烟草科技  2017, Vol. 50 Issue (13): 86-96   PDF    

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文章信息

ROULET Steve, MAINY Nelly, CHREA Christelle, MAGNANI Pierpaolo, WEITKUNAT Rolf, KALLISCHNIGG Gerd, RAMAZZOTTI Antonio
Pre-market studies from five countries in Asia and Europe to measure the adoption of the tobacco heating system (THS) in smokers
Tobacco Science & Technology, 2017, 50(13): 86-96.
DOI: 10.16135/j.issn1002-0861.2017.0564

文章历史

Received: 25 July 2017
revised: 7 November 2017
accepted: 23 November 2017
Pre-market studies from five countries in Asia and Europe to measure the adoption of the tobacco heating system (THS) in smokers
ROULET Steve1, MAINY Nelly2, CHREA Christelle2, MAGNANI Pierpaolo1, WEITKUNAT Rolf2, KALLISCHNIGG Gerd3, RAMAZZOTTI Antonio1     
1. Philip Morris International Management S. A., Avenue de Rhodanie 50, 1007 Lausanne, Switzerland;
2. Philip Morris Products S. A., Quai Jeanrenaud 3, 2000 Neuchatel, Switzerland;
3. ARGUS-Statistics and Information Systems in Environment and Public Health GmbH, Berlin, Germany
Abstract: To predict potential public health impact of a candidate Modified Risk Tobacco Product (MRTP) requires pre-market information on how adult consumers actually use the product under close to real-world conditions. In this context, a Tobacco Heating System (THS) was assessed with regard to product adoption, use in conjunction with other tobacco products, and switching back to smoking cigarettes. Single group, four-week, consumer use studies were conducted between 2013 and 2015 in five countries (Germany, Italy, Japan, South Korea, and Switzerland). In total the analysis assessed how 2 809 adult smokers used THS based on participants' self-reported stick-by-stick consumption of THS and of conventional cigarettes (CC), using pre-defined product use categories (THS use, combined use, CC use). The results showed that:1) After four weeks, between 10% and 37% of the study participants switched either exclusively or predominantly to THS Tobacco Sticks, with highest adoption rates observed in Japan and South Korea. 2) Across countries, between 27% and 39% of the study participants used both cigarettes and THS during the study period. This combined use decreased over time, with dual users either returning to CC use or, to a lesser extent, transitioning completely to THS use. 3) Across countries, the daily average total tobacco product consumption (THS Tobacco Sticks plus CC) was lower than the self-reported consumption of cigarettes prior to entering the study. The introduction of the candidate MRTP THS in various countries would result in adoption by some adult smokers who would otherwise continue to smoke cigarettes, and with varying level of adoption, as suggested by the studies' results in Europe and Asia.
Key words: Modified risk tobacco product     Heat-not-burn     Harm reduction     Consumer use study     Actual use study    
Introduction

Smoking causes many serious diseases including cardiovascular disease (ischemic heart disease, stroke), lung cancer, and chronic obstructive pulmonary disease[1]. The best way to reduce tobacco related health risks is to quit tobacco use altogether[2]. However, as smoking cessation is difficult to achieve[3], a growing number of public health authorities and experts now believe that giving smokers access to less harmful alternatives can be a major benefit to public health[4-6]. This approach is often referred to as "tobacco harm reduction"[7].

Philip Morris International(PMI) has developed and is assessing a portfolio of novel tobacco and nicotine-containing products to address a wide range of adult smoker preferences, with each product designed to significantly reduce or eliminate the formation of harmful and potentially harmful constituents (HPHCs) in the aerosol [8]. HPHCs in conventional cigarette (CC) smoke are generated at temperatures of up to 900 ℃ and result, with minor exceptions, from the thermal decomposition of organic compounds present in tobacco through pyrogenesis and pyrosynthesis mechanisms[9-11]. The Tobacco Heating System (THS) is a heat-not-burn tobacco product that heats rather than burns tobacco. The absence of combustion offers the possibility of significantly reducing both the number and the levels of HPHCs that form at the high temperatures associated with combustion, whilst retaining an acceptable sensory experience for current adult smokers[8, 12-19].

