Vuse Solo e-cigarettes do not provide net benefits to public health: A scientific analysis of FDA’s marketing authorization

Abstract

In October 2021, the US Food and Drug Administration authorized marketing of RJ Reynolds Vapor Company’s Vuse Solo e-cigarette through FDA’s Premarket Tobacco Product Application pathway. FDA concluded that RJR demonstrated Vuse products met the statutory standard of providing a net benefit to public health. A review of FDA’s scientific justification reveals deficiencies: (1) Not adequately considering Vuse’s popularity with youth and evidence that e-cigarettes expanded the nicotine market and stimulate cigarette smoking; (2) trading youth addiction for unproven adult benefit without quantifying these risks and benefits; (3) not considering design factors that appeal to youth; (4) not addressing evidence that e-cigarettes used as consumer products do not help smokers quit and promotes relapse in former smokers; (5) not discussing evidence that dual use is more dangerous than smoking; (6) narrowly focusing on the fact that e-cigarettes deliver lower levels of some toxicants without addressing direct evidence on adverse health effects; (7) downplaying significant evidence of other substantial harms; (8) not acting on FDA’s own study showing no all-cause mortality benefit; and (9) improperly considering e-cigarettes’ high abuse liability and potential for high youth addiction and undermining tobacco cessation. Because marketing these products is not appropriate for the protection of the public health, FDA should reconsider its Vuse marketing order as statutorily required and not use it as a template for other e-cigarette PMTAs. Policymakers outside the US should anticipate that tobacco companies will use FDA’s decision to try to weaken tobacco control regulation of e-cigarettes and promote their products.

On October 12, 2021, the US Food and Drug Administration (FDA) authorized the marketing of British American Tobacco’s US subsidiary RJ Reynolds Vapor Company’s (RJR) Vuse Solo e-cigarette products through the Premarket Tobacco Product Application (PMTA) pathway.¹ Similar to what happened following FDA’s authorization of Philip Morris’ IQOS heated tobacco product,^{2, 3} FDA’s decision was quickly promoted around the world as an endorsement of e-cigarettes, including in Egypt⁴ and China.⁵ By December 2021, Vuse brands moved into second place in the US e-cigarette market, with 34% market share (behind Juul’s 38%).⁶

To authorize the marketing of a product for which a PMTA has been submitted, FDA must determine that allowing its sale is “appropriate for the protection of the public health”⁷ (APPH). According to FDA:

FDA interprets the APPH standard to require a showing [by the applicant company] that permitting the marketing of a new tobacco product would have a net benefit to public health based upon the risks and benefits to the population as a whole, which includes youth, young adults, and other vulnerable populations. In determining whether permitting the marketing of a new tobacco product would result in a net benefit to public health, FDA weighs the potential negative public health impacts (e.g., harm from initiation and use among nonusers, particularly youth) against the potential positive public health impacts (e.g., benefit from adult users of more harmful tobacco products completely switching).^{8, p. 4} [emphasis added]

Section 910 of the Family Smoking Prevention and Tobacco Control Act requires that FDA must make a finding based on a submitted PMTA that the applicant demonstrated that the specific tobacco product which is the subject of that application is APPH. Despite this clear requirement, FDA said in an August 31, 2020 memo outlining FDA’s “Office of Science (OS) Premarket Application Review Prioritization Plan”⁹ that one of its goals was to “Ensure a variety of ENDS [electronic nicotine delivery systems] have an opportunity to remain on the market to facilitate adult smokers switching to less harmful tobacco products.” This memo suggests that before reaching its October 2021 decision on the specific evidence presented in the Vuse Solo PMTA, FDA may have already made a policy decision to “ensure” that some e-cigarette products would be authorized for sale. The problems we highlight about the Vuse Solo TPL may reflect the fact that FDA had already decided to authorize e-cigarettes in general before it considered any particular PMTAs.

