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Methods for Investigating Addictive Potential

EVALUATION OF REINFORCEMENT AND ADDICTIVE POTENTIAL

As specified by the Family Smoking Prevention and Tobacco Control Act of 2009 (FSPTCA),1 the evaluation of a modified risk tobacco product (MRTP) with regard to the public health standard concerns, in part, an evaluation of the product with regard to its tendency to promote the following:

•   Initiation and continuation of its regular use

•   Switching to its use and cessation of the consumption of more harmful tobacco products (e.g., aid in cessation of use of conventional cigarettes)

•   Dual use (use of the MRTP concurrent with continued use of an existing harmful form of tobacco use such as smoking conventional cigarettes)

•   Relapse back to more harmful tobacco use (e.g., resume smoking conventional cigarettes after an extended period of abstinence)

All of these outcomes can be logically related to the reinforcing value of the MRTP (how rewarding it is).

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1 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat. 1776 (June 22, 2009)



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4 Methods for Investigating Addictive Potential EVALUATION OF REINFORCEMENT AND ADDICTIVE POTENTIAL As specified by the Family Smoking Prevention and Tobacco Control Act of 2009 (FSPTCA),1 the evaluation of a modified risk tobacco prod- uct (MRTP) with regard to the public health standard concerns, in part, an evaluation of the product with regard to its tendency to promote the following: • Initiation and continuation of its regular use • Switching to its use and cessation of the consumption of more harmful tobacco products (e.g., aid in cessation of use of conventional cigarettes) • Dual use (use of the MRTP concurrent with continued use of an existing harmful form of tobacco use such as smoking conventional cigarettes) • Relapse back to more harmful tobacco use (e.g., resume smoking conventional cigarettes after an extended period of abstinence) All of these outcomes can be logically related to the reinforcing value of the MRTP (how rewarding it is). 1 Family Smoking Prevention and Tobacco Control Act of 2009, Public Law 111-31, 123 Stat. 1776 (June 22, 2009). 149

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150 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS The chief reason for testing reinforcement value in the laboratory setting is that measures yielded by such testing show a good corre - spondence to a product’s addiction potential in real-world use (Haney and Spealman, 2008). Specifically, drugs that have a positive subjective evaluation and are self-administered in laboratory tasks are ones that tend to be used and abused recreationally in real-world use (Comer et al., 2008; Haney, 2009). The reinforcement value of an agent (e.g., a specific drug, such as nicotine) or a product (i.e., a drug[s] provided via a particular delivery system, such as smokeless tobacco or cigarettes) can be gauged through animal research; however, in the present situation, animal research on reinforcement value does not appear optimal. First, animal research is especially warranted when the product poses significant immediate health risks. However, to the extent that an MRTP has been adequately screened in preclinical work, it seems that the MRTP could be safely used in labo- ratory assessments of reinforcement value or self-administration (where toxic effects of possible prolonged dual use would not pertain). Second, because of the difficulty in modeling certain kinds of delivery systems with particular tobacco products (e.g., snus), human research may present the most externally valid research option. Third, human research methods afford an array of research paradigms that should yield meaningful assess- ment of MRTP reinforcement potential. Finally, human research requires less extrapolation because of a lack of interspecies differences, which can be substantial in terms of nicotine reinforcement (Rogers et al., 2009). Key Considerations for Reinforcement and Self-Administration Studies Almost by definition, an addictive agent must support self- administration. Moreover, there is a long history of research that shows a rough correspondence between the reinforcement capacity of an agent in the laboratory setting and its abuse potential in real-world contexts (Comer et al., 2008; Haney, 2009). Reinforcement is generally defined as the capacity of an agent to sustain self-administration. Therefore, one meaningful step in assessing the ability of an MRTP to support self- administration in real-world contexts is to determine whether it supports self-administration in laboratory or controlled settings. Evaluating reinforcement is complicated by several factors, one of which is a continuum of reinforcement potency. Therefore, methods must capture the reinforcement potential of a product relative to other prod- ucts or agents to provide meaningful comparisons. In theory, a desirable MRTP should be somewhat more reinforcing than nicotine replacement therapies (NRTs), but perhaps less reinforcing than conventional cigarettes (at least among current smokers who have demonstrated considerable

