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The reporting of the results of this study is far from complete, which is concerning given the highly politicised controversy that surrounds this product. I hope the authors should respond to this comment by publishing supplementary material with all the data they collected in a an accessible form such a CSV file and summarised in tables in a supplementary memo.
In particular, the authors should provide all data on the following:
+ Vaping and JUUL current use (used in past 30-days) prevalence stratified by age, clearly differentiating between 18 and over and under-18s
+ Frequency of use of vaping products and JUUL within the 30 days among current (past-30 days) users, ideally using the same frequency breakdown used in the National Youth Tobacco Survey
+ Breakdown of vaping status by smoking status and frequency of vaping and JUUL use - to help determine the extent to which regular JUUL use is concentrated among smokers
+ Smoking prevalence and frequency
There is a rare opportunity to gain insights into a live controversy, yet the reporting of the survey is so incomplete it is difficult to draw any serious conclusions from it about the overall effect. For example, JUUL maybe displacing other vaping products used by youth as it is in the market overall. JUUL may be functioning as an alternative to smoking in both adolescents and adults and contributing to achieving smoke-free public health objectives.
NOT PEER REVIEWED
The reporting of the results of this study is far from complete, which is concerning given the highly politicised controversy that surrounds this product. I hope the authors should respond to this comment by publishing supplementary material with all the data they collected in a an accessible form such a CSV file and summarised in tables in a supplementary memo.
In particular, the authors should provide all data on the following:
+ Vaping and JUUL current use (used in past 30-days) prevalence stratified by age, clearly differentiating between 18 and over and under-18s
+ Frequency of use of vaping products and JUUL within the 30 days among current (past-30 days) users, ideally using the same frequency breakdown used in the National Youth Tobacco Survey
+ Breakdown of vaping status by smoking status and frequency of vaping and JUUL use - to help determine the extent to which regular JUUL use is concentrated among smokers
+ Smoking prevalence and frequency
There is a rare opportunity to gain insights into a live controversy, yet the reporting of the survey is so incomplete it is difficult to draw any serious conclusions from it about the overall effect. For example, JUUL maybe displacing other vaping products used by youth as it is in the market overall. JUUL may be functioning as an alternative to smoking in both adolescents and adults and contributing to achieving smoke-free public health objectives.
The Truth Initiative is proud of its advocacy for young people, but as far as presentation and interpretation of data are concerned, such activist commitment amounts to a competing interest. For that reason, everyone, including Truth, is served by full disclosure of the survey data in an appropriate and accessible form and answers to key data questions that would help understand the JUUL phenomenon.
NOT PEER REVIEWED
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 a...
NOT PEER REVIEWED
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
NOT PEER REVIEWED
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 a...
NOT PEER REVIEWED
The potential presence of formaldehyde cyanohydrin in the polylactic acid (PLA) filter of Marlboro Heatstick when heated was reported by Davis and al. PLA is a biodegradable thermoplastic derived from renewable resources such as corn starch. This tentative identification is based on the GC-MS analysis of the headspace of a heated piece of PLA, and the subsequent compound identification by mass spectra matching (acceptance criteria >85%) with the spectra library of the National Institute of Standard and Technology (NIST). However, this was not confirmed by injecting a purchased analytical grade reference standard, in order to unambiguously prove the presence of formaldehyde cyanohydrin. Therefore, we decided to repeat the experiment using headspace injection gas chromatography coupled to high resolution mass spectrometry under similar conditions as described in the publication. Our headspace GC-HR-MS analyses showed four peaks, at retention times of 16.38, 16.47, 17.14, and 18.58 min, in good agreement with the reported data reported (figure 4).
From the analysis of reference standards, we have confirmed the presence of both e-caprolactone (CAS# 502-44-3) and (S,S)-lactide (CAS# 4511-42-6) eluting at 16.47 and 17.14 min, respectively. We identified triacetin (CAS# 102-76-1) at 18.58 min, based on the reference standard, instead of 1,2-diacetin (their EI mass spectra are very similar).
However, we have demonstrated unambiguously the absence of formaldehyde cyanohydrin by injecting the reference standard (Sigma, CAS# 107-16-4, ref. 50640). The formaldehyde cyanohydrin is eluting at 11.53 min and does not correspond to the peak eluting just before e-caprolactone that the authors tentatively identified as formaldehyde cyanohydrin (17.97 min under their conditions). This peak has been confirmed, using the purchased reference standard (NatureWorks, CAS # 13076-19-2), to be meso-lactide, the third isomers of lactide. The experimental details are available on PMIScience.com (https://www.pmiscience.com/library/publication/analysis-of-polylactic-ac...).
