Background Philip Morris Products SA (PMPSA) submitted a premarket tobacco application (PMTA) to US Food and Drug Administration (FDA) seeking an order permitting it to market IQOS in the USA. US law requires FDA to deny marketing authorisation if applicants fail to demonstrate that their product is ‘appropriate for the protection of the public health’. FDA issued a marketing order for IQOS in April 2019, which Philip Morris is using to promote IQOS outside the USA.
Methods We analysed FDA’s Technical Project Lead Review and marketing order for IQOS, relevant law and guidance on PMTAs and independent research on the health impacts of IQOS.
Results FDA found that the evidence PMPSA submitted did not demonstrate reduction in long-term disease risks and that IQOS aerosol emits toxins with carcinogenic and genotoxic potential, some at higher levels than conventional cigarettes. PMPSA did not appropriately consider the health impacts of dual use, the product’s attractiveness to youth or data showing that consumers do not accurately perceive the addiction risks of IQOS. Despite FDA’s own scientists’ recommendations and independent research showing that IQOS presents serious risks to users including cytotoxic, genotoxic, hepatotoxic, cardiovascular and pulmonary risks, FDA concluded that IQOS is ‘appropriate for the protection of the public health’.
Conclusion FDA’s decision allowing IQOS to be marketed in the USA disregarded valid scientific evidence and misapplied the public health standard mandated by law. This decision may have important health impacts, influence marketing IQOS outside the USA and erode public confidence in FDA’s future PMTA decisions.
- electronic nicotine delivery devices
- non-cigarette tobacco products
- public policy
- tobacco industry
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
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The tobacco industry tried to minimise the ‘lung-cancer scare’ of the early 1950s by introducing and marketing filtered products,1 and has been marketing various tobacco products as ‘safer’ since the 1960s.2–4 These claims were found to be unsubstantiated and misleading5 and contributed to the US Congress enacting the 2009 Family Smoking Prevention and Tobacco Control Act6 (TCA) with specific provisions requiring rigorous premarket review of all tobacco products (TCA § 910) and requiring that modified risk claims be demonstrated by fully verified evidence (TCA § 911, §§ 2(36)–(49)). The law requires that before marketing any new tobacco product in the USA, the Food and Drug Administration (FDA) must approve a premarket tobacco application (PMTA) for the product. In particular, TCA § 910 requires manufacturers to demonstrate that marketing the new tobacco product would be ‘appropriate for the protection of the public health’ (APPH) and requires FDA to evaluate, among other things, the tobacco product’s toxicological profile, individual and population health impacts, and labelling.
In May 2017, Philip Morris Products SA (PMPSA) submitted PMTAs seeking an order permitting it to sell the IQOS heated tobacco product2 (HTP) in the USA.7 IQOS is an integrated tobacco device that electronically heats PMPSA’s proprietary cigarettes (‘Heatsticks’) to generate an inhalable nicotine aerosol7 (figure 1). FDA has not made PMTA applications available for public comment, so it was not possible for the public to give input into the PMTA process or assess the appropriateness of FDA’s decision until after IQOS was authorised. In April 2019, FDA issued a marketing order8 authorising the sale of IQOS and three flavours of Heatsticks (Marlboro, Marlboro Smooth Menthol and Marlboro Fresh Menthol) after concluding that marketing IQOS is APPH. FDA’s 122-page Technical Project Lead Review7 (TPL; online supplementary file l) explains how FDA arrived at its decision to grant marketing authorisation for IQOS.
As of 10 March 2020, IQOS was sold in 51 countries outside the USA.9 In at least some promotional materials (figure 2) and websites (figure 3) outside the USA, Philip Morris International (PMI) uses FDA’s marketing authorisation and quotes FDA Center for Tobacco Products Director Mitch Zeller to advertise that FDA determined that IQOS was ‘appropriate for the protection of the public health’.
Our analysis of FDA’s IQOS decision assesses whether FDA appropriately applied the statutory requirements for PMTAs considering the available scientific evidence, and what precedents and public health concerns this set for future PMTAs, including for e-cigarettes. In considering the IQOS PMTA, FDA appears to have turned the law on its head and based its decision to authorise sales of IQOS on its finding that IQOS was not proven to be more dangerous than cigarettes. Although the law squarely puts the burden on the applicant to demonstrate that its product confers public health benefits, FDA’s IQOS decision established a new, weaker de facto standard: a new tobacco product is APPH if the FDA cannot clearly demonstrate, based on the information submitted in the application, that the proposed product is more dangerous than cigarettes. Rather than using FDA’s static interpretation of the APPH standard based on the state of the market when the law passed (ie, cigarettes), FDA should adopt a dynamic interpretation based on the market when the PMTA is submitted.
