1. Potential Reduced Exposure Products for Tobacco Users: What Do We Need to Know, What Do We Know, and How do We Get There From Here? Thomas Eissenberg, Ph.D. Department of Psychology and Institute for Drug and Alcohol Studies VCU Supported by NIH DA11082, DA06052, DA07027, RWJF’s Tobacco Etiology Research Network, VCU’s IDAS and Dept. of Pharm/Tox, VCU’s NCI-supported Massey Cancer Center

2. Topics to cover. What PREPs are currently available for tobacco users? What do we need to know about these PREPs? What do we know now? How do we get there from here?

3. What PREPs are currently available? Cigarette-like PREPs for smokers: - RJR’s Eclipse ® – reduces carcinogenic compounds? - PM’s Accord ® – reduces secondhand smoke? - B&W’s Advance™ – reduces nitrosamine exposure? - Vector’s Omni™ – reduces PAHs, nitrosamines, catechols? - Vector’s Quest™ – reduces nicotine exposure? Oral PREPs for smokers intended to provide tobacco exposure when/where smoking is forbidden (Ariva™, Exalt™, Revel™). Oral PREPs for smokeless tobacco users: - Star’s Stonewall™ – reduces nitrosamine exposure? - Small label products (“Bacc-off”) – reduces nicotine exposure? - Swedish “snus” products – reduces carcinogen exposure?

4. What do we need to know about these PREPs? At a minimum: Will they perform as advertised? More importantly: Will they decrease tobacco-related death and disease in today’s tobacco users? Especially: Will any PREP-associated reduction in health risk be offset by: - Increased prevalence tobacco use initiation. - Decreased prevalence of tobacco use cessation.

5. Problem and Question: Problem: PREPs are marketed now, but establishing PREP effects on death and disease may take decades. Question: Can we use limited information now to predict PREP effects in the future? - Using scientific methods that are objective, rigorous, and transdisciplinary (combining basic and clinical research). - Decisions that are made within a regulated environment.

6. Despite advertising claims and widespread acceptance, previous PREPs (“low-yield” cigarettes) failed to decrease death and disease (Samet, 1996; Thun et al., 1995). Failure attributable to human/cigarette interaction: - Smokers block vent holes (Kozlowski et al., 1988). - Alter smoking style (more/bigger puffs; Baldinger et al., 1995). Machine testing fails to capture effects of human/cig interaction. What do we know: “PREP History 101”.

7. Lessons learned from “PREP History 101”. Evaluating PREPs involves measuring PREP users’: - Exposure to toxicants, because, for example, machine- smoking yield (e.g., FTC) does not predict what a smoker receives. - Behavior, to assess product-induced behavioral changes. - Effects of use, including withdrawal suppression. This information: - Can be used to test product claims. - May be valuable in predicting effects on death and disease. Some of this work has already started, especially with cigarette- like PREPs.

8. * 0 4 8 12 16 20 24 Plasma nicotine (ng/ml) * * Eclipse ® Own Accord ® What we know about Eclipse ® and Accord ®. Data from Breland et al., 2002a 90 Post 2.5-hour session Pre 2.5-hour session 0 10 20 30 40 50 * * * Expired air CO (ppm)   Own Eclipse ® Accord ® Eclipse ® 0 15 30 45 60 75 Withdrawal Score Own * * *  Accord ®  

9. What we know about Advance™ -- I pre 2.5-hour session post 2.5-hour session 0 10 20 30 40 50 Expired air CO (ppm) Own * * Advance™  0 5 10 15 20 25 30 Plasma nicotine (ng/ml) * Own * Advance™  0 6 12 18 24 30 36 42 48 54 60 66 Withdrawal score Own Advance™ * * Data from Breland et al., 2002b

10. What we know about Advance™ -- II 0 100 200 300 400 500 600 700 800 NNAL (pg/ml) 12345 Day No Smoking Own Brand Advance TM     Data from Breland et al., 2003

11. Conclusions: Accord ®, Eclipse ®, and Advance™ Relative to normally marketed cigarettes: - Eclipse ® Delivers less nicotine; suppresses withdrawal fully. × Delivers about 30% more CO. - Accord ® Delivers less nicotine and CO. × Suppresses withdrawal inadequately. - Advance ™ Delivers less CO; less NNK; suppresses withdrawal. × Delivers more nicotine in lab. Based on these results: - Some marketing claims substantiated; - Reduction in CO and/or NNK may be relevant to harm reduction.

12. Other PREPs. Cigarette-like PREPs for smokers: - Omni™ – Delivers about 20% less NNK and 5% pyrene than normally marketed brands (Hatsukami et al., submitted) - Quest™ – Delivers less nicotine. Oral PREPs for smokers: no data available. May represent exposure increase. Oral PREPs for SLT users: - Stonewall™ – No data available. - Small label products – Some deliver no measurable nicotine. - Swedish “snus” products – Delivers about 50% NNK than U.S. brands (Hatsukami et al., submitted).

13. How do we get there from here? Much work needed. Will they perform as advertised? - Exposure reduction can (and should) be tested now. - Unsubstantiated claims must not be allowed. Will they decrease tobacco-related death and disease in today’s tobacco users? - Restrict marketing until rigorous, objective data can be used to make reasonable hypotheses regarding harm reduction. - Implement post-marketing surveillance to test hypotheses. Will any PREP-associated reduction in health risk be offset by increased initiation/decreased cessation: methods development needed.

14. Why PREP evaluation is needed now. Source: Dr. Ken Warner.