It is well known among analytical chemists that unit mass matching with a single data base is insufficient to prove the identity of a compound. Therefore, we typically use commercially available reference standards to verify our findings. This is important to us, as we are focused on developing reduced risk alternatives to combustible cigarettes. In this context, it is key that our science is always verified to the highest possible standards.
NOT PEER REVIEWED
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 th...
NOT PEER REVIEWED
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
NOT PEER REVIEWED The Jawad et al systematic review and meta-analysis examining price effects for non-cigarette tobacco and nicotine products appears methodologically sound and was a registered analysis. It provides information that could be used productively by advocates and policymakers seeking to reduce harm. The cross-elasticities reported in this paper can be used to the advantage of public health by increasing the impact of policies that seek to drive down smoking.
However, this work does not take into account the fact that not all tobacco and nicotine products cause the same level of health harms as combustible cigarettes. The paper examines own- and cross-price elasticity across a wide array of products – from combustible tobacco products such as kreteks and little cigars to nicotine-only products such as e-cigarettes and nicotine patches – and then discusses consumption patterns in terms of an undifferentiated aggregate of nicotine use. Jawad and colleagues do not consider the health implications of policies to move nicotine users from more-harmful to less-harmful means of administration (see, for example, Chaloupka, Warner and Sweanor, 2015, recommending differential taxation according to differential risk).
From a public health perspective, any analysis of nicotine-use patterns should consider differential harm levels. A focus on nicotine use as the sole outcome variable can be seriously misleading and detrimental to the goal of reducing smoking....
NOT PEER REVIEWED The Jawad et al systematic review and meta-analysis examining price effects for non-cigarette tobacco and nicotine products appears methodologically sound and was a registered analysis. It provides information that could be used productively by advocates and policymakers seeking to reduce harm. The cross-elasticities reported in this paper can be used to the advantage of public health by increasing the impact of policies that seek to drive down smoking.
However, this work does not take into account the fact that not all tobacco and nicotine products cause the same level of health harms as combustible cigarettes. The paper examines own- and cross-price elasticity across a wide array of products – from combustible tobacco products such as kreteks and little cigars to nicotine-only products such as e-cigarettes and nicotine patches – and then discusses consumption patterns in terms of an undifferentiated aggregate of nicotine use. Jawad and colleagues do not consider the health implications of policies to move nicotine users from more-harmful to less-harmful means of administration (see, for example, Chaloupka, Warner and Sweanor, 2015, recommending differential taxation according to differential risk).
From a public health perspective, any analysis of nicotine-use patterns should consider differential harm levels. A focus on nicotine use as the sole outcome variable can be seriously misleading and detrimental to the goal of reducing smoking.
Cited Reference
Chaloupka, FJ, Sweanor D, Warner KE. Differential taxes for differential risks—toward reduced harm from nicotine-yielding products. N Engl J Med 2015 Aug 13;373(7): 594-7.
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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...
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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.
NOT PEER REVIEWED The main problem with the claim of equivalence between smoking and switching to iQOS is that some biomarkers of potential harm change over a much longer timeframe than the 90-day duration of the trials. Biomarkers of potential harm can reflect years of accumulated physical changes arising from smoking and only improve slowly after smoking cessation. The trial did, of course, pick up very substantial reductions in biomarkers of exposure, which would, over time, emerge as reductions in biomarkers of potential harm.
This would have been apparent and obvious to readers if the paper had also shown the results for the third arm of the trial, smoking abstinence. The biomarkers of potential harm for smoking abstinence and for switching to iQOS are quite similar in this trial. This is a curious omission. Furthermore, biomarkers of exposure turned quite similar for both switching to iQOS and smoking abstinence - both are greatly reduced, which is an encouraging finding about the iQOS product.
It is unlikely that anyone would argue against smoking abstinence on the basis of the biomarkers of potential harm in the original PMI study. However, the author has selectively used the iQOS data from these trials without the context of the smoking abstinence data to oppose the Modified Tobacco Product Application that PMI made to the U.S. FDA - the author's attempt to block this reduced-risk product from entering the US market. ...
NOT PEER REVIEWED The main problem with the claim of equivalence between smoking and switching to iQOS is that some biomarkers of potential harm change over a much longer timeframe than the 90-day duration of the trials. Biomarkers of potential harm can reflect years of accumulated physical changes arising from smoking and only improve slowly after smoking cessation. The trial did, of course, pick up very substantial reductions in biomarkers of exposure, which would, over time, emerge as reductions in biomarkers of potential harm.
This would have been apparent and obvious to readers if the paper had also shown the results for the third arm of the trial, smoking abstinence. The biomarkers of potential harm for smoking abstinence and for switching to iQOS are quite similar in this trial. This is a curious omission. Furthermore, biomarkers of exposure turned quite similar for both switching to iQOS and smoking abstinence - both are greatly reduced, which is an encouraging finding about the iQOS product.