We analysed FDA’s TPL7 and marketing order for IQOS8 against the TCA’s statutory requirements. We also compared the TPL against FDA’s Guidance for Industry: Applications for Premarket Review of New Tobacco Products 10 (Guidance), which explains both statutory requirements and non-binding recommendations for submitting and reviewing PMTAs, including what information should be submitted to support a claim that the product is APPH.
We conducted a line-by-line analysis of the TPL and reviewed the full range of evidence available to FDA on IQOS, including previous FDA submissions and published research, to determine whether, as required by TCA § 910 and the Guidance,10 the IQOS PMTA provided sufficient scientific evidence to support the required demonstration that IQOS is APPH. We summarise the TPL’s review of the toxicological risks, individual health impacts, population health effects and product labelling, and for each topic discuss evidence that FDA seemingly did not consider.
PMI (PMPSA’s parent company) also submitted modified risk tobacco product applications11 (MRTPA) in May 2017 to obtain authorisation to market IQOS with claims of reduced risk or reduced exposure. Unlike PMTAs, MRTPAs are required to be made available for public comment (TCA § 911(e))and submitted to FDA’s Tobacco Products Scientific Advisory Committee (TCA § 911(f)). (As of 20 May 2020, FDA had not issued a decision on the IQOS MRTPAs.) While a separate process from the PMTA, it is clear from the TPL that many of the studies submitted for the MRTPA were the same as for the PMTA. We considered public comments that had been submitted in response to the MRTPA and were available to FDA when it was assessing the PMTA.
Additionally, although issued in September 2019 after FDA’s decision on the IQOS PMTA, we referred to FDA’s proposed rule12 on requirements for submitting and reviewing PMTAs to glean what information FDA currently believes is essential to allow FDA to thoroughly evaluate a product’s public health impacts.
The FDA’s toxicology review found that there are lower levels of some harmful and potentially harmful constituents (HPHCs) in IQOS aerosol than smoke from 3R4F standard reference research cigarettes and commercially available conventional cigarettes (CCs) (TPL p. 41). However, FDA also found that 80 chemicals in Heatstick aerosols, including 4 that are possibly carcinogenic, are unique to IQOS or present in higher levels than 3R4F smoke (TPL p. 41). Additionally, IQOS aerosol contains 15 other chemicals that are possibly genotoxic, and 20 more generally recognised as safe for ingestion (GRAS) compounds that have potential adverse health effects (TPL p. 41). The TPL concluded that ‘although some of the chemicals are genotoxic or cytotoxic, these chemicals are present in very low levels and potential effects are outweighed by the substantial decrease in the number and levels of HPHCs found in CC’ (TPL p. 42) and that these chemicals ‘do not raise significant concerns from a public health perspective’ (TPL p. 41).
Evidence FDA did not discuss
Evidence in the IQOS MRTPA13 demonstrated that in addition to presenting lower exposure to some HPHCs, IQOS produced higher levels than CC for at least 56 toxins not on FDA’s HPHC list. St Helen et al found14 15 that PMI initially reported levels for only 40 of 93 HPHCs, and levels of 56 other constituents not included in their ‘PMI-58 study’ (including glycerol and propylene glycol) or FDA’s HPHC list were higher in IQOS emissions than in 3R4F reference cigarette smoke, including 22 that were >200% higher and 7 that were >1000% higher, and the impact of these substances on the overall toxicity or harm of IQOS is unknown. Additionally, Auer et al 16 found (and FDA acknowledged (TPL pp. 30–31) that other unmeasured constituents may be formed at temperatures below the combustion threshold for tobacco.
Leigh et al 17 published independent evidence on the cytotoxic effects on human bronchial epithelial cells of IQOS compared with e-cigarettes and CC and found that, while not as bad as cigarettes, IQOS emissions were more cytotoxic than e-cigarettes.
