My colleagues and I at the UCSF TCORS submitted this public comment to the FDA. The Regulations.gov tracking number is kta-koyn-mf7k. A PDF is available here.
PMPSA’s Population Health Impact Model for IQOS underestimates the health impact of IQOS, does not adequately address new published research and information on population health impacts, and does not demonstrate benefits to individual or population health, so FDA should not issue an exposure modification MRTP order for IQOS 3
Wendy Max, PhD; Lauren Lempert, JD, MPH; Yingning Wang, PhD; Tingting Yao, PhD; Hai-Yen Sung, PhD; Stanton A. Glantz, PhD; Bonnie Halpern-Felsher, PhD; Pamela Ling, MD, MPH
University of California San Francisco TCORS
Docket No. FDA-2021-N-0408
Modified Risk Tobacco Product Application: Application for the IQOS 3 System Holder and Charger Submitted by Philip Morris Products S.A.
September 7, 2021
The Population Health Impact Model (PHIM) developed by Philip Morris and used to support its supplemental modified risk tobacco product application for IQOS 3 (sMRTPA) is the same model used to support its modified risk tobacco product application for IQOS 2.4, and therefore suffers from all the same flaws that were identified in that application. (The US Food and Drug Administration (FDA) has posted application materials[1] for both the IQOS 3 and IQOS 2.4, although as of August 12, 2021 some sections for the IQOS 3 sMRTPA are missing, and many sections in both applications are heavily redacted.) The model is based on questionable assumptions and insufficient health impact measures. While it considers mortality from four tobacco-attributable diseases, it underestimates mortality and excludes morbidity, excludes tobacco products other than cigarettes, does not include FDA-recommended impacts on non-users, and underestimates the impact on other population groups. Among other findings, all applicants are required to demonstrate that their proposed MRTP products will “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,”[2] and FDA is required to base its determination on whether to issue a MRTP order on “(A) the scientific evidence submitted by the applicant; and (B) scientific evidence and other information that is made available to the Secretary.”[3] However, Philip Morris’s sMRTPA does not address new published research providing scientific evidence on population health impacts and does not demonstrate benefits to individual or population health. Therefore, FDA should not issue an MRTP order for IQOS 3.
- Background
Philip Morris Products S.A. (PMPSA) submitted to FDA a supplemental modified risk tobacco product application (sMRTPA) for its IQOS 3 system holder and charger on March 18, 2021. In its sMRTPA, PMPSA stated that the IQOS 3 is essentially the same as the IQOS 2.4 and therefore PMPSA did not conduct additional studies with the IQOS 3 or provide any new health risk information or data about the IQOS 3. Instead, PMPSA cross-referenced to its previous MRTP and PMTA applications to demonstrate that the IQOS 3 system generates an aerosol that is comparable to that generated by the IQOS 2.4 system, exposes users to similar levels of the harmful and potentially harmful chemicals (HPHCs) it analyzed in its IQOS 2.4 applications, and that therefore there is sufficient evidence to support the modified risk claim that this process “significantly reduces the production of harmful and potentially harmful chemicals.”[4] However, as we discuss below, since these premarket applications were submitted, important new evidence has been published that PMPSA did not report to FDA.
These new studies strengthen the case that IQOS is not appropriate for the protection of the public health and FDA should not have authorized the marketing of IQOS in the first place. Because PMPSA did not address these new studies in its sMRTPA, the application does not satisfy the statutory requirements for MRTPAs[5] nor FDA’s MRTPA Guidance that calls for applications to contain scientific studies and analyses and all research findings, “both favorable and unfavorable.”[6] In light of the new evidence, FDA should revisit and revoke its premarket tobacco product marketing orders for IQOS 2.4[7] and IQOS 3 and its reduced exposure modified risk order for IQOS 2.4,[8] and these orders should not be relied on to support the sMRTPA for IQOS 3.
On August 31, 2018, PMPSA submitted as Amendment 2 to its MRTP for IQOS 2.4 the last update to its list of references, which included 7733 references (see PMPSA’s spreadsheet attached to this comment). Since PMPSA submitted its MRTPA for the IQOS 2.4, more than 100 papers have been published on IQOS (see attached spreadsheet). PMPSA’s Supplemental Premarket Tobacco Product Application (sPMTA)[9] for IQOS 3, which is cross-referenced in and used to support the IQOS 3 sMRTPA, includes references for only 14 additional papers, only six of which were published since August 2018 (one of which is written in French). However, several papers published since 2018 that address Philip Morris’s Population Health Impact Model and/or the impacts of IQOS on population health are not discussed in PMPSA’s sMRTPA for IQOS 3. We discuss this new literature below.