The United States Food and Drug Administration (US FDA) has defined a modified risk tobacco product (MRTP) as"any tobacco product that is sold or distributed for use to reduce harm or the risk of tobacco-related disease associated with commercially marketed tobacco products". Reflecting on previous recommendations[20-22], the 2012 MRTPA FDA Draft Guidance identifies key behavioral aspects to be addressed with regards to current tobacco product users in pre-market consumer studies, namely, (ⅰ) the likelihood that current tobacco product users will start using the product, (ⅱ) the likelihood that current tobacco users who adopt the product will switch to it or switch back to other tobacco products that present higher levels of individual health risk, and (ⅲ) the likelihood that current tobacco users will use the product in conjunction with other tobacco products[23]. The Institute of Medicine recommends multiple complementary studies providing real-world product use evidence, including on ad libitum use of an MRTP alone or in combination with cigarettes [22]. The FDA also states that such actual use studies should allow consumers to interact freely with the product in real-world conditions[23]. Such approaches have also been applied in studies on over-the-counter (OTC) drugs, with consumers being provided with the product together with labeled directions for use[24-28].

Five Whole Offer Test (WOT) studies were conducted between 2013 and 2015 as part of PMI's pre-market research program on the candidate MRTP THS[29]. The research setting followed the home-use test approach[30], with ecological momentary assessment methods to measure cigarette and THS use[31]. The design of the WOT studies aimed at reflecting real-world conditions, by providing the product for actual use ad libitum and adopt a similar approach to the mixed method observational cohort study conducted from 2014 to 2016 in the US on alternative nicotine delivery systems such as e-cigarette[32-33]. The WOT studies were carried out in five different countries (one study per country: South Korea, Japan, Germany, Italy, and Switzerland), in a total of 16 urban cities (with at least two urban cities per country). These countries were selected for the WOT studies, as they were the first countries where THS was planned to be commercialized. By observing a wide range of use patterns across a broad geographic and cultural spectrum, the WOT studies aimed at providing data and insights before the actual commercialization of THS in those countries. Across countries, differences of smoking prevalence by age, sex and socio-economic status have been characterized and further investigated to analyze prevalence trends, based on survey data or derived from indirect sources such as sales data[34-37]. In each country, such smoking prevalence trends support the definition and monitoring of the tobacco control policy. International Smoking Statistics (ISS) provides data and statistics related to smoking for 30 countries but none(ⅰ) related to South Korea, nor(ⅱ) to taste preferences[38]. In the absence of a common source of smoking prevalence trends for South Korea, Japan, Germany, Italy, and Switzerland, study participant recruitment was defined and designed to approximate the demographic and taste preference characteristics of the adult smoking population of each country based on internal data. These internal data on the prevalence of tobacco use were gathered through unpublished cross-sectional studies conducted previously. One of the key areas of investigation of the WOT studies was to provide data on the likelihood that current adult cigarette smokers will start using THS. Adopting a heat-not-burn product, a potentially less harmful alternative, such as the candidate MRTP THS may be beneficial to the health of smokers who would otherwise continue to smoke cigarettes by reducing the harm or the risk of tobacco-related disease associated with the use of commercially marketed tobacco products[39-41].

1 Materials and methods 1.1 Design

The WOT studies were designed as single group observational studies of adult smokers to describe self-reported product use over a period of four weeks, based on pen-and-paper recording of stick-by-stick tobacco product consumption. Each study consisted of two phases: Phase 1 focused on assessing the responses to THS and hypothetical communication materials (e.g., pack design and other communication materials). Phase 2 focused on the actual use of THS and THS Tobacco Sticks (Fig. 1).

Fig. 1 Study design.