Individual health impacts
FDA’s medical review found that IQOS has ‘the potential to benefit certain individuals’ by reducing exposures to HPHCs if they ‘completely switch’ from CC to IQOS (TPL p. 64). FDA found that data in the PMTA about biomarkers of potential harm (BOPH) were ‘insufficient to draw meaningful conclusions’ about IQOS’s impact on disease risk, but biomarkers of exposure (BOE) in those that completely switched to IQOS indicated reduced HPHC exposures (TPL p. 64). FDA noted that ‘experience with IQOS is limited, even when considering data from other countries’ (TPL p. 65)
Evidence FDA did not discuss
Consistent with FDA’s assessment that ‘overall, the studies conducted by the applicant have not demonstrated evidence of reduction in long-term disease risks (emphasis added)’ (TPL pp. 58–59), an independent analysis18 19 of studies in the IQOS MRTPA concluded that PMI’s own data failed to show consistently lower risks of harm in humans using IQOS compared with CC because there were not statistically significant differences between IQOS and CC users for 23 of the 24 BOPH studied.
Although BOE are a less direct measure of harm than BOPH, and despite finding that PMPSA’s BOPH data did not demonstrate positive clinical impacts (TPL p. 59), FDA concluded that reductions in 15 BOE seen after switching from CC to IQOS ‘may lead to reduced likelihood of smoking-related diseases (emphasis added)’ (TPL p. 55). However, FDA noted several limitations to these studies, including: (1) the data did not evaluate long-term disease risk; (2) because the study participants were ‘moderate smokers’ only, the studies were not nationally representative of the smoking population and therefore may not generalise to other smokers including ‘light or non-daily smokers’, youth or minorities (TPL pp. 55–56); (3) IQOS, but not CC, was provided to experimental subjects for free; (4) dual use of IQOS and CC use was not considered; (5) never-users were not studied; (6) secondhand exposure to IQOS was not studied and (7) IQOS was not compared with other tobacco products currently on the market such as e-cigarettes (TPL pp. 55–56).
While FDA’s toxicology review acknowledged carcinogenic and genotoxic chemicals present in IQOS, cytotoxic and mutagenic potential and a higher incidence of neoplastic lesions in some groups exposed to IQOS (TPL pp. 41–42), FDA did not discuss independent analyses suggesting other carcinogenic, hepatotoxic, cardiovascular and pulmonary impacts. Chun et al 20 21 found that PMI’s preclinical and clinical data in the IQOS MRTPA indicated that IQOS exposure may be associated with hepatotoxicity and other possible toxicities not associated with CC. In addition, Nabavizadeh et al 22 23 presented independent experimental evidence that IQOS adversely affects vascular endothelial function, a major factor in cardiovascular disease, as much as CCs. Moazed et al 24 25 found that data in PMI’s MRTPA showed IQOS is associated with significant pulmonary and immunomodulatory toxicities. Nevertheless, FDA concluded that IQOS’s potential adverse health effects are outweighed by the decreased amount of HPHCs compared with CC (TPL p. 42).
Population health effects
The social science review found that the PMTA lacked sufficient information to address concerns about youth under age 18 years, potential for initiation among young adult never smokers and potential for dual use among current smokers (TPL p. 83). FDA recognised that ‘dual use of IQOS and CC was common in all countries in the premarket and postmarket studies’ (TPL p. 72) and ‘dual use of CC and IQOS appears likely’ (TPL p. 73). Nevertheless, FDA concluded that ‘IQOS is appropriate for protection of public health, even if there is some dual use among smokers as they potentially transition to the product’ (TPL p. 84).
Evidence FDA did not discuss
FDA’s decision depends in large part on its finding that the PMTA demonstrated that smokers will ‘switch completely’ from CC to IQOS, and that IQOS users will not smoke CC at the same time (‘dual use’). However, the studies PMPSA submitted in its PMTA (and PMI’s publicly available MRTP application) did not support the conclusion that smokers would ‘switch completely’ to IQOS. PMPSA’s Actual Use study conducted in the USA (THS-PBA-07-US) measured the total number of Heatsticks/(CC+Heatsticks) used per week. They defined ‘dual use’ as ‘combined use’ of Heatsticks and CC when they used 30%–70% Heatsticks out of the total, and considered a person who smokes CC up to 30% of the time to have ‘switched completely’ to IQOS. (TPL p. 72) Even using this definition, 22.4% of participants were dual users.
