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. 2017 Oct 4;20(11):1292–1300. doi: 10.1093/ntr/ntx228

Consortium on Methods Evaluating Tobacco: Research Tools to Inform US Food and Drug Administration Regulation of Snus

Micah L Berman 1,2, Warren K Bickel 3, Andrew C Harris 4,5,6, Mark G LeSage 4,5,6, Richard J O’Connor 7, Irina Stepanov 8, Peter G Shields 9, Dorothy K Hatsukami 8,
PMCID: PMC6154989  PMID: 29059363

Abstract

Introduction

The US Food and Drug Administration (FDA) has purview over tobacco products. To set policy, the FDA must rely on sound science, yet most existing tobacco research methods have not been designed to specifically inform regulation. The NCI and FDA-funded Consortium on Methods Evaluating Tobacco (COMET) was established to develop and assess valid and reliable methods for tobacco product evaluation. The goal of this article is to describe these assessment methods using a US manufactured “snus” as the test product.

Methods

In designing studies that could inform FDA regulation, COMET has taken a multidisciplinary approach that includes experimental animal models and a range of human studies that examine tobacco product appeal, addictiveness, and toxicity. This article integrates COMET’s findings over the last 4 years.

Results

Consistency in results was observed across the various studies, lending validity to our methods. Studies showed low abuse liability for snus and low levels of consumer demand. Toxicity was less than cigarettes on some biomarkers but higher than medicinal nicotine.

Conclusions

Using our study methods and the convergence of results, the snus that we tested as a potential modified risk tobacco product is likely to neither result in substantial public health harm nor benefit.

Implications

This review describes methods that were used to assess the appeal, abuse liability, and toxicity of snus. These methods included animal, behavioral economics, consumer perception studies, and clinical trials. Across these varied methods, study results showed low abuse-liability and appeal of the snus product we tested. In several studies, demand for snus was lower than for less toxic nicotine gum. The consistency and convergence of results across a range of multi-disciplinary studies lends validity to our methods and suggests that promotion of snus as a modified risk tobacco products is unlikely to produce substantial public health benefit or harm.

Introduction

The Family Smoking Prevention and Tobacco Control Act of 2009 (TCA)1 provided the US Food and Drug Administration (FDA) with broad authority to regulate the manufacture, marketing, and sale of tobacco products. Among other provisions, the TCA authorizes the FDA to set “product standards” designed to reduce the addictiveness or toxicity of a tobacco product, and it requires tobacco companies to submit “modified risk tobacco product” (MRTP) claims to the FDA for review and approval before such claims are made. MRTP claims are those that assert, directly or indirectly, that a product is less harmful than other tobacco products or significantly reduces exposure to toxic constituents. The TCA provides that FDA decisions must be based on what is “appropriate for the protection of public health,” applying a population-level perspective that takes into account potential impacts on both cessations (or transitions to other products) by current tobacco product users and initiation by current nonusers, including adolescents. The law itself, however, does not specify the types of studies necessary to inform this assessment.

The National Cancer Institute (NCI)-funded Tobacco Product Assessment Consortium (TobPRAC) proposed a four-phased review framework that recommends testing procedures to evaluate potential harms at both the individual and population level.2 Recommended studies range from laboratory experiments (smoke chemistries, in vitro cell culture, and in vivo animal testing) to human studies including laboratory-based studies, clinical trials in the naturalistic environment, and population-based epidemiological surveillance. The TobPRAC framework is outlined in Figure 1. As noted by the TobPRAC researchers, “[a] considerable amount of research is needed to update and further validate methods and approaches for testing tobacco products as described in the framework.”2

Figure 1.

Figure 1.

Tobacco Product Assessment Consortium conceptual framework.

Building on the work of TobPRAC, the NCI-funded Consortium on Methods Evaluating Tobacco (COMET) was established in 2012 to develop validated methods for the evaluation of tobacco products. Over the last 4 years, COMET researchers have conducted a wide range of studies designed to provide a multi-dimensional assessment of tobacco products, particularly as related to the issues of abuse liability (addictiveness), consumer perception, and toxicity. These elements of tobacco product evaluation can inform the potential public health harm or benefit of a product.3–5

Abuse liability refers to “the likelihood that individuals will engage in persistent or problematic use of (eg, become addicted to) a drug and the likelihood that individuals will experience undesirable consequences as a result of its use (eg, adverse medical or psychological effects, impaired psychomotor or cognitive performance effects, physical dependence).”6 Abuse liability is influenced by pharmacokinetics of the drug, as well as “contextual, environmental, economic, and social factors,” including price and product marketing.6,7

Consumer perception of a product is associated with attitudes, knowledge, and beliefs about a product,8 as well as sensory perceptions of and prior experiences with a product. Some of these factors are influenced by descriptions of a product via advertisements, mandated health warnings, and product labeling, as well as by peer and parental attitudes toward the product. All of these factors contribute to the appeal of the product and its potential uptake and continued use.