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151 METHODS FOR INVESTIGATING ADDICTIVE POTENTIAL susceptibility to cigarette reinforcement). The relative value of products will be affected by the dose of product tested. Doses may reflect what is considered a meaningful dose in terms of real-world use, they may be based upon brief ad libitum use, or they may be established via dose band- ing methods. Ideally, an MRTP would be sufficiently reinforcing so as to attract smokers away from conventional cigarettes but not encourage the widespread dependent use of the product by individuals who were previ- ously nonusers or who would have quit smoking. NRTs represent a mean- ingful lower bound of reinforcement magnitude because they tend not to support addictive or dependent use (Shiffman et al., 2008a). Further, there appear to be interactions between specific products and individuals, such that individuals differ in terms of the hierarchy of reinforcement poten- tial across products (Perkins, 2009). The determinants of such individual differences in product-relative reinforcement are unknown but no doubt reflect multiple influences such as prior experience (because reinforcement changes with exposure), genetic factors, and social influences. Thus, the level of reinforcement value may lie more in the type of research partici- pant than in the type of product. Reinforcement and Self-Administration Methods Likelihood of initiation, as well as maintenance or persistence of use, can be studied across multiple types of studies ranging from labora- tory studies, to randomized controlled trials (RCTs), to population-based cohort studies. Different methodological principles and standards apply to each type of study. As in all research, research methods are determined in part by the question(s) being addressed. In the case of the evaluation of an MRTP, the core questions in this area involve the extent to which the product will attract and support heavy self-administration and abusive use. Several relevant experimental contexts can be used in the effort to determine the self-administration and use or abuse potential of an MRTP: 1. Subjective evaluation of the product both initially, and with repeated exposure or use in laboratory contexts relative to appropriate comparison products 2. Acute self-administration in laboratory contexts (only reflecting use within laboratory sessions), relative to appropriate comparison products 3. Use in extended residence facilities 4. Natural environment contexts where long-term use can be studied in real-world contexts, via a. long-term use in RCTs, b. cross-sectional survey studies, and c. longitudinal cohort studies.

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152 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS Additionally, methodological approaches must be tailored to each research context. Unless otherwise specified, these considerations apply to both acute laboratory and residential stay experiments. Size and Nature of the Sample Recruited participants must permit appropriate inferences regarding the populations and questions to be addressed. No standard sample size can be specified confidently for the studies described in this section. Each study must be powered consistent with the study questions posed and the comparison products used. Some guidance on power might be gleaned from studies in which high- and low-preference products are evaluated (e.g., conventional cigarettes and NRT products [Johnson et al., 2004; Perkins et al., 2004a, 2009]). Clearly the nature of the sample will differ with regard to the particular research question posed. Relative Reinforcement Value in Regular Smokers One question of key importance is the extent to which an MRTP is reinforcing among current heavy smokers. This would be relevant to the extent to which the product would be used heavily enough by smokers to serve as a cessation aid or a long-term substitute with regard to smoking conventional cigarettes. A very high reinforcement value in smokers of conventional cigarettes would suggest the product could serve as a cessation aid or long-term substitute to conventional cigarettes and could also present a meaningful risk of initiation of use among nonsmokers or ex-smokers. The use of a popu- lation of current smokers has the advantage of ensuring that the tested population is sensitive to nicotine reward (Carter and Griffiths, 2009). If current smokers are used, the researcher should ensure that the research participants have no strong desire to quit, so the findings relate to smok - ing behavior in regular smokers and not quitting behavior (Perkins et al., 1997). About 45 percent of current smokers attempt to quit each year (CDC, 2009), and including such smokers in the sample might not only produce greater within-cell error, but also distort outcomes systematically. Such smokers, for instance, might be especially willing to self-administer a perceived safer alternative to smoking conventional cigarettes and more likely to try to avoid smoking conventional cigarettes. Thus, their self- administration data might not validly reflect the actual reinforcement value of the product. Relative Reinforcement Value in Nonsmokers, Ex-Smokers, and Ado - lescents Testing an MRTP among nonsmokers would provide some evi- dence of attractiveness and reinforcement potential in people who are