‘Dual use’ is defined by the US Centers for Disease Control and Prevention as ‘adding another tobacco product26 and is the working definition in the peer-reviewed literature. Using FDA’s ‘alternative definition of dual use’ which includes ‘predominant use’ of Heatsticks (70%–95%) or CCs (5%–30%), a majority (57.6%) were dual users, with only 7.5% ‘exclusive’ Heatstick users (95%–100%) (TPL p. 72)
In another PMPSA ‘actual use’ study (ZRHR-ERS-09-US) intended to demonstrate favourable changes in eight BOPH after 6 months for those switching completely from CC to IQOS, ‘dual use’ was defined as between 1%–70% IQOS and ‘switching’ to IQOS defined as >70% IQOS. (TPL p. 80)
An independent analysis of PMI’s population health impact model found that dual use of IQOS with CC could lead to negative public health impacts,27 and a study of young Korean adults showed that current IQOS users were more likely to smoke CC and/or e-cigarettes, rather than switch completely to IQOS.28 FDA recognised that ‘dual use of IQOS and CC was common in all countries in the premarket and postmarket studies’ (TPL p. 72) and ‘dual use of CC and IQOS appears likely.’ (TPL p. 73)
FDA concluded there is no evidence suggesting that the proposed labelling is false or misleading. (TPL p. 85)However, the TPL also found that ‘study data (submitted by PMPSA) show that consumers do not accurately perceive and tend to underestimate the addiction risk of IQOS.’(TPL p. 87) FDA also stated that the findings raise concerns that young adult never smokers do not fully comprehend the addiction risk of IQOS based on the proposed labelling and may mistakenly believe IQOS to be less addictive and therefore start using it when they would not have otherwise initiated tobacco use. (TPL p. 88) Based on these findings, the TPL recommended that product labels include the warning: ‘WARNING: This product contains nicotine. Nicotine is an addictive chemical.’(TPL p. 89)
Evidence FDA did not discuss
A federal court found5 Philip Morris and other tobacco companies liable for their inherently deceptive labelling that deliberately targeted youth and misled consumers to believe their products were safer. Recognising this history (TCA §§ 2(36)–(49)) and that deceptive labelling negatively impacts quit attempts and leads to increased disease and death, (TCA § 2(38))the TCA requires FDA to deny a PMTA for any product whose proposed labelling is ‘false or misleading in any particular’ (TCA § 910(c)(2)(C))) and FDA’s Guidance on PMTAs (Guidance pp. 16–17) instructs applicants to address how product labelling may enhance the attractiveness of the product, especially to youth, and thereby increase the likelihood of tobacco use initiation. Studies conducted by scientists who were not employed or commissioned by any tobacco company (‘independent research’)29 30 supports FDA’s conclusion that IQOS labelling misleads consumers. Although FDA sought to address this by requiring the ‘nicotine is an addictive chemical’ warning, this warning is problematic because adolescents do not sufficiently understand the concept of addictiveness, the harms of addiction or the notion that a substance is addictive.30–32
FDA’s decision on the IQOS PMTA authorising IQOS to be marketed in the USA reversed the mandated legal standard requiring the applicant to demonstrate that IQOS reduces tobacco-related harms and is therefore APPH and was instead based on a finding that IQOS was not more dangerous than cigarettes. This decision raises serious questions about how FDA applied the law and assessed the scientific evidence concerning the individual and population health impacts of IQOS, and about how this decision will affect future tobacco product regulation of new tobacco products.
The TCA requires FDA to ‘deny an application…if… there is a lack of a showing that permitting such tobacco product to be marketed would be appropriate for the protection of the public health (emphasis added).’ (TCA § 910(c)(2)(A), Guidance p. 15) In determining whether a new product would be APPH, the TCA requires FDA to consider ‘the risks and benefits to the population as a whole, including users and non-users (including youth and former users) of the tobacco product,’ (TCA § 910(c)(4)) taking into account the increased likelihood of initiation among non-users, and decreased likelihood of cessation among current users. The law clearly places the burden on PMTA applicants to demonstrate these impacts.
FDA’s Guidance recommends (Guidance p. 16) that applicants compare the new product with other products currently on the market (eg, e-cigarettes, snus and other HTP, as well as CC). The statute also requires FDA to deny a PMTA if it finds, among other things, that the proposed labelling is false or misleading. (TCA § 910(c)(2)) Additionally, the statute (TCA § 910(b)(1)(A)) requires the application to contain full reports of all information known to or which should be known to the applicant concerning the health risks of the product.
Congress established the APPH standard to focus on ‘reducing the number of individuals who die or are harmed by tobacco products,33 34 which are defined to include not only cigarettes, but also cigars, smokeless tobacco, e-cigarettes and other new products as they are developed. (TCA § 101, 901(b))35 Therefore, when evaluating a PMTA, FDA must consider whether the applicant demonstrated that marketing the proposed product would reduce the overall burden of tobacco product use by considering actual use patterns, which, in particular, requires comparing the proposed product’s potential harms with those of tobacco products that were on the market at the time the PMTA was evaluated (see online supplementary file on the APPH standard).
