Flavours have been a focal point of the debate about safer nicotine products, with calls to ban or restrict flavours often receiving significant media coverage. This workshop highlighted the growing evidence supporting the use of flavours in smoking cessation and explored changing attitudes to these products and the challenges regulators face in creating risk-proportionate legislation.
Transcription:
00:11 - 12:43
[Ian Fearon]
Good morning, everybody. Welcome to this session on flavors. We appreciate you coming to this workshop. I'm Ian Fear and I'm going to be hosting this session. I'll introduce the speakers in a moment. Could I have the introductory slide deck put up, please? Thank you. Yeah, so I'll introduce the panelists, as I say, in a few moments. I was looking this morning. Between us, we have a century of collective experience in tobacco harm reduction. So this is a once in a lifetime opportunity to quiz these experts. I'll talk about why we're here, what this workshop's all about. And then my speakers will each give a presentation, 10 or 15 minutes or so. And then we'll have an audience participation, a moderated Q&A session before we wrap up for lunch. So the panelists, we have Elizabeth. I'll introduce them in a bit more detail in a moment. Elizabeth, Christopher, Autumn, and Piotr. As I said, I'm Ian Fearing. I've been working in harm reduction, tobacco harm reduction, for 17 years. I run a consulting company providing science and research support to tobacco companies, nicotine companies, drug manufacturers, and CROs. Just in terms of disclosure, I am a scientific advisory board member with Qnovia, who are a medtech company looking at... getting an e-cigarette as a prescription medication and I'm also a non-executive director and board member with Advanced Intelligent Rituals. Christopher is Director of Russell Burnett Research and Consultancy. He's a research psychologist, 15 years working on tobacco and nicotine products, primarily on behavioural studies, behavioural science, and he leads and runs perception and behavioural studies of non-combustible tobacco and nicotine products to help manufacturers submit regulatory applications. Elizabeth works for Altria Client Services in Richmond, Virginia. She leads a team of scientists who also conduct perceptions and behaviour studies in support of product applications and regulatory submissions. Before working in regulatory affairs, she led Altria's corporate responsibility efforts and has 20 years of experience in tobacco across research, communications, innovation and corporate responsibility. Autumn Bernal has 20 years of experience as a toxicologist, provides consulting support, toxicology support in the tobacco harm reduction space. She's the founder of Tox Creative, which supports tobacco companies, nicotine companies, med device manufacturers, drug companies, and CROs. And she specializes in the human health risk assessment of innovative new products and has global experience in North America, UK, Europe, Australia, New Zealand and Asia. And then last, but by no means least, Piotr Kasarewicz, 25 years. He works for Philip Morris International, 25 years of experience in regulatory affairs, nine of those years spent in the tobacco industry working with smoke-free products. He's a pharmacist from the Medical University of Warsaw. He's actually come home to come to this conference. He spent 11 years with the European Medicines Agency and is a believer and keen advocate, as we all are, I think, of tobacco harm reduction and supports the ambition of delivering a smoke-free future. So why are we here, and what is this all about? It's about flavors. And flavors are ubiquitous. This is an image I just found on Google. It's a vape store somewhere in the United States. And it just shows the variety of flavored vaping products which are available. And I think one noticeable thing about this, you probably can't quite see it, but there's only one tobacco flavored product amongst all of these products. And there obviously has to be a reason for that. And I think that's what we're going to talk about today. What is the reason why we have these flavored vaping products? What do they do? What are the pros and cons of these flavored vaping products? And we're also going to focus on tobacco harm reduction. I've taken this from the Imperial Brands website. And it's an equation which describes how you determine population level tobacco harm reduction. To support tobacco harm reduction, you need a reduced risk product, an electronic cigarette, a heated tobacco product, a nicotine pouch, et cetera. And then there were two kind of almost conflicting factors which contribute to determining whether a product supports or opposes tobacco harm reduction. And these are what we colloquially call the off ramp. So this is whether a product appeals to adult smokers and whether it's used by adult smokers. Opposing this is use of these products by non-users, nicotine non-users, and the appeal to nicotine non-users. We call this sometimes the on-ramp into nicotine use. Again, we're going to touch on these factors today, talking about the on-ramp and the off-ramp, and overall talking about tobacco harm reduction. So there are various arguments about flavors. On the negative side, they're suggested to promote youth appeal and use by youth. They're suggested to make tobacco and nicotine products more palatable for a vapor product. They're suggested to make the inhalation easier, more smoother, et cetera. There are concerns around addictiveness. of flavors. Flavors are suggested to promote addictiveness. And there are toxicological concerns. You know, not all flavors are safe for inhalation, so there are some toxicological concerns. On the positive side, flavors are proposed to support switching away from more harmful forms of tobacco use, such as cigarette smoking, and certainly Chris and Elizabeth will talk in a lot more detail about this switching factor. The flavors are appealing to adult smokers. Yes, youth kids like flavors, but so do adult smokers. That's why the vape shops are full of all those flavors, because people want to buy them. Addictiveness is a good thing, and I'll talk very briefly about that in a moment. And Autumn will talk about risk assessment. Proper risk assessment can mitigate the risk of flavour ingredients in novel tobacco products. On this benefit of addictiveness thing that I just mentioned, I've taken this from a paper by Mary Gates, who works at the University of Minnesota and Dorothy Hatzikami's group. And in this paper, they said that flavor varieties associated with a higher abusive potential and appeal of e-cigarettes. And by abuse potential, what they really mean is the potential of that product to induce dependence on its use or its addictiveness. So higher addictiveness products may help facilitate complete switching from cigarettes to e-cigarettes. And if you regulate flavors aimed at stopping non-users of nicotine from initiating nicotine use with a flavored product, you have an inadvertent decrease in the uptake and switching amongst adult smokers. So you target one population, your impact is actually on a different population, and probably those who need the most support, the smokers who you need to convince to stop smoking. And this reduces the harm reduction potential, and therefore regulation should be evidence-based. And importantly, you should consider the adult smoker. You can't just look at one segment of the population. You need to look at the population as a whole and include adult smokers and adult smokers' needs in regulation. And Piot will talk about effective regulation of flavors later on. So there is calls for regulating flavors across the world. I've just taken this newspaper article from a UK newspaper, The Guardian, a couple of years ago, I think, that the UK government is planning to limit flavors. And the motive is always to stop children getting hooked. But as we said just a moment ago, the impact is on the adult smoker as well. And we really have to think about that. There is, of course, a new kid on the block in tobacco harm reduction, and this is the nicotine pouch, which its use is becoming increasingly prevalent in all of those countries in which it's marketed. I think in the United States in the last three years, the use of nicotine pouches has quadrupled. So it's on a really rapid rise. And again, these products come in a variety of flavors. There's mint flavors, citrus flavors, apple flavors, a whole host of different flavors. But what we're seeing is the same arguments being put forward about we need to ban these, we need to restrict them. Youth use is often cited as a reason for banning flavored nicotine pouches. But we also, as I keep saying, we also have to think about those who we want to be using these products, the adult smoker. The environment may be changing, and I think this was one of the reasons that Jess wanted us to talk about flavors, is that there might be a changing of the environment. In the United States, the Food and Drug Administration last year authorized four menthol flavored electronic cigarettes, taking into account the health of the population as a whole. And then earlier this year, the FDA further authorized Zyn nicotine pouches. Again, taking into account all of the evidence on these products helping to convert smokers, not being appealing to youth, et cetera, and considering the population as a whole. Recently, though, the World Health Organization has increased its calls for banning flavored tobacco products. And again, it's utilizing the kids' issue. It's maybe not considering the adult smokers' needs for a safer alternative to their combustible cigarettes. I'm also not sure why they've got kids holding up pictures of jewel pods, but that's something maybe they can answer. So what do we need to think about? And this is where our speakers come in. Do flavored tobacco and nicotine products support tobacco harm reduction? Do they promote switching? Do they promote abstinence? Can the risks of unintended use be mitigated by age verification procedures at point of purchase or on device technology which stops kids from using these products? Can the toxicological risk be minimized for flavored vaping products, nicotine pouches? And finally, how should regulators regulate? What should they do? What should they consider when they're thinking of setting regulation of flavored tobacco and nicotine products? So I'm going to stop there. I'm going to turn it over to, as I say, each of the speakers. We'll give a short presentation on their views on flavors, and then we'll turn into a Q&A session for some audience participation. So first up, Elizabeth.
