Clearing the air

Editor's note: Michael Feehan is a vice president consulting, Health Division, Kantar LLC, New York, and an adjunct professor in the Department of Population Health Sciences at the University of Utah School of Medicine, Salt Lake City.

Combustible cigarettes pose an enormous population health burden through the dangers of exposure to tobacco smoke. Tobacco manufacturers are actively repositioning themselves and their product lines to bring potentially reduced-harm tobacco or nicotine continuing products (TNP) to market as alternatives to combustible cigarettes. To legally market such new TNP, manufacturers need to receive U.S. Food and Drug Administration (FDA) “marketing orders,” supported by extensive research that includes primary research with consumers, that can help inform the population health risk and benefits of a new product. Outlined here is the rationale for this change in positioning, a snapshot of FDA oversight of the industry and a quick guide to the major primary research approaches used to gauge consumers’ perceptions and likely use of potentially reduced harm TNP.

No risk-free level of exposure

Cigarette smoking is responsible for many diseases as well as the reduction of overall health. According to the U.S. Department of Health and Human Services, Centers for Disease Control and Prevention Centers (CDC),¹ smoking is the leading cause of preventable death and one of every five deaths (438,000 deaths) in the United States annually is attributable to cigarette smoking. As noted by the U.S. surgeon general, science suggests that there is no risk-free level of exposure to tobacco smoke.² 

Recognizing the risk posed by combustible cigarettes the American Cancer Society (ACS) position statement states: 

“In recognition of the disproportionately large role that combustible tobacco use plays in causing morbidity and mortality in the United States, ACS will expand its existing tobacco-control efforts and execute new comprehensive strategies to eliminate all combustible tobacco use, with the goal of substantially reducing cancer incidence and mortality and other adverse health effects.”³

Manufacturers are thus focused on bringing to market TNP that present a reduced risk of harm to the adult populations’ health versus combustible cigarettes. Altria Group Inc.’s vision “… is to responsibly lead the transition of adult smokers to a non-combustible future.”⁴ Philip Morris International Inc. is “… designing a smoke-free future,”⁵ and Reynolds American Inc. wishes to encourage “… smokers who do not quit entirely to consider switching to these tobacco products.”⁶ These non-combustible TNPs comprise a range of product types and mechanisms for nicotine delivery including electronic nicotine delivery systems (ENDS), commonly referred to as e-cigarettes or vaping; heated tobacco products (“heat-not-burn” tobacco-leaf-containing products); snus (tobacco-leaf-containing pouches); and derived-nicotine pouches without tobacco-leaf.

This movement to encourage adult cigarette users to convert to potentially reduced-harm TNP use can arouse cynicism from anti-tobacco advocates. Particularly with concerns around the potential marketing of such products to youth (expressly forbidden by the FDA) and as yet, the lack of long-term health outcome data for these products. Nonetheless, the acceleration of reduced harm TNP applications to FDA and an increased likelihood of those applications being successful is dramatic. This is a tide that will not be turned as manufacturers and research organizations gain more familiarity with FDA requirements for consumer research. Also contributing to this change is increased public accountability, as companies are now being tracked on their commitment and progress towards non-combustible TNP.⁷

Address potential health risks

The FDA regulates all TNP under the Family Smoking Prevention and Tobacco Control Act (FSPTCA)⁸ through the FDA Center for Tobacco Products (CTP) a final deeming rule (81 FR 28973),⁹ extending authority to all products meeting the statutory definition for tobacco products. The process to bring a new TNP to market with an FDA-issued marketing order, is through a premarket tobacco product application (PMTA).^10,11 Applications are required to address the new product’s potential health risks and CTP recommends that data is collected to gauge the potential impact of the new TNP’s marketing on tobacco use behaviors of current users of combustible cigarettes, ex-users and non-users. Another application process is used when the manufacturer wishes to demonstrate to FDA that the new TNP is likely to provide lower population health risk than combustible cigarettes and they will want to market the product with claims communicating that reduced risk. The modified risk tobacco product (MRTP)¹² application must “demonstrate that the product will, or is expected to, benefit the health of the population as a whole.” 

It is important to appreciate that MRTPs can reduce the harm to the population, even if they themselves carry risk. The Institute of Medicine (IOM)¹³ notes: 

“A product is harm-reducing if it lowers total tobacco-related morbidity and mortality, even though use of that product may involve continued exposure to tobacco-related toxicants.”