In Phase 2, study participants were able to take part in a four-week observational period during which they were free to consume both CC and THS Tobacco Sticks ad libitum. During the observational period, study participants also participated in interim interviews to ensure that they did not have any issues with THS and they were comfortable with the study procedures.

The studies were conducted between June 2013 and June 2015 (June to August 2013 in Japan, September to October 2013 in Italy, September to October 2014 in Germany, October to December 2014 in Switzerland, and April to June 2015 in South Korea).

1.2 Sampling

For each WOT study a convenience sampling method was used to recruit study participants. For each country, to approximate as closely as possible, in a pre-market setting, the possible uptake of THS once available in the respective country, sample quotas aimed at frequency-matching the adult smoker population of the particular country regarding sex, age, socio-economic status, and taste preference (i.e., menthol or regular) based on the main cigarette brand used. In South Korea, the sample was restricted to male adult smokers due to legal restrictions.

Though the number of participants varied by country, the sample size was sufficient to obtain, in each country, an adequate precision of the estimation of the prevalence of the pre-defined product use categories (THS use, combined use, CC use).

1.3 Study participants

Adult smokers aged between one year above the country-specific legal smoking age and 65 years, provided they had resided in the country for at least one year, were eligible to participate. Eligible participants had smoked at least three commercially available cigarettes per day over the previous seven days, had smoked for at least the past six months, and at least 100 cigarettes since reaching the legal smoking age. Lifetime consumption of 100 or more cigarettes is a threshold proposed in the literature to characterize established use[42-43].

To reflect as closely as possible the market in each country, eligible participants in Japan, Switzerland and South Korea were smokers of either regular (non-menthol) or menthol cigarettes, while eligible participants in Germany and Italy were all smokers of regular cigarettes, reflecting the limited number of adult smokers smoking menthol cigarettes in those two countries.

Study participants were recruited from databases maintained by market research agencies and screened for eligibility. Enrollment was conducted through interviews at local facilities.

Following a single product trial and based on exposure to communication materials in Phase 1, participants that did not indicate a negative intention to purchase THS(scoring at least 3 on a 5-point purchase intention scale, with 1=definitely not, 2=probably not, 3=might or might not, 4=probably and 5=definitely), were eligible to continue with the Phase 2 of the study.

All participants were asked to sign a confidentiality agreement, to provide written consent to participate, and were free to withdraw at any time without any obligation, penalty, or loss of the benefits to which they were entitled. The participants received financial compensation in accordance with local consumer research standards for their time and their participation in the study. The compensation ranged from the equivalent of about 60 to 150 €, depending on the country, for the complete participation.

1.4 Products

THS, developed by PMI, has three distinct components: (ⅰ) a tobacco stick -a novel tobacco product with processed tobacco, (ⅱ) a holder into which the tobacco stick is inserted and which electronically heats the tobacco, and (ⅲ) a charger that is used to recharge the holder after each use[8]. THS and regular or menthol THS Tobacco Sticks were provided by the Sponsor (PMI), through the Contract Research Organization.

1.5 Procedures

To reflect as closely as possible the taste preferences of the participants in each country, adult smokers in Japan, Switzerland and South Korea received either regular or menthol THS Tobacco Sticks, while participants in Germany and Italy received only regular THS Tobacco Sticks. In the WOT conducted in Japan, adult smokers of regular cigarettes received regular THS Tobacco Sticks, and adult smokers of menthol cigarettes received menthol THS Tobacco Sticks. After this first WOT, a change of procedures was implemented to assess the interactions between the type of the cigarettes (i.e., menthol or regular) smoked and the type of THS Tobacco Sticks consumed. Consequently, in the WOT studies conducted in Switzerland and South Korea, where both variants of the THS Tobacco Sticks were provided, adult smokers were assigned to regular THS Tobacco Sticks or menthol THS Tobacco Sticks regardless of the type of cigarettes they were smoking at recruitment.

