As discussed in our earlier post, the U.S. Food and Drug Administration’s (FDA) new draft guidance on flavored electronic nicotine delivery system (ENDS) products represents a meaningful effort to provide additional clarity about the Agency’s evidentiary expectations for premarket tobacco product applications (PMTAs). That clarity is welcome. At the same time, the draft guidance would better align with the statutory mandate in Section 910 of the Family Smoking Prevention and Tobacco Control Act (TCA) if it more clearly recognized that (1) comparative-efficacy evidence as framed in the marketing denial orders issued by FDA to date cannot be treated as an across-the-board requirement for every flavored ENDS application; and (2) when comparative-efficacy analysis is relevant, the more meaningful public-health comparator is combustible cigarettes, not tobacco-flavored ENDS.
The starting point is the statute itself. The comparative-efficacy requirement appears nowhere in the Tobacco Control Act, FDA’s 2021 PMTA final rule, or 2023 final ENDS PMTA guidance. Section 910 does not condition marketing authorization for a flavored tobacco product on proof that the product offers greater cessation or cigarette-reduction benefits than a tobacco-flavored ENDS comparator. Rather, it directs FDA to determine whether marketing the product would be “appropriate for the protection of the public health,” (APPH) based on the risks and benefits to the population as a whole, including the likelihood that current tobacco users will quit and that nonusers will initiate use. The statute also permits FDA to rely on well-controlled investigations or other valid scientific evidence it finds sufficient. None of those authorities, however, makes FDA’s strict tobacco-flavor vs. non-tobacco flavor comparative-efficacy standard a distinct legal prerequisite to authorization.
FDA’s own PMTA practice underscores this point. The same Tobacco Control Act and the same APPH standard apply across tobacco-product categories, not just to ENDS. Yet in the public materials for flavored nicotine pouch authorizations (see our posts here and here), FDA has framed the inquiry in APPH and totality-of-the-evidence terms, rather than as a categorical requirement that a flavored pouch prove added adult benefit over a tobacco-flavored pouch. The same general point can be seen in FDA’s public materials for IQOS menthol authorizations, which likewise do not articulate a flavored-ENDS-style versus tobacco-flavor comparator requirement. That matters because it suggests that comparative efficacy is best understood not as a statutory command, but as an evidentiary framework FDA has chosen to apply in the flavored-ENDS context because of the Agency’s youth-risk concerns. For that reason, the draft guidance would be stronger if it made clearer that comparative efficacy is one evidentiary tool FDA may consider where the facts warrant it, rather than a universal threshold requirement for flavored ENDS. There may well be cases in which comparative evidence is especially relevant, such as where the record suggests that a specific product is attracting youth or where the applicant’s theory of APPH depends on demonstrating incremental benefit over another ENDS product. But Section 910 does not require FDA to apply that framework mechanically in every case, regardless of the product-specific evidence before it. Where an applicant can present persuasive evidence that its product has low youth uptake or limited youth appeal, meaningful benefits for adult smokers, and appropriate controls on marketing and access, the statute calls for FDA to weigh that evidence on its own terms.
The Supreme Court’s decision in FDA v. Wages and White Lion Investments, LLC does not suggest otherwise. Properly understood, Wages confirms FDA’s discretion to identify the kinds of evidence it may expect in particular cases; it does not transform comparative efficacy into a statutory prerequisite written into Section 910. Read that way, Wages leaves intact the central point that FDA may consider comparative efficacy where appropriate, but the Agency’s ultimate obligation remains the one Congress imposed—an APPH determination grounded in the full evidentiary record for the product under review.