Although PMPSA apparently failed to report this recent literature in any of its PMTA and MRTP applications for IQOS 2.4 and IQOS 3, FDA must base its decisions on the best available current science. The new research, summarized and attached to this comment, reinforces our earlier comment concluding that the PHIM underestimates the health impacts of IQOS and that Philip Morris failed to prove that IQOS will significantly reduce harm and the risk of tobacco-related disease to individuals and failed to prove that IQOS would benefit the health of the population as a whole as required by section FSPTCA section 911(g). Importantly, section 911(g)(4) unambiguously states that this showing is required for reduced exposure as well as reduced risk MRTPAs.
To obtain an exposure modification MRTP marketing order, applicants are required to demonstrate that the product, as it is actually used by consumers, will “benefit the health of the populations as a whole taking into account both users of tobacco products and persons who do not currently use tobacco products” (FSPTCA section 911(g)(2)(B)(iv)) and that issuance of an exposure modification order would be “appropriate to promote the public health.” (FSPTCA section 911(g)(2)(A)(i)) To assess the potential effect that marketing the product with the proposed exposure modification claims may have on tobacco-related morbidity and mortality in the population as a whole, FDA recommends that MRTP applicants submit quantitative estimates that “integrate all of the information regarding the marketing of the product and its potential effects on health, tobacco use behavior and tobacco use initiation.”[10]
Moreover, to help FDA determine whether continued marketing of IQOS is appropriate for the protection of public health or if there are grounds for FDA to withdraw marketing authorization, the marketing orders for IQOS 2.4[11] and for IQOS 3[12] each require under FSPTCA section 910(f) PMPSA to submit to FDA on an annual basis:
A summary of significant findings in publications not previously reported and full copies of the article. This must include any new scientific data (published or otherwise) on the likelihood of product use by current users of tobacco products within the same tobacco product category, current users of tobacco products in other tobacco product categories, former users of any tobacco product, and youth and young adults.
As discussed above, PMPSA did not follow this instruction, so their application is incomplete and should be rejected by FDA.
- Philip Morris’s Population Health Impact Model underestimates the health impact of IQOS so it cannot be used to justify PMPSA’s reduced exposure MRTP claims for IQOS 3
In November 2017 we submitted a public comment regarding the IQOS 2.4 MRTPA (Docket Number: FDA-2017-D-3001). This sMRTPA for IQOS 3 is supported by the same PHIM as was used in the initial IQOS 2.4 MRTPA. The model was evaluated and critiqued in detail in our previous public comment[13] and a review of the model subsequently published in the peer-reviewed literature[14] attached and incorporated by reference. We determined that it is based on questionable assumptions and insufficient health impact measures. Because PMPSA did not update its model to reflect the latest literature (or criticisms of the earlier model, which are all publicly available), our previous critiques of the PHIM also apply to this sMRTPA:
- Morbidity is not included in the model.
- Mortality is underestimated for several reasons: it is limited to only 4 smoking-attributable diseases, based on relative risks (RR) from studies in other countries rather than published estimates for the US, and the RR of dual use of cigarettes and IQOS is assumed to be the midpoint of the two RRs, contrary to some evidence to that the RR of dual use is greater than the RR of sole cigarette smoking.
- Transition rates for smoking and IQOS use are not well-justified.
- The model starts with the US population and smoking prevalence from 1990, a time when smoking prevalence was much greater than it is today.
- It ignores other tobacco products, notably excluding e-cigarettes, which may have lower risk than cigarettes. A comparison of IQOS and lower-risk tobacco products would likely lead to different results.
- It underestimates the impact on other population groups including youth and young adults;
- It uses estimates derived from studies funded by Philip Morris, although better estimates are available.
- The impact of IQOS on non-users is ignored, despite FDA-recommendations that they be considered.