In addition, FDA’s Guidance (Guidance pp. 15–20) recommends that PMTAs include data from well-controlled scientific investigations allowing for an evaluation of the impact of the new tobacco product on morbidity and mortality of the whole population, including data on: the health risks of switching to the new product compared with quitting, using other tobacco products and never using tobacco products; (Guidance p. 16) the attractiveness, addictiveness and cessation rates of the new product and its labelling compared with other tobacco products currently on the market; (Guidance p. 16) the likelihood of dual use; (Guidance p. 16) and ‘what product features may enhance the attractiveness/appeal of (the) product to children and adolescents.’ (Guidance p. 17) The Guidance also recommends PMTAs include information on product chemistry and the levels of HPHCs; (Guidance p. 17–18) non-clinical studies evaluating the toxicity, abuse liability and carcinogenicity of the new tobacco product compared with other tobacco products on the market; (Guidance p. 18) studies in adult human subjects to evaluate user exposure to tobacco-related compounds, user health risk and disease incidence, product use patterns including by age groups and dual use; abuse liability and addictiveness, consumer perceptions and risk perceptions based on the product and its labelling and cessation rates for users of the new product. (Guidance p. 19) The Guidance makes clear that these studies should be ‘generalizable to the population of US tobacco users and non-users’ (Guidance p. 19) and the study’s duration should be sufficient to ensure ‘clinically meaningful and statistically valid and robust findings.’(Guidance p. 20)
FDA did not consider all the available science
FDA overlooked or dismissed data submitted in the PMTA, concerns raised by its own scientists and information available in the peer-reviewed literature and public comments submitted on the IQOS MRTPA showing that IQOS is not APPH. Although FDA is authorised (TCA § 910(c)(5)(B)) to use valid scientific evidence that was not submitted in the application, FDA ignored available independent research that may have led to a different conclusion. Instead, FDA’s decision appears to be based primarily on PMPSA’s representations that the exposure levels to some HPHCs appeared lower than CCs.
FDA’s toxicological risk assessment minimised the fact that data submitted by PMI show that each IQOS Heatstick exposes the user to substantially higher levels of glycerol and propylene glycol (PG) than a CC. This is concerning because the respiratory irritants and carcinogens formaldehyde and acrolein are produced by heating these chemicals.36 Indeed, in August 2019 FDA proposed37 adding glycerol and PG to the list of HPHCs (which, as of 20 May 2020 had not been finalised), and a September 2019 study38 found that glycerol and PG in e-cigarette aerosol disrupts lung epithelial cells and resident immune cells and promotes poor response to infectious challenge. The TPL acknowledged that glycerol (52.3% mg/Heatstick) is 26% of the tobacco weight compared with 1%–5% in CC. (TPL p. 17) St Helen et al 14 15 found that PMI reported that each Heatstick contained 175 µ/stick PG compared with 23.7 µ/stick in the 3R4F cigarette.
Although FDA acknowledged several other toxicological risks presented in the PMTA, it nevertheless concluded that IQOS is APPH. PMPSA argued that the four possible carcinogens in IQOS aerosol do not pose a toxicological concern because the levels are below recognised dietary or occupational exposure limits. The FDA accepted this argument despite the TPL’s statement that PMI’s assessment of carcinogens in IQOS ‘is not considered adequate’ because PMI’s comparison of estimated exposures from IQOS to occupational exposure limits (OELs) ‘is not appropriate for a risk assessment of chemicals found in tobacco product smoke and aerosols’ and OELs are ‘not intended for use to evaluate potential health hazards from inhaled tobacco products.’ (TPL p. 32) Indeed, dietary intake is fundamentally different from inhalation39 40 and occupational exposure levels are not intended for evaluating potential health hazards from inhaled tobacco products. FDA also found (TPL pp. 32, 33, 36) that although IQOS produced higher genotoxic and cytotoxic effects than 3R4F cigarettes, it is APPH because ‘it is difficult to determine’ from the in vitro evaluations provided in the PMTA ‘whether long-term use of Heatsticks will have the same carcinogenic potential as CC smoke.’ (TPL p. 37) FDA also ignored its own conclusion that ‘the data (PMI submitted) are not sufficient to show’ (TPL p. 59) positive long-term clinical impacts of IQOS.