The fact that e-cigarettes have been sold in the United States for 15 years and their impact on adult smokers and youth has been quantified simplifies FDA’s task because it does not need to make a premarket prediction about the health impact of a completely new consumer product that has never been used by the public. In particular, in 2021 Vuse was the second most popular brand among high school e-cigarette users.¹⁰ (This study did not distinguish whether this was the “Original” flavored Vuse Solo product or a different Vuse line extensions.) As discussed below, the evidence as of 2021 showed that e-cigarettes in general did not demonstrate a net benefit to public health that meets the legal standard for two reasons: (1) there is no population benefit of e-cigarettes on smoking cessation when used as consumer products, and (2) millions of youth are attracted to e-cigarettes. Without cessation benefit (what the FDA and the tobacco companies call “switching completely”), there is not only no adult benefit to balance against the harm to millions of kids being recruited to nicotine addiction, but there may be harm because of increased dual use. Therefore, to obtain a marketing order for Vuse Solo (a particular e-cigarette), RJR (the applicant) would have to demonstrate that it is APPH by presenting evidence that the specific features of Vuse Solo made it behave substantially differently than e-cigarettes in general as described in the literature.

FDA’s October 12, 2021 press release¹¹ announcing its decision said RJR met the legal standard and demonstrated “FDA’s robust, scientific premarket evaluation.” However, our detailed analysis of FDA’s Technical Project Lead¹² (TPL) decision summary of its scientific justification for the Vuse Solo authorization reveals that it is filled with incomplete and contradictory information and identifies serious flaws. In addition, FDA failed to engage the broad scientific literature on e-cigarettes. Further, although the law⁷ places the burden on the applicant (RJR) to demonstrate that its product is APPH, FDA consistently gave RJR the benefit of the doubt in the face of weak evidence. These factors suggest that the order should be withdrawn as required by law.¹³

In FDA’s August 2021 press release, FDA explicitly described the trade-off between costs to youth and potential benefits to adults of e-cigarettes: “Companies who want to continue to market their flavored ENDS [electronic nicotine delivery systems, in this context e-cigarettes] products must have robust and reliable evidence showing that their products’ potential benefit for adult smokers outweighs the significant known risk to youth.”¹⁴ (This policy directly contradicts a recommendation in the 2020 Surgeon General’s report on smoking cessation: “The potential benefit of e-cigarettes for cessation among adult smokers cannot come at the expense of escalating rates of use of these products by youth.”^{15, p. 25}) While FDA is explicitly willing to trade off addicting new youth to Vuse to help current cigarette smokers purportedly reduce their risk, FDA failed to explicitly state how many youth it was willing to sacrifice, discuss the immediate adverse health effects on these youth, or estimates the number of adult smokers who will benefit and by how much. This failure to quantify the benefits vs. the risks is a fatal flaw because it makes it impossible for FDA to substantiate its determination that authorizing the marketing of Vuse Solo will actually provide a net improvement to public health.

As of August 2022, FDA had authorized the sale of RJR’s Vuse Ciro and Vuse Vibe,¹⁶ JTI Logic,⁸ and NJOY,¹⁷ using the Vuse Solo authorization as a template despite its problems, with thousands of PMTAs still in the queue. Equally important, other jurisdictions both inside and outside the United States should not rely on FDA’s Vuse Solo decision in their own policy deliberations regarding the sale of e-cigarettes.

Vuse brand popularity with youth

In determining whether to permit the marketing of Vuse Solo, FDA is required⁷ and recognizes the need^{8, page 4} to consider the likelihood that nonusers, including youth, will start using the product. Despite the importance of youth use, FDA did not require specific direct evidence on youth use of or susceptibility to Vuse Solo.¹⁸

The TPL recognized Vuse’s popularity with kids, but downplays it: “the proportion of reported youth use of the brand ‘Vuse’ significantly increased from 2019 (1.2%) to 2020 (7.3%).”¹⁹ The TPL did not discuss FDA and CDC’s 2021 National Youth Tobacco Survey that showed Vuse brand use among youth grew to 10.5%, the second most popular e-cigarette brand with 200,000 youth users (behind Puff Bar’s 26.8%).¹⁰ The TPL also stated, “However, the [2019] study did not specify the type of Vuse-branded products or the flavor used by youth, so it is uncertain whether use of Vuse Solo products increased among youth [emphasis added].” The TPL assumes that the increase in Vuse brand popularity does not apply to Vuse Solo “original” flavor. As of August 2022, RJR sold Vuse Solo alongside Vuse Solo Menthol and Vuse Alto on the same Vusevapor.com website.²⁰