In light of these concerns, we concluded that the Population Health Impact Model underestimates the health impact of IQOS products and the model predictions do not justify the MRTP claim. We demonstrated that Philip Morris had failed to prove that IQOS will significantly reduce harm and the risk of tobacco-related disease to individuals and failed to prove that IQOS would benefit the health of the population as a whole as required by section 911(g). Importantly, section 911(g)(4) unambiguously states that this showing is required for reduced exposure as well as reduced risk MRTPAs. Our published paper[15] further concluded that to support an MRTP claim, an assessment of its impact on population health should include a comprehensive measure of health impacts, consideration of all groups impacted, and documented and justifiable assumptions regarding model parameters.
In November 2018, we submitted an additional public comment[16] to the IQOS 2.4 MRTPA docket, attached and incorporated by reference, in response to amendments that FDA had posted to the docket in October 2018. In that comment, we noted that PMPSA’s December 22, 2017 response to FDAs information request did not adequately address discrepancies between data provided by PMPSA and FDA’s own analysis regarding the extent to which smokers switch completely to IQOS vs using IQOS concurrently with cigarettes and do not adequately determine if people will become dual or poly users as found in other studies. Further, PMPSA’s response did not adequately address FDA’s questions regarding perceptions of IQOS or intention to try or use IQOS among current, former, or never smokers, including under-age youth and did not consider the role of flavors in the onset and continuation of IQOS usage. Finally, PMPSA’s response failed to address several concerns about its Population Health Impact Model.
- New scientific evidence in the peer-reviewed literature demonstrates that PMPSA underestimated the population health impacts of IQOS
Since 2018 (when our paper was published[17]) at least 14 additional peer-reviewed papers discussed and cited below have been published that analyze the population health impacts of IQOS and/or Philip Morris’s Population Health Impact Model. (See attached table of IQOS publications since 2018.) The new research finds that reliable data on the impact of IQOS on health are still lacking, that the PHIM does not follow the FDA suggested approach for risk assessment, and that model assumptions such as that heated tobacco product users will completely switch from smoking cigarettes are not borne out by experience in the real world. These new papers reinforce the conclusion that PMPSA has underestimated the population health impacts of IQOS and that therefore it should not be permitted to market IQOS 3 with reduced exposure MRTP claims. We summarize the new literature next.
Evaluation of the PHIM and modelling approaches
A recently published review[18] of the FDA’s IQOS 2.4 decision memo raised issues about how the public health standard is being applied. Areas of concern included comparing toxicity of IQOS only to cigarettes (“a disturbingly low bar”), overreliance on tobacco industry studies, and using the Philip Morris PHIM rather than an FDA-developed risk assessment approach to model health effects.
A recent largely industry-funded review[19] compared different modeling approaches for assessing the population health impact of new tobacco products. Included were studies of e-cigarette use and of more general MRTPs. The authors compared 13 mostly cohort-based models. They acknowledge that models only consider two products, only mortality (not morbidity) is analyzed, demographic risk factors are not included, and indirect effects on other risk factors are ignored. While the authors conclude that most models suggest that the introduction of an MRTP product is likely to have a beneficial impact on the outcomes studied, this result is dependent on the assumptions implicit in the model. Thus, they conclude, “Further model development, supplemented by preliminary results from well-designed epidemiological studies, should enable more precise prediction of the anticipated effects of MRTP introduction.” In other words, this largely-industry-funded review questioned the reliability of these models.
Model assumptions and data used
A systematic review of the literature[20] focused on public health impacts of heated tobacco products reviewed 15 studies. The authors concluded that while there is potential for heated tobacco products to have reduced risks compared to cigarettes, further studies must be conducted to determine the impact of the product in practice. Another study[21] analyzed retailer panel data from Japan and found that the introduction of IQOS was associated with declining cigarette sales, but “The net population health impact, however, cannot be assessed without resolving several key uncertainties related to the direct harms of IQOS and the precise patterns of both smoking and IQOS use.”
Several studies have been conducted in Japan, one of the earliest countries to introduce IQOS. Lee and colleagues,[22] with funding from PMPSA, used the PHIM to model the introduction of a reduced-risk tobacco product in Japan. Different iterations of the model assumed the new product would completely replace cigarette smoking, or uptake rates would reflect the experience with IQOS. The authors concluded that there would be a substantial reduction in tobacco-related deaths over a 20 year period after the introduction of a reduced risk tobacco product such as IQOS. Some of the same authors, with support from British American Tobacco, published a related study[23] that focused specifically on heated tobacco products (HTP). The authors conclude that “the introduction of HTPs may play an important role in tobacco harm reduction by displacing smoking without increasing overall nicotine use”. They define displacement as smokers transitioning to exclusive HTP use. Interestingly, it is assumed that “any health benefits obtained from switching to HTPs or quitting all tobacco products are lost if there is a relapse to smoking or dual use”. However, as we discuss below, the assumption that smokers will “switch completely” to IQOS and use IQOS exclusively is contrary to findings from several studies.