Toxicity of a product is determined by the amount of harmful and potentially harmful constituents (HPHCs) in the product along with how an individual uses a product (eg, exclusively or with other products), how much of the product is used, and the adverse biological effects from product use. Therefore, toxicity is assessed by examining the type and levels of harmful constituents in the product itself and exposures in vitro and in vivo (cell cultures, animals, and humans). Studies in humans rely on biomarkers of exposures to different classes of harmful constituents (eg, nicotine, tobacco specific nitrosamines, volatile organic compounds, polycyclic aromatic compounds, metals) or biomarkers of harm (eg, inflammation, oxidative stress, gene expression) that are reflective of different pathophysiology of diseases.3–11

COMET embarked on the development and validation of methods, using snus (a “spit-free,” low-nitrosamine smokeless tobacco product) as the prototype, for four distinct types of studies, namely (1) in vivo animal abuse liability assessments using product self-administration and intracranial self-administration procedures in adolescent and/or adult rats; (2) behavioral economic models to assess abuse liability and relative abuse liability across products6,12–15 in animals and humans (Behavioral economics, as the term is used here, uses economic concepts to “examine conditions that influence the consumption of commodities, including drugs of dependence.”16 Behavioral economic experiments can be used to examine demand and inter-product substitution under differing price and income conditions, with lower demand elasticity (sensitivity to price) suggesting higher levels of abuse liability. In nonhuman animal studies, the number of lever presses required to obtain a dose serves as a proxy for price); (3) consumer perception/response experiments involving different types of reduced risk claims; and (4) a randomized clinical trial to assess product substitution and resultant toxicant exposures.

To provide consistency across the COMET studies, all studies utilized Camel Snus, a product of Reynolds American, Inc. The choice of this product was based on a prior study showing that Camel Snus, with higher levels of nicotine than other US manufactured snus, led to greater substitution for cigarettes, craving and withdrawal relief, and product satisfaction compared to other snus or tobacco lozenge products.17 In prior experiments, Camel Snus (Robust and Winterchill) produced similar blood concentrations and pharmacokinetic profiles of nicotine as 4 mg nicotine gum (M. Kotylar, personal communication) and similar urinary cotinine concentrations.18

This article reports on the results of COMET projects, supplemented by other studies conducted by the investigators that evaluated the abuse liability, toxicity, and consumer appeal of snus. The article then discusses the potential regulatory implications of these study findings. Our varied approaches produced striking consistency in results, providing evidence-based validity of our assessment methods.

Methods and Results

Constituent Levels in Camel Snus (Robust and Winterchill)

Analysis of the chemical composition of a tobacco product can provide important insights into its addictive and carcinogenic potential. The types of smokeless tobacco products on the market have distinctly different chemical constituent profiles.19,20 Initial analyses have shown that the levels of nicotine and the biologically available unprotonated nicotine in Camel Snus were similar to those found in traditional moist snuff, while levels of some carcinogens, such as tobacco-specific nitrosamines (TSNA), were relatively low.21 However, certain changes in constituent content have been occurring in the US-manufactured snus products over time, such as decreasing total nicotine and increasing TSNA levels per gram.22 In addition, constituent variations have been documented for Camel Snus samples purchased in different locations.23,24

We tested the product samples purchased in retail stores in Minnesota during the time of the COMET study. The nicotine content was 8.9 mg/g in Camel Snus Winterchill and 9.5 mg/g in Camel Snus Robust (wet weight of product). The levels of unprotonated nicotine were 1.6 and 2.1 mg/g, respectively; slightly lower than those reported in earlier versions of Camel Snus.24 Levels of the carcinogenic TSNA, 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and -nitrosonornicotine (NNN), were similar in both varieties, averaging 0.92 and 0.37 µg/g, respectively. These levels are similar to those found in some moist snuff brands and are consistent with the previously reported increases in TSNA content in Camel Snus.22