Individual health impacts
FDA noted that there were significant limitations in PMPSA’s BOE studies, and independent research18 19 showed that PMPSA’s own data failed to show statistically significant differences between IQOS and CC users for 23 of the 24 BOPH studies. BOPH are a more direct measure of health effects than BOE. Nevertheless, FDA concluded that ‘for those that switch completely from CC to IQOS, the reduced BOE exposures indicate reduced HPHC exposures that are likely to result in reduced risk of tobacco-related disease, ‘although that reduced risk has not been demonstrated in the studies submitted by the applicant (emphasis added).’ (TPL p. 56) However, PMPSA did not demonstrate that reduced exposures result in decreased risk of tobacco-related diseases, so the reduced exposures are not determinative of public health benefit that would support issuance of a new tobacco product marketing order. Additionally, FDA overlooked independent research showing cytotoxic,17 hepatotoxic,20 21 cardiovascular22 23 39 and pulmonary24 25 impacts that does not support FDA’s conclusion that IQOS’s potential adverse health effects are outweighed by the decreased amount of HPHCs compared with CC. (TPL p. 42)
Population health effects
FDA also ignored independent research about dual use27 28 and misleading labelling.29 30 FDA acknowledged ‘concerns about dual use (TPL p. 83) and that the studies submitted did not demonstrate reduction in long-term disease risk.’ (TPL p. 84) Nevertheless, FDA concluded, based on ‘the reduced exposures combined with the other available information,’that ‘IQOS is appropriate for protection of public health, even if there is some dual use among smokers as they potentially transition to the product.’ (TPL p. 84)
Because of PMPSA’s unorthodox definition of ‘switching completely’ (up to 30% CC use), none of their studies appropriately informed FDA on the likely health effects of actually ‘switching completely’ from CC to IQOS or of dual use. FDA noted its concerns about PMPSA’s failure to evaluate dual use in its discussions of toxicological risks, individual health impacts, and population health impacts. For example, in their 8-month mouse switching and cessation study intended to investigate the toxicological risks of IQOS and determine whether switching completely to IQOS could be beneficial to smokers, dual exposure to cigarette smoke and Heatstick aerosol was not evaluated. (TPL pp. 39–40) In PMPSA’s BOE studies to determine the individual health impacts of IQOS, dual use was not considered. Indeed, FDA noted: ‘Dual use was particularly common in the Actual Use study and may account for a substantial proportion of IQOS users in a real-world setting. Whether this user population will achieve an exposure reduction when compared with exclusive CC use, and to what magnitude, is unclear.’ (TPL p. 56)
PMPSA’s eight clinical trials analysing adverse events associated with exposure to IQOS did not specifically evaluate the possible risks of dual use. (TPL p. 60) Considering data from PMPSA’s Actual Use and Whole Offer Test consumer studies in five countries outside the USA evaluating population health impacts, FDA expressed concerns about the effects of dual use (compared with complete switching) on long-term reduction of HPHC exposures and the health risks for tobacco-related diseases, and concluded that ‘the health benefits of reducing cigarette consumption instead of quitting completely are unclear.’ (TPL p. 73)
FDA did not properly consider IQOS’ attractiveness to youth. FDA’s assertion that ‘the limited options in terms of flavour choice and the price of the IQOS device may reduce the appeal to youth’ (TPL p. 76) is surprising in light of the rapidly increasing flavoured e-cigarette use among US youth. In November 2018, >5 months before issuing the IQOS marketing order, FDA released National Youth Tobacco Survey (NYTS) findings showing that >3.6 million middle school and high school students were current e-cigarette users in 2018, a dramatic increase of >1.5 million students over the previous year.41 The Survey showed that use of menthol-flavoured or mint-flavoured e-cigarettes increased among e-cigarette users from 42% to 51%,42 consistent with a peer-reviewed study showing that 27% of youth used menthol-flavoured or mint-flavoured Juul, and 12% used menthol-flavoured or mint-flavoured other e-cigarette styles.43 Preliminary data from the 2019 NYTS showed that 28% of high school students used e-cigarettes in the past 30 days, up from 21% in 2018 and 64% of them used menthol or mint flavours.44
Tobacco industry documents reveal that the industry has long manipulated menthol levels to target youth and facilitate smoking initiation.45 FDA presented overwhelming evidence in its draft Deeming Rule (giving FDA authorisation over all tobacco products including heated tobacco products) that menthol products attract youth to tobacco use, deter quitting and should be prohibited.46 Two of the three approved IQOS Heatsticks are menthol flavours. Menthol can be expected to become even more popular if FDA puts tighter restrictions on other kid-friendly flavours as announced.44 Indeed, a former Juul executive alleged that the former CEO of Juul said, “You need to have an IQ of 5 to know that when customers don’t find mango they buy mint”.47