FDA did not invoke the “common liability theory” that posits that youth who initiate tobacco product use with e-cigarettes would simply have started with cigarettes had e-cigarettes not been available because of shared risk profiles.²¹ In any event, there are two problems with this theory: First, while it is true that some youth who initiate nicotine use with e-cigarettes have risk profiles similar to youth who historically initiated nicotine use with cigarettes, a substantial fraction have risk profiles that do not predict smoking,^22–25 Second, between 2013 and 2021 increases in youth e-cigarette use were larger than the drops in cigarette smoking, resulting in a net increase in total nicotine product use,^{25, 26} the new low-risk (of cigarette smoking) youth e-cigarettes brought into the market. Most important, the TPL does not quantitatively discuss this evidence that e-cigarettes are likely contributing to increased nicotine dependence among youth by attracting youth who are unlikely to initiate nicotine use with cigarettes.

In addition, FDA’s statement, “Overall, the available evidence to date does not adequately address whether new product use in youth and young adults leads to regular smoking [emphasis added]” (TPL page 18) is simply wrong. Of at least 27 studies on the effect of e-cigarette use on subsequent cigarette smoking, all but one²⁷ found e-cigarette use increases the risk of cigarette smoking. Two meta-analyses found that youth who initiate with e-cigarettes have 3–6 times the odds of going on to add cigarettes^{28, 29} (Figure 1). Three of the newer studies^30–32 not included in these meta-analyses showed higher risks. Another newer study³³ showed e-cigarette use was associated with increased risk of cigars, little cigars, or cigarillos. Moreover, youth smoking need not be “regular” to predict long-term use: there is a dose-response relationship between past 30-day smoking in adolescence--even a single day in the month--and daily smoking in young adulthood.³⁴

Figure 1.

All the longitudinal studies show that among youth who had never smoked a cigarette at baseline, e-cigarette use elevated the relative risk of smoking at follow-up. Combining all the studies the adjusted risk ratios for cigarette smoking was about tripled (ever smoking: OR 3.01, 95% CI: 2.37 to 3.82; p<0·001; current smoking: OR 2.56, 95% CI: 1.61 to 4.07; p<0·001, not shown) at follow up.²⁹ (Copyright: © 2021 Yoong et al. available open access under the terms of the Creative Commons Attribution License.)

FDA’s Vuse Solo decision rests heavily on the assumption that tobacco-flavored e-cigarettes are not attractive to youth. The TPL does not present any evidence that youth will perceive “original” flavor e-cigarettes to be “tobacco” flavor. FDA stated in its announcement of the Vuse Solo marketing granted order that it had also “issued 10 marketing denial orders (MDOs) for flavored ENDS products submitted under the Vuse Solo brand by RJR.”¹¹ However, youth can easily transform their tobacco-flavored e-cigarettes to their favorite flavors using add-on flavor enhancers such as Puff Krush³⁵ and menthol flavor cards.³⁶ FDA recognized this fact and incorporated it in its proposed rule prohibiting menthol in cigarettes and prohibits components or parts such as flavor cards or other add-ons that might alter the flavor or other characteristics of the product.³⁷

FDA did not disclose what flavoring ingredients are used to make “Original” flavored Vuse Solo or why it determined that this “applicant provided characterizing flavor” is “tobacco-flavored” (TPL, page 13, footnote 3) Tobacco product manufacturers add low levels of menthol in tobacco products not characterized as “menthol” because menthol makes the products less harsh and easier to inhale, reduces aftertaste, and interacts with nicotine to make the products more addictive.^37–42