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153 METHODS FOR INVESTIGATING ADDICTIVE POTENTIAL essentially nicotine naïve.2 If multiple sessions are used, the research could yield some evidence on how much drug experience might be needed to show an increase in reward value. To increase the likelihood that the tested population comprises at-risk individuals, some selection factors could be used such as high levels of impulsivity, extreme delay dis- counting (Bickel et al., 2010), use of other abused drugs, or risk haplotypes for tobacco dependence (Weiss et al., 2008). Also, because there may be a relation between age and reaction to nicotine and vulnerability to depen - dence (Weiss et al., 2008), it may be important to use relatively young individuals in such research. Adolescents might be optimal, but research methods and oversight would have to be appropriate for their participa - tion. Adolescents who have experimented with smoking might constitute a particularly high-risk population with high public health significance. Finally, the use of ex-smokers would suggest the potential reinforcement value of MRTP use in this population, which has demonstrated sensitiv - ity to nicotine reinforcement. Of course, inclusion of ex-smokers would require a careful assessment of the risks and benefits of participation. In addition, because reinforcement from nicotine or tobacco can vary with gender, age, tobacco experience, and other factors, the researchers should ensure that such dimensions are appropriately represented or controlled (e.g., used for blocking or as exclusion criteria) in the sample to the extent that it is compatible with the question addressed. Characterization of the Sample A comprehensive characterization of the sample is important because it defines the population to which the conclusions may be most directly related. It also permits tests of the interaction of person factors with MRTP liking or use—factors that appear to modulate product reinforcing value. Variables that may be important to measure, based on prior research on tobacco reinforcement, are gender, age, ethnicity, educational and socio- economic status, tobacco and nicotine use history (including peak tobacco use levels, prior quitting history, age of initial use, and use histories of different tobacco and nicotine products), expectations about the effects of the products to be tested, tobacco or nicotine dependence, blood or breath levels of tobacco or nicotine exposure, health and mental health status and history, and use of psychoactive products including psychiatric medica - tions. These variables are important because they have been related to nicotine dependence, tobacco self-administration, and ability to control tobacco use. 2 Non-tobacco users are defined as those who have never smoked more than 10 cigarettes and who have never used any other form of tobacco.

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154 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS In terms of tobacco dependence assessment, the Fagerstrom Test for Nicotine Dependence or one of the new multifactorial dependence assess- ments (the Nicotine Dependence Syndrome Scale [Shiffman and Sayette, 2005; Shiffman et al., 2004] or the Wisconsin Inventory of Smoking Dependence Motives [Smith et al., 2010]) appear to provide more accu- rate appraisal of dependence than do the Diagnostic and Statistical Manual of Mental Disorders criteria (Hughes et al., 2011). In addition, researchers should ensure that the dependence instrument used is one that is appro- priate to the population in question. For instance, there is concern that some dependence instruments may not be appropriate for young or light smokers, so researchers should use an instrument validated with such populations (Colby et al., 2000). Standardization of Pre-Session Experiences Investigators should ensure that research participants have similar experiences prior to experimental sessions. Standard durations of absti- nence from, or controlled use of, nicotine, caffeine, and other psychoactive agents or products before sessions is needed so subjects enter sessions at similar motivational states. Deprivation tends to significantly increase motivation to use tobacco and its self-administration (Fant et al., 1995; Perkins et al., 1994a; Zinser et al., 1999). Studies designed to test maxi- mal motivation would impose a period of deprivation, such as overnight deprivation, which could be tested with a carbon monoxide (CO) test in the case of deprivation of combustible products. Another approach would be to impose a modest but standard level of deprivation (e.g., 1–2 hours) to model a motivational state that would typically occur throughout the day. The most comprehensive approach to assessing self-administration would be to test products across a variety of deprivation levels. Deprivation prior to clinical studies may add complications in data interpretation. An alternative, although more costly and time consuming, is observation of ad libitum self-administration so that the response measured reflects real use. It is probably not a concern if subjects take their normal prescription medication, including psychiatric medication, on the days of sessions or measurement. This is because the main outcome data will be relative preference for, or use of, the tested products, and this presumably will not be differentially affected by chronic use of psychiatric medications. It is important that subjects have similar expectations about the experi- ment and what it entails (e.g., the nature of the tested products) unless manipulation of expectations is an explicit element of the study design (because expectations can significantly affect response to a tobacco product [Perkins et al., 2010]). One possible strategy is to provide subjects with con- siderable superfluous information, which may reduce disparities in expec-