Will smokers switch completely to IQOS?
Studies of the actual use of IQOS (or heated tobacco products – HTP – more generally) and other tobacco products have addressed the question of whether IQOS will be taken up primarily by current cigarette smokers to replace cigarette smoking. A study[24] conducted among Korean adults found that while dual use of heated tobacco products (including IQOS) and electronic cigarettes was associated with increased attempts to quit cigarette smoking, the use of HTPs alone or with electronic cigarettes was associated with lower odds of successful cessation.
The assumption that smokers will switch completely to IQOS is contrary to findings from several studies. A study[25] that used the 2018 International Tobacco Control Japan Survey queried regular HTP users as to why they used the product. Just over half used them to help in smoking cessation, but almost the same number used the product to partially replace cigarette use so they would not have to completely quit smoking. The authors concluded that in the latter case, “the harm reduction potential of HTPs suggested by the toxicity studies will be diminished”. Another study[26] using the same 2018 ITC Japan survey found that 68% of HTP users also currently used cigarettes. Kim and colleagues conducted an online survey[27] of young Korean adults. They found that “Current IQOS users were more likely to smoke conventional cigarettes and/or e-cigarettes, which contradicts the tobacco industry’s claims that conventional cigarette smokers will switch to heated tobacco products”. Another study of Korean adults,[28] entitled Heated tobacco products: Cigarette complements, not substitutes, used data from a large health survey and found that 96% of current HTP users were dual users of cigarettes.
Impact on youth
The systematic literature review by Ratajczak et al,20 mentioned above, reported that there is substantial interest in heated tobacco products, including among nonsmokers and youth, suggesting that these products may “create new nicotine addicted populations”. A study[29] examining consumer perceptions and attitudes about IQOS in Japan and Switzerland found that the product was marketed and packaged in a way that is particularly appealing to youth and young adults, raising concerns about youth appeal. A survey[30] of Italians aged 15+ queried participants about their awareness and use of IQOS. They found that more never smokers than smokers had already tried IQOS, suggesting “that IQOS may create new nicotine addicted generations”. A study[31] using data on US adolescents from the 2019 National Youth Tobacco Survey reported that youth who use tobacco products, particularly dual and poly tobacco users and those who use flavored products, are at increased risk of using heated tobacco products. Many other studies have documented the appeal of IQOS to youth (e.g., McKelvey, Popova et al.[32] ) concluding that heated tobacco products likely appeal to adolescents and young adults and are discussed in a separate public comment submitted by UCSF TCORS,[33] incorporated by reference and attached.
PMPSA’s sMRTPA for IQOS 3 does not include or discuss any of these new papers. Although PMPSA apparently failed to report this recent literature in any of its PMTA and MRTP applications for IQOS 2.4 and IQOS 3, FDA must base its decisions on the best available science and therefore reject PMPSA’s sMRTPA for IQOS 3.
- Conclusion
Scientific evidence and published literature demonstrate that PMPSA’s sMRTPA for IQOS 3 and its Population Health Impact Model underestimate the health impact of IQOS. Because PMPSA and FDA have not presented or made publicly available evidence refuting these points and failed to otherwise demonstrate that IQOS 3 would benefit the health of individuals and of the population as a whole, we strongly recommend that FDA deny PMI’s Supplemental MRTP application for IQOS 3.
[1] Philip Morris Products S.A. Modified Risk Tobacco Product (MRTP) Applications, IQOS 3 System Holder and Charger Supplemental MRTP Application. Available at: https://www.fda.gov/tobacco-products/advertising-and-promotion/philip-morris-products-sa-modified-risk-tobacco-product-mrtp-applications
[2] Family Smoking Prevention and Tobacco Control Act section 911(g)(1)(B), Pub. L 111-31, June 22, 2009.
[3] Family Smoking Prevention and Tobacco Control Act section 911(g)(3), Pub. L 111-31, June 22, 2009.
