WVS NEWS: Navigating the US FDA’s PMTA Maze
The recent marketing granted orders (MGOs) the US Food and Drug Administration (FDA) issued for Juul and, earlier, for Vuse Alto show there are multiple ways to get through the premarket tobacco product application (PMTA) pathway. Essentially, Juul succeeded by accentuating the positive, while Vuse’s owner, RJ Reynolds Vapor Company, minimised the negative.
However, all approaches must still show the new product can provide an overall net gain in public health. That evidence has to be in the form of randomised controlled trials (RCTs) or cohort study designs, rather than cross-sectional surveys or other forms of evidence.
Regardless of confusion over previous advice, this is now the established standard for any company wanting to get products officially on the US market. In the Juul MGO, the FDA provides some justification for why this must be the case.
Evaluating user behaviour over time
In the decision summary, Lynn C Hull, technical project lead for the Juul assessment and deputy director of the Division of Individual Health Science at the FDA’s Center for Tobacco Products (CTP) Office of Science, said any scientific evidence on uptake and transition to e-cigarettes needed to show changes over time. This is because the transition from smoking conventional cigarettes to exclusively vaping typically involves a period of dual use.
Therefore, evaluating behavioural changes requires observing the actual behaviour of users over time, said Hull. “With both RCT and cohort study designs, enrolled participants are followed over a period of time,” she added, “with periodic and repeated measurement of relevant outcomes.”
Randomised controlled trials and cohort studies vs cross-sectional surveys
An RCT, often considered to be a gold standard for clinical evaluation, randomly assigns participants to an intervention group or a control group to assess effectiveness. A cohort study observes a group over time to investigate changes at certain intervals. This approach can be used to evaluate an intervention and requires regular follow-ups of participants to observe developments.
“In contrast, cross-sectional surveys entail a one-time assessment of self-reported outcomes: although participants can be asked to recall and report on their past behaviour, the single data collection does not enable reliable evaluation of behaviour change over time,” Hull said. “Consumer perception studies (surveys or experiments) typically assess outcomes believed to be precursors to behaviour, such as preferences or intentions related to the new products, but are not designed to directly assess actual product use behaviour.”
This does lead to some confusion when comparing the Juul MGO with other MGOs, such as the one granted to RJ Reynolds for its Vuse Alto vaping product. For now, the most important point is that Juul was able to prove its products were “appropriate for the protection of public health” – as required by the Tobacco Control Act. It did so by providing evidence that the attractiveness of its devices would plausibly lead to more adult smokers quitting or significantly cutting down their conventional cigarette intake than it would lead to negative outcomes through youth uptake of vaping.
Limiting youth attraction by limiting flavours
Regarding youth attraction, Juul gave itself the best chance of success by limiting its application to two strengths of tobacco- and menthol-flavoured e-liquids (alongside the device itself). The FDA said Juul submitted studies showing “moderately low to moderate” interest in the product flavours, with adolescent tobacco product users somewhat more likely than nicotine-naive adolescents to try them. This is despite some non-users reporting some curiosity or intention to try them. Instead of flavour, current adolescent Juul users cite “social reasons” as why they ended up using the products.
What this means for Juul and its role in the start of the “youth vaping epidemic” scare in the US is unclear. However, the FDA evidently found that the higher rate of youth attractiveness to Juul products – particularly compared with some other vaping products granted MGOs – was outweighed by the benefits to adults.
Higher cessation rates
The benefit to adults came from studies showing significantly higher cessation rates when switching to Juul from conventional cigarettes compared with other current alternatives. The technical project lead noted three studies that found switch rates ranged from 38.4% to 51.9% (depending on the methodology used) across two years of follow-up. This was markedly higher than the switch rates reported in literature for other methods of switching, such as unaided quitting (5%-6%) or nicotine replacement therapy (8%-9%).
Hull added that the data showed significant higher switching rates for Juul’s menthol-flavoured products compared with the tobacco-flavoured ones, which was important for overcoming the higher levels of youth attraction for menthol- and mint-flavoured products.
