variations that may be masked in the national aggregated data. We also note an inconsistency, as the reference 11, pertaining to year 2013 was used to support the statement, “On May 1, 2018, Georgia fully implemented the FCTC SF policy…” that suggested an activity of future. The global death toll due to secondhand smoke (SHS) in 2019 was 1.3 million not 1.2 million as reported in the reference 1, citing a Global Burden of Disease study. However, a study titled “Global, regional, and national deaths, disability-adjusted life years, years lived with disability, and years of l...
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We value the opportunity to respond to the Special Communication by Soule et al. that reviewed our three publications [1]. We believe that continued discussion of methods and findings is both healthy and necessary to advance the science and foster more accurate understandings.
Turning to the more specific points raised in their paper, for each of the three cited studies, we provide responses to the most pertinent issues discussed.
Goldenson et al., 2020, Drug and Alcohol Dependence, 217, 108395:
We agree that experimental design and procedure are critical elements of clinical laboratory studies that should be carefully considered and evaluated. Particularly for pharmacokinetic studies of tobacco products, the product use procedure can influence nicotine uptake. In the cited publication by Goldenson et al. [2], it was noted that the controlled use procedure (i.e., 10 uniform puffs 3 s in duration for all products) enabled standardized comparisons among the seven study test products, resulting in high internal validity, whereas an ad libitum use procedure would facilitate more naturalistic use patterns and enhance external validity. Subsequent pharmacokinetic studies of JUUL products that have in fact used ad libitum use procedures [3] or both controlled and ad libitum use procedures [4, 5] consistently demonstrate that JUUL products deliver significantly lower levels of nicotine than combustible cigarettes, confirming the conclu...
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How can the special communication promoting the 2040 Tobacco- Free Generation goal of the European Union (1) flew in the face of the warning “we are still waiting for the European political commitment to quit tobacco.”(2)
Firstly, the communication of the goal by the Commission in 2021 remains empty words yet. Of note, the most recent directive for tobacco control, proposed by the Commission in 2012, only became applicable in 2016.
Secondly, promises only bind those who believe in them. Europe will be the only WHO region not to reach the global non-communicable diseases target by 2025,(2) Could the new goal be achievable : a) when smoking prevalence only decreased form 24% in 2010 to 19% in 2020;(3) b) when the reduction in nicotine content, a silver bullet vs young uptake, is totally ignored and when responses about measures were only obtained from 19 of 27 EU Member states,(1) questioning their implication.(1) As a French, I want to stress that in 2019, France was among the six countries globally with a smoking prevalence above 33% among people aged 15-24.(4) Its recent plan raises cigarette retail prices to €12 in 2025, and to €13 in 2026, is less than the 10% threshold for a 4% impact on sales, not to account the present high inflation rates that seriously blunt the true increase. This deliberate strategy from experts in Laffer curve accounts for the low price elasticity of a highly addictive substance in order to increase reven...
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I respectfully request answers to the following questions:
1. Was public use or restricted PATH data used. This is important, since Table 2 contains a cell, n=7, that is not generally approved by NAHDAP.
2. Was the PATH cohort drawn from Waves 1 and 4, with follow-ups to age 17 years as needed from the other waves?
3. There were significant differences in youth smoking-vaping between Wave 1 (2013-14) and Wave 4 (2016-18) that might have affected the results. Was each wave analyzed separately as well as together?
4. The analysis included a variable relating to “parent(s) smoking of cigarettes, cigars, or pipes.” Did the analysis include other combustible tobacco product consumption by the subjects themselves?
5. Did the authors account for age at first smoking or vaping (public use, < 12 years and 12-14 years) or which product(s) had been used first?
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Regarding the first two questions, the analyses were based on the public use data from both the PATH Study and the MCS, with links to their archives, and the PATH study sample was drawn from the original cohort, the replenishment cohort, and the shadow cohorts (see 1st and 2nd paragraphs of Methods Section). Regarding the remaining questions, please note that our stated goal was to make the MCS and PATH analytical samples as comparable as possible when testing our hypotheses using both cohorts (3rd paragraph of Methods section). As we note in the limitations section (5th paragraph of Discussion section), the MCS had relatively limited items on e-cigarette use and tobacco smoking compared to PATH. The MCS did not assess other combustible tobacco product consumption in early adolescence, nor did MCS measure the sequencing of early adolescent tobacco and e-cigarette use (noted in the limitation section). Also, MCS youth answered survey questions about ever using e-cigarettes from 2015 to 2016 (3rd paragraph of Methods section), which gave us limited variability to test for a wave x e-cigarette interaction in both datasets.
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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 o...
Show MoreThe 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).
Show MoreAn 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...