[4] Philip Morris Products S.A. Modified Risk Tobacco Product (MRTP) Applications, IQOS 3 System Holder and Charger Supplemental MRTP Application Executive Summary, Module 2.4 and Summary of Health Risk Investigations, Module 6.1. Available at: https://www.fda.gov/tobacco-products/advertising-and-promotion/philip-morris-products-sa-modified-risk-tobacco-product-mrtp-applications
[5] Family Smoking Prevention and Tobacco Control Act section 911(g), Pub. L 111-31, June 22, 2009.
[6] US Food and Drug Administration, Guidance for Industry: Modified Risk Tobacco Product Applications, Draft Guidance (March 2012).
[7] Lempert LK, Glantz S. Analysis of FDA’s IQOS marketing authorisation and its policy impacts. Tob Control. 2020 Jun 29:tobaccocontrol-2019-055585. doi: 10.1136/tobaccocontrol-2019-055585. Epub ahead of print. PMID: 32601147; PMCID: PMC7952009.
[8] Lempert LK, Bialous S, Glantz S. FDA’s reduced exposure marketing order for IQOS: why it is not a reliable global model. Tob Control. 2021 Apr 2:tobaccocontrol-2020-056316. doi: 10.1136/tobaccocontrol-2020-056316. Epub ahead of print. PMID: 33811155.
[9] Philip Morris Products S.A. IQOS 3 System Holder and Charger Supplemental Premarket Tobacco Product Application (PMTA), Module 9 (m9): References, posted July 1, 2021. Available at: https://digitalmedia.hhs.gov/tobacco/hosted/mrtpa/pmi/Cross-referenced%20PMTA%20Submission%20%28PM0000364%29.zip
[10] FDA, Guidance for Industry: Modified Risk Tobacco Product Applications, Draft Guidance, March 2012. Available: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/modified-risk-tobacco-product-applications
[11] FDA, Marketing Order IQOS System Holder and Charger, Marlboro Heatsticks, Marlboro Smooth Menthol Heatsticks, and Marlboro Fresh Menthol Heatsticks, April 30, 2019, FDA Submission Tracking Numbers (STNs): PM0000424-PM0000426, PM0000479,Available: https://www.fda.gov/media/124248/download
[12] FDA, Marketing Granted Order IQOS System Holder and Charger, December 07, 2020, FDA Submission Tracking Number (STN): PM0000634. Available: https://www.fda.gov/media/144700/download
[13] Max W, Lempert L, Sung HY et al, Philip Morris’s Population Health Impact Model Based on Questionable Assumptions and Insufficient Health Impact Measures Does Not Adequately Support its MRTP Application, UCSF TCORS public comment to docket Number: FDA-2017-D-3001, November 22, 2017. Available: https://www.regulations.gov/comment/FDA-2017-D-3001-0121
[14] Max WB, Sung H, Lightwood J, et al. Modelling the impact of a new tobacco product: review of Philip Morris International’s Population Health Impact Model as applied to the IQOS heated tobacco product. Tobacco Control 2018;27:s82-s86.
[15] Max WB, Sung H, Lightwood J, et al. Modelling the impact of a new tobacco product: review of Philip Morris International’s Population Health Impact Model as applied to the IQOS heated tobacco product. Tobacco Control 2018;27:s82-s86.
[16] Popova L, Max W, Lempert LK et al. PMI’s December 22, 2017 amendment to its IQOS MRTP application failed to address concerns about dual use, flavors, risk perceptions, and its Population Health Impact Model. UCSF TCORS public comment to docket Number: FDA-2017-D-3001, November 14, 2018. Available: https://www.regulations.gov/comment/FDA-2017-D-3001-0233
[17] Max WB, Sung H, Lightwood J, et al. Modelling the impact of a new tobacco product: review of Philip Morris International’s Population Health Impact Model as applied to the IQOS heated tobacco product. Tobacco Control 2018;27:s82-s86.
[18] Berman ML, Glasser AM. The Public Health Standard in Action-Analysis of the US Food and Drug Administration’s IQOS Review. JAMA Oncol. 2020 Dec 1;6(12):1864-1865.
[19] Lee PN, Abrams D, Bachand A, Baker G, Black R, Camacho O, Curtin G, Djurdjevic S, Hill A, Mendez D, Muhammad-Kah RS, Murillo JL, Niaura R, Pithawalla YB, Poland B, Sulsky S, Wei L, Weitkunat R. Estimating the Population Health Impact of Recently Introduced Modified Risk Tobacco Products: A Comparison of Different Approaches. Nicotine Tob Res. 2021 Feb 16;23(3):426-437.