As the IOM asserted (p. ix):¹³  “The fundamental issue is that if a product is going to be marketed as being ‘safer,’ then the claim must be true.” Amy claims made by manufacturers through TNP marketing need to be evaluated from a consumer perception perspective to reassure the FDA’s CTP that the claim contents are correctly interpreted and do not give rise to perceptions that the TNP is safe.

This, then, is the role of consumer behavior and perception researchers: to conduct real-world evidence and other regulatory-focused consumer studies generalizable to the population that can be viewed as rigorous to exacting FDA standards, that manufacturers can rely on in their PMTA and MRTP filings. The IOM has identified minimum standards for research studies that an applicant would need to complete to obtain an MDA order to market the product.¹³ Such guidance, increased familiarity with the PMTA and MRTP study requirements by manufacturers and research suppliers and the growing experience of FDA reviewers with such applications has seen a rise in the number of applications being submitted and a greater proportion being approved. As of August 31, 2020, from 2011 to then, 33 MRTP applications were submitted to FDA but only 12 were successful. However, all those successes were achieved through applications reviewed in 2019 and 2020.¹⁴

Be of most relevance

MRTP applications must submit to the FDA scientific evidence to demonstrate the product has the potential to reduce health-related harms compared to combustible cigarettes. Many kinds of laboratory, pre-clinical and biomarker studies can address the TNP constituent’s potential toxicity and potential for addiction but it is the consumer behavioral and perceptual studies that may be of most relevance here. To approve MRTP marketing orders, the FDA needs to consider the relative health risks to individuals of the TNP; the increased or decreased likelihood that existing users of tobacco products who would otherwise stop using such products will switch to the TNP; and the increased or decreased likelihood that persons who do not use tobacco products will start using the TNP.¹²

The IOM¹³ notes that observational epidemiological studies over time can inform applications, reporting out the health outcomes of users as inputs into population health models aiming to demonstrate the potential gain in public health through the adoption of MRTPs. However, other kinds of studies can inform these models that may not necessitate following users over long enough periods to determine actual health outcomes. Among these are three major study types: understanding consumer perceptions of health risk; measurement of conversion behaviors away from combustible cigarette use; and evidence from behaviors and perceptions tracked after product launch.

Comprehension of claims

Consumer risk-perception studies explore consumers’ beliefs about the likely disease or addiction risk of the product and their (and others around them) exposure to possibly harmful constituents; how those perceived risks compare to other products available and their intention to use the product if it becomes available. Explicitly required is research that demonstrates that consumers do not erroneously come to believe the product is risk-free. Another class of these studies can explore the comprehension of claims about the potential lower health risk posed by the product (for use in an MRTP application) and any resultant change in beliefs about the health risks of product and associated changes in intent to use it.

One example of this kind of study is the study done by Pillitteri, Schiffman and Sembower, et al. (2020),¹⁵ which was sponsored by the RAI Services Company in support of regulatory submission to the FDA for snus, a smokeless tobacco product. The goal of the research was to see if effectively communicating health risk information for the product could facilitate smokers switching completely to snus (a requirement of FDA in reporting such studies), thereby benefiting public health. The cross-sectional study assessed comprehension and perceptions of modified-risk information regarding snus among almost 4,000 smokers, former tobacco users and never tobacco users from a U.S. internet panel. Participants reviewed an advertisement stating that smokers who switched completely to snus could greatly reduce their risk of lung cancer, respiratory disease, heart disease and oral cancer. The results of the study confirmed that “respondents demonstrated good understanding and application of the modified-risk information and did not develop misperceptions that snus is completely safe.”¹⁵

Use and potential misuse 

Actual use studies (AUS) involve a prospective cohort design and provide information on both the use and potential misuse of the novel product. In these studies, respondents are supplied TNP and followed over time to gauge their levels of product use (and potential misuse) and measure any corresponding changes in their use of combustible cigarettes. In an AUS, participants are given the option of using the study product and any other TNP including combustible cigarettes ad libitum (as much or as often as necessary or desired). In an AUS, respondents will typically be cigarette smokers (who may or may not use other TNPs) who will be followed in a baseline period to ascertain their daily TNP use, then provided the study product at no charge and followed-up with at regular intervals, while recording their daily consumption of all TNP. 