12:43 - 23:14
[Elizabeth Becker]
Thank you. Thank you, Ian. All right. I appreciate the opportunity to be here. This is my first time at GFN, so I'm very excited. I unfortunately am not quite tall enough to see my slides that are down there, so I apologize if you see me turning to the side to make sure that I'm on the right one. So I'm going to go into this journey of flavors and why it really does matter to adults who smoke. So I'm going to touch on three different topic areas. The first is really the landscape in the US. What are we seeing in the marketplace? From there, I will shift to how flavors can support the journey for adults who smoke to switching to smoke-free products. And then lastly, I'll speak a little bit to the trends of underage use in the US. All right, so what are we seeing? So this is data from our adult tobacco tracker study. So in the United States, we see flavors preferred across various tobacco product platforms. But what's most striking are the data for those who use evapor or nicotine pouches. What you can see is that close to 90% of those consumers prefer using flavors. And if we dig into eVapor, I'm going to show you two figures here. The first represents those who use pod-based systems. And so this is data from 2016 to 2024. And what it shows are the number of consumers who use these products, and the blue represents those who use flavors most often, and the brown are those who use tobacco. And across the years, you can see that the preference has been for flavored products. What's interesting is that between 2019 and 2020, flavored pods were banned in the US, but you still see the blue. Consumers want these products and they're finding ways to get them. Oh, sorry about that. See, this is not quite tall enough. Okay, so if we shift elsewhere in the marketplace, what else happened around that time? It was the emergence of disposable products. And so you see the growth there from 2020 to current day. And again, flavors are dominating this product. Close to 13 million consumers use disposable products today, and the vast majority of them are using flavors. And so what do those flavors look like? So if we look at the 12.2 million consumers, they're gravitating to fruit, but you see other varieties represented here as well, from menthol down to things like coffee or chai. So this is just a picture, a very quick snapshot, of what we see in the US. But now what I want to shift to is what these products mean to adults who smoke and their journey. So I'm going to share with you data from three different studies across three different product platforms. The first is going to be Enjoy. So I'm sharing with you data for Enjoy, which is an evapor pod-based product, and it was available in four different varieties. So classic tobacco, menthol, blueberry, and watermelon. And for the purposes of the PMTA, so authorization of this product through the FDA, ENJOY conducted an in-market longitudinal cohort study. And the data that I share here is from month three. So at month three, among those who initially used tobacco, you see that about 17% switched completely to ENJOY at the three-month time point. Now, what's important is the values for flavor. You see that flavors essentially outperform tobacco. There are higher switching rates across menthol, blueberry, and watermelon as it compares to tobacco. So this is looking at everyone at the three-month time point. If we shift a little bit and just focus on those individuals who switched, what we see is the vast majority of those individuals initially used flavors. Only about 16% used classic tobacco, so this really shows the prominence of flavors in their switching journey. So next I'm gonna shift to a heated tobacco product. So this is data for the Plume heated tobacco product system. Altria is partnering with JTI to bring this product to the US through the PMTA process. And so Plume is a heated system that's available in four different stick varieties, two that are tobacco variants and two that are menthol varieties. And for the purposes of the PMTA, we conducted a six-week actual use study. This was among adults who smoke, and we evaluated the behaviors at the end of the study. What we saw was similar. So while we saw very strong switching rates across, those who used menthol had significantly higher switching rates than those who used tobacco exclusively. I'm going to shift the data one more time, just like we did last, to focus just on the switchers. When we look at those who switched at the end of the six-week study, what we see is that, again, the majority used menthol either exclusively or in combination with tobacco. All right, my last data set is gonna be a little bit different. And so this is data for the on nicotine pouches. So on comes in a variety of flavors. What we did here was a randomized study where participants were either randomized to use only the original variety or they could use original in all of the flavor varieties. And so participants were adults who smoke, and what we saw, I'm gonna share data that's a little bit different here. This is the proportion of participants with smoke-free days over each of the six weeks. What's interesting is at the beginning of the study, you see flavor outperform original. But by the end of the study, they start to converge. I also share liking data. Now, this is data among the gray are those who received the original variety. And as you can see, those who received flavor preferred. They liked the flavors more so than the original. So this is important because it has real-world implications. If you think about a consumer going to the store and purchasing original, let's say that's all they're able to access, would they stick with purchasing a product that they kind of like and they don't actually see any benefit until maybe three weeks? It definitely raises the question against prohibition. So I've shared with you different studies, different products, and how flavors can play a role in switching, but let's shift to the other side of the story. And to do that, I'm gonna go back in history, so please just bear with me a moment. Okay, so this is data, and it's specific to cigarettes. And this is from the National Survey on Drug Use and Health among 12 to 17 year olds in the United States. And what we saw was from 2002 to 2010, the overall trend of cigarette prevalence was going down. But the FDA made the comment in the quotes, which is that, you know what, we're seeing a different trend for a rate of decline, I should say, for those who use non-menthol versus those who use menthol. In fact, that menthol trend isn't declining at the same rate. And so, therefore, we think that menthol cigarette use among youth is actually leading to progression in cigarette smoking. So there was this heightened focus on menthol. So what happened next? Was menthol banned in the US? Did use smoking rates go up? No. You all are well aware of this. Fortunately, we have seen underage cigarette prevalence continue to decline across both non-menthol and menthol cigarettes. This is older data, but it continues to kind of paint the picture of, hey, you know what, you can still have prevalence come down without prohibition. So now I want to shift to data in the noncombustible space. So this is data from the National Youth Tobacco Survey. Again, it's among middle school and high school students. The black line represents those who use any tobacco product, blue is evapor, and then red again is cigarettes. So we see a similar trend with cigarettes. Many of you all are familiar that in 2019, we saw a peak in underage use of evapor at about 20%. And at that time, the majority of those underage reported using a flavored e-cigarette type, so close to 70%. Now, you can see the trend line. What's happened? It's gone down. Prevalence has declined to below what it was in even 2014. So what does it look like now? Actually, more of those underage are reporting using flavors. But we have to look at the big picture. Prevalence can in fact go down despite flavors being in the market. I've shared with you data from kind of both sides of the coin, so those who are smokers and the value that these flavors can play for them, as well as the prevalence of underage use going down despite flavors being in the market. So in conclusion, we believe that really a consumer-centric approach makes sense. Availability and choice of flavors in the marketplace can help accelerate harm reduction while also minimizing those unintended consequences. And with that, I have colleagues who helped me get here, and I very much appreciate their support. And I think I'm handing it over to Chris. Thank you.