Participants had access to THS (THS Tobacco Sticks, THS holder and charger) at no expense, while they had to purchase cigarettes themselves due to ethical concerns related to potential increased exposure to nicotine, and as done in other studies [44]. They were provided with a number of THS Tobacco Sticks corresponding with their 28-fold self-reported daily consumption of cigarettes at baseline, to cover the 28-day observational period. Participants could order additional THS Tobacco Sticks through a telephone hotline, also available for reporting any issues or asking study-related questions. Potential excessive ordering of additional THS Tobacco Sticks by study participants was prevented by setting up an individual maximum threshold. Any order was limited to 'D'-fold the self-reported daily consumption of cigarettes at baseline, 'D'being the number of remaining days of the observational period. This upper limit was established for ethical reasons, to avoid a too high nicotine exposure of participants compared to their self-reported cigarette consumption, especially for participants with a self-reported daily consumption of less than five cigarettes per day at baseline. During the study conduct, no participant ordered additional THS Tobacco Sticks. At the end of the observational period (Phase 2), participants returned the THS and any unused THS Tobacco Sticks.

Products available to participants during the observational period were blank (i.e., unbranded) with study identification elements and country-specific mandated health warning label for tobacco products, to (ⅰ) ensure confidentiality of the THS material, given the pre-market nature of the WOT studies, and (ⅱ) ensure that participants were aware of the risks associated with the use of THS.

1.6 Measurements

Self-reported baseline characteristics included demographic information such as sex, age, education, occupation and income, and information on smoking habits including the average number of cigarettes smoked per day, taste preference (i.e. menthol or regular) based on the main cigarette brand used, and whether study participants were currently using e-cigarette or not.

Product consumption was assessed daily by recording the number of cigarettes and THS Tobacco Sticks used.

1.7 Analysis

Descriptive analyses were performed to characterize product use categories defining use patterns. These product use categories were derived from the self-reported number of THS Tobacco Sticks and the number of cigarettes consumed on a weekly basis, regardless of the taste (i.e., menthol or regular) of product self-reported. This aggregation of data allowed for comparison between countries that differ in terms of taste preference. Results are reported as absolute and relative frequencies together with confidence intervals, when appropriate.

The percentage of THS Tobacco Stick use was calculated by dividing the number of THS Tobacco Sticks by the number of total tobacco products used (THS Tobacco Sticks plus CC). Product use was categorized (ⅰ) into three product use main categories (THS use, combined use, CC use), and these categories were further divided (ⅱ) into seven product use sub-categories (exclusive THS use, predominant THS use, combined mostly THS use, combined balanced, combined mostly CC use, predominant CC use, exclusive CC use) (Fig. 2).

Fig. 2 Product use categories regarding THS Tobacco Sticks and CC. CC=Conventional Cigarettes; THS=Tobacco Heating System. %THS=Proportion of THS Tobacco Sticks used out of the total tobacco consumption (i.e., THS Tobacco Sticks plus CC).

Weekly product use main categories transition was derived prospectively over the observational period. Total daily average tobacco product consumption (THS Tobacco Sticks plus CC) was compared to baseline self-reported cigarette consumption.

Data were analysed for all enrolled participants with self-reported product consumption for at least 26 out of 28 days, with no imputation of missing data. In case of missing values (i.e., no indication of product use on a particular day), weekly product use was determined based on the available data of the corresponding week. STATA 12.1 was used for the statistical analysis.

2 Results 2.1 Study participants

Table 1 provides enrolment, eligibility and participation details. A total of 2 809 adult smokers (843 in South Korea, 638 in Japan, 377 in Germany, 535 in Italy, and 416 in Switzerland) provided self-reported tobacco product consumption for at least 26 days and were thus part of the Full Analysis Set (FAS).

Tab. 1 Number of study participants enrolled, eligible and participating.