Research conducted by Kantar’s Health Division, sponsored by Philip Morris International Inc. (Roulet, Chrea and Kanitscheider, et al., 2019)¹⁶ contributed to an FDA MRTP application for its tobacco heating system (THS). This AUS study had a six-week observational period in which adult participants made periodic visits to research sites in eight cities, were provided a non-combustible THS at no charge and completed a daily electronic diary of all their TNP use. A telephone hotline was provided for participants to report any adverse health experiences. This AUS showed that after a six-week period of ad libitum use of the THS, almost 15% of the daily adult smokers substituted combustible cigarettes with the novel product. FDA granted the manufacturer a PMTA marketing order in 2019 and a subsequent marketing order as a modified risk tobacco product (MRTP) in 2020. In its MRTP press release, the FDA noted that: “Data submitted by the company shows that marketing these particular products with the authorized information could help addicted adult smokers transition away from combusted cigarettes and reduce their exposure to harmful chemicals, but only if they completely switch.”¹⁷

Postmarketing surveillance studies

A third major class of research around new TNPs are postmarketing surveillance (PMS) studies. In making MRTP marketing orders, FDA also requires that manufacturers annually conduct PMS studies in order to determine the impact of the order on consumer perceptions and their behavior and health. A comprehensive review of the FDA requirements for MRTPs and their origins in pharmacovigilance for medicines is available.¹⁸ However, given the very few MRTP marketing orders issued to date by the FDA and the possibility of a wide variety of research methods that can be explored, this research growth area can still be considered relatively fledgling. 

One recent PMS example from Kantar’s Health Division (Adamson, Kanitscheider, Prasad, et al., 2020)¹⁹ is a PMS pilot study sponsored by British American Tobacco to evaluate behaviors and perceptions of 4,154 adult respondents in Japan after the launch of heated tobacco products (HTP) in that country in 2014. This study was a cross-sectional epidemiological survey, with paper-based questionnaires administered door-to-door. A total of 779 respondents were current TNP users and among those, 254 respondents self-identified as HTP users. Compared with 12 months before the survey, 12% of sole combustible tobacco product users were now using HTPs exclusively. While allowing for multiple responses in the survey, the majority selected “reduced harm to people around them and themselves compared to conventional cigarettes” as a reason for HTP use and 10% indicated an intent to reduce or quit cigarette consumption. 

As the FDA continues to grow the number of issued marketing orders for MRTPs and products such as HTP become more commonly used in the U.S., appropriate PMS methods will need to be developed and refined to demonstrate conversion away from combustible cigarette use and the potential health benefits for the population. 

Can be challenging

Doing consumer research with a regulatory focus in the TNP arena can be challenging given the rigor required by the FDA in documenting the study design and its conduct and the specificity required in the reporting of findings. For example, some studies may necessitate that all data be managed in CFR Part 11-compliant electronic data systems²⁰ and conform with rigorous client-approved statistical analysis and reporting standards.²¹

There is not a roadmap of a long history of successful applications to draw from, so there is ample opportunity to be creative in approaches while maintaining FDA rigor. Any studies will require a detailed protocol approved by an institutional review board and often specify how independent monitoring of the research is to be conducted to ensure adherence of the oversight research team, client and third-party research suppliers to that protocol and ensure the well-being of study participants. Designs are increasingly required to be flexible in recruiting strategies to accommodate changing demographic and TNP usage patterns of the population (e.g., the rise of dual use of combustible cigarettes and other TNP) and also be responsive to ever-changing U.S. federal or state restrictions on the availability of TNP (e.g., “flavor bans” in some U.S. states which may necessitate research waivers). One emerging need accelerated by the COVID-19 pandemic is the trend seen with some clinical trials to move to decentralized approaches, where participants are interviewed remotely using videostreaming capabilities, complete surveys online and receive product through other channels than in-person at a research site.^22,23 The unique requirements around ensuring the product recipient is the correct one of the right age and sound logistical, legal and ethical procedures for TNP distribution and accountability are in place can make remote product distribution a challenge in the TNP space.

Conducting primary consumer research in this area can be demanding, especially with an eye to the acute level of detail needed to ultimately support successful FDA submissions. However, the research is intellectually stimulating, creative and can be personally rewarding. Ultimately there are few arguments against the population health goal of reducing or eliminating combustible cigarette use (and the prevalence of preventable cancer and other disorders) and contributing consumer research to the knowledge base that can shape that smoke-free future. 