23:21 - 44:11
[Christopher Russell]
Thank you, Elizabeth. I don't thank Ian for putting me after Elizabeth. Elizabeth is a blockbuster movie, and now you're going to hear from the guy who comes in at the end of the movie to sweep up the popcorn. Let's see if I am tall enough. So I'm going to talk about the strength of the evidence supporting the continued marketing of non-tobacco flavored ENDS products specifically. Just a quick disclosure about myself. My company has received funding from manufacturers of tobacco nicotine products to conduct perception behavioral studies on their behalf for submissions to regulators, primarily in the US for PMTAs and MRTPAs. Just to start, I was reminded by Facebook that I was here nine years ago. I've actually been here, I think, every year apart from the COVID years, but this popped up in my Facebook today. I thought that was quite... Interesting, it looks like it's the same room as well. So I'm going to quickly go through or touch upon the evidence pertaining to one specific question. Do people who use non-tobacco flavored ENDS flavors have a higher likelihood of quitting smoking than people who use tobacco flavored ENDS? And how strong is the evidence for that hypothesis? Now, many in this room through your personal use of the products may attest to the fact that non-tobacco flavored ENDS products have helped you. You may know three, four, five people each who have also benefited from the use of ENDS in non-tobacco flavors. And you may argue that to such an extent that removing retail access to those non-tobacco flavoured products would diminish interest among those who currently smoke from ever trying vaping products. And you may also argue that people who currently have already successfully completely switched from smoking to vaping may be... tempted or incentivized to go back to smoking cigarettes if their preferred non-tobacco flavored ends were no longer available. And all this would lead to a general conclusion that preserving access to a diverse marketplace of non-tobacco and non-menthol ends flavors can help to complement conventional tobacco control policies and interventions to accelerate reductions in adult smoking prevalence and associated health consequences. But there are people who disagree. And the opposing view is that actually, no, non-tobacco-flavored end products are not necessary. As an example of this view, an editorial published in the New England Journal of Medicine in 2019 argued that FDA should simply ban the sale of flavored nicotine products for use in e-cigarettes. And the reason for arguing for this is that The authors argue that the public health problem that e-cigarettes were designed, intended to solve, that is helping users of combustible tobacco products. to stop by switching to vaping is adequately addressed by liquids that are not flavored to appeal to adolescents, so essentially flavored vape products. And so the argument was that we believe, the authors believe, that tobacco-flavored ENDS products can help smokers just as well as non-tobacco-flavored products. And this position has been taken up by many in tobacco control and people who are opposed to vaping or skeptical of vaping and its contribution to population health. And subsequently, the onus has been put back on manufacturers, industry to demonstrate that the marketing of ENDS and non-tobacco flavors provides the smoker population with an added benefit over and above that delivered by tobacco flavored ENDS. So what then has been the evidence on the role of non-tobacco, non-menthol flavors in smoking cessation? What's the quality of this evidence? And most importantly, do we have sufficient high quality evidence to draw reliable conclusions? So to answer these questions, we must first be clear about what qualifies as high quality evidence, what constitutes high quality evidence when it comes to policy and regulatory decision making. This is the hierarchy of evidence pyramid, which you may be familiar with. The pyramidal shape qualitatively describes the amount of evidence that's generally available from each type of study design and the strength of evidence that's generated by each study design. And as we go up the levels of the pyramid, the amount of available evidence typically declines, but the quality of that evidence increases and the risk of bias reduces. And additionally, as we go up the pyramid, we gain confidence in drawing conclusions about causal relationships between an exposure and an outcome. Healthcare policy and regulatory decision making is ideally determined by evidence that's available towards the top end of the pyramid. Now, with respect to e-cigarettes, the most robust evidence of the efficacy of e-cigarettes for smoking cessation comes from the Cochrane Review Group's systematic reviews The CRG's systematic reviews of e-cigarettes, which have long been supported by Cancer Research UK, exist to provide healthcare professionals and policy makers, primarily in the UK, but also internationally, with the best available evidence upon which to base. their advice and recommendations to people who want to stop smoking. In 2023, the CRG published a systematic review of 319 randomized controlled trials incorporating over 157,000 participants. And the authors concluded that on the basis of that available evidence, there's high-certainty evidence that nicotine-containing e-cigarettes, virionicline, and cytosine are the most effective options that are currently available for helping smokers to quit long term, which they define as no smoking for at least six months. And specifically, the review found that for around every 100 people who are trying to quit, around 14 are likely to succeed. in quitting by using a nicotine-containing e-cigarette, varenicline or cytosine, which is a better rate of efficacy compared to other available options. So what then, Having found that there is strong, high-quality evidence demonstrating the efficacy of e-cigarettes in general for smoking cessation, what then have Cochrane systematic reviews found about the role of non-tobacco, non-menthol flavours in smoking cessation? And to anyone who is familiar with this, the answer is not good. There have been three systematic reviews of... ends flavor use studies published in the past three years two from the Cochrane review group This first one from 2022 Found that there was only one study that directly compared different flavors between randomized groups and given that lack of evidence there is essentially then no clear evidence that e-liquid flavors affect smoking or vaping outcomes at six months or longer, but this I emphasize is is not due to evidence of the absence of an effect, but rather to do with an absence of high quality evidence. So as of 2022, with the available randomised control trials that were published at that point in time, there was no clear evidence that non-tobacco flavours did provide an added benefit over and above tobacco flavoured products. The update review in 2025 reaffirmed that conclusion, finding again no clear evidence was emerging the e-cigarette flavor was moderating smoking abstinence outcomes at six months or longer. And based on the available intervention studies, there's no clear association between the use of e-cigarette flavors and smoking cessation, again, due to a paucity of data. Again, only one study had randomized participants to use either a tobacco-only flavored ENDS versus a choice of e-liquid flavors. And the authors conclude, therefore, that to more reliably conclude upon this question, more RCTs should be carried out in which participants are randomized to different flavor conditions because, in the author's words, this is the only study design that can be used to establish causality, a causal relation between flavor use and smoking cessation. And just to go a little two years back in time, a systematic review by Alex Lieber and colleagues found essentially the same... arrived at the same conclusion, that from their review of 29 cross-sectional and longitudinal studies, that the evidence on the role of different flavoured ends, use in smoking cessation, at that point in time was inconclusive. But again, this was not due to evidence of no effect, but rather the... insufficient quality of the studies that were available at that time, reflecting highly heterogeneous study definitions and various methodological limitations. And Lieber and colleagues reiterate the conclusion from the CRG, one method to address this dearth of convincing evidence would be to randomly assign ENDS flavors to study participants. More high quality evidence ideally from randomized control trials is required. So the type of randomized control trial that the authors of these systematic reviews are pointing towards, calling for more of, would look something