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155 METHODS FOR INVESTIGATING ADDICTIVE POTENTIAL tations (Griffiths et al., 2003). Finally, to the extent that measures are com- plex (e.g., with certain types of cognitive performance tasks) it is important that practice effects be reduced by pre-session task familiarization. Reinforcement and Self-Administration Measures Biochemical Measures Biochemical measures of tobacco or nicotine exposure are important because they reflect prior self-administration intensity or tolerance, and therefore they should serve as useful covariates for laboratory-based self- administration. The appropriate measure could be CO level for cigarette smokers, or nicotine or cotinine levels (from blood, saliva, or urine) in other types of nicotine or tobacco users (those using smokeless tobacco or NRT). In particular, acute blood nicotine absorption profiles in response to both single and repeated use of products is a relevant component in assessing the addictive potential of MRTPs. Cotinine might be preferred to CO and nicotine because of its longer half-life. This could be extremely useful if long-term abstinence is imposed prior to experimental sessions or if subjects have engaged in only infrequent use of a nicotine or tobacco product. Also, if a noncombustible MRTP is studied, CO levels during or after the experiment will not provide measures of effective dosing. Therefore, to obtain a true baseline for such later measures, either nicotine or cotinine should be measured at baseline. In deciding between assess - ing cotinine versus nicotine, if the intent is to study effective self-dosing acutely (over minutes or 1–3 hours), then nicotine is the measure of choice, while cotinine would be the measure of choice if the effects of dos- ing over an extended time period (many hours or days) are targeted. The best predictor of plasma cotinine may be measurement of urine cotinine corrected for creatinine concentration (Benowitz et al., 2009). Finally, the investigator might wish to measure both nicotine and 3-hydroxy-cotinine in order to estimate nicotine metabolism (Schnoll et al., 2009). However, cotinine may be a poor choice for dual-use studies because it can reflect nicotine from multiple sources. Selection of a biochemical assay depends upon the particular experi - ment, the questions posed, and the nature of the product. If relatively sensitive determination of nicotine receipt is sought, then it would be necessary to measure venous or arterial nicotine levels (typically via a venous catheter) and to obtain multiple measures over time to determine boost peak (peak baseline level) and area under the curve (see Benowitz [2006] for calculation). Imaging methods such as positron emission tomography or func- tional magnetic resonance imaging could be used to further characterize

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156 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS the addiction potential of MRTPs. There is increasing evidence that par- ticular neurotransmitter systems and associated brain regions are criti - cally involved in the motivational processing of nicotine cues and nicotine anticipation: e.g., the dorsal striatum, nucleus accumbens, and anterior cingulate cortex (Gloria et al., 2009; McClernon et al., 2009). Therefore, amongst experienced MRTP users, MRTP cues or anticipation of MRTP delivery would be expected to activate such brain regions. However, at present there is little evidence that such measures possess the sensitivity to yield accurate rank-orderings of the addictive potential of different products or delivery systems. Nature of the Comparison Stimuli The selection of products or stimuli to be compared should be deter- mined by the goals of the experiment and the need to obtain a sufficient number of comparators to permit an informative interpretive context. However, as discussed elsewhere, it seems that use of both conventional cigarettes (when smokers or ex-smokers are used as subjects) and NRT would be informative, because these represent products with very high versus modest reinforcement value. The study by Kotlyar et al. (2007) reveals how MRTPs can be meaningfully compared with NRTs on the basis of subjective evaluation and effective nicotine delivery. It may be important to compare the product with nonpharmacologic stimuli as a means of providing a generally meaningful anchor point for the comparison of the pharmacologic products (including the MRTP). For instance, nicotine or tobacco products might be compared with pictorial stimuli (e.g., the International Affective Picture System), attractive music, compounds that stimulate taste buds, or money (Perkins et al., 1997). It is especially important to use nonpharmacologic stimuli as compari - son stimuli (e.g., money) when using nonsmokers as subjects because it would be important to compare the MRTP with a stimulus of meaningful reinforcing value. If the study is using current smokers as subjects, it would be informa - tive to use the subject’s own or preferred brand of cigarettes, as this could represent an optimally reinforcing product against which to compare the MRTP. However, another strategy would be to use cigarettes with a range of known nicotine contents, which would provide a range of reinforce- ment value against which the MRTP could be compared. Operant Self-Administration One standard method of evaluating reinforcement value is to use an operant self-administration paradigm in which some sort of instrumen-