References

1 www.cdc.gov/tobacco/data_statistics/fact_sheets/health_effects/effects_cig_smoking/index.htm [Accessed January 19, 2021]

2 Centers for Disease Control and Prevention (U.S.); National Center for Chronic Disease Prevention and Health Promotion (U.S.); Office on Smoking and Health (U.S.). How Tobacco Smoke Causes Disease: The Biology and Behavioral Basis for Smoking-Attributable Disease: A Report of the Surgeon General. Atlanta: Centers for Disease Control and Prevention (U.S.); 2010. Available from: www.ncbi.nlm.nih.gov/books/NBK53017

3 Douglas, C.E., Henson, R., Drope, J., Wender, R.C. The American Cancer Society public health statement on eliminating combustible tobacco use in the United States. CA: A Cancer Journal for Clinicians. 2018;68:240-245. https://doi.org/10.3322/caac.21455

4 www.altria.com/moving-beyond-smoking [Accessed January 19, 2021]

5 www.pmi.com/glossary-section/glossary/harm-reduction-equation [Accessed January 19, 2021]

6 http://sustainability.reynoldsamerican.com/tobacco-harm-reduction [Accessed January 21, 2021]

7 https://tobaccotransformationindex.org/ [Accessed January 21, 2021]

8 Family Smoking Prevention and Tobacco Control Act (Public Law 11-31, 22 June 2009) 2009.

9 U.S. Department of Health and Human Services. 81 FR 28973. Vol. 81. Washington, D.C. May 10, 2016:28973-29106.

10 www.fda.gov/news-events/press-announcements/fda-marks-historic-public-health-milestone-finalization-two-key-rules-companies-seeking-market-new [Accessed January 31,2021]

11 www.fda.gov/tobacco-products/market-and-distribute-tobacco-product/premarket-tobacco-product-applications [Accessed January 19, 2021]

12 www.fda.gov/tobacco-products/advertising-and-promotion/modified-risk-tobacco-products [Accessed 19 January 19, 2021]

13 Institute of Medicine. 2012. Scientific Standards for Studies on Modified Risk Tobacco Products. Washington, D.C.: The National Academies Press. https://doi.org/10.17226/13294.

14 www.fda.gov/tobacco-products/advertising-and-promotion/modified-risk-tobacco-products#under-review [Accessed January 19, 2021]

15 Pillitteri, J.L., Shiffman, S., Sembower, M.A., Polster, M.R., Curtin G.M. “Assessing comprehension and perceptions of modified-risk information for snus among adult current cigarette smokers, former tobacco users, and never tobacco users.” Addict Behav Rep. 2020;11:100254. doi:10.1016/j.abrep.2020.100254

16 Roulet, S., Chrea, C., Kanitscheider, C., Kallischnigg, G., Magnani, P., Weitkunat, R. “Potential predictors of adoption of the Tobacco Heating System by U.S. adult smokers: An actual use study.” F1000Res. 2019;8:214. Published 2019 Feb 24. doi:10.12688/f1000research.17606.1

17 www.fda.gov/news-events/press-announcements/fda-authorizes-marketing-iqos-tobacco-heating-system-reduced-exposure-information [Accessed Jan 19, 2021]

18 O’Connor, R.J. “Postmarketing surveillance for ‘modified-risk’ tobacco products.“ Nicotine Tob Res. 2012;14(1):29-42. doi:10.1093/ntr/ntq243

19 Adamson, J., Kanitscheider, C., Prasad, K., et al. “Results from a 2018 cross-sectional survey in Tokyo, Osaka and Sendai to assess tobacco and nicotine product usage after the introduction of heated tobacco products (HTPs) in Japan.“ Harm Reduct J. 2020;17(1):32. Published 2020 May 26. doi:10.1186/s12954-020-00374-3

20 www.fda.gov/media/75414/download [Accessed January 19,2021]

21 www.fda.gov/media/84857/download [Accessed January 19, 2021]

22 Dahne, J., Tomko, R.L., McClure, E.A., Obeid, J.S., Carpenter, M.J. “Remote Methods for Conducting Tobacco-Focused Clinical Trials.“ Nicotine Tob Res. 2020 Dec 12;22(12):2134-2140. doi: 10.1093/ntr/ntaa105. PMID: 32531046; PMCID: PMC7454765.

23 Meier, E., Burris, J.L., Wahlquist, A., et al. “Perceptions of Snus Among U.S. Adult Smokers Given Free Product.“ Nicotine & Tobacco Research: Official Journal of the Society for Research on Nicotine and Tobacco. 2017 Dec;20(1):22-29. DOI: 10.1093/ntr/ntw392.