like this. An eligible sample recruited from the general population, randomized to use, in this example, either a tobacco-flavored ENDS, a menthol-flavored ENDS, a fruit one, fruit two, or fruit three. Let's call it mango, strawberry, or pineapple. And those participants randomized to those conditions would have access to and be encouraged or required to use only the assigned flavor for a minimum duration, ideally six months. And this is the proposed rough design that researchers are calling for more of. to deliver more convincing evidence. I would argue however that, I would argue that RCTs are not the best context for assessing the effects or the efficacy of ENDS or ENDS flavors for smoking cessation and that would apply to any consumer product. The RCT design is long established as the best method for evaluating health outcomes, changes in health resulting from use of a specific drug according to a tightly controlled schedule of conditions and a homogeneous group of people. The high degree of control over the characteristics of study participants, the random assignment to conditions, and instructions on how and when to use a drug, make an RCT an extremely useful design for isolating the effects of controlled use of a drug. However, I would argue that these same features make RCTs likely to be of less or limited use for yielding valuable information about the drivers of natural adoption and actual use of consumer products in particular, and how these products are used in everyday life under real world market conditions. For example, randomized controlled trials of ENDS flavors would likely be unable to capture the characteristics of natural adopters of ENDS products, their reasons and motivations for trialing a product and progressing to regular use. It would be unable to capture the effect of real world market and social influences on tobacco use behavior, so price, retail availability, media coverage, social attitudes. And importantly, it would not be able to capture how individuals' initial flavor preferences and use patterns change over time, as Elizabeth mentioned in relation to the Altria study. That is that RCTs don't capture the individual's continuous process of curiosity and discovery and adjustment to find out what satisfies them, what works for them. And as Elizabeth mentioned, there are people who, if given a product, a flavor to use, then they may use it because they're given it. But in the real world, it's likely that a high proportion of people would use that thing, but then probably give up on it once, go and experiment with something else, and find something else that they liked, and never return to the flavor that we would give them as part of a trial. It's also important to emphasize that ENDS users are heterogeneous. Their reasons for using ENDS are varied. The experiences that they're seeking from using an ENDS are varied. And most importantly, really most importantly, most people who use ENDS products don't use those products in the narrow, stable ways that may be required of participants in an RCT. RCTs will typically constrain the factors that we know are important to switching, such as having access to a variety of flavors, the freedom to choose from among those flavors, and as I mentioned, the evolving preferences and journey of discovery that many vapors tell us about. But in order to isolate the effect of a specific end's flavor, RCTs would typically be designed to eliminate or constrain participants' flavor access and their choice so as to minimize the variation in flavor use, therefore pulling the findings away from what would happen in the real world. So this constraint, this restriction, has the effect of inhibiting the natural heterogeneity among end users and the evolution of end use preferences that are common in the real world. And the randomization process also means that, as I've just mentioned, many participants would be assigned to use flavors they wouldn't naturally choose to use in the real world. And therefore, the switching or cigarette abstinence outcomes that are observed in an RCT may substantially underestimate the outcomes that we may see in the real world. So just to summarize this last bit, the RCT is undoubtedly the design that will yield the strongest evidence of the comparative efficacy of a flavored ENDS product versus a tobacco flavored ENDS product for quitting smoking under tightly controlled conditions, but people in the real world don't live under tightly controlled conditions. Participants of RCTs of ENDS are therefore unlikely to resemble the population who will naturally trial and use ENDS flavors in the real world. And to the extent that trial conditions constrain individual choice and use of products and the patterns of use of a flavored ENDS observed in an RCT may have quite limited generalizability for describing how real world users will actually use ENDS flavors in their everyday lives. and relatedly to the extent that trial conditions differ from real-world market conditions, and they often very much do, then the impact of a flavoured ends product on cigarette smoking among trial participants may have limited utility for predicting levels of smoking cessation and reduction that would be observed among real-world users of flavoured products. So a solution to this, regulators, policymakers are seeking the highest quality of evidence, which in the traditional medical paradigm means evidence from a randomized controlled trial. So how do we give policymakers the types and strength of evidence that they are seeking, but making those trials more closely resemble how these products are used in the real world? This is one suggestion. subject to further refinement, but rather than assigning people to use only a tobacco, only a menthol, only fruit one, fruit two, or fruit three, one approach, which I think now several companies are taking an approach along those lines, is to have a tobacco group, which represents a future hypothetical universe in which, let's say, the FDA prohibit retail sale of anything other than tobacco flavor. So this is modeling that or simulating that future regulatory environment. randomization to a menthol product, and then randomization to an arm in which the participants have free choice of all flavors in the portfolio of flavors being tested. Tobacco, menthol, fruit, one, two, three. People can use any one they want. They can start using any one they want. They can change at any time, go back to flavors. use one flavor, two flavors, three flavors, et cetera. The choice is up to them. And from that, we learn what people choose and how those choices relate to efficacy of each individual flavors and of flavor combinations. And what this allows us to say is, screen's disappeared. OK. that's gone off here. What this allows us to conclude is that is the added benefit of having access to a choice of flavors versus access to a single flavor, which really is no choice at all. So to summarise, where we sit at the moment in the evidence landscape is there is inconclusive evidence that using non-tobacco flavoured ends flavours increases a person's likelihood of quitting smoking relative to use of tobacco flavoured ends. But this is due to a lack of high-quality evidence from RCTs. And one remedy, therefore, to this, we need... because regulators are calling for it, we need to provide regulators with more convincing evidence from RCTs that better enable observation of how people use ENDS flavours in the real world. And this part of that would include having RCTs with arms that compare current versus potential future scenarios of ENDS flavour availability. So right now the question is, what would adults who smoke do if overnight their preferred non-tobacco flavored ENDS products were to disappear? Right now, the authors of the New England Journal editorial that I said at the start would say, well, right now there's no evidence that keeping these non-tobacco flavours on the market will provide any added benefit. And that is the challenge that we're all faced with, is demonstrating with appropriate study designs that... Removing people who smoke access to a variety of non-tobacco flavored products will hurt them and their families by extension by disincentivizing people from trying vaping as an alternative to smoking, reducing their motivation for attempting to quit smoking, and ultimately reducing their success. in quitting smoking if their preferred flavors are not available to them. But as I say, right now, the evidence landscape is that there's inconclusive evidence that non-tobacco flavors provide that benefit. And it's on us in this room and beyond to provide policymakers, decision makers with higher quality evidence on which to base future regulatory decisions. Thank you very much and happy to take questions after.