Abuse Liability Testing in Animals

Animal studies are necessary for the science base to support tobacco control policy because ethical, safety, and logistical constraints limit what can be done in human studies. For example, clinical trials cannot be conducted to assess factors influencing initiation of use in adolescents, the period in which the vast majority of people begin using tobacco products. Animal models avoid other limitations (eg, inability to isolate the central nervous system [CNS] effects of nicotine and other constituents from other factors such as taste, smell, etc.), and have therefore been specifically recommended for tobacco regulatory research.2,25,26

While preclinical models of tobacco addiction typically involve exposure to nicotine and/or other isolated tobacco constituents, this approach does not provide insights into how the numerous constituents in tobacco products interact to impact abuse liability. To address this issue, this project compared the abuse liability of nicotine alone to that of Camel Snus extracts containing nicotine and a range of non-nicotine constituents. Because some of these isolated constituents (eg, minor alkaloids) can enhance nicotine’s addiction-related effects (eg, Hoffman and Evans,27 Belluzzi et al.,28 Caine et al.29), Camel Snus extract was hypothesized to have greater abuse liability than equivalent doses of nicotine alone.

Nicotine alone and extracts of Camel Snus and Kodiak smokeless tobacco were compared in two animal models that have been used extensively to study abuse liability in animals and have strong predictive validity for abuse liability in humans30–32: intravenous self-administration (SA) and intracranial self-stimulation (ICSS). We found that acquisition of SA of nicotine alone and nicotine dose-equivalent concentrations of Camel Snus and Kodiak extracts was similar in adult and adolescent rats under limited access (2 h/day) conditions.33 Relative reinforcing efficacy of these formulations measured using a progressive ratio (PR) schedule34 was greater in adolescents than in adults, consistent with some previous reports of age differences in nicotine reinforcement.35,36 However, no difference was observed between nicotine alone and extracts in either age group. In a second experiment, acquisition of SA of nicotine alone, Camel Snus, and Kodiak extracts was similar in adolescent rats under unlimited (23 h/day) access conditions. Consistent with the first study, reinforcing efficacy as measured by elasticity of demand (sensitivity to increases in “unit price”) did not differ between formulations. Complementing the SA studies, Camel Snus, Kodiak, and nicotine alone had similar addiction-related effects in adults in an ICSS model.37 A follow-up study found that some of the minor alkaloids in snus (nornicotine and anabasine) did have addiction-related effects in an ICSS model, but only at levels considerably higher than those found in the Camel Snus extracts.38

These findings suggest that nicotine content or yield is the primary determinant of the abuse liability of Camel Snus and Kodiak. Although current levels of non-nicotine constituents do not appear to contribute important CNS effects, the ICSS studies suggest that higher levels of some minor alkaloids would have the potential to do so. Current levels of non-nicotine constituents (eg, flavorants, odorants) may, however, contribute to abuse liability via peripheral sensory mechanisms. Taken together, the animal studies suggest that choice between Camel Snus and medicinal nicotine in human studies is likely primarily driven by differences in nicotine content/yield, product appeal (eg, taste, product design, marketing), or both. The animal studies also suggest that these issues may apply to initiation and maintenance of use in both adolescents and adults.

Behavioral Economic Demand in Humans

Human research has shown a high correlation between measures of demand in behavioral economic experiments examining abuse liability with dependence in real-world settings.39–41 A series of behavioral economic experiments compared measures of demand for cigarettes, snus, and medicinal nicotine gum using a naturalistic method in which participants purchased these products for use outside the laboratory.42 In the first set of experiments, current cigarette smokers were provided with an experimental income and completed purchase tasks for either their usual brand of cigarettes, snus (Camel Snus), or nicotine gum (Nicorette, 4 mg); only one product was available in each purchasing session. Participants were instructed to purchase as many products as they would like to use for the next week. Both experimental income and unit prices were varied in different conditions, and at the end of each purchase session, participants received the products they had purchased in one randomly selected condition. Research suggests that “potentially real” purchasing experiments have greater predictive validity than purely hypothetical purchase tasks (at much lower cost than fully “real” experiments).42

When only one product was available per purchase per session, demand elasticity (sensitivity to price) was higher for snus than both cigarettes and gum, with no difference observed between the latter two products. This suggests low abuse liability for snus, relative to the other products. Demand intensity (consumption at the lowest price) was similar between snus and gum, and in both cases was lower than cigarettes.

