The US perspective on e-cigarettes and harm reduction

The reality of the nicotine marketplace in US is that today, unlike 60-70 years ago, nicotine can be delivered without having to burn tobacco leaves and inhale the tobacco smoke. And that’s significant because while there are misperceptions about the safety of nicotine, the reality is that nicotine does not directly cause the cancer, the lung disease and the heart disease associated with the use of cigarettes and other combustible products. Now nico­tine doesn’t get off the hook entirely, because of course there’s the potential for addiction. And then when we start thinking about the role of flavors and attracting young people to experiment with tobacco products, the potential for nicotine addiction is a real concern.
There are also a lot of unanswered questions about something that we call dual use. The great benefit of any of these alternative products is if a smoker completely substitutes all of their cigarettes for an e-cigarette or a heated tobacco product or smokeless tobacco product. But dual use is that pattern of use where the health concerned smoker, rather than stopping to smoke completely, continues to smoke while also using one or more of these other products.
According to one survey from last year of adult vapors in the US, 65% of adult vapors continue to smoke, 84% of adult pouch users continued to smoke. To be fair, there are other surveys where the proportion of dual use is not as high as we see it here, but still significant and still raising all kinds of questions. One of the questions is, well, what does it mean in terms of exposure to the toxins in the products?
According to the results of a paper that was published by the e-cigarette company Juul and some of their consultants last year [1], and this is a secondary analysis from what’s known as the PATH study, a longitudinal study in the United States called the Population Assessment of Tobacco and Health that follows 46,000 adults and kids, users and non-users of tobacco products. For two tobacco specific nitrosamines, NNK and NNN, carcinogenic compounds that the user is being exposed to, we see no real difference between exclusive smoking and dual use, where the vaper is still smoking 10 or more ciga­rettes a day.
As for heavy metals and other compounds of concern, you also see no real difference.
What did the authors Juul and their consultants conclude from this analysis? Well, for dual users that were smoking 10 or more cigarettes a day, and interestingly, the average cigarette consumption for dual users was similar to that of exclusive cigarette smokers, the authors concluded that the levels of BOE’s, or biomarkers of exposure, were not significantly lower for the dual users compared to smokers. They concluded that for dual users that are still smoking 10 or more cigarettes a day, none of the biomarkers of exposure significantly differed from that of exclusive cigarette smokers.
There is a more recent analysis from the PATH study that looked at the association between e-cigarette use and respiratory symptoms [2]. The authors said that among current combustible tobacco users, the combined use of e-cigarettes increased the adjusted odds of reporting important respiratory symptoms, suggesting that e-cigarette use increases the risk of developing important respiratory symptoms for current users of combustible tobacco products. Their conclusion? Current combustible tobacco smokers who have ever used any cigarette may be at elevated risk for developing the respiratory symptoms compared to those who only smoked cigarettes. So this is a cause for concern and something to keep in mind.
We have historically low adult and youth cigarette smoking rates. In fact, more young people in the United States experiment with mass produced flavored cigars each day than cigarettes. And there has been a real decline in youth use of e-cigarettes in the United States, though it remains by far the most popular category of products with kids. We do have a concern when it comes to the frequency with which current young e-cigarette users are vaping. Amongst current high school youth e-cigarette users, over 40% of them were so-called frequent vapors, meaning that they vaped on 20 or more of the past 30 days, and about 30% of them vaped every single day. Frequent use is a clear sign that those kids have progressed beyond mere experimentation to regular use and may be on the pathway to addiction to nicotine. And I’ve shown you that there’s lots of dual use and we have lots of unanswered questions about what all of that dual use means.
As for harm reduction and the reality of premarket review, the continuum of risk is real. There absolutely are more harmful and less harmful ways to deliver nico­tine. And the hypothetical pack-a-day smoker who completely switches to e-cigarettes will reduce their risk, and probably by a substantial amount, if they completely substitute all of their cigarettes. But you’ve seen the story with dual use and the legal reality here in the US is that the marketing authorization decision that the regulator at the Food and Drug Administration has to make is not made on some kind of abstract or categorical basis. When the US Congress passed the Tobacco Control Act in 2009, it clearly placed the burden on each company to demonstrate in a premarket review process that the bene­fits of some new product or potential claim outweigh the risk and that this needs to be proven on a product-by- product and case-by-case basis.
All of this is happening under a relatively new statutory standard for the regulation of certain tobacco products. The standard is APPH or appropriate for the protection of the public health, and this requires the regulator to look at population level health conside­rations. The law orders the regulator to take into account benefits and risks of potential regulatory actions to both users and non-users of products… intended and unintended consequences, if you will. In essence, the regulator has to assess the net population level health impacts of new products coming to market and certain new poli­cies being put into place.
What that leaves us with in the United States is what I call inconvenient truths. For those on both sides of the harm reduction debate here and for certain members of the US Congress.