FDA did not act on RJR’s PMTA for Vuse Solo Menthol,¹¹ which allowed it to remain on the market. While fruit was the most popular flavor among youth in 2021, 28% of youth e-cigarettes users used menthol.²⁶ In addition, results published in 2022 indicated that, while fruit flavors were more popular initial flavors than menthol, youth who started with menthol were more likely to still be using e-cigarettes as young adults: 79% of those beginning with menthol/mint were still using e-cigarettes as young adulthoods, compared to 54% who started with fruit/sweet and 52% of those beginning with tobacco/flavorless/other.⁴³ Youth who started with menthol also used e-cigarettes more days per month as young adults. As of August 2022 RJ Reynolds was continuing to market Vuse Solo Original and Vuse Solo Menthol side-by side on its website.²⁰

In addition to flavors, multiple other product features contribute to youth appeal.^{44, 45} FDA recognizes that Vuse Solo’s design appeals to youth, stating, “Although the new products are not pod mods, they are sleek and small in design, user friendly cartridge-based, and easily rechargeable,” but argues, “Although there is some risk of youth uptake of these products, in general, tobacco-flavored ENDS are less appealing to youth compared to non-tobacco flavored ENDS, making the risk of youth initiation low for these products” (TPL page 17). This statement assumes that the numerous youth-friendly features of the product (sleek and small design, user friendly, easy to charge) will be outweighed by the product’s “original” flavor (as opposed to youth-attractive menthol/mint, candy or fruit flavors). Of particular concern, e-cigarette products like Vuse Solo that use nicotine salt formulations increase product appeal, especially among never smokers, by increasing perceptions of sweetness and smoothness and decreasing perceptions of bitterness and harshness, including for tobacco-flavored e-cigarettes.⁴⁶

FDA is required to deny a PMTA if, based on the application or “any other information” before FDA, “there is a lack of a showing” that permitting the marketing of the product would be APPH.⁴⁷ FDA did not adequately explain why permitting the marketing of Vuse Solo in light of these other design features would be APPH.

FDA failed to discuss the consistent evidence that when used as consumer products, e-cigarettes do not help smokers quit

In assessing FDA’s discussion of the effects of Vuse Solo and e-cigarettes in general on stopping smoking, it is important to remember that e-cigarettes and other tobacco products that are “customarily marketed” for recreational purposes fall under FDA’s Center for Tobacco Products jurisdiction. A company wanting to market e-cigarettes for cessation or other therapeutic purposes,⁴⁸ must apply to FDA’s Center for Drug Evaluation and Research where the randomized clinical trials which show increased cessation would be relevant.⁴⁹ For consumer tobacco products, population-based observational studies are relevant.

FDA’s statement, based on the population-based studies, that “daily and exclusive users have an increased likelihood of switching completely compared to non-daily and dual-users” (TPL page 15) is correct, but fails to discuss the evidence that non-daily users – the larger group – are less likely to “switch completely” (i.e., stop smoking cigarettes) than smokers who do not use e-cigarettes.⁴⁹ FDA failed to discuss several meta-analyses showing among all smokers, e-cigarettes as customarily used are not significantly associated with smoking cessation. Both a 2020 meta-analysis⁴⁹ (not cited by the FDA) based on 55 population observational studies and a 2021 one⁵⁰ based on 26 population cohort studies find e-cigarettes used as consumer products in the real world are not associated with increased smoking cessation (Figure 2). (The 2020 meta-analysis⁴⁹ considered both cohort and cross-sectional studies; analyzing them separately showed no significant difference in the results.) The 2021 meta-analysis⁵⁰ is particularly relevant because it limited the studies to cohort (longitudinal) studies that follow people forward in time, precisely the kind of studies that the FDA said it prioritized.

Figure 2.

E-cigarette use has no detectable effect on smoking cessation in cohort (longitudinal) studies. The overall odds ratio for quitting is 0.95 (95% CI 0.70–1.28; p=0.73), which is indistinguishable from 1.0 (no effect). Among all the studies in this meta-analysis, only 2 showed significant increases in cessation compared to 3 that showed significant depression in cessation. All the others showed no significant effect.⁵⁰ (This figure is available open access under the terms of the Creative Commons Attribution License, CC by 4.0.)