In a second set of experiments, both product choice and behavioral economic procedures were integrated. Cigarettes, nicotine gum, and snus were available concurrently in varying combinations (cigarettes and snus; cigarettes and nicotine gum; cigarettes, nicotine gum and snus; and snus and nicotine gum) at equivalent prices, but across a range of prices. This experiment also was conducted in the naturalistic setting. Smokers preferred cigarettes over snus and nicotine gum, and no differences were observed between snus and nicotine gum when concurrently available. In fact, very few participants purchased any gum or snus.42

In a third behavioral economic study, current smokers were provided a free trial of snus (Camel Snus), dissolvable tobacco (Arriva), and nicotine gum (Nicorette Mini-Lozenge), and their demand for the three products was then evaluated using experimental auctions. Experimental auctions—where participants bid on products and the winners actually pay for the products—have been shown to accurately elicit the demand curve for tobacco products. Allowing for the free trial provided an opportunity to gauge the impact of product experimentation on demand. Fewer smokers were willing to try snus (44%) than dissolvable tobacco (64%) or nicotine gum (68%). However, the minority who did try snus then exhibited increased demand for the product. Nonetheless, overall willingness to pay for snus was lower than for dissolvable tobacco or nicotine gum. This suggests low demand for snus as compared to both cigarettes and other nicotine products. The unwillingness of most participants to even try snus when offered a free trial suggests exceedingly low demand among a segment of current smokers.43

Product Perception, Response, and Appeal

From a marketer’s perspective, shaping consumers’ perceptions about a product is fundamental to encouraging people to try and to ultimately adopt a product. Consumer perceptions are shaped by a wide range of factors including reactions to product messaging (including health- or risk-related claims) and to initial use of the product. For the FDA to complete assessments of new product applications and MRTP submissions, consumer perceptions of new products and their associated marketing claims will be critical to consider. Thus, we conducted a series of studies aimed to identify and validate measures that could be used to predict how consumers are likely to respond to new and modified risk tobacco products. The conceptual framework exploring the interrelationship between the influences on product adoption (including cognitive, affective, and sensory elements) that were explored in these studies is provided in Figure 2.

Figure 2.

Figure 2.

Conceptual framework of influences on product adoption.

Three separate studies were conducted that focused on consumer perceptions—and, in particular, to consumer responses to modified risk claims. MRTP anticipates two pathways for claims—exposure modification (change in levels of a harmful constituent(s)) and risk modification (change in likelihood of disease(s)). Both require the same basic supporting information, though exposure modification claims are permissible when long-term epidemiological data is unavailable and there is a reasonable scientific inference to be made from exposure biomarkers to disease risk. The MRTP guidance (and the IOM report that preceded it) are silent on the form of the claim; the proposed ads must be provided to FDA and show in premarket testing that they are not misleading. What we tested is based on approaches seen for pharmaceuticals and foods, where graphs/charts and testimonials are common. In the first study using internet samplings and a web-based survey, 1000 youths (14–17) and 2000 adults (18–65), including current, never, and former smokers, were randomized to view one of five Camel Snus print advertisements. Four of the advertisements presented claims related to the lower nitrosamine content of snus relative to cigarettes using four formats: (1) text; (2) bar chart; (3) text/testimonial; (4) bar chart/testimonial. The fifth format, used as a control, was a current manufacturer’s advertisement for Camel Snus, which does not have the explicit claims made about nitrosamine content. Participants exposed to advertisements that contained an explicit reduced risk message rated that product as posing fewer health risks than cigarettes. However, advertisements containing the reduced risk messages were also viewed as containing less truthful information and respondents were more skeptical of the information presented.44 This pattern of findings was comparable between adolescent and adult participants.

In the second study, 3001 participants were recruited from a web-based panel and randomized to view one of five Camel Snus print advertisements. Four of the advertisements presented information related to a reduced risk for lung cancer (eg, “scientific evidence suggests that snus does not cause lung cancer”) in one of five formats as above. Following the advertisement presentation, participants reported on truthfulness and skepticism of advertisement content, and perceived health risks associated with product use. The bar chart/testimonial advertisement was viewed with greater skepticism than all other formats and was rated as less truthful than the bar chart and control formats. The text/testimonial advertisement was associated with perceptions of lower health risks compared to all other advertisement formats, but was viewed as less truthful than the control advertisement. Although current smokers were less skeptical of the health claims made in the advertisements, perceptions of health risks associated with snus use did not differ significantly by smoking status. Exposure to a particular advertisement was not associated with intention to purchase snus within the next month (unpublished data).