That distinction is especially important today because the factual landscape is not the same as it was in 2020 and 2021, when FDA first crystallized the comparative-efficacy approach amid peak youth vaping rates and greater uncertainty about the role ENDS could play for adult smokers. Since then, the public-health calculus has evolved in several important respects. In the draft guidance, FDA now expressly acknowledges that ENDS can help adult smokers move away from cigarettes and that non-tobacco flavors may matter for adult switching. At the same time, youth vaping has fallen dramatically from its 2019 peak, and the developing literature increasingly suggests that flavor is only one of several factors influencing youth experimentation and use. None of that eliminates youth-risk concerns, and nothing in Section 910 permits FDA to discount those concerns. But it does underscore why a case-by-case APPH inquiry is so important and why an across-the-board comparative-efficacy requirement sits uneasily with the statutory scheme.
The draft guidance would also benefit from reexamining the comparator itself. As written, it appears to assume that tobacco-flavored ENDS is the natural baseline from which other ENDS flavors deviate. But that premise does not fit the way ENDS products are actually designed and formulated. For traditional tobacco products, comparing a flavored product to its tobacco-flavored counterpart can make intuitive sense. Combustible cigarettes, cigars, pipe tobacco, smokeless tobacco, and similar products naturally possess a tobacco taste and aroma because they contain, and often burn, tobacco leaf. When flavors such as menthol or fruit are added to those products, the flavoring can mask the taste and harshness of the tobacco and smoke, potentially making initiation easier, particularly for inexperienced users. That history helps explain why flavored combustible products raise distinct public-health concerns and why comparisons to their tobacco-flavored counterparts can be meaningful.
ENDS products are different. E-liquids do not contain tobacco leaf, and they do not begin with any inherent tobacco flavor that must be masked. They are manufactured formulations made from ingredients such as propylene glycol, vegetable glycerin, nicotine, and flavoring compounds. A tobacco-flavored ENDS product, then, is not the default or natural version of the product. It is simply one manufactured flavor profile among many, created by adding tobacco-flavor compounds to an otherwise neutral liquid base, just as a manufacturer would add fruit, mint, or dessert flavor compounds to create some other profile. In that sense, a tobacco-flavored ENDS product is no more natural or baseline than a watermelon- or menthol-flavored ENDS product. All are engineered formulations.
Once that distinction is recognized, the appropriate public-health comparator becomes much clearer: combustible cigarettes, not tobacco-flavored ENDS. Combustible cigarettes are the baseline against which public-health benefit should be measured because they remain the primary source of tobacco-related harm that the statute seeks to reduce. The central APPH question is whether a product is likely to help adult smokers move away from combustible cigarettes without creating meaningful risk to youth. Comparing a flavored ENDS product to combustible cigarettes speaks directly to that question. Comparing it to a tobacco-flavored ENDS product often does not. Indeed, anchoring the analysis to tobacco-flavored ENDS can have the practical effect of discounting the very benefits Congress directed FDA to consider. A fruit-, mint-, or menthol-flavored ENDS product may provide real public-health benefit if it helps adult smokers switch away from combustible cigarettes, even if the applicant cannot show that it performs better than a tobacco-flavored ENDS product that is commercially irrelevant or not part of the applicant’s portfolio at all.
None of this is to say that comparative efficacy has no place in FDA’s review of flavored ENDS. It may. But Section 910 is better read to permit the Agency to use that kind of evidence where warranted by the facts of a particular application, rather than to impose it categorically across the board. And when comparative analysis is used, the more meaningful benchmark should be combustible cigarettes—the products Congress was principally concerned with displacing—not a tobacco-flavored ENDS product that may have little real-world relevance to the applicant’s marketing plan or to adult switching behavior.
The final guidance should more clearly reflect these principles and align FDA’s evidentiary expectations with the individualized APPH inquiry required by Section 910. To remain faithful to that statutory mandate, the Agency should move beyond categorical, across-the-board approaches and instead apply a product-specific APPH analysis that weighs a product’s real-world benefit in helping smokers move away from combustible cigarettes against its actual risk to youth.
Continue the discussion with us at Keller and Heckman’s 10th Annual E-Vapor, Nicotine, and Tobacco Law Symposium on May 4-5, 2026, in Las Vegas, Nevada. Register here.