Moreover, another meta-analysis⁵¹ of studies examining the effects of e-cigarettes on former smokers found using e-cigarettes doubled the odds of relapse to smoking, a result reinforced in a subsequent study⁵² using FDA’s PATH Study dataset that followed smokers who quit with e-cigarettes forward in time.

In addition to failing to address these facts and relying on incomplete information in RJR’s PMTA application for Vuse Solo (as reported by FDA; the PMTA is not made publicly available), FDA’s health assessment assumed that smokers would “switch completely” and overlooked RJR’s own data showing only 1.5% to 6.7% of Vuse users stopped smoking cigarettes (“switched completely;” TPL, page 15).

The fact that the literature shows no smoking cessation benefit – and increased relapse risk – for e-cigarettes in general means there is no benefit to trade off against the thousands of kids being recruited to nicotine addiction. Absent specific evidence that Vuse Solo has effects different from the average e-cigarette, these two facts alone make it impossible to justify FDA’s decision authorizing Vuse’s marketing as APPH.

FDA does not address the appeal of Vuse Solo to adult nonsmokers

In addition to evaluating youth effects, the law requires FDA to consider whether permitting the marketing of a new tobacco product will increase the likelihood that former users will start using the product.⁷ FDA noted, “The applicant study findings indicate that among most adult non-tobacco users, both former (84.3%) and never users (74.7%), indicated they were not interested in the new products” and accepts RJR’s conclusion “that adult never users are not likely to become users on the new products” (TPL page 16). An alternative reading of these observations is that 15.7% of former adult smokers and 25.3% of adult never smokers were interested in Vuse Solo.

In 2018 the adult (18+ years old) prevalence of current, former, and never smoking were 13.8%, 20.9% and 65.3%, respectively,⁵³ which means, based on RJR’s numbers, a total of 73 million former and never smokers would be interested in Vuse. This compares to between 0.5 and 2.2 million current smokers (based on RJR’s claim that 1.5% to 6.7% of current smokers would switch completely to Vuse). As a result, only 0.7% to 3.0% (0.5/73 and 2.2/73) of the interested former and never smokers would have to start using Vuse for RJR to see a net increase in customers. FDA does not address the fact that there is no public health benefit of recreational e-cigarette use for these millions of adult former and never tobacco users.

FDA did not do this simple calculation even though Vuse’s potential to promote relapse among former smokers^{51, 52} and attract never smokers should have been included in a quantitative assessment of the net public health impact of authorizing the sale of Vuse Solo.

FDA’s discussion of health effects is narrow

The discussion of toxicity and health effects of Vuse Solo emphasized FDA’s 2012 Harmful and Potentially Harmful Constituents⁵⁴ (HPHC) list that is focused mainly on combustion products and carcinogens. This narrow focus is an important limitation because heart and lung disease kill more smokers than cancer,⁵⁵ and the current HPHC list does not include many cardiovascular and pulmonary toxicants. In 2019 FDA proposed⁵⁶ a well-justified⁵⁷ expanded HPHC list that, as of August 2022, was awaiting finalization.

Propylene glycol (PG) and glycerol (also called glycerin, vegetable glycerin, or VG) are ingredients found in Vuse Solo that FDA considered to be harmful constituents on their proposed updated HPHC list.⁵⁶ (The literature on harmful effects of PG/VG used in e-cigarettes has continued to grow.^58–63) FDA did not comment on risks associated with PG/VG in the Vuse Solo TPL.

Rather, FDA drew sweeping toxicological conclusions based on very limited evidence and despite the fact that RJR did not assess dual use (concurrent use of cigarettes and e-cigarettes) that FDA acknowledged “would be more likely to occur in real-world conditions (TPL page 25). FDA justified this limitation, saying:

While the effects of dual use were not assessed, significant reductions in systemic exposures after short-term switching and the available evidence suggest that daily use of the new products with concomitant reduction in CPD [cigarettes per day] may provide health benefits from a harm reduction perspective in terms of reducing exposure to HPHCs relative to continued use of cigarette smoking alone. [emphasis added] (TPL page 26)

FDA’s conclusion is based on speculation, not evidence. Continuing to focus on the outdated HPHC list is a serious problem that substantially increases the risk that FDA will miss important toxicities in new products.