It is unlikely that anyone would argue against smoking abstinence on the basis of the biomarkers of potential harm in the original PMI study. However, the author has selectively used the iQOS data from these trials without the context of the smoking abstinence data to oppose the Modified Tobacco Product Application that PMI made to the U.S. FDA - the author's attempt to block this reduced-risk product from entering the US market. https://tobacco.ucsf.edu/pmi’s-own-data-biomarkers-potential-harm-americans-show-iqos-not-detectably-different-conventional-cigs
The "serious criticism" that Mr. Bates refers to is from him (on another website).
In order for the FDA to issue an order allowing Philip Morris International to market IQOS in the United States as a reduced risk tobacco product, the law required that, among other things, FDA "determines that the applicant [PMI] has demonstrated that such product [IQOS], as it is actually used by consumers will significantly reduce harm and the risk of tobacco- related disease to individual tobacco users."
That is why PMI provided the information of biomarkers of potential harm to the FDA. and how they compare to values observed in smokers. My paper shows that, using PMI's own data, IQOS will not significantly reduce risk to consumers compared with cigarettes.
Bates ignores this reality and instead talks about biomarkers of exposure, which is a different question.
NOT PEER REVIEWED
This study has some important findings that could, if replicated, guide FDA decision making on applications from manufacturers to make modified risk tobacco product claims. However, while it does not detract from the study’s findings, the article does not accurately describe the standards FDA must apply when evaluating those applications. The abstract inaccurately suggests that tobacco products in the U.S. may make reduced-risk or reduced-exposure claims so long as they are not misleading, and does not mention that any explicit or implicit reduced-exposure or reduced-risk claims may not be legally made without first submitting an application to FDA and receiving a permissive order, which considers various other factors, as well.
The introduction of the paper does a bit better, accurately stating that the Tobacco Control Act requires prior review by FDA before making lower-exposure or lower-risk claims. But it then suggests that manufacturers can receive that permission if they either demonstrate that the product lowers harm or risk compared with other tobacco products or if they demonstrate that the product is free of or contains reduced levels of harmful chemicals and the related claims don’t mislead consumers to believe that the reduced-exposure means lower risk. While that description is accurate as far as it goes, it leaves off the enormously important requirement, in both cases, that a manufacturer’s application for permission to...
NOT PEER REVIEWED
This study has some important findings that could, if replicated, guide FDA decision making on applications from manufacturers to make modified risk tobacco product claims. However, while it does not detract from the study’s findings, the article does not accurately describe the standards FDA must apply when evaluating those applications. The abstract inaccurately suggests that tobacco products in the U.S. may make reduced-risk or reduced-exposure claims so long as they are not misleading, and does not mention that any explicit or implicit reduced-exposure or reduced-risk claims may not be legally made without first submitting an application to FDA and receiving a permissive order, which considers various other factors, as well.
The introduction of the paper does a bit better, accurately stating that the Tobacco Control Act requires prior review by FDA before making lower-exposure or lower-risk claims. But it then suggests that manufacturers can receive that permission if they either demonstrate that the product lowers harm or risk compared with other tobacco products or if they demonstrate that the product is free of or contains reduced levels of harmful chemicals and the related claims don’t mislead consumers to believe that the reduced-exposure means lower risk. While that description is accurate as far as it goes, it leaves off the enormously important requirement, in both cases, that a manufacturer’s application for permission to make a modified-risk claim must also show that the proposed claim will benefit the health of the population as a whole (taking into consideration impacts of the product and its marketing with the modified-risk claim on implementation, cessation, relapse, etc.).
This study’s findings could have been presented even more powerfully if the article had also discussed their relevance to FDA’s consideration of how reduced-risk or reduced-exposure claims would impact the public health based on the claims likely influence on youth and adult consumer behaviors.
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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 3...
NOT PEER REVIEWED
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
The reporting of the results of this study is far from complete, which is concerning given the highly politicised controversy that surrounds this product. I hope the authors should respond to this comment by publishing supplementary material with all the data they collected in a an accessible form such a CSV file and summarised in tables in a supplementary memo.
In particular, the authors should provide all data on the following:
+ Vaping and JUUL current use (used in past 30-days) prevalence stratified by age, clearly differentiating between 18 and over and under-18s
+ Frequency of use of vaping products and JUUL within the 30 days among current (past-30 days) users, ideally using the same frequency breakdown used in the National Youth Tobacco Survey
+ Breakdown of vaping status by smoking status and frequency of vaping and JUUL use - to help determine the extent to which regular JUUL use is concentrated among smokers
+ Smoking prevalence and frequency
There is a rare opportunity to gain insights into a live controversy, yet the reporting of the survey is so incomplete it is difficult to draw any serious conclusions from it about the overall effect. For example, JUUL maybe displacing other vaping products used by youth as it is in the market overall. JUUL may be functioning as an alternative to smoking in both adolescents and adults and contributing to achieving smoke-free public health objectives.