44:28 - 56:33
[Autumn Bernal]
So thank you so much for the two speakers that preceded me. I'm going to give you a look at the flavors from a toxicologist perspective. So Elizabeth and Chris did a great job. What's happening? Okay. Okay. Okay, sorry about that. So Elizabeth and Chris did a great job of talking about their role in examining consumer acceptance and looking at adult smoker appeal for flavored tobacco products. So I work on the other side of the equation, the green circle around scientifically substantiated reduced risk products. So that's what I'm going to be talking about today. And with that in mind, I hope the key points that come across are that health risk assessment is key to supporting the development of flavored products to support global harm reduction, that relative risk to cigarettes is a critical evaluation to conduct, that we should be approaching misperceptions with appropriate risk assessment paradigms, and that we should explore and utilize available tools to improve health risk reduction of flavored products. So when it comes to the potential health risks of flavored products, much of the public encounters headlines like this. And we all know that these sorts of headlines can lead to pervasive misperceptions. We've seen this with Evali. We've seen this with popcorn lung. Yesterday in one of the workshops, Ariel talked about that there are some in public health that will pinpoint potential toxicological effects of flavored ingredients and use that as a lever to deter youth use of those products with little scientific substantiation. And so this is a real challenge for us, especially as toxicologists, and we need to be able to approach these headlines with extreme caution and follow accepted risk assessment paradigms. So what is the human health risk assessment process? Well, it involves four key steps. The first is hazard identification. Then you have dose response assessment, followed by exposure assessment, and lastly, risk characterization. You'll see in those headlines that most of that is just about identifying potential chemicals in the flavored products. And so you're up on that first step of hazard identification. And so what I'm going to show you is how essential the next few steps are going to be when looking at the relative risk of flavored products to cigarettes. So firstly, the health risk assessment process is really essential in flavored product development and is critical in contributing to product stewardship of flavored products. So when thinking about integrating a risk assessment framework, you're going to want to do that early on during product development. And you're going to want to consider guidance to develop consistent frameworks across the different markets that the product is going to be sold in. The risk assessment framework can also be used to select ingredients to conduct accurate hazard identifications and to select those ingredients and also to exclude ingredients of the highest toxicological concern. The risk assessment framework can be used to conduct quantitative risk assessments. And these can be considered to look at cumulative cancer risks when formulating the product. So you can look at the overall risk of what the ingredients, what the HPHCs in the aerosol, what leachables, how they're all contributing to the overall risk of the product. You can use literature, predictive tools, or analytical testing to determine potential thermal degradation of reaction products in the aerosol. Chemistry evaluations may include aerosol instability testing of the product to support health risk assessments of the flavored ingredients. And these are also essential to conduct a health risk assessment after such chemistry evaluations. So all of this can contribute to our evaluation of producing a flavored product that smokers can benefit from. Lastly, there's experimental toxicology that can be conducted to investigate the biological significance of these products. There are some limitations in the experimental evidence, experimental toxicology, to support the hazard evaluation and the relative risk, but they can be used in a really effective way to look at the biological significance of these products. And so how do we use this framework to look at the relative health risk assessment? So relative risk to cigarettes and other tobacco products is a critical evaluation and is supported by recent FDA correspondence. the final PMTA rule and memoranda emphasize the importance of conducting a cancer risk evaluation and looking at the excess lifetime cancer risk. So this figure here, this pie chart, is essentially showing what FDA's risk management decisions are. So you can see that when they looked, when they published their memoranda, or it wasn't published but it was released through Avoya Act, they demonstrated that ends with marketing granted orders had about 1% the risk of cancer as combustible cigarettes. And you'll see here, according to their risk management decision, that falls within about a low risk compared to combustible cigarettes. we can use the risk assessment process to also quantify non-cancer risk. So here we have some evaluations of respiratory toxicity hazard, cardiovascular toxicity, as well as reproductive and developmental toxicity. And these are also the ends with marketing granted orders. So just as similar with the cancer risk, there are meaningful reductions in levels of HPHCs in target constituents across these products, and also greater than 99% calculated risk for these non-cancer hazards. So the health risk assessment process can be a really valuable tool in looking at relative risk to cigarettes and quantifying that risk for both cancer and non-cancer. What I've shown you now is data from menthol and tobacco flavored ends. But what about other flavors, like fruity flavors? So we know that these are of high concern. And most of the headlines, again, are pinpointing different ingredients from these products. Again, we need to approach these headlines with caution and follow accepted risk assessment paradigm. So most of these are really looking at just hazard identification and looking at chemicals that are identified in those products. One way that I like to contextualize the data is to look at the aerosol as a whole. So here we have in this figure one of my collaborators' publication from a couple of years ago where they looked at non-targeted analysis of the aerosol. So you'll see from this figure that over 99% of the aerosol mass contains PG, VG, nicotine, benzoic acid, and targeted compounds. Those targeted compounds are HPHCs or other major flavor ingredients. Less than 0.1% of the aerosol mass was what we call either reaction products or other flavorants. So it's a very small percentage of the aerosol mass. So when we look at those headlines and we see sort of that hazard identification, we need to contextualize it and think about the overall exposure and what the potential risk might be to the consumer. Importantly, what's shown here is that there were about only 100 compounds detected in this menthol. This is a Juul e-cigarette. And cigarette smoke has over 5,000 compounds with a high chemical complexity. So the cancer and non-cancer risk reductions are driven by the reduction in targeted compounds, which comprise over 99.9% of the aerosol. And the other reaction products, such as flavorants or products that are not recognized, like not rationalized products, excuse me, are less than 0.1% of the aerosol mass and may contribute a much lower risk. So what about other flavors? What I've shown you is menthol. The aerosol profile's unlikely to differ significantly for other flavored ends, especially if those are developed with a comprehensive product stewardship program and risk assessment framework. And indeed, we have seen a lot of data. We've conducted a lot of risk assessments on flavored products. Much of it is not published, so I haven't shown it here today. But other fruity flavors can demonstrate just as much of a reduced risk potential as menthol and tobacco flavored products. So what I want people to really take home is that identification of hazards does not equal risk. And reduction in risk from the most potent targeted compounds, which comprise 99.9% of the aerosol masses, is really what's driving that risk reduction to cigarettes. When we think about other flavoring ingredients and potential irritants, there may be a contribution to non-cancer risk of irritation, but the major aldehydes are greatly reduced compared to combustible cigarettes. And so how do we use these tools to improve the risk reduction potential of flavored products? There are many different ways. We can look at improving our hazard identification tools by using in silico predictions or read across methods. We can understand the heating of our products better. We can use that to investigate predictive models and understanding the chemical kinetics. We can definitely improve our quantitative methods for non-cancer and cancer risk assessment. There's always a little bit of uncertainty around these methods, and those can always be improved. We should also be looking into new approach methodologies to improve the hazard identification of the potential health effects of these products. And then lastly, we can look at different approaches for bridging to innovate new flavored products. And so we've come full circle. Health risk assessment supports the development of flavored products to support global harm reduction. The relative risk to cigarettes is critical. That's what our goal is here. We need to approach these misperceptions that we see in the headlines with appropriate risk assessment paradigms, and we can be using new tools to improve health risk reduction of flavored products. And I have some collaborators I'd like to thank whose work was shown in this. Dr. Charlene Liu, Dr. Mark Crosswhite, Perla Landestoy, and Richard Young and Charles Johnson. Yeah.