[20] Ratajczak A, Jankowski P, Strus P, Feleszko W. Heat Not Burn Tobacco Product-A New Global Trend: Impact of Heat-Not-Burn Tobacco Products on Public Health, a Systematic Review. Int J Environ Res Public Health. 2020 Jan 8;17(2):409.
[21] Stoklosa M, Cahn Z, Liber A, Nargis N, Drope J. Effect of IQOS introduction on cigarette sales: evidence of decline and replacement. Tob Control. 2020 Jul;29(4):381-387.
[22] Lee PN, Djurdjevic S, Weitkunat R, Baker G. Estimating the population health impact of introducing a reduced-risk tobacco product into Japan. The effect of differing assumptions, and some comparisons with the U.S. Regul Toxicol Pharmacol. 2018 Dec;100:92-104.
[23] Camacho, O. M., Hill, A., Fiebelkorn, S., Jones, J. D., Prasad, K., Proctor, C., & Murphy, J. (2021). Modeling the Population Health Impacts of Heated Tobacco Products in Japan. Tobacco Regulatory Science, 7(3), 221-231.
[24] Kim, J., Lee, S., Kimm, H., Lee, J. A., Lee, C. M., & Cho, H. J. (2021). Heated tobacco product use and its relationship to quitting combustible cigarettes in Korean adults. Plos one, 16(5), e0251243.
[25] Xu SS, Meng G, Yan M, Gravely S, Quah ACK, Ouimet J, O’Connor RJ, Sutanto E, Yoshimi I, Mochizuki Y, Tabuchi T, Fong GT. Reasons for Regularly Using Heated Tobacco Products among Adult Current and Former Smokers in Japan: Finding from 2018 ITC Japan Survey. Int J Environ Res Public Health. 2020 Oct 31;17(21):8030.
[26] Sutanto E, Miller C, Smith DM, O’Connor RJ, Quah ACK, Cummings KM, Xu S, Fong GT, Hyland A, Ouimet J, Yoshimi I, Mochizuki Y, Tabuchi T, Goniewicz ML. Prevalence, Use Behaviors, and Preferences among Users of Heated Tobacco Products: Findings from the 2018 ITC Japan Survey. Int J Environ Res Public Health. 2019 Nov 21;16(23):4630.
[27] Kim J, Yu H, Lee S, Paek YJ. Awareness, experience and prevalence of heated tobacco product, IQOS, among young Korean adults. Tob Control. 2018 Nov;27(Suppl 1):s74-s77.
[28] Hwang JH, Ryu DH, Park SW. Heated tobacco products: Cigarette complements, not substitutes. Drug Alcohol Depend. 2019 Nov 1;204:107576. doi: 10.1016/j.drugalcdep.2019.107576. Erratum in: Drug Alcohol Depend. 2020 Mar 1;208:107872.
[29] Hair EC, Bennett M, Sheen E, Cantrell J, Briggs J, Fenn Z, Willett JG, Vallone D. Examining perceptions about IQOS heated tobacco product: consumer studies in Japan and Switzerland. Tob Control. 2018 Nov;27(Suppl 1):s70-s73.
[30] Liu X, Lugo A, Spizzichino L, Tabuchi T, Pacifici R, Gallus S. Heat-not-burn tobacco products: concerns from the Italian experience. Tob Control. 2019 Jan;28(1):113-114.
[31] Lee J, Thompson LA, Salloum RG. Heated tobacco product use among US adolescents in 2019: The new tobacco risk. Tob Prev Cessat. 2021 Jan 8;7:01.
[32] McKelvey K, Popova L, Kim M, Chaffee BW, Vijayaraghavan M, Ling P, Halpern-Felsher B. Heated tobacco products likely appeal to adolescents and young adults. Tob Control. 2018 Nov;27(Suppl 1):s41-s47.
[33] Halpern-Felsher B, McKelvey K, Kim M, et al. PMI’s MRTP Application for IQOS Does Not Consider IQOS’s Appeal to Youth or Adolescents, or the Likelihood that Youth and Adolescents will Initiate Tobacco Use with IQOS or Use IQOS with Other Tobacco Products, Docket Number: FDA-2017-D-3001, December 7, 2017. Available at: https://www.regulations.gov/document?D=FDA-2017-D-3001-0148.
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