Higher switching rates for menthol flavour
This is similar to the justification for the granting of an MGO to Njoy’s Daily Extra menthol-flavoured e-cigarette. There, the FDA found the menthol product had switching rates of 21%-32% – significantly higher than general estimates for e-cigarettes in the submitted literature.
“Additionally, the results provide consistent and robust evidence that the menthol-flavoured new products are associated with statistically significant and substantially higher rates (32%-43%) of complete switching than the tobacco-flavoured Njoy Daily at three or six months,” the MGO added.
Little attraction for youth
But it is a marked contrast to the justification for issuing an MGO to the most recent tobacco-only flavoured PMTA, RJ Reynolds’s Vuse Alto. In that case, the FDA’s decision focused primarily on how little attraction the product would have for potential youth users rather than its potential for adult cessation.
It additionally focused on how there was little potential for abuse among adults and that those who did choose to switch would likely see benefits to their health, rather than focusing on just how many of those adult consumers would switch over because of the product.
Potential for addiction lower
In the MGO decision, the technical project lead for the Vuse Alto PMTA, Apostolos Alexandridis, epidemiologist at the Division of Population Health Science in the FDA CTP’s Office of Science, found that the prospect of “abuse” for the Vuse Alto product – in other words, its ability to promote addiction and continued use – was lower for nicotine-naive groups, such as youth, than it was for current smokers, although higher than the possibility for abuse of somewhat similar strength nicotine gum.
Alexandridis said studies that assessed perceptions, appeal and intent to use showed those who currently use tobacco products reported the greatest intent to purchase Vuse Alto e-cigarettes.
Studies to show intention to stop smoking not robust enough
“Among current tobacco users who indicated any interest in purchase of Vuse Alto, ‘to stop smoking’ was a main reason for interest in using the products,” he added. “These findings demonstrated that the new products are appealing to adults who use CC [conventional cigarettes] and are interested in completely switching to ENDS [electronic nicotine delivery systems].”
This injects a degree of confusion into proceedings. Such a justification would appear to be an assessment of consumer intent. But in the Juul MGO, Hull – as technical project lead in that assessment – said: “Consumer perception studies (surveys or experiments) typically assess outcomes believed to be precursors to behaviour, such as preferences or intentions related to the new products, but are not designed to directly assess actual product use behaviour.”
She grouped the studies in with cross-sectional surveys, saying both types of studies were not sufficiently robust enough to be considered to be showing switching or reduction in smoking habits. This is because, to demonstrate this, evidence submitted must evaluate actual behaviour of users (not just intentions, like consumer perception studies) over time (and not just the one-time assessment of self-reported outcomes that would be the primary data in a cross-section survey).
Likelihood-of-use surveys
But this appears to be at least partly what was submitted in other successful PMTAs, such as the one for Vuse Alto that used online likelihood-of-use (LOU) surveys. These only demonstrated intentions on their own and not actual behaviour. For example, LOU surveys suggested perceived risk and appeal as well as intent to purchase.
This was to demonstrate that the products were more attractive to current smokers than to non-smokers, and also showed that current smokers had significant, higher purchase intentions compared with non-smokers. For instance, current tobacco users generally indicated stopping smoking was a main reason for interest in using Vuse Alto.
However, the MGO also oddly noted that: “Current established CC smokers rated Vuse Alto as significantly less appealing than CCs.” Similarly, it pointed out the tobacco flavours in the PMTA were generally of less interest to smokers than other flavours, such as menthol and non-menthol, non-tobacco flavours.
Given the studies were only of intentions rather than behaviour, those latter comments raise the question of whether those surveyed tobacco users would follow through with their intentions to purchase the vaping products in order to quit. And, even if they got that far, whether they would then stick with them over time.
The Vuse PMTA did combine this information with other studies showing transition to dual use or complete switching in adult smokers. But not all of these studies were product specific, bringing up another difference between the justifications in the decision summaries for the Juul and Vuse PMTAs.
General subject studies vs product-specific studies
In the Juul PMTA, Hull also expanded further on the use of general subject studies versus product-specific studies and the use of “bridging” studies from near-comparison products to the products under review in the PMTA.