56:34 - 66:55
[Piotr Kozarewicz]
I fall in the group of short ones. Thank you very much to the panelists for providing insight into the scientific considerations, other scientific aspects related to the flavors. I would like to add regulatory perspective to the discussion. It's really important topic, polarizing topic. Polarizing and opposite views are often expressed in the public. And those are driving regulatory policies and influencing regulators. And unfortunately, not always this influence is actually going the right direction. Some of those considerations are based on on our experience with interacting with European, with Food and Drug Administration based on products and applications we filed to the agency. PMI has a portfolio of products which are authorized for commercial, for sale in the States. And these are also flavored products. So we understand the importance of flavors in the portfolio of products. Additional considerations in this talk are coming from observations and analysis of decision-making process of the agency. Maybe let's start with a rhetorical question. If, actually, regulatory policy can be driven by the science. And I think I call it a rhetorical question because the answer is yes, obviously, it must be driven by the science. So what needs to be done that the science is actually considered in the policy making because we often see not only in the United States but also outside that policies are driven by beliefs, by false statements and not necessarily supported by scientific evidence. We've heard from previous panelists that flavors are important. What we see actually is ban or restrictions of flavors, which is opposite to what science is saying. So what we should consider. First thing, and Elizabeth already demonstrated this, that adults and young people, they desire flavors. So it's not only young people, but also adults. What is actually, where's the problem is, is that false belief that flavors that adults desire are different from those that are desired by youth. And actually, regulators tend to put flavors for adults they consider mostly tobacco and menthol. Anything else is youth appealing, it's a youth flavor. And even when driving the developing policies, this is the driving force into defining what is actually or could be used by adults and what should be banned in tobacco products. Reality is that actually flavors that are liked by adults almost are identical with the flavors liked by youth. So there is a problem. Tobacco harm reduction, it's all about successful transition from combustible cigarettes to better alternatives. we need flavors then to facilitate this switch. And we cannot base the policy on assumption that blueberries just youth appealing flavor. Adults like blueberry flavor. So this needs to be considered in the policy making. Another Another element often seen in the policy, and also I'm glad I saw it as well in Elizabeth's presentation given by Elizabeth, is that there's this belief that actually youth uptake of tobacco products is correlated with availability of flavored products. and the flavors are actually promoting the youth uptake. And again, when looking at the NYTS data, it can be clearly demonstrated that there is no correlation. We've seen from Ian a photograph from a shelf in the US. This is the reality. There are a lot of many products which are flavored products, which are widely available. When you look at NYTS data, you actually can see that the vaping prevalence, youth vaping prevalence, is actually not correlated to the sales of vaping products, to the volume. Why is that? It's not because of regulatory actions. It's not because FDA authorized only few tobacco-flavored cigarettes and only even fewer menthol-flavored electronic cigarettes. this has nothing to do because flavored products are on the market and they are widely available. When you think about the time point when actually this correlation is now, the difference is so prominent, you can see that you can associate this with other practices that were put in place. It was the educational campaigns, And I would also say more responsible marketing campaigns by tobacco companies. So all these actually, in my opinion, contribute to this change of the trend, rather than actually banning flavors from use in vaping products. So another argument that should be considered in policymaking, banning is not always a solution. maybe educational campaigns, maybe stricter post-market surveillance requirements. These are additional elements that can actually prevent you from unintended use of tobacco products. I would like as well to present a case study which actually reflects current approach of the agency in the decision making. Agency meaning food and drug administration in the decision making. So in application, combining three flavored product and tobacco flavored product, FDA would authorize flavor one and two because those flavors through the scientific data are proving that actually the conversion power of flavor one and flavor two is greater than tobacco flavored product However, flavor number three would be rejected. Flavor number three would be rejected because its converting power is actually inferior to flavor one and flavor two, and it's also inferior to tobacco-flavored products. So assumption would be this is nice to have, but it's actually not contributing a lot to the overall switching of smokers. And we ask the agency, we ask regulators to look at the data. So one could claim this is a scientific data. It's proven through the study. But we ask as well, we should be asking as well, not only look to the numbers, but to have a deeper look into what is behind those numbers. When you analyze actually a real situation and you will see what is behind the numbers, it clearly can happen that actually flavor one and flavor two is liked by the same group of smokers. So actually, by authorizing flavor one and flavor two, we would only address a small group, a subpopulation of smokers. By rejecting flavor three, we are actually missing opportunity to activate yet another subgroup of smokers who would probably switch if the flavor tree was authorized. So it's not only numbers, but also the analysis of what is behind the numbers. And this should be considered in the policy making. This would be the example of public health-driven authorization. So I try not to be too long with the slides. I think a good summary would be flavors are needed in tobacco products. And we should not be basing our decisions on misconception that flavors are only for youth and they are actually facilitating, that they facilitate abuse of tobacco products. Adults as well desire flavors. We need to base the decision-making process, so regulatory policies should be based on the scientific facts. And scientific facts should be well analyzed, not only data, what is behind the data as well. We should also be looking into the real situation on the market, what's going on when drawing the conclusions. And actually, again, I think this confirms the need for the well-defined studies, well-defined risk assessment consideration, what's in the product, and analysis, who is using the product and why is using the product. And with this, I believe we can have really successful regulatory policies implemented not only in the United States, but also outside the United States. Thank you.
67:02 - 67:26
[Ian Fearon]
Can I get this? Oh, it's working now. Thank you. Thank you so much for those invaluable insights, I think, into a diverse range of topics which get at this issue of flavours. So now we want to open it up for questions. There's a lady there with a green dress. Is there a microphone? Would you want me to walk around? I can bring this one.
67:34 - 68:15
[Carolyn Beaumont]
Thank you. Such a wonderful presentation. I'm Carolyn Beaumont, General Practitioner from Australia. I have two questions I'm going to be cheekily asking. One is for Autumn. So in my work, I've helped probably about 4,000 adult ex-smokers get their vaping script in Australia because I did it. And many have said that the nice, high-quality, regulated vapes, they're great. They don't make them cough. sometimes are forced, because they can't access that, to go back to the illicit vapes. They cough a lot. Any toxicology sort of thoughts on that? Why the illicit vapes are making people cough a lot more? What sort of irritants are happening?
68:16 - 68:17
[Autumn Bernal]
Is this on?
68:18 - 68:18
[Carolyn Beaumont]
Great.
68:20 - 69:15
[Autumn Bernal]
That's a great question, and it's so nice to get your insight as a medical doctor and hear what you're seeing actually in the clinic with real people. There could be a lot of reasons for that, but there really could just be more. It could have to do with the device itself. So the device itself could be emitting more metals with the heating. There could be different ingredients that are in fact irritants that are at higher levels that are exceeding that threshold that we would like to see for toxicological concern. So, yeah, they're basically when you have these illicit vapes, they're not going to be conducting the appropriate product stewardship practices. And so they won't be minimizing the risk as much as they can do. So but yeah, it could be anything from the product formulation to the actual device itself. But that's really interesting to hear.