For those who are so opposed to consideration of harm reduction or risk reduction principles and so negative about e-cigarettes, the reality is that there are heated, smokeless and e-cigarette products that have met that appropriate for the protection of public health or APPH standard and have deserved the marketing authorization that they have received from the regulator. This even includes a very low nicotine cigarette. Some of the heated and smokeless products have also passed a more rigorous test and gotten authorization to make either exposure or harm reduction claims. More marketing authorizations are certain to follow.
On the other hand, those who are so open to and so pro-harm reduction or pro e-cigarette have to reco­gnize that non-menthol-flavored e-cigarettes so far have failed on a case-by-case basis to pass that very same test. Primarily because the case for benefit was not made. So whatever was in an application where there were proposed restrictions on marketing or youth access to date at least, those risk mitigation strategies have been insufficient to overcome the deficiencies at the front end where the company failed to prove the added benefit from the presence of a particular flavor.
Dozens and dozens of lawsuits have been filed against FDA after the agency started issuing negative marketing orders to companies. 8 federal appellate courts have ruled in those cases in the US, and six of the eight federal appellate courts have sided with FDA. Two ruled against FDA. The government appealed one of those cases to the United States Supreme Court, and there will be oral argument in that case in the coming weeks with a decision by next June. And of course, for the pro e-cigarette, pro harm reduction forces, they still have to account for all of the dual use and what I would say at this point are just a bunch of unanswered questions that we have about what the dual use means.
Let’s look at the state of regulation today.
Starting in 2021, we saw an increasing number of ENDS products (ENDS stands for electronic nicotine delivery systems) that used or at least claimed to be using synthetic nicotine instead of nicotine that was derived from tobacco. And why is that? It has to do with what was then the statutory definition of a tobacco product, which was anything that was made or derived from tobacco. If the nicotine that’s in there was not derived from tobacco, then the companies saw it as a way to avoid FDA regulation and evade enforcement. In fact, several companies, after they had received negative marketing orders from FDA, went public and said that they were going to switch to synthetic nicotine to keep their pro­ducts on the market. And here’s one example. One company, and apologies for the tone of the language, went to social media to say “F the FDA and their overreaching, overburdensome regulations.” Fortunately, the United States Congress stepped in and solved the problem. They reopened the Tobacco Control Act and passed legislation that changed the definition of a tobacco product so that today, if there’s nicotine in the product, it doesn’t matter what the source is. Whether it’s derived from tobacco or synthetically manufactured it meets the statutory definition of a tobacco product.
More recently, we are dealing with something called nicotine analogues. We are aware that there are companies that are looking at compounds that would have the same pharmacological effects and pharmacological activity of nicotine, but wouldn’t actually be nicotine. The open question is: were this to be in a tobacco product would it even meet the statutory definition of a tobacco product if there actually isn’t any nicotine, regardless of the source that present?
I also want to share what’s going on with application review. Public health and tobacco control groups in 2018 filed a lawsuit against FDA and they were successful. In 2019, the court ruled that the submission for applications was shortened by three years. Applications for 26,000,000 products have been submitted to FDA. More than 99% of those applications have been reviewed and action has been completed. Forty seven products have received an authorization and to date the only authorized flavor to get the green light from FDA is a menthol- flavored e-cigarette.
There is also some ongoing and disturbing industry behavior. There are available products, nicotine deli­very devices, containing nicotine purposely designed to resemble kid-friendly and kid-appealing drink containers. There’s no place for products like this in the marketplace, regardless of one’s views on harm reduction in e-cigarettes. The marketing of these kinds of products is completely inappropriate. The problem is the burden is on FDA to find them and then take enforcement action.
Is it too late in 2024 to try to reframe the debate, at least in the United States, if not globally? And by reframing, I mean rather than focusing on end game, which has been getting a lot of attention lately, how about starting with a focus on the end state? And by that I mean a somewhat binary choice between one of two possible desired end states or outcomes. In the first, the world is free of combustible tobacco products, but the less harmful nicotine containing products remain on the market. In the second end-state world, the world is free of both tobacco products and nicotine.
My suggestion is that we start by picking one of the two desired end states and have a discussion, a dialogue and a debate. Pick your preferred end state. And then get at the issues that have so divided our field, at least in the United States, to date. In the context of end state considerations, how should we be thinking about the continuum of risk? How should we be thinking about the role of alternative and less harmful products? How should we be thinking about any of the end game strategies that have been getting lots of attention lately, whether it’s mandated reductions in the nicotine content of combustible tobacco products or annual reductions in the allowable supplies of tobacco?
The benefit of starting at the end state and working back is it would give us a high likelihood of avoiding starting in a much more divisive place where we immediately dive into things like the pros and cons of harm reduction or the pros and cons of e-cigarettes. I think this is worth a shot.
So I will end on this optimistic note that as divisive as the harm reduction debate has been in the United States and abroad, perhaps starting with the end state and working backwards is a way to reframe so many of the issues that have resulted in us having this very unproductive, counterproductive debate.

DISCLOSURE

Mr. Zeller is an advisor to Qnovia, a start-up company seeking marketing authorization in the U.S. and U.K. for a new smoking cessation product.

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