Moving beyond this limited consideration of FDA’s outdated HPHC list is particularly important because e-cigarettes deliver thousands of chemicals⁶⁴ with a risk profile different from cigarettes, not simply a subset of cigarette toxicants.⁶⁵ FDA failed to engage the large biological literature indicating e-cigarettes have substantial pulmonary and cardiac toxicity,^66–70 often with different effects or adverse effects as large as those identified for combusted cigarettes.

For example, FDA did not address a 2021 review of 106 papers, “Cardiorespiratory and Immunologic Effects of Electronic Cigarettes,”⁶⁶ that explains why just avoiding the combustion products in conventional cigarettes does not mean e-cigarettes are safer than cigarettes:

… even though per puff, e-cigarettes may generate lower levels of toxins; their toxicity may approach that of combustible cigarettes if the use of e-cigarettes (exposure/dose) is higher than that of combustible cigarettes. For instance, if e-cigarettes are half as harmful as combustible cigarettes, but are used twice as much, there would be little harm reduction by using e-cigarettes over combustible cigarettes. Therefore, for both e-cigarettes and combustible cigarettes, harm could be reduced only by reducing exposure. Here too, the relationship is not straightforward. The dose response relationship between smoking and ischemic heart disease, for instance, is non-linear. It shows that smoking just 3 cigarettes a day imparts 80% of the harm attributable to smoking 20–40 cigarettes per day. In other words, 85–92% reduction in exposure results in only 20% harm reduction. Therefore, reducing toxin exposure by using e-cigarettes may not result in proportional harm reduction. [emphasis added, citations removed]

FDA does not act on its own study showing no overall mortality benefit from smoking reduction

As highlighted in its press release,¹¹ FDA saw the “potential” of smoking reduction as contributing to the public health benefits of authorizing Vuse Solo.

To draw this conclusion, FDA implicitly assumes dual use (smoking cigarettes and using e-cigarettes at the same time) is safer than smoking exclusively, at least as long as the number of cigarettes smoked per day drops. On page 22 the TPL says, “The impact of dual use on BOE [biomarkers of exposure] levels and the associated health risks were not assessed; however, based on the currently available evidence, reducing CPD likely leads to less exposure to harmful toxicants than continued smoking and may help for eventual quitting [citations dropped].” But on page 23 the TPL reports that dual users have higher exposures to some toxicants than exclusive cigarette smokers.

Most important, FDA’s own research (TPL reference 62⁷¹) finds, “reductions in cigarette smoking have not been found to lower the risk of all-cause mortality, all-cancer risk, or other smoking/tobacco-related cancers (TPL page 23–24). In addition, a meta-analysis of e-cigarette use and lung disease⁷⁰ not cited by FDA found increases in risk associated with e-cigarette use after controlling for smoking (i.e., among dual users). Cross-sectional studies of e-cigarette use and heart disease,^72–74 stroke,⁷⁵ hypertension⁷⁶ and erectile disfunction⁷⁷ also show increased risks associated with dual use.

The risks of dual use are particularly important because, according to RJR (as quoted by FDA on TPL page 14), similar numbers of smokers intended to become dual users as to switch (quit smoking): “Most respondents indicated that their intended behavioral change with the new products was to switch to the product (38.5–52.8%) or to dual use (combusted cigarettes and the new products, 39.7–52.8%) with the intention of using fewer combusted cigarettes.”

Like its failure to provide quantitative estimates of the claimed general cessation benefit of e-cigarettes, FDA failed to quantify the effects of dual use even with reduced cigarette consumption. In both cases, it is likely that there are no such benefits to offset the risks to youth.