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157 METHODS FOR INVESTIGATING ADDICTIVE POTENTIAL tal response (key presses for instance) is executed to “earn” doses of the product. How hard an individual is willing to work for a dose is related to the addictive potential of the product. For example, the subject might be given the opportunity to earn either puffs of a conventional cigarette, inhalations from a nicotine inhaler, or doses from an MRTP. Such operant paradigms permit collection of many different sorts of measures, such as: (1) response rates including peak response rates for each type of product; (2) relative response rates on concurrent schedules (Perkins et al., 1997); and (3) demand elasticity for each type of product (the extent to which responding is affected by increasing the response requirement or dose). The last index may be especially useful because it permits meaning- ful interproduct (or interstimulus) comparisons on the basis of demand curves (Johnson and Bickel, 2006), in essence permitting more direct infer- ences regarding reinforcement magnitude. Timing and Exposure Parameters Experiments aimed at characterizing reinforcement value could pres- ent MRTPs and other products in diverse ways. The mode of presenta- tion should be dictated by the experimental paradigm used, as well as the research question. In acute dose-effect comparison studies conducted in laboratories settings, presentation of discrete doses of products or stimuli should be counterbalanced, controlling for amount and order of delivery. In self-administration studies or behavioral economic studies, the researcher could use progressive ratio schedules in separate sessions for each product or concurrent schedules (e.g., comparing each product with monetary payment) or could test products individually across dif - ferent response requirements to construct demand curves. In either acute dose-effect studies or self-administration studies, relatively standard doses with cigarettes can be achieved either with puff duration signals or with devices that control puff volume mechanically (Perkins et al., 1997). Timing signals might be the best way to manage dose parameters with products such as smokeless tobacco or NRT (Shiffman et al., 2003). There are many things to consider in setting up and interpreting such experiments. One concern is how much experience or exposure to permit in the experiment. There is certainly evidence that preference or reinforc- ing value changes over exposure. This could occur because of tolerance to aversive effects, sensitization, familiarity (learning how to self-dose), development of dependence, and so forth. Thus, the researcher must struc- ture the study so the person’s experience prior to the study and the expo- sure during the study are designed to match the experimental goals. An important principle, however, is that the best estimate of the ultimate rein - forcement potential of an MRTP may be obtained after fairly extensive use.

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158 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS Another concern is the interdose interval and amount of exposure (dose) to the products. Different delivery systems may deliver differ- ent doses of nicotine and doses with different pharmacodynamics. The investigator must consider whether standard dosing or exposure parameters do not “unlevel” the playing field for the various products (e.g., creating toxic effects or different levels of withdrawal for one product versus another). Investigators may also want to mimic extreme use, because some users may overuse the product. Interdose intervals should be determined based on the anticipated pharmacodynamics of the tested products. Because the ordering of stimuli or products might affect the response (such as when an earlier product might satiate the subject, thereby reduc - ing his or her motivation to self-administer additional nicotine), it is espe - cially important to counterbalance stimulus presentations in acute dose- effect comparison studies so order effects are not inextricably confounded with stimulus effects. In essence, great care must be taken to ensure that exposures to products relatively late in the exposure sequence are mean - ingful. To the extent that earlier exposures result in high nicotine levels, reduced withdrawal, or priming effects, the subject’s motivational state is altered and therefore the subject’s responses are not similarly meaningful across the sequence. One strategy that could be used to address this is to have subjects “earn” dosings during a session but not consume them until after the session (Perkins et al., 1997). This may not be appropriate where delay would distort the motivational value of exposure. There is evidence that immediate versus delayed access to addictive agents or products makes a substantial difference in motivational and evaluative response (Gloria et al., 2009; Sayette and Hufford, 1994). Another concern with timing of the experimental sessions is to ensure the anticipated end of the experimental session does not bias subjects’ responses. For instance, if one of the measures of product evaluation is instrumental to secure a dose of the product or amount of money needed to purchase a dose of the product from the subject, these measures could be distorted if the subject knows that he or she will shortly be released from the session and have ready access to nicotine or tobacco. Therefore, a postsession waiting period (which might range from 30 to 90 minutes) is often imposed so the only prospect of imminent tobacco receipt is that which will occur in the session (Perkins et al., 1999). Additionally, with some procedures such as instrumental self- administration (behavioral economic strategies) or with unusual con - trolled dosing procedures, it may be desirable to allow the subjects some practice with the procedure so learning or familiarization effects are not confounded with changes in reinforcement value that develop with drug use experience.