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The objective of the systematic review by Braznell et al. was “𝘵𝘰 𝘤𝘳𝘪𝘵𝘪𝘤𝘢𝘭𝘭𝘺 𝘢𝘴𝘴𝘦𝘴𝘴 𝘵𝘩𝘦 𝘮𝘦𝘵𝘩𝘰𝘥𝘰𝘭𝘰𝘨𝘪𝘤𝘢𝘭 𝘤𝘩𝘢𝘳𝘢𝘤𝘵𝘦𝘳𝘪𝘴𝘵𝘪𝘤𝘴 𝘢𝘯𝘥 𝘲𝘶𝘢𝘭𝘪𝘵𝘺 𝘰𝘧 𝘪𝘯𝘵𝘦𝘳𝘷𝘦𝘯𝘵𝘪𝘰𝘯𝘢𝘭 𝘤𝘭𝘪𝘯𝘪𝘤𝘢𝘭 𝘵𝘳𝘪𝘢𝘭𝘴 𝘪𝘯𝘷𝘦𝘴𝘵𝘪𝘨𝘢𝘵𝘪𝘯𝘨 𝘵𝘩𝘦 𝘦𝘧𝘧𝘦𝘤𝘵𝘴 𝘰𝘧 𝘩𝘦𝘢𝘵𝘦𝘥 𝘵𝘰𝘣𝘢𝘤𝘤𝘰 𝘱𝘳𝘰𝘥𝘶𝘤𝘵𝘴 (𝘏𝘛𝘗𝘴).” ¹ The review was intended to examine the quality of HTP clinical trials “𝘣𝘦𝘧𝘰𝘳𝘦 𝘤𝘰𝘯𝘴𝘶𝘮𝘦𝘳𝘴 𝘢𝘯𝘥 𝘳𝘦𝘨𝘶𝘭𝘢𝘵𝘰𝘳𝘴 𝘮𝘢𝘬𝘦 𝘪𝘮𝘱𝘰𝘳𝘵𝘢𝘯𝘵 𝘥𝘦𝘤𝘪𝘴𝘪𝘰𝘯𝘴 𝘣𝘢𝘴𝘦𝘥 𝘰𝘯 𝘵𝘩𝘦 𝘳𝘦𝘴𝘶𝘭𝘵𝘴 𝘰𝘧 𝘵𝘩𝘦𝘴𝘦 𝘴𝘵𝘶𝘥𝘪𝘦𝘴.” We have three important observations in relation to Philip Morris International’s (PMI) clinical program, which impact the interpretation of the authors’ broad-reaching conclusions.
(𝟭) 𝗥𝗲𝗴𝘂𝗹𝗮𝘁𝗼𝗿𝘆 𝗱𝗲𝗰𝗶𝘀𝗶𝗼𝗻𝘀 𝗵𝗮𝘃𝗲 𝗯𝗲𝗲𝗻 𝗺𝗮𝗱𝗲 𝗯𝗮𝘀𝗲𝗱 𝗼𝗻 𝗣𝗠𝗜’𝘀 𝗰𝗹𝗶𝗻𝗶𝗰𝗮𝗹 𝘀𝘁𝘂𝗱𝗶𝗲𝘀, 𝘄𝗵𝗶𝗰𝗵 𝘄𝗲𝗿𝗲 𝗷𝘂𝗱𝗴𝗲𝗱 𝘁𝗼 𝗯𝗲 𝗮𝘁 𝗹𝗼𝘄 𝗿𝗶𝘀𝗸 𝗼𝗳 𝗯𝗶𝗮𝘀
Whilst we will only comment on the clinical studies performed by PMI, we were pleased to see the confirmation that the study designs in our clinical assessment program were not significantly associated with a risk of bias. The authors judged that all Tobacco Heating System (marketed as IQOS) clinical studies submitted to the United States Food and Drug Administration (FDA) and other regulators were at low risk of bias when the authors excluded “blinding of participants and personnel” to the product, due to the impracticality of concealing visually distinctive products. The authors also noted that the scoring was slightly improved when compared to a similar exercise performed as part of the recent Cochrane review. ²
We agree that regulatory decisio...
Show MoreWe thank Cummings and colleagues for their interest in and comments on our umbrella review published recently in Tobacco Control.[1] The authors criticize us for not including the latest studies. Yet, for an umbrella review, those studies need to be in a published review to be included, as we indicated in our methods and limitations. Generally, given the lengthy review and publication processes, any review will not be inclusive of all studies in a field that has as high a publication breadth and intensity as tobacco regulatory science. In addition, the authors mentioned that our meta-analysis was not available in PROSPERO pre-registration. This is because the review registration was completed in the very early stages of the review. We have updated this information in PROSPERO now to include the meta-analysis. The issue of overlap was addressed in our limitations, as we had to screen over 3,000 studies included in our selected reviews. However, given the importance of this issue for the meta-analysis, we performed a new meta-analysis that included the individual studies in each domain instead of using the odds ratio reported by the review to eliminate the effect of including the same study more than one time on our results. We confirm that the results of the new meta-analysis, which includes each study only once, are similar to the original meta-analysis (Supplement A: https://www.publichealth.me...
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