She said in order for general e-cigarette literature to be bridged over to a specific product PMTA, it would, for one, have to be clear and consistent in its general conclusions. For example, the use of general vaping studies to prove the appeal of flavours leads to better switching results among smokers is “far from conclusive”.
The mixed findings are further beset by differences in design/methods but, more importantly – according to Hull – are likely due to a combination of product features, including flavours, nicotine concentration and sensory, as well as subjective, use experience, such as taste, throat hit and actual delivery. They could also be due to device design, she added.
Gaps in MDO and MGO decision summaries
Again, on the face of it, this looks like a significant contrast to the use of bridging studies in the Vuse Alto PMTA. There does not appear to be a full summary of the argument or justification used by RJ Reynolds to bridge the general studies cited to its specific products. Instead, the MGO only said that the Vuse application provided justification that users of the new products are demographically similar.
Meanwhile, it is also unclear what precisely changed from when the original Juul submission was issued a marketing denial order (MDO) to now. At times, the FDA refers to a 6th June deficiency letter, but full text of that does not appear to be available. Similarly, a full MDO decision summary – like that given for the MGO – does not appear to be publicly accessible.
What changed for Juul?
There are a few indications of changes throughout the MGO decision summary. For example, Juul appears to have submitted further studies on shelf life and leaching from device components. It also redid its evaluation of cancer risk and performed further in vivo studies. Arguably most importantly, it appears Juul added citations to the Adult Juul Switching and Smoking Trajectories (ADJUSST) study to its application, which provided important support for the high switch rates enjoyed by both flavours of Juul products among smokers.
While the PMTA process remains a quagmire, the Juul MGO clears up some of the perplexity. For one, it showed that products of higher nicotine strength can generally be bridged to cover equivalent products of lower nicotine strength, with abuse liability and pharmacokinetic justifications, though the same would not apply in the other direction.
In essence, a lower-strength, identical product can be shown to be no worse in terms of abuse and no more powerful pharmacokinetically. This means that if data for the higher-strength product shows acceptable levels of risk or harm, it can be assumed, at worst, that those same numbers would apply to the lower-strength product.
Comparator products and manufacturing control
The Juul MGO also supports a few already established theories. For example, it confirms that the FDA wants to see a variety of comparator products. The regulator appears to agree that e-cigarettes are safer than conventional cigarettes. But only comparing the two has left previous PMTAs in trouble. Instead, as both the Juul and Vuse PMTAs did, providing a variety of comparator products – including conventional cigarettes, other reduced-risk tobacco products and, most importantly, other similar vaping products – is necessary to gain an MGO.
It also shows that demonstration of control over manufacturing processes and standards as well as product design and components is necessary. Hull said Juul was able to demonstrate its system was designed and manufactured with appropriate controls, components, e-liquid ingredients and packaging using appropriate methods, standards, facilities and processing. This suggests that any PMTAs utilising a third-party manufactured device will struggle unless they can demonstrate significant knowledge of, and control over, the systems and processes.
Marketing plans not enough to mitigate risk to youth
More broadly, it also confirms that marketing plans on their own are not sufficient to prove deterrence of youth interest. This was already suggested by various MDOs and lawsuits, but it is now made explicitly clear in the Juul MGO.
“Thus far, [the] FDA’s experience shows that advertising and promotion restrictions and sales access restrictions cannot mitigate the substantial risk to youth from flavored ENDS sufficiently to reduce the magnitude of adult benefit required to demonstrate [a product is appropriate for the protection of public health] APPH,” the decision summary said. “Rather, for flavored ENDS, only the most stringent mitigation measures have such potential; to date, the only such measures identified with the potential for that kind of impact have been device access restrictions. [The] FDA is currently aware of no other restrictions with the potential to alter the overall net benefit assessment for flavored ENDS.”
FDA now prefers closed-pod systems
The FDA also said in the Juul MGO, possibly for the first time, that it had a preference for closed-pod/cartridge systems, while also acknowledging its enforcement priority against those products likely led to the proliferation of disposable vaping products, with which it has even greater concern.