69:15 - 70:06
[Carolyn Beaumont]
Thank you. And if I may, just one for the general panel. The other one is on the use of tobacco-flavoured ends. So something I've noticed with many of my patients, customers, clients, whatever you want to call them, is that they'll initially switch from smoking and they'll start a tobacco ends and very, very successful, but they'll find after two weeks, maybe up to two months, when their taste and smell returns because they've stopped smoking, they realize how horrible tobacco flavor actually is so from that they'll then go on to other flavors usually sort of mint methyl or a fruit flavor um i just wondered was there is there some um yeah data that supports my clinical um experiences there about the return of of taste and smell that then drives the change from tobacco ends to other flavors
70:09 - 70:56
[Elizabeth Becker]
I'm happy to jump in a little bit here. So it's a really good question, and I can see you around the corner. So I'll actually start with some qualitative data that we've seen, which is that as smokers decide to transition to noncombustible products, they want a different experience. So they want to kind of distance themselves from tobacco flavors, and that's often a reason for choosing the flavored products. But that said, we are seeing some, anecdotally, and there may be firmer evidence that I haven't dug into, that some of the benefits of taste and things like that do return within a certain point of time and a different flavor is desired. Okay.
70:58 - 71:58
[Christopher Russell]
Just a further comment on that. What you're describing there and the people who say that to you is quite representative of what studies show about smokers will predominantly, although less so now, less so as time goes forward, be initiating vaping with a tobacco flavor vape because it's the shorter bridge from cigarettes, but experimentation then happens and fairly quickly, people move away from tobacco-flavored vapes. And just to reiterate the point I was making, That type of evolution of preference and process of discovery gets beaten out of participants in randomized controlled trials, and we don't get to discover how people change over time. And actually, Elizabeth's studies, where people are given choice to take flavors or leave them or go back and forth, are much better context for showing us the time course of change and how preferences change over time.
71:59 - 72:34
[Piotr Kozarewicz]
Can I only... add to this, I would like to encourage you to publish this data or think about publicizing this data, because I think it's a very important point in the discussion. It's something new, not necessarily seen in the public domain. And I think it's an important aspect, especially for the regulators. especially in Australia. So yes, please, please be vocal about it, because it's also another argument why flavors are needed, why they shouldn't be bound.
72:41 - 73:54
[Carolyn Beaumont]
Unfortunately, as a doctor in Australia, I am so hampered and limited by what I'm allowed to say by the Feminine Goods Association. There's very little I can say. at all, my medical licence is at risk. It's tragic, absolutely tragic. I just can't get it. It's a jam. Yeah, really just an observation, get Christopher's opinion on this. I hadn't been aware of that, you know, the difference, there isn't, on the available evidence we have, a difference in outcomes between whether it's tobacco flavour or other flavours. But it did have me thinking, we all know how this is going to be picked up by the ANZ side, which is, well, why do we need flavours if there's no difference in the outcomes? That's going to be a bit of a problem for us, and that's not what it's saying. It doesn't say anything about how many people use flavours and how many people are attracted to electronic cigarettes because of flavours, which you know is extensive. I don't know exactly what the figures are, but certainly well over 80% of people that use probably electronic cigarettes would use flavours and would cite flavours as very important. But that is going to be a little bit of a... It's going to be used probably against electronic cigarettes.
73:55 - 76:20
[Christopher Russell]
Yeah, absolutely. And so to be clear, there's not evidence of no difference. It's just an absence of evidence showing differences one way or the other. And yeah, my opinion on this is that the studies that Elizabeth described, observational studies, real world consumers who purchase products of their own volition with their own money and either keep using them or stop using them or change using them. That's the type of data that better informs the added value of non-tobacco flavoured ends because these are consumer products, they're not medicines. Medicines are designed to be tolerated, they're not designed to be enjoyable. Vape products are designed to be enjoyable, so people go where the pleasure is, and it takes them a while to find where the pleasure is, but once they find it, they'll stick with it and have better outcomes because they found something that works for them. And I just think that the traditional trial design of telling a person, you use this, you use that, and you use something else, is going to tell us something. It's going to tell us what would happen in a world where the FDA takes away all flavors and they're left with only tobacco. It will help to answer that question. But it doesn't tell us much about the world we currently live in, where people have the choice of 10, 20 flavors at their local store. They have the choice of vapes, pouches, heated tobacco products. And so, yes, I was concerned in putting the presentation together say what I wanted to say and not let it be interpreted as this means we don't need flavors. I absolutely believe we do need flavors. I just think regulators and industry need to find a common ground where we agree on the best way of demonstrating this for a consumer product that's not... meant to function like a medicine, be used like a medicine. Take it twice a day, this dose. It's not that. So the utility of applying that medical paradigm to this recreational consumer product makes little sense to me. But I think we need to keep discussing with regulators to emphasize the importance of longitudinal observational data as the more informative type of data.
76:26 - 77:18
[Garrett McGovern]
Hello, thank you very much for the panels and the presentations. I think we all agree that flavors are important and are there and have to play a role. And you just mentioned now that how do we find that middle ground from a policy-making perspective? I haven't seen many data, but what do you think conceptually, and then maybe explore? Because at the end of the day, from a consumer perspective, there are two main things, flavors and nicotine strength. So what do you think if you play inversely? So the highest nicotine strength, the lower flavor availability, or the lower nicotine, you compensate with more flavors. I don't know, for example, in the European context, any product above 10 milligrams, just tobacco menthol, below 10 milligrams, you can play with a wider range of flavor. What do you think like from a policy design perspective?
77:24 - 79:19
[Piotr Kozarewicz]
Again, policy should be driven by the science. And we know that above certain concentrations, like certain content of nicotine in electronic cigarettes, it's very difficult to use the product. The sensory element, the nicotine kick, is just too much. And only a small group of smokers is actually willing to use really high concentrations of nicotine. I think it really complexifies the whole deliberation. We haven't yet reached any consensus with the current situation about what to do with flavors considering available strengths of nicotine. Maybe we should do it step by step because the concept is nice, but the concept would need to be justified with data, with scientific evidence, generating this scientific evidence will take time. And also the question is how we define what is the lower strength and higher content of flavors, what is the higher strength of nicotine and lower content of flavors. Again, we've probably spent years discussing that with concentration for, I don't know, one milligram, it's no flavor above 10 milligram certain flavors are allowed and also why you want to only why you would like to only have like one cut of maybe you should have like staggered approach three or four different concentrations with three or four different differences in flavors like mental it's after one threshold fruity flavors after the other threshold you know I think it's endless. It's interesting point for the discussion, but I don't think that in the current environment, regulators are ready to have these discussions.