T...
Show MoreNOT PEER REVIEWED
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).
Show MoreHowever, we have demonstrated unambiguously the a...
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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).
Show MoreHowever, we have demonstrated unambiguously the a...
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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 th...
Show MoreNOT PEER REVIEWED The Jawad et al systematic review and meta-analysis examining price effects for non-cigarette tobacco and nicotine products appears methodologically sound and was a registered analysis. It provides information that could be used productively by advocates and policymakers seeking to reduce harm. The cross-elasticities reported in this paper can be used to the advantage of public health by increasing the impact of policies that seek to drive down smoking.
However, this work does not take into account the fact that not all tobacco and nicotine products cause the same level of health harms as combustible cigarettes. The paper examines own- and cross-price elasticity across a wide array of products – from combustible tobacco products such as kreteks and little cigars to nicotine-only products such as e-cigarettes and nicotine patches – and then discusses consumption patterns in terms of an undifferentiated aggregate of nicotine use. Jawad and colleagues do not consider the health implications of policies to move nicotine users from more-harmful to less-harmful means of administration (see, for example, Chaloupka, Warner and Sweanor, 2015, recommending differential taxation according to differential risk).
From a public health perspective, any analysis of nicotine-use patterns should consider differential harm levels. A focus on nicotine use as the sole outcome variable can be seriously misleading and detrimental to the goal of reducing smoking....
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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...
Show MoreNOT PEER REVIEWED The main problem with the claim of equivalence between smoking and switching to iQOS is that some biomarkers of potential harm change over a much longer timeframe than the 90-day duration of the trials. Biomarkers of potential harm can reflect years of accumulated physical changes arising from smoking and only improve slowly after smoking cessation. The trial did, of course, pick up very substantial reductions in biomarkers of exposure, which would, over time, emerge as reductions in biomarkers of potential harm.
Show MoreThis would have been apparent and obvious to readers if the paper had also shown the results for the third arm of the trial, smoking abstinence. The biomarkers of potential harm for smoking abstinence and for switching to iQOS are quite similar in this trial. This is a curious omission. Furthermore, biomarkers of exposure turned quite similar for both switching to iQOS and smoking abstinence - both are greatly reduced, which is an encouraging finding about the iQOS product.
It is unlikely that anyone would argue against smoking abstinence on the basis of the biomarkers of potential harm in the original PMI study. However, the author has selectively used the iQOS data from these trials without the context of the smoking abstinence data to oppose the Modified Tobacco Product Application that PMI made to the U.S. FDA - the author's attempt to block this reduced-risk product from entering the US market.
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The "serious criticism" that Mr. Bates refers to is from him (on another website).
In order for the FDA to issue an order allowing Philip Morris International to market IQOS in the United States as a reduced risk tobacco product, the law required that, among other things, FDA "determines that the applicant [PMI] has demonstrated that such product [IQOS], as it is actually used by consumers will significantly reduce harm and the risk of tobacco- related disease to individual tobacco users."
That is why PMI provided the information of biomarkers of potential harm to the FDA. and how they compare to values observed in smokers. My paper shows that, using PMI's own data, IQOS will not significantly reduce risk to consumers compared with cigarettes.
Bates ignores this reality and instead talks about biomarkers of exposure, which is a different question.
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This study has some important findings that could, if replicated, guide FDA decision making on applications from manufacturers to make modified risk tobacco product claims. However, while it does not detract from the study’s findings, the article does not accurately describe the standards FDA must apply when evaluating those applications. The abstract inaccurately suggests that tobacco products in the U.S. may make reduced-risk or reduced-exposure claims so long as they are not misleading, and does not mention that any explicit or implicit reduced-exposure or reduced-risk claims may not be legally made without first submitting an application to FDA and receiving a permissive order, which considers various other factors, as well.
The introduction of the paper does a bit better, accurately stating that the Tobacco Control Act requires prior review by FDA before making lower-exposure or lower-risk claims. But it then suggests that manufacturers can receive that permission if they either demonstrate that the product lowers harm or risk compared with other tobacco products or if they demonstrate that the product is free of or contains reduced levels of harmful chemicals and the related claims don’t mislead consumers to believe that the reduced-exposure means lower risk. While that description is accurate as far as it goes, it leaves off the enormously important requirement, in both cases, that a manufacturer’s application for permission to...
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Show MoreMore 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 3...
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