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159 METHODS FOR INVESTIGATING ADDICTIVE POTENTIAL In most self-administration experiments it would probably be impor- tant to determine the efficiency of self-administration, meaning the rela - tion between self-administration and effective drug delivery of doses consumed (measured by biochemical indices of product receipt, such as CO and nicotine). This would allow one to distinguish gross self- administration behaviors from effective drug delivery. This distinction, for instance, might be relevant to questions about whether compensation occurs because of use of an MRTP. For instance, use of an MRTP might decrease the number of conventional cigarettes that a person smokes. However, this does not necessarily mean the person is actually exposed to less smoke or takes in less nicotine (Benowitz et al. [2006] provides a compensation determination formula for cigarettes with known machine determined yields). Multiple measures are available to assess self-admin - istration behavior so as to capture effective delivery more accurately (Rose et al., 2003; Strasser et al., 2007). This could be done by the use of especially sensitive assessments of self-administration. One example of this is the use of smoking topography measures that permit assessment of puff duration, inhalation force, and so on via force or flow transducers (Strasser et al., 2009). Video cameras and monitors have also been used to assess puff number and duration (Benowitz et al., 2006). Finally, one could indirectly infer the effective dose by repeatedly measuring physiological responses that are acutely sensitive to nicotine dose and rise-time effects (e.g., nicotine-induced tachycardia or skin tem - perature effects [Benowitz et al., 2006; Perkins et al., 1994b]) and deriving peak and area under the curve indices. Reinforcement and Self-Administration Study Designs Acute Dose-Effect Comparison Studies This approach has been labeled as a standard with regard to human abuse liability drug testing, because of the correspondence between sub - jective ratings of drug effects and real-world abuse potential (Carter and Griffiths, 2009). This sort of research is faster and more economical to con- duct than human self-administration studies. In this research, appropriate subject groups are given discrete agent or product exposures and asked to rate them on validated scales. These are generally placebo-controlled, blinded, within-subject crossover designs. However, the apparent differ- ences among some tobacco products (snus versus conventional cigarettes or e-cigarettes) may compromise the ability to achieve true placebo con - trol or blinding. Each product, though, could have a placebo preparation, which should control for some expectancy effects. Ideally, subjects should be allowed to rate a variety of dose levels or exposures to the products

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180 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS providing little support for MRTP use (i.e., providing the MRTP at least nominal cost, providing no more use information than would be provided by package instructions). In addition, the MRTP would be offered by itself with no provision of adjuvant therapy or encouragement for its use. How - ever, it might be that this approach would provide even less use support than would occur in real life, where a person’s social network for instance, might encourage use and provide information. A related consideration is that the RCTs will probably be used to address multiple questions (even if only one or two are deemed primary). For instance, not only is it of interest to determine if the MRTP affects future use of conventional tobacco, but also it is important to obtain additional information on the health risks that might attend chronic and unsupervised use, or the extent to which MRTP use affects tobacco with- drawal symptoms. Unless a meaningful portion of the sample uses the MRTP regularly, then no inferences can be made about such topics (Does heavy use increase liking? How does heavy real-world use affect nicotine and toxicant exposure?). Therefore, it seems that a good compromise strategy is to conduct at least one efficacy trial and one effectiveness trial. The effectiveness trial could perhaps start out with free use in the early stages of the trial to ensure some initial trial of the product, and then weaning the subjects off supported use, with their eventual request of the product reducing their supported payments by some meaningful amount. With regard to the issue of placebo control, it seems as though use of a placebo would be desirable in an efficacy trial but not in the effectiveness trial. The reasons that it would be desirable in the efficacy trial are that (1) there is a history of very strong and persistent responses to placebo tobacco products (e.g., cigarettes that contain no nicotine [Perkins et al., 2008]) and (2) even if the MRTP were compared with another “active” product that contained nicotine (e.g., NRT), this would not control for effects of novelty and “newness” that might accompany the provision of a new or less familiar nicotine delivery system. (If the research occurred in a postmarketing context, then this could affect the need for a placebo control.) If a placebo were used, the research should be double blind. However, subjects would not be blind to the product they were using in an effectiveness study. In any study, to the extent possible, the staff collecting assessment and outcome data should be blinded to treatment assignment or product use. Steps to ensure this and quality assurance measures should be described. Also, if placebo control is used, then data should be collected on subjects’ beliefs about the product they were given. Other intervention procedures should be similar to those used in any well-designed RCT evaluating the use and effectiveness of a cessation aid. Subjects should receive enough product to permit optimal dosing, they should be given instructions for product use that fit the nature of the RCT