Finally, a third study was conducted using similar methods, where 3001 participants were randomized to view either a text-based advertisement, a bar chart/testimonial advertisement, or the manufacturer’s Camel Snus advertisement without the explicit health claims. In this limited replication, the direction and strength of the associations were similar. Current smokers reported significantly less skepticism/more truthfulness of advertisement content compared to former smokers and non-smokers.45

To summarize, consumers perceived that snus products with modified risk claims posed lower health risks than other tobacco products. The specific claim format did not seem to impact risk perceptions. However, consumers perceived the claims as less truthful and were more skeptical of the advertisement content compared with the control advertisements.

Use Patterns and Toxicity

Toxicity can be measured through clinical trials involving switching a person from their usual product to a study product.46 In one of our clinical trials, daily smokers motivated to switch to alternative nicotine products were randomized to either snus (Robust or Winterchill Camel Snus) or nicotine gum (4 mg Nicorette) for 12 weeks.47 In general, the results showed no differences in use patterns between the snus and the nicotine gum conditions; both groups self-administered the same amount of product. Slightly over half of both groups engaged in dual use of cigarettes and the assigned product, but reduced the number of cigarettes smoked per day (from 18/day at baseline to approximately 3/day). However, higher levels of exposure to NNK and NNN were observed in the snus users and dual users, as compared to those who used only nicotine gum. NNK and NNN are potent lung and oral/esophageal carcinogens, respectively. Levels of phenanthrene tetraol, a biomarker of polycyclic aromatic hydrocarbon exposures, were similarly low across products in both exclusive and dual users.48 The percent of smokers who were able to avoid smoking for a 7-day period at the end of the trial was similar between the snus and nicotine gum conditions (21.9% vs. 24.6%, verified through carbon monoxide testing). Similarly, no differences were observed between the groups in suppression of withdrawal symptoms and cravings, and both groups rated the products as significantly less satisfying than cigarettes.

In summary, in a population of smokers interested in switching to alternative products, the extent of uptake and patterns of use were strikingly similar for snus and nicotine gum. Snus (with levels of nicotine similar to nicotine gum) was no better than nicotine gum in sustaining abstinence from smoking, but was significantly more toxic.

Discussion

The COMET studies provide a series of methods demonstrating how the abuse liability, appeal, and toxicity of a tobacco product can be examined in a multi-dimensional manner that takes into account not only the product’s pharmacological characteristics, but also key environmental factors (price, product messaging, available alternatives), consumer perceptions, and use patterns. In these studies, results were strongly concordant as related to the Camel Snus product. They consistently demonstrated low abuse liability of snus—no greater than the abuse liability of nicotine gum. (The results could potentially be different for snus sold in Sweden, which has higher levels of nicotine than comparable US products.) Likewise, they consistently demonstrated low levels of consumer appeal for snus among current smokers, former smokers, and never smokers, even when modified risk claims were presented. Based on the animal self-administration studies and the consumer perception study with adolescents, these findings could potentially also be generalized to adolescents. These studies suggest that snus is not of interest to most smokers. Other studies have also reached similar findings regarding the appeal (or lack thereof) of snus to current smokers.49,50 These results could help explain why snus, though launched in the United States with an aggressive marketing campaign a decade ago, remains an extremely small part of the smokeless tobacco market (and even smaller part of the tobacco market as a whole). In 2015, snus products accounted for only 4% of smokeless tobacco sales in US convenience stores.51

Simply put, these results indicate that because of low demand and its low abuse liability, snus (with product characteristics similar to Camel Snus) is unlikely to lead to significant public heath harms, despite having some toxicity. When provided the option between snus and nicotine gum, current smokers appear to gravitate toward the less harmful nicotine gum as a preferred alternative to cigarettes. Recent COMET studies52 and prior studies53 indicate that electronic nicotine delivery systems, or e-cigarettes, may be more attractive to current smokers than snus or nicotine replacement products. This is most likely because these electronic devices provide similar sensory aspects of smoking, and for some devices, contain higher concentrations of nicotine.54