FDA did not discuss IQOS product features especially attractive to youth such as its sleek design imitating Apple products48 and ignored studies showing that IQOS marketing techniques are likely to appeal to adolescents and young adults.49–51 FDA either did not discuss or redacted discussion of the ‘firmware’ (TPL p. 27) embedded in the IQOS device that can extract information about a user’s smoking routine and use it to reprogram IQOS’ puffing delivery pattern to one that may be more reinforcing and with a higher addiction potential, as well as for marketing purposes.52 53
Indeed, FDA’s social science review concluded that the PMTA lacked information about youth, lacked a discussion of the data’s applicability to youth and lacked a presentation of the data in stratified categories that would allow FDA to make inferences about youth and the potential for initiation among young adult never smokers. (TPL pp. 73–76) FDA disregarded these limitations and instead relied on data from Italy and Japan showing low uptake by youth and non-smokers and recommended issuing a marketing order for IQOS. (TPL p. 83) However, independent research concluded that because of cultural factors, uptake data are likely to significantly vary from country to country.48
FDA misapplied the law
FDA reversed the legal standard and authorised the marketing of IQOS based on its conclusion that IQOS was not more dangerous than cigarettes, rather than on finding that PMPSA demonstrated that allowing the sale of IQOS would improve public health. While evaluating the specific toxicity of a new product is a first step in determining whether that product is APPH, reduced exposure to toxicants is not alone sufficient for an APPH determination. In addition to considering whether the product reduces individual health harms, TCA § 910(c)(4) also requires FDA to consider population impacts, including the increased or decreased likelihood that non-users (including never smokers, former smokers and youth) will start using a new tobacco product, when evaluating a PMTA. (TCA § 910(c)(4)(B)) In particular, FDA’s Guidance provides that PMTAs should address the attractiveness of the product and the specific product features that may enhance the attractiveness of the product and product labelling to never-users and former-users (Guidance p. 16) and ‘should specify what product features may enhance the attractiveness/appeal of (the) product to children and adolescents.’ (Guidance p. 17) As discussed above, FDA failed to adequately consider the impact of IQOS on youth.
FDA must deny a PMTA if it finds that the proposed labelling is false or misleading in any way. (TCA § 910(c)(2)(C)) In addition to proposed labels, applicants must submit studies evaluating consumer perceptions including risk perceptions based on the product itself, as well as on the product’s packaging and labelling. (Guidance p. 19) FDA concluded that the applicant’s submitted study data ‘show that consumers (including young adult never smokers) do not accurately perceive and tend to underestimate the addiction risk of IQOS’ (TPL p. 87) and ‘consumers, including young adult never smokers, who mistakenly believe IQOS to be less addictive, may start using it when they would not have otherwise initiated tobacco use.’ (TPL p. 88) As discussed above, requiring the nicotine addictiveness warning does not cure this defect.
Outside the USA, tobacco companies exploit FDA’s marketing authorisations to imply that those products that obtained marketing authorisation are ‘FDA approved’ and therefore determined to be safe or safer than other tobacco products (figures 2 and 3). The WHO Framework Convention on Tobacco Control (FCTC) requires parties to adopt measures that prohibit packaging and labelling that promotes a tobacco product ‘by any means that are false, misleading, deceptive or likely to create an erroneous impression about its characteristics, health effects, hazards or emissions’, including any figure ‘that directly or indirectly creates the false impression that a particular tobacco product is less harmful than other tobacco products.’54 When PMI labels or promotes (implicitly or explicitly) IQOS outside the USA as less harmful than cigarettes (figures 2 and 3), it violates the FCTC because these claims have not been substantiated with scientific evidence and are false or misleading.52
FDA’s decision to authorise sales of IQOS was based on its finding that IQOS is no more dangerous than cigarettes. FDA’s approach is at odds with the clear dictates of the law because: (1) FDA did not require the applicant to prove that the new product would likely reduce tobacco-related harms and confer public health benefits; 55 (2) FDA did not consider the health effects of IQOS compared with other tobacco products currently on the market (including e-cigarettes), but instead only compared IQOS with cigarettes; and (3) FDA did not adequately consider the health impacts of dual use and misleading labelling.