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181 METHODS FOR INVESTIGATING ADDICTIVE POTENTIAL (efficacy versus effectiveness), they should be given clear information on health risks and how to spot adverse reactions or effects, they should be given a way to communicate about health concerns and get professional advice, and they should have their use of the products tracked in multiple ways (e.g., “pill counts,” self-report, ecological momentary assessment self-report, medication recording devices). Finally, it would be impor- tant that the subjects not be given clear messages about the possible or targeted effects of the products because this could produce biases in sub - sequent ratings or behaviors (e.g., disappointment, placebo effects, and so on). Perhaps the subjects could merely be told that the MRTP is being evaluated to determine how much people will use it, how it might affect their use of other forms of tobacco, and their attitudes about it. There may be instances where cluster assignment of participants may be warranted (e.g., where communities or schools are assigned to various products). This would permit assessment of product effects within larger social units (spread of use within peer groups) and also permit assess - ment of environmental impacts (community cardiac events or bronchitis incidence). Long-Term Follow-up Methods Certain methods have been shown in prior research to boost trial participation and adherence: 1. Clear information early on about the assessment burden 2. Timely payment for assessment information and visits 3. Ability of a subject to reschedule assessments 4. Use of brief, clear questionnaires 5. Use of the same assessor over time to promote the development of a personal relationship 6. Collection of information via multiple contact routes (multiple phone numbers, e-mail addresses, home and work addresses, and col- lateral informants) to facilitate long-term contact 7. Regular inquiries about the subject possibly moving and likely future addresses 8. Explicit permission for a subject to skip a follow-up contact with the understanding that s/he may resume participation at some future point in time These methods should be adopted in an effort to reduce attrition and boost ascertainment rates. With such methods it may be possible to track clinical trial participants over several years. As suggested above, tracking of outcomes should occur via multiple

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182 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS routes: phone calls, mailed questionnaires, Internet questionnaires, and in-person visits. In general, use of multiple data collection routes yields more comprehensive data and higher ascertainment rates. For instance, in-person visits could be made at a periodicity of 6 months to obtain cal - endar data on smoking and MRTP use (and biochemical samples or physi- cal health tests as needed), but at that periodicity, fine-grained use data (how many cigarettes or MRTP doses were consumed each day) could be obtained only for the past week. Therefore, interval sampling methods using cell phone calls, perhaps on a monthly basis, could provide infor- mation on intervening product use and symptoms. Data Analysis Important elements of an analytic report include 1. as per CONSORT recommendations, primary and secondary out- comes specified a priori; 2. a description of any significant protocol deviations; 3. a complete CONSORT diagram; 4. adherence to intent-to-treat analytic principles and description of exact subject counts included in each analysis; 5. use of experiment-wise error correction, except where primary hypotheses are tested or outcomes important to subject welfare are being evaluated; 6. evaluation of covariates to determine their ability to reduce type II error; and 7. reporting of all adverse events and their relation to MRTP use described. In addition, the analysis plan should examine relations of MRTP use to outcomes, perhaps with use of formal mediation analytic strategies (MacKinnon et al., 2002; Piper et al., 2008). As with some pharmaceuti- cal products, there may be particular patterns of use that are especially beneficial or harmful; such patterns may be most identifiable through the use of real-time assessments of use patterns, perhaps via electronic monitoring strategies (Cramer et al., 1990; Matsui et al., 1992; Metry, 1999). At the minimum, it is critical that RCTs analyze the following in order to comprehensively capture the effect of MRTP availability on public health and to support later modeling of such effects: 1. Use of the MRTP 2. Relations of MRTP availability (treatment assignment) and use with measures of use of conventional tobacco products (e.g., cigarette