Table 2 contains an overview of demographic characteristics and smoking habits. The sex distribution was balanced in Europe (51.0% male in Italy, 51.7% in Germany and 51.9% in Switzerland), while in Asia the sample was predominantly male (70.8% in Japan, 100.0% in South Korea), reflecting the difference in smoking prevalence between adult males and females in those countries. The average age of participants ranged from 38.2 years in South Korea to 43.5 years in Japan. The average number of cigarettes consumed per day ranged from 12.7 cigarettes per day in Italy to 17.4 cigarettes per day in Germany.

Tab. 2 Demographic characteristics and smoking habits (FAS).
2.2 Use patterns

Fig. 3 shows the use pattern distributions in week 4. Between 9.9% (Switzerland) and 37.1% (South Korea) of the study participants reported THS use. Of these, between 4.3% (Switzerland) and 15.7% (South Korea) reported exclusive THS use.

Fig. 3 Product use by use category in week 4. CC=Conventional Cigarettes; THS = Tobacco Heating System.

The proportion of participants with combined use ranged from 27.3% (Germany) to 39.4% (Switzerland), while the proportion of participants with CC use ranged between 25.9% in South Korea and 51.2% in Germany.

In Germany, Italy, South Korea and Switzerland, the overall proportion of participants with THS use remained stable during the observational period, while it gradually increased in Japan over time (from 20.4% in week 1 to 29.8% in week 4). In all five countries, the proportion of participants with combined use decreased over time (from 48.4% in week 1 to 36.3% in week 4 in South Korea, from 48.1% to 39.4% in Switzerland, from 47.9% to 37.9% in Italy, from 46.7% to 27.3% in Germany and from 43.3% to 32.3% in Japan). At the same time, in all five countries, the proportion of participants with CC use increased (from 16.6% in week 1 to 25.9% in week 4 in South Korea, from 34.5% to 51.2% in Germany, from 39.8% to 49.9% in Italy and from 40.1% to 50.5% in Switzerland). The exception was in Japan, where the overall proportion of participants with CC use remained similar (36.2% in week 1 to 37.8% in week 4).

The THS uptake in week 1 varied strongly across countries, with 11.8% in Switzerland and 34.9% in South Korea (Table 3). Continued use in week 4 resembled the week 1 uptake rate distribution, with Switzerland and Italy having had the lowest continuation rates (49.0% and 54.6%, respectively) and South Korea and Japan the highest ones (72.5% and 78.5%, respectively). Consistent with this observation, the highest transition rates to combined use occurred in Switzerland and Italy (33.3% and 38.8%, respectively). Across all countries, few participants (between 0.8% in Japan and 12.2% in Switzerland) switched back to CC use in week 4.

Tab. 3 Transition of use patterns (Week 1 to Week 4).
2.3 Tobacco product consumption

The average number of tobacco products (THS Tobacco Sticks plus CC) consumed per day ranged from 10.1 sticks per day in Italy to 14.6 sticks per day in Japan. Across all countries, the average number was approximately two sticks below the self-reported consumption of cigarettes prior to the observation period (Table 4).

Tab. 4 Average daily tobacco consumption (THS Tobacco Sticks plus CC).
3 Discussion and conclusions

By the end of the four-week observational period, between 10% and 37% (in Switzerland and South Korea, respectively) of the study participants reported THS use. Of these, between 4% and 16% (in Switzerland and South Korea, respectively) reported exclusive THS use. This suggests that a proportion of adult smokers substituted cigarettes, exclusively or predominantly, with THS Tobacco Sticks during the study period. The proportion of participants substituting cigarettes with THS was higher in Asian (Japan and South Korea) than in European countries (Germany, Italy and Switzerland) which may reflect a higher likelihood of adoption of THS among adult smokers living in Asia compared to Europe. From one country to another, the regulatory framework and the tobacco control approach differ, including smoking prevalence and policy impact assessment, smoke-free policies, cessation programs, health warnings, advertising bans, and taxation[45]. These factors may impact the adoption of THS.