FDA’s incomplete assessment of Vuse Solo’s high addictive potential

FDA is allowing a high level of nicotine in Vuse Solo because “if a new tobacco product has a low abuse liability, current addicted tobacco users may find it to be an inadequate substitute for the product they are currently using” (TPL page 11). The level of nicotine that FDA is permitting in Vuse is three times the nicotine concentration that is legally permitted in Canada, the UK and Europe.⁷⁸

FDA recognizes, “The nicotine levels may pose an addiction risk for non-tobacco users” (TPL page 12) but goes on to assert that “the risk is no higher than other currently available tobacco products due to relatively low abuse liability of the new [Vuse Solo] products.” But FDA does not present or cite any actual data on abuse liability of Vuse Solo or e-cigarettes generally for youth or other non-users.

Moreover, FDA does not address the issue that abuse liability for youth and other non-users may have a different dynamic than among adult current tobacco users, especially because the nicotine salt formulation in Vuse Solo reduces its harshness and enhances the products’ appeal.⁴⁶

FDA rejected RJR’s quantitative estimates of the net benefit to public health but did not present its own estimate

While FDA did not present its estimate of the net benefit to public health of authorizing Vuse Solo, FDA did state that it rejected RJR’s population health impact model because it used “an approach known to overestimate actual use of the product (i.e., using likelihood of use data without comparison to prevalence data observed under real-world conditions), overestimate[d] product switching due to lack of consideration for periods of sustained dual use, and overestimate[d] the net population health effect in the event of a marketing authorization given the optimistic risk reduction estimates used in the main analysis (i.e., the assumption of a 95% lower excess relative risk compared to cigarettes)” (TPL page 26). The detailed discussion of RJR’s model in the TPL demonstrates that FDA understands what credible risks must be evaluated to determine net population health benefit. Nevertheless, FDA did not present its estimate of the net benefit to public health even though it stated that such an estimate is at the core of determining whether or not a particular product is APPH.^{8, page 4}

FDA accepted admittedly incomplete product stability data

E-cigarettes have finite shelf lives because they become more toxic over time while they sit on the shelf. E-cigarettes are often contaminated with bacteria and fungus that grow while the e-cigarettes sit on the shelf.⁷⁹ In addition, the chemicals in the e-liquid continue reacting with each other after they are mixed,⁸⁰ growing more toxic over time.⁶⁰ That is why FDA appropriately considers the microbial and chemical stability of e-cigarettes when deciding whether or not to authorize the sale of particular products. Nevertheless, FDA determined that Vuse Solo was APPH despite the fact that RJR did not submit complete data on chemical and microbial stability for the shelf life that RJR claimed:

Regarding product stability, the applicant stated that the shelf life of the new products is [redacted]. The applicant provided chemistry data to support that the new products are chemically stable over [redacted]. However, the applicant did not provide microbial data that would allow FDA to evaluate whether the products are microbially stable over [redacted]. The applicant instead provided data that supports microbial stability of the products over [redacted]. Because the microbial stability data for [redacted] is acceptable and indicates that the products are low-risk for microbial growth over a [redacted] period and because there are no other stability concerns, the lack of microbial data for [redacted]does not preclude an APPH finding for the products (TPL, page 4).

Even though the FDA included this fact in its Marketing Granted Order for Vuse Solo, FDA did not place any limits on its shelf life.⁸¹

FDA e-cigarette actions since authorizing Vuse Solo

Between October 2021, when FDA authorized Vuse Solo, and October 2022,⁸² FDA authorized Vuse Ciro and Vuse Vibe in May 2022 as well as Logic Power, Logic Pro, and Logic Vapeleaf⁸ (March 2022) and NJOY Ace (April 2022) and Daily disposable e-cigarettes⁸³ (June 2022). These marketing authorizations used similar justifications as for Vuse Solo, including arguing that the products are likely not popular with youth because they are “tobacco-flavored” and that the products deliver lower levels of some HPHCs. Like the Vuse Solo decision, these authorizations did not adequately consider dual use, did not address evidence that e-cigarettes used as consumer products do not help cessation, and did not quantify the net benefit to public health.

In October 2022, FDA issued Marketing Denial Orders for several Logic’s Menthol e-cigarette products, making them the first menthol e-cigarettes to receive a marketing decision based on a full FDA scientific review.⁸⁴ Although FDA has not made the marketing denial order or TPL available public, CTP Director Brian King stated, “the applicant did not provide sufficient scientific evidence to show that the potential benefit to adult smokers outweighs the risks to youth.”