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183 METHODS FOR INVESTIGATING ADDICTIVE POTENTIAL smoking), with use reflected in both binary and continuous measures (abstinence versus smoking rate data; dual-use rate versus smoking rate data) 3. Relations of MRTP use with occurrence of quit attempts and dura - tion of abstinence achieved in such attempts, and whether MRTP use reduces quit attempts with other sorts of cessation aids (e.g., there may be no net effect on smoking cessation per se, only a shift in type of quitting, as in use of the MRTP versus NRT) 4. Effect of MRTP use on withdrawal and craving during quit attempts and when individuals reduce their use of conventional tobacco products 5. Nicotine dependence with regard to use of both the MRTP as well as conventional tobacco products 6. Changes in perception of conventional tobacco products and of the MRTP as a function of MRTP use over time (e.g., liking, addictiveness, safety) 7. Quitting self-efficacy and quitting intentions in response to use of both conventional tobacco products and the MRTP. Such outcomes should be measured both at discrete endpoints (e.g., abstinence rates at 6-month visits) as well as via ecological momentary assessments that generate data for intensive longitudinal data analysis (e.g., assessment of smoking over time with MRTP use serving as a time varying covariate in growth curve models). Inferences Interpretations of the obtained data need to be synthesized in order to attain a comprehensive assessment of the potential public health impact of approving a product as an MRTP. RCTs can yield data on the use of the MRTP over time on the proportion of people who use it and how heavily they use it, the extent to which it produces or sustains nicotine depen - dence, and the extent to which it reduces use of conventional tobacco products (e.g., smoking) or reduces use of cessation aids. Data from all relevant measures must be integrated, for instance, taking into account not only the size of the effects of the MRTP on important outcomes but also the prevalence of use and safety findings. For instance, if the product is unappealing and infrequently used, then its potential for a positive public health impact is reduced even if it can boost smoking cessation success. Evaluation of the effects of MRTP will be an iterative process, because information gained from postmarket observations may inform or correct assumptions for laboratory and preclinical investigations. In addi- tion, such synthesis may take into account projected costs to the user and society (e.g., via health care impacts). By supplying data on the outcomes noted above (heaviness of use, duration of use, impact on smoking), RCTs

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184 STUDIES ON MODIFIED RISK TOBACCO PRODUCTS should yield evidence that would be useful for modeling of population based health and economic impacts. Models can account for and poten - tially predict the effect of marketing an MRTP on initiation, cessation, or relapse. Simulation models that use mathematical formulas need to account for population dynamics, because initiation and cessation rates can depend on demographic differences and social behaviors. The synthesis of all of this information will be challenging because it involves explicit or implicit weightings of the various possible outcomes. No well-defined cut scores are available for gauging benefit, and inter- relations of variables may be complex. For instance, an MRTP should be compared with one or more NRTs in RCTs (Kotlyar et al., 2007); however, note that the MRTP need not necessarily be “better” or even equivalent to the NRT in order to exert a public health benefit. An MRTP that is inferior to NRTs (more toxicants, less effective at boosting cessation of smoking conventional cigarettes) could still exert a net public health benefit if its modest effects were additive, meaning they occurred on top of those of NRTs. For example, while not being very effective at helping smokers quit when used as a sole product, it is possible that the combination of NRT plus the MRTP yields additive (or even positive synergistic) effects on smoking cessation when in combination. This is entirely possible because combinations of NRT medications are more effective than single medi- cations (Fiore et al., 2008; Piper et al., 2009; Smith et al., 2009). Another possibility is that dual use reduces the rate of cigarette use and exposure to toxicants and therefore results in a net benefit to both individual and public health. Conversely, the net public health impact of the MRTP may be compromised to the extent that it reduced use of NRTs that ultimately led to smoking cessation. Or, the MRTP might benefit a different popula- tion of smokers than do NRTs. Ideally, an experimental design should permit the testing of a broad range of MRTPs and MRTP effects. REFERENCES al’Absi, M., D. Hatsukami, G. L. Davis, and L. E. Wittmers. 2004. Prospective examination of effects of smoking abstinence on cortisol and withdrawal symptoms as predictors of early smoking relapse. Drug and Alcohol Dependence 73(3):267-278. Baker, T. B., T. H. Brandon, and L. Chassin. 2004a. Motivational influences on cigarette smok- ing. Annual Review of Psychology 55:463-491. Baker, T. B., M. E. Piper, D. E. McCarthy, M. R. Majeskie, and M. C. Fiore. 2004b. Addiction motivation reformulated: An affective processing model of negative reinforcement. Psychological Review 111(1):33-51. Benowitz, N. L., P. Jacob, and B. Herrera. 2006. Nicotine intake and dose response when smoking reduced-nicotine content cigarettes. Clinical Pharmacology and Therapeutics 80(6):703-714.

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