“Following the FDA’s prioritised enforcement of premarket review requirements for certain ENDS such as flavoured cartridge-based or pod-based ENDS, use of these types of ENDS declined while a substantial increase in use of disposable flavoured ENDS, which were not subject to the prioritized enforcement, was observed,” the FDA said. It noted a climb in disposable use among high schoolers and middle schoolers from 2.4% and 3% in 2019 to 26.5% and 15.2% in 2020, respectively.
The FDA did not outright say the enforcement strategy may have been a mistake. But it did note that closed-pod systems provide less potential for tampering, abuse or poisoning than open systems. This suggests that any open-system device or e-liquid PMTA would have to either demonstrate it can minimise public health risks from abuse – essentially getting too much nicotine, tampering or poisoning. Alternatively, the PMTA would have to prove a significant advantage in adult smoker cessation conversion to counterbalance these risks.
The latter is what Juul did, the former effectively what Vuse did. This makes sense. At its height Juul was significantly more popular among both youth and adults than Vuse Alto. Therefore, it had to demonstrate high cessation success to prove a net public health benefit.
Key takeaway: prove a net positive for public health
Ultimately, any new vaping products looking to go through the PMTA process must first and foremost demonstrate they form a net positive for public health. But exactly how they do that can be achieved through multiple means. They can go the route of Juul and demonstrate significant potential for adult cessation to outweigh marginally higher youth uptake risk (which still must be mitigated as much as possible).
Alternatively, they can go the Vuse Alto route and concentrate on minimal youth appeal and presumptive net health benefits for adults who use the product to cut down or switch completely from conventional cigarettes. They can do this without really getting into just how many more adults might do so through such means compared with other cessation products available on the market.
Support with RCTs or cohort studies
Regardless of the path chosen, the arguments need to be backed by RCTs or cohort studies. Other types of studies may or may not be permitted. The circumstances in which they can contribute are not clear, and they should not be relied upon to form a major support in any PMTA argument.
General vaping studies can potentially be used, but only when there is broad scientific consensus and clear justification for bridging.
The recent MGOs do suggest it is fine to only perform tests on the highest nicotine strength for each individual flavoured product and then bridge those results to identical, lower-strength products.
Closed systems face fewer hurdles than open systems
Closed systems (ideally pod/cartridge, given scepticism over disposables) will also likely have an easier time, as it appears easier to demonstrate the risk of tampering, abuse or adulteration is minimised compared with open systems.
Regardless, a holistic approach is required, with all aspects of manufacturing, product, labelling and packaging considered. Marketing plans are useless for proving youth deterrence on their own and can only supplement other efforts to mitigate youth attraction. The FDA appears to believe technological deterrence is a possibility, which is a good sign for innovations like Ispire’s blockchain age-gate technology that has also been submitted to the FDA.
FDA getting better at weighing up positive vs negative impact
The FDA seems to be getting a firmer idea of what it is looking for in PTMAs. It is hard to say for certain – particularly without being able to read previous MDOs – but parts of the Juul MGO conclusion suggest a clearer framework for judging whether the now acknowledged potential positive impact e-cigarettes can have on adult smokers outweighs the potential negative impact of youth uptake – with more scope for more flavours to play a role.
But significant work would have to be done to show cessation benefits outweigh youth attraction for non-menthol, non-tobacco flavours. Meanwhile, it does not appear the FDA will get much quicker at reviewing outstanding PMTAs.
It was theorised that work had ceased on PMTAs during the changeover under president Donald Trump’s administration. However, a spokesperson for the Department of Health and Human Services told ECigIntelligence this was not true.
“Work on PMTAs never stopped,” the spokesperson told ECigIntelligence. “FDA posts final authorisations when they are issued in the Searchable Tobacco Products Database. We also post information on certain PMTA marketing denial orders here.”
Given this, it remains difficult to determine expectations, predictions and timelines for future decisions.
– Freddie Dawson ECigIntelligence senior contributing editor