In June 2022, FDA denied Juul Labs’ PMTA for its e-cigarettes.⁸⁵ Juul released the marketing denial order and TPL as well as its appeal to the FDA.⁸⁶ FDA justified its denial based on issues with the toxicological data in Juul’s application; FDA did not discuss addiction, youth use, or net benefit. In July, Juul Labs requested a supervisory review of FDA’s marketing denial order, arguing that the order was substantively and procedurally flawed and should be rescinded. Among other things, Juul complained that FDA applied a different standard from that applied to earlier authorized products. As detailed in this paper, as well as our earlier evaluation of FDA’s authorization of Philip Morris’ IQOS heated tobacco product,^{2, 3} FDA should be applying a more scientifically rigorous standard to PMTA applications than it had to date.

Limitations

The primary limitation is that FDA did not make the PMTA application publicly available, even in redacted form, so this analysis is solely based on FDA’s summary of the data RJR presents and citations to the literature FDA chose to present in the TPL.

Conclusion

FDA made significant errors in analyzing the evidence that the TPL suggests was presented in the Vuse Solo PMTAs and did not discuss the opposing scientific literature. (This situation contrasts with FDA’s 2022 proposed product standard eliminating menthol in cigarettes;³⁷ where FDA cited papers that did not support its proposed standard and explained why it was discounting them.) FDA de facto authorized Vuse Solo Menthol by not acting on that PMTA. The law¹³ not only justifies, but requires, FDA to withdraw a PMTA order if FDA finds, among other reasons, that the continued marketing of the product is no longer APPH or the application contains or was accompanied by an untrue statement of a material fact. Indeed, FDA stated in the Vuse Solo Marketing Granted Order,¹ “The products subject to these marketing granted orders are subject to withdrawal or temporary suspension as described in section 910(d) of the FD&C Act.” FDA could and should find that marketing Vuse in not APPH based on the evidence of significant errors we highlight. Since we have no access to the application itself, we cannot know if it contained or was accompanied by an untrue statement of material fact. But the discussion of FDA’s analysis (TPL) of the application suggests that either material facts were left out or FDA did not appropriately consider facts that are material to finding Vuse Solo APPH. For the same reasons, FDA should withdraw the other PMTAs it has authorized modeled on the Vuse Solo TPL^{8, 16, 17} and avoid such errors when analyzing pending e-cigarette PMTAs. FDA should also deny the PMTA for Vuse Solo menthol and the menthol versions of other e-cigarettes it has allowed to remain on the market through inaction. Further, based on experience following FDA’s authorization of the sale and marketing of Philip Morris’ heated tobacco product IQOS with modified risk tobacco product claims in the US,^{2, 3} policymakers should anticipate that tobacco companies will use FDA’s decision to weaken tobacco control regulation of e-cigarettes and to promote their products outside the US and should be prepared to withstand this pressure.

KEY MESSAGES.

What is already known on this topic

• In October 2021, the US Food and Drug Administration authorized marketing of RJ Reynolds Vapor Company’s Vuse Solo e-cigarette products through FDA’s Premarket Tobacco Product Application (PMTA) pathway, its first authorization of an e-cigarette.

What This Study Adds

• A review of FDA’s scientific justification for this decision reveals many deficiencies, including that FDA did not demonstrate positive net benefits to public health.

• FDA did not adequately address youth issues, evidence that as consumer products e-cigarettes do not help smokers quit, dual use, and the full range of literature on heath harms of e-cigarettes.

How this study might affect research, practice or policy

• Because these deficiencies suggest that the continued marketing of the product is not appropriate for the protection of the public health, FDA should withdraw the Vuse Solo marketing order as statutorily required and not use it as a template for other e-cigarette authorizations.

• Policymakers outside the US should anticipate that tobacco companies will use FDA’s decision to try to weaken tobacco control regulation of e-cigarettes and promote their products and not accept the FDA decision as justification for similar decisions in other countries.

DATA AVAILABILITY

Original data are not reported in this paper.