Though the low abuse liability of snus protects against public health harms, the same low abuse liability likely limits the potential of snus to produce significant public health gains through “tobacco harm reduction.” “Tobacco harm reduction” refers to efforts to improve public health by encouraging consumers to move from more toxic combustible tobacco products to less harmful—though still toxic—alternatives. Snus, which is less harmful than cigarettes by a wide margin,55,56 has been proposed as a candidate product for tobacco harm reduction57–59 and appears to be successful in Sweden.60 To serve as an effective substitute for cigarettes, however, a product needs to have sufficient reinforcing effects and appeal. Otherwise, current smokers will not switch to the new product, will not switch completely (ie, they will continue to engage in dual use), or will revert back to cigarettes after some period of time. Medicinal nicotine, including nicotine gum, has been criticized for similarly lacking sufficient reinforcing effects and appeal to be an effective substitute for cigarettes. This low reinforcing efficacy was intentional, as these products were designed to not create or sustain addiction.61 The COMET studies suggest that the abuse potential of snus may be even lower than that of medicinal nicotine products because of its lack of consumer appeal. Thus, the COMET studies suggest that both the public heath harms and benefits of snus use may be limited.

Regulatory Implications

The findings from COMET related to snus suggest important regulatory implications for the FDA relating to product standards and modified risk tobacco product (MRTP) claims.

Product Standards

For the purposes of tobacco harm reduction, the benefits of switching from a more toxic to a less toxic class of products would be optimized if product standards were designed to minimize the toxicity of these products.62,63 At least some formulations of snus have been shown to have significantly lower levels of carcinogenic TSNA, such as NNK and NNN, than other smokeless tobacco products, although considerable variation across products and over time have been observed, with some products increasing in carcinogen content19,20,22 including Camel Snus products. Based on this evidence, Stepanov and Hatsukami have called on the FDA to adopt product standards that would specify maximum levels for TSNA and other toxicants in smokeless tobacco products.64 Such a product standard could set the highest permissible levels of TSNA at the levels currently found in very low-TSNA snus products and minimize any drift towards higher TSNA levels. The FDA recently took the first step in this direction, issuing a proposed rule that would limit the level of NNN in smokeless tobacco products to no more than 1.0 µg/g of tobacco (on a dry weight basis).65 Reducing NNN would likely also reduce NNK levels because the changes in manufacturing process for NNN would also lower NNK levels.

The FDA could also consider developing products standards for abuse liability. Although abuse liability is more complex to measure than carcinogen levels, the FDA has decades of experiences evaluating abuse liability assessments of new drugs, as required by the Controlled Substances Act, if the drug has the potential for abuse. Given the FDA’s extensive experience evaluating pharmaceuticals based on their abuse liability, as well as the additional experimental methods developed by COMET investigators, it should be possible to design a product standard that would set a ceiling on abuse liability in smokeless tobacco products. Limiting the abuse potential of smokeless tobacco products would reduce the public health danger of these products, but, as discussed above, this would potentially come at the cost of making these products less effective substitutes for cigarettes for harm reduction purposes. Therefore, consideration of such a product standard needs to be based on whether the product should be viewed primarily as a harm reduction tool for smokers (which might require higher abuse liability17) or, alternatively, as a means of reducing uptake among never users.

While abuse liability of a product may depend on constituents in tobacco products other than nicotine, COMET animal studies suggest that current levels of minor alkaloids do not contribute to the addiction-related CNS effect of Camel Snus, but that higher levels could do so. Following the logic for TSNA standards discussed above, standards for certain minor alkaloids with known abuse liability (eg, nornicotine) could be set based on levels in current snus products to avoid increases in these constituents that might contribute to smokeless tobacco addiction.

Modified Risk Tobacco Products

The premise of the TCA section permitting MRTP claims is that such claims could direct consumers to less harmful tobacco products and thereby promote public health (if they do not increase initiation, increase intensity of use, prompt prolonged dual use, or otherwise increase health risks or harms). The COMET findings indicate that including reduced exposure/risk claims in product advertising may not necessarily lead to public health gains. Specifically, at least some types of reduced exposure/risk messages may, instead of stimulating snus substitution, have the opposite effect of increasing skepticism and decreasing interest. Note, however, that the COMET studies only examined short-term exposure to discrete marketing claims; the impact of sustained mass media campaigns could be substantially different.