79:21 - 80:44
[Elizabeth Becker]
Yeah, I'll just jump in. Similar to Pioche, I would argue we have to follow the evidence. And I can speak to a little bit of data that we have on the on-product. So we conducted a different study that included all varieties. So it was seven flavors, or original and six flavors, and then I guess five different nicotine strengths. And so in the study, it was an actual youth study over six weeks, we included adults who smoke as well as those who use dip or moist smokeless tobacco. We saw that participants came in and used about three to four products and then kind of narrowed it down to two products that they preferred by week six. It ranged the entire portfolio of products. There were individuals who used two milligrams. There were individuals who used eight milligram products and across the different varieties of flavors. So I think to one of the figures that was shared by Pioche is when you look at it, you almost have to do a little bit of like a turf analysis to capture the greatest number of switchers. What are the products that you need to have available? The other angle that I would offer that's going to be focused on by regulators is the abuse liability of the product. So we need to evaluate that against cigarettes or whatever their incoming product use is.
80:45 - 81:50
[Autumn Bernal]
Can I just jump in there and add a little bit of a risk assessment perspective too? So it's something I've been thinking about a lot because of the recent memoranda released by FDA and how they would like to look at cancer risk and normalize it to nicotine uptake and just knowing that smokers tend to self-titrate when they switch to an ENDS. And when we look at risk and relative risk, we're basically normalizing to the amount of nicotine that would be in like a pack of cigarettes And so if we have a really low nicotine product, the levels of an ingredient might look really, really high, and the acceptable intake might not look great on a risk assessment. And so there needs to be, I think, some more in the toxicological community and the risk assessment community to make sure that we're not overestimating risks for those folks that like to use the lower nicotine content but maybe aren't consuming so much a day. So yeah, there needs to be like discussion across the clinical and the non-clinical for that.
81:53 - 83:09
[Mohamadi Sarkar]
Yeah, hi. This is Mohamadi from Altria. Great presentation and very timely topic given the debate that's going on in flavors. I would, Chris, I would push back on your comment about RCTs simply because with FDA, the good thing about in the U.S., FDA's thinking evolves as more evidence starts coming in. So recently, FDA has been willing to consider not only just RCTs but also longitudinal studies. So I think that the RCT does not give you the full picture of the availability of choice. And I hear your point about finding the middle ground, and that's always beneficial, right? But that middle ground if it does not reflect a real-world situation. And you made a pretty compelling case in your introduction, some of the challenges of RCTs. So I would caution about relying on RCT just to make the case that flavors are important. There is a lot of real-world evidence. Elizabeth showed some really nice, compelling data from our adult tobacco consumer tracking study, which
83:09 - 85:08
[Christopher Russell]
clearly demonstrates as well as the parts that he demonstrates that you know flavors are really important yeah and to be if it wasn't crystal clear let me try and be crystal clear now i give more weight to the the data that come from longitudinal observational studies of ends products than i do to rcts rct data because i don't think rcts i think rcts um conceal more than they reveal about how people use ENDS products. My reason for raising this is the RCT is what regulators globally, that's the standard or the strength of evidence they're seeking. They are the ones who give more weight to the data from RCTs than from cohort studies. because they think of these products as other medicines or in the medical framework. I don't. I'm arguing for a movement away from RCTs or towards RCTs that have arms that allow or enable direct observation of actual real world behaviors. So I didn't mean to say that RCT, we should all be out there doing RCTs and giving up longitudinal studies, not at all, because that's not what I do, that's not what I believe. I believe the best evidence of how people use consumer products comes from non-interventional studies letting people live their lives and seeing what they do and trying to be as least intrusive in their life as possible to measure what they do and when they do it. But I'm all about trying to give the regulator what they're asking for. And if we can find a way of making RCTs more resemble how people use products in the real world, some sort of integration of a design that retains randomization, but also then enables that observation in at least one of the arms, I think might be a nice middle ground.
85:10 - 85:43
[Mohamadi Sarkar]
I just have one comment. The reason why flavors are getting so much attention is probably because there's such a wide variety of flavors. Do we really need flavors that are representing kids' cereals, Cap'n Crunch in the US, or Bloody Unicorn, or whatever those names people are using? And maybe just limiting the number of flavors that adults are using and not necessarily attracting kids would be one way to overcome this issue.
85:43 - 86:49
[Christopher Russell]
Yeah, I absolutely agree with that. Proponents of flavors, just to be devil's advocate, I would say, well, how many flavors are needed to adequately solve the problem? At what point do we have a diminishing level of return? So is it 10 flavors, 20 flavors, 100? Surely we don't need 1,000. OK, so which of the 900 to go? How do we determine that? And I think, again, FDA or other regulators would look at this and say, what do we lose when we get rid of flavor X, flavor Y? We're only going to lose 0.1%, 0.2%. OK, they can go. And it's up to industry and others to demonstrate that whether it's watermelon, blueberry, or cherry, or so on, that there are some flavors that make meaningful contributions to switching and cigarette abstinence, and those are being defended with data. But I think it's reasonable to conclude that there are probably hundreds, if not thousands, of flavors out there that don't have data and likely won't have data to defend their continued marketing. Just one more question, and then we'll wrap up.
86:50 - 88:21
[Mark Tyndall]
Okay, let me get this quick. My name's Mark Tyndall. One observation with your randomization is that there's some default that people would want tobacco, menthol, or flavors, and we know that 85 or 90% of people are buying flavors, so it seems like it's an odd default that you'd randomize people to tobacco when we know that most people don't even want tobacco. But just, obviously this is a really important topic, this flavors, but we're really arguing on two sides. One is we're trying to discourage people from vaping, and that's youth, and then we're trying to encourage people to vape, and if we put 50-50, then we're into this flavor argument, but it should be 90% of our audience efforts should be to get people off combustible cigarettes. And there wouldn't be any argument. People can use whatever they want. And the toxicology thing is really important, that the flavors doesn't really matter to the toxicology. It's really just what people want. If the youth was taken out of that equation, then people could have any flavour they want. Who cares? And it's unfortunate that we're backed into this corner where the emphasis is trying to make sure that kids might not like these flavours. So that's a broad comment. But I think we want to get people off tobacco and combustible tobacco. And who cares what flavour they like?
88:23 - 89:34
[Christopher Russell]
Two very quick points over time. My final point on this is that an RCT is undoubtedly the best design for answering the question, what would happen if we banned all flavors? We have people only using tobacco and we have people using a choice. So FDA wants to know, what would we lose if we got rid of all the flavors and we leave people only with a tobacco option? And RCT is undoubtedly the strongest design for answering that question, but it's the least helpful design for answering other questions about the current marketplace. What products, flavors do people choose? exclusively in dual use, poly use, et cetera, in the current environment, and how are they benefiting from that current landscape? And the final point about, I'm sure there are some flavors that don't help switching. I'm sure there are some flavors that just add to nicotine use and don't help people reduce cigarette consumption. I completely agree that the real, we should keep our eye on the prize here, which is reducing the number of people who smoke. But I just want smoke-free alternatives to be available that demonstrably do that.
89:36 - 89:57
[Ian Fearon]
We're going to wrap up there. I just want to do a couple of things. First, to thank the panellists, Elizabeth, Christopher, Autumn and Piot for their valuable insights and just to thank you all for attending and we are going to still be here for the rest of the conference. If anybody does have any further questions, come and have a chat with us and enjoy the rest of your day. Thank you.