Implications for future tobacco control regulation
FDA’s permissive marketing order for IQOS is disconcerting because of its likely impact on future regulatory actions. Notably, the precedents FDA set in evaluating the IQOS PMTA may influence its assessment of whether to issue marketing orders for other PMTAs. As a result of a successful lawsuit against FDA by health groups, a federal court set a deadline of 12 May 2020 (subsequently extended to 9 September 2020) for manufacturers of e-cigarettes (and other newly ‘deemed’ products including other HTPs, cigars, pipe tobacco and hookah) to apply for FDA marketing authorisation.56 Therefore, FDA will be presented with hundreds of PMTAs for e-cigarettes and other currently unauthorised tobacco products that are submitted for review by the deadline. FDA’s IQOS decision seems to suggest that showing a product is ‘less harmful than cigarettes’ is sufficient to demonstrate that it is APPH.
This is not a correct application of the law. The proposed rule for PMTAs12 appropriately requires applicants to compare their product not only with cigarettes, but with other products in the same category (ie, e-cigarettes or HTP) to show less risk. This makes sense, since it is possible for a product to present significantly lower health risk than cigarettes, but more health risks than another product currently available.
FDA’s determination that a PMTA applicant demonstrated that their new tobacco product is APPH is not the same as FDA finding that a product exposes consumers to reduced levels of dangerous constituents or that a product may be marketed with MRTP claims. The decision to allow a product to be marketed with reduced risk or reduced exposure claims is a separate regulatory decision. As of May 2020, FDA was still considering PMI’s MRTP application for IQOS that includes reduced exposure and reduced risk claims. FDA’s inappropriate focus on inconclusive data regarding possible reduced exposure to a limited selection of HPHCs suggests that FDA has predetermined the outcome of the IQOS MRTP application.
Altria’s IQOS launch in the USA in August 2019 coincided with a serious lung disease outbreak connected to vaping products57 and with Juul’s market dominance challenged by multiple lawsuits.58–60 Manufacturers are developing ‘next-generation’ nicotine products including HTPs, new versions of electronic cigarettes, nicotine pouches and other novel products to encourage smokers to switch to products marketed as ‘less harmful’ alternatives. These factors suggest that consumers, including youth, may turn to IQOS as a ‘safer’ alternative, regardless of what FDA decides regarding the MRTPA application because they mistakenly believe FDA determined that IQOS is ‘appropriate for the protection of the public health’ (figures 2 and 3).
In the USA, premarket authorisation requirements are perhaps FDA’s most significant tool for protecting public health. The public relies on FDA to rigorously review new tobacco products to determine if they are, in fact, APPH. Regulatory bodies in other countries also may rely on FDA’s reports, and companies inappropriately cite FDA’s marketing orders as evidence that the products are ‘FDA approved’. FDA’s decision in the IQOS case raises concerns that FDA will not appropriately apply the law to the data submitted. FDA should reconsider its decision on the IQOS PMTA. Otherwise, the public will not have confidence that FDA’s decisions are based on sound scientific evidence and the law.
What this paper adds
Before marketing a new tobacco product in the USA, manufacturers must submit a premarket tobacco product application to FDA, and FDA is required to deny a marketing order unless the application demonstrates that the product is ‘appropriate for the protection of the public health’.
FDA issued marketing orders for Philip Morris’ IQOS heated tobacco device and three flavours of IQOS Heatsticks in April 2019.
FDA’s scientific review of the IQOS application and independent research show that IQOS does not reduce long-term disease risks, emits toxins with carcinogenic and genotoxic potential and the application did not adequately consider the health impacts of dual use, the product’s attractiveness to youth or consumers’ incorrect perceptions of addiction risks.
FDA’s decision allowing IQOS to be marketed in the USA did not properly consider the science or the law, which may have adverse public health impacts in the USA and in other countries where IQOS is sold.
Data availability statement
All data relevant to the study are included in the article or uploaded as supplementary information.
The authors would like to thank Stella Bialous, Benjamin Chaffee, Neil Sircar, Tanner Wakefield and Thomas Rotering for their suggestions on the manuscript.
Contributors Both authors contributed equally to this paper.
Funding This work was supported by cooperative agreement U54HL147127 from the National Heart, Lung, and Blood Institute and the Food and Drug Administration Center for Tobacco Products; and the University of California. The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH or the Food and Drug Administration.
Disclaimer The funding agencies played no role in study design; collection, analysis and interpretation of data; writing the report or the decision to submit for publication.
Competing interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.
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