Across all countries, the majority of participants who adopted THS by the end of the four-week observational period did so already during the first week, suggesting a rapid transition from cigarettes to THS among smokers interested in THS and finding the product acceptable. Also, the proportion of participants switching back to cigarettes after having initially switched to predominant or exclusive THS use was low in all countries, suggesting that once adult smokers adopt THS, there is a limited likelihood to return to cigarettes.

Combined use of THS and cigarettes was reported across studies by between 27% and 39% of the participants. It seems likely that part of the combined use could be attributable to the fact that, (ⅰ) THS was provided at no expense to study participants, (ⅱ) some participants may have needed more time to experiment with THS, (ⅲ) some participants may have had difficulty to ensure that THS was properly charged prior to use, and (ⅳ) some participants may have felt uncomfortable to use THS in public given that the product was not commercially sold in any of the countries. However, the dual use of THS and cigarettes did no lead to an increase in daily average total tobacco consumption, suggesting that availability of THS does not increase overall tobacco consumption.

Although THS Tobacco Sticks were provided at no expense to study participants, the proportion of participants with CC use tended to increase over time, with final values varying between 26% and 51%. This may indicate that, even when THS will be commercially available, a proportion of adult smokers is likely to continue smoking cigarettes. Although numerous differences between the study settings and the real-world settings may have contributed to this, it appears likely that THS adoption may be influenced by factors such as repeated exposure to product communication, peer-to-peer information sharing, increasing familiarity and acceptability of an alternative tobacco usage behavior (i.e., use of THS), not only among those adult smokers who are usually the first to try and adopt innovative tobacco products, but also among adult smokers who tend to adopt new tobacco products only when they have become more generally accepted (Rogers' model, cited by [46]). This also suggests that in order to transition all adult smokers who would otherwise continue to smoke cigarettes, additional products with different characteristics may be helpful to address the range of smoking preferences.

Key strengths of the WOT studies are: (ⅰ) high ecological validity with study settings close to the real-world conditions, (ⅱ) broad regional coverage, and (ⅲ) four-week duration, consistent with previous studies[47-48], allowing enough time for the participants to try, experiment with, and establish a pattern of THS use.

Limitations relate to the study being conducted in a pre-market environment: (ⅰ) study participants did not pay for the THS Tobacco Sticks, while they continued to pay for their cigarettes, which may have upward biased THS use, (ⅱ) self-reported tobacco consumption and THS use may be lower than actual consumption, due to the method of data collection[33], (ⅲ) the samples cannot be considered nationally representative, and (iv) assessing switching back to cigarettes would benefit from a longer study duration. Despite these limitations, the data suggest that a proportion of adult smokers may switch from cigarettes to THS. Post-marketing studies will be necessary following product launch to understand and monitor the potential public health impact of the availability of THS.

In conclusion, the results of the WOT studies indicate that THS is an acceptable alternative to cigarettes for a proportion of adult smokers, with as many as one out of ten to one out of three adult smokers adopting THS during the study period, and with higher adoption observed in Asian countries compared to European countries. At the same time, switching back to cigarettes was rare once THS was adopted. Once the product will be commercially available, factors like taste preference, openness to novelty, price, regulatory framework and the tobacco control approach, and proper communication of the benefit of the product may lead to different adoption and use patterns of THS across countries.

Notably, the data on tobacco product consumption is encouraging as it suggests that the availability of THS is unlikely to increase the overall tobacco product consumption.

The results suggest that the introduction of the candidate MRTP THS in various countries may result in adoption by adult smokers who would otherwise continue to smoke cigarettes. As part of the assessment program of the candidate MRTP THS, our results pave the way towards substantiating that THS has the potential to benefit public health by having a positive impact on this particular population of adult smokers. Epidemiologic and post-marketing studies will provide further insights on the impact of the candidate MRTP THS at the individual and the overall population level, including initiation and use by non-adult smokers, as well as on factors impacting THS use prevalence.

Acknowledgements: The authors would like to thank Peter N Lee for providing the ISS data, review comments and suggestions for improvements on the revised version of the manuscript, which was funded by Philip Morris Products S.A.
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