Companies wishing to make MRTP claims must demonstrate to the FDA that allowing the claim would be “appropriate to promote the public health.” Given the low abuse liability of the snus that we tested, the lack of appeal to current smokers, and distrust of modified risk claims, permitting MRTP claims for these products would not pose a substantial risk to public health. However, under the statutory standard, demonstrating that allowing a claim would be unlikely to cause significant public health harms would not be enough; the manufacturer must be able to demonstrate a likely public health benefit. In theory, allowing MRTP claims for snus could further public health by promoting less harmful forms of tobacco use. But given that the majority of smokers appear to find less-toxic nicotine gum to be an equally, if not more attractive option than the snus product that we tested, it seems questionable whether manufactures would be able to demonstrate that MRTP claims would provide an affirmative benefit to public health.

In addition, we note that snus manufacturers have historically promoted snus products in ways that appear designed to recruit new (primarily young) users and promote dual use.66 Such advertising tends to increase or sustain—rather than decrease—tobacco-related harms. Thus, allowing snus companies to make MRTP claims would be unlikely to promote public health unless the FDA concurrently moved to restrict forms of advertising (such as the promotion of dual use) that undermine harm reduction.

Limitations, Conclusions, and Future Directions

Some important limitations exist in the studies discussed in this article, and how they are placed together in context. For one, most of the human tobacco use studies focused on adult smokers. A broader assessment of abuse liability would need to also conduct similar experiments with non- or infrequent smokers (if ethically possible), dual users, and users of other tobacco products. In addition, although some types of human studies with adolescents may be infeasible, studies involving young adults would be particularly important, as this is the age cohort that typically displays the highest levels of tobacco use. Also important to study would be other populations that are disproportionately impacted by tobacco use, including individuals with mental health diagnoses and low-SES populations. Longer-term studies with snus might also be necessary to uncover any transitional patterns of use (such as dual users eventually quitting smoking) and related toxicity. Finally, an integration of messaging claims—as well as counter-marketing efforts in use by the government and public health groups—into abuse liability studies and clinical trials is likely to provide a more complete picture of the potential public health impact of a product once available in the market.7

The studies outlined here all relate to the premarket or pre-claims phases of the TobPRAC framework. Other types of data would be needed to inform other parts of the framework, particularly the postmarket activities, to determine the population-level impact of snus in real-world settings, especially if MRTP claims were made. Even though the COMET studies incorporate some elements of the environment (such as price, marketing claims, and alternative product availability), the assessment of these factors was limited. Moreover, even if environmental factors are incorporated into premarket studies, postmarket surveillance is nonetheless essential, as contextual influences on tobacco use can change over time.

Looking forward, more work is necessary on risk assessment methodologies for tobacco products. Methods are needed for using the results from diverse types of studies (such as the COMET studies) to build mathematical projections or modeling of the likely impact of potential regulatory decisions. These risk assessment methodologies are foundational to regulatory decision-making in other policy contexts, but have not been well developed for use in tobacco-related regulations. Tobacco use poses unique challenges, due to the fact that tobacco use causes a broad spectrum of different diseases, is heavily influenced by marketing, and impacts different segments of the population differently. These factors, as well as others, will make the development of risk assessment methodologies for tobacco-related regulations a uniquely complex task.

Conclusion

In conclusion, the systematic and complementary studies that were conducted under COMET demonstrated consistency in results across various methods of assessments and different aspects of tobacco product evaluation. This concordance, along with results from existing epidemiological studies, lends validity to the methods that were used to help determine the potential public health impact of one brand of snus. The validation of methods and measures to assess addictiveness, appeal, and toxicity are the cornerstone for accurately understanding the likelihood that a product will result in reduced or potential harm. Future research should be focused on further integration of these methods, applying them to evaluate other products or product designs, and using the results to conduct risk assessment analysis.

Funding

Funding was provided by the National Cancer Institute of the National Institutes of Health (NIH) (U19CA157345 and 5K07CA197221 to MLB) and the Food and Drug Administration (FDA) Center for Tobacco Products. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Food and Drug Administration.

Declaration of Interest

PGS served as a consultant and expert witnesses in litigation against tobacco companies. WKB is a principal for HealthSim LLC and NotifiUs LLC, is on the Scientific Advisory Board for SoberGrid, DxRxm and General Genetic Corporation, and consults for Prophase LLC and Teva Branded Pharmaceuticals. The other authors declared no conflict of interest.

Acknowledgments

We are grateful to the whole COMET investigative team, including postdoctoral fellows, for their valuable contributions to the studies.

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