Peter G. Shields, MD Tobacco Products Scientific Advisory Committee (TPSAC) August 16, 2013
Conceptual Framework for Evaluating MRTPs: Objectives Provide a framework for evaluating all tobacco products that includes MRTPs Improve the public health related to tobacco products, and prevent a worsening of it Prevent unwarranted health claims Minimize consumer misperception Provide an early warning for unintended consequences for MRTPs Identify research gaps for evaluating tobacco products 2
Weight of Scientific Evidence Review Evaluation of claims and data that is evidence-based, using causation-type criteria in the context of health claims Qualitative final assessment Quantitative weighting and criteria to be decided Considers all studies and data conducted and disclosed Needs to be developed for MRTPs 3
Risk Assessment 4 Quantitative estimate for the reduction in risk for individuals and general population Accounts for delayed quitting, new users, relapse Accounts for a heterogeneous population Assesses specific disease outcomes, and competing risks (e.g., trading one disease for another) Assesses overall morbidity and mortality Determines both the quantitative linkage of tobacco toxicant exposure to disease and a reverse-dose response relationship 4
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Even the best-designed observational studies cannot establish cause and effect between an intervention and an outcome... However, because cross-sectional studies measure the exposure to the substance and the disease risk at the same time, they cannot establish... a cause and effect relationship. Randomized, controlled intervention studies provide the strongest evidence of whether or not there is a relationship between a substance and a reduced risk of a disease.... For these reasons, such studies can provide convincing evidence of a cause and effect relationship between an intervention and an outcome. 6
Surveillance methods for identifying, characterizing, and monitoring tobacco products: potential reduced exposure products as an example. O'Connor RJ, et al., CEBP 2009 Dec;18(12):3334-48. Cigarette filter-based assays as proxies for toxicant exposure and smoking behavior--a literature review. Pauly JL, et al., CEBP 2009 Dec;18(12):3321-33. Evaluation of in vitro assays for assessing the toxicity of cigarette smoke and smokeless tobacco. Johnson MD, et al., CEBP 2009 Dec;18(12):3263-304. Reconciling human smoking behavior and machine smoking patterns: implications for understanding smoking behavior and the impact on laboratory studies. Marian C, et al., CEBP 2009 Dec;18(12):3305-20. Assessing consumer responses to potential reduced-exposure tobacco products: a review of tobacco industry and independent research methods. Rees VW, et al., CEBP 2009 Dec;18(12):3225-40. Methods used in internal industry clinical trials to assess tobacco risk reduction. Rees VW, et al., CEBP 2009 Dec;18(12):3196-208. Clinical trials methods for evaluation of potential reduced exposure products. Hatsukami DK, et al., CEBP 2009 Dec;18(12):3143-95. 7
Theoretical Outcomes of MRTP Use in Individuals Hypothesis: Cancer risk depends on the determinants of the slope for the dose-response curve. Assumption: MRTPs Determinants reduce smoke of slope exposure enough to affect risk (but not proven as of today), which is MRTP antagonistic type and to inherent characteristics dangers of the MRTP; risk remains mostly dependent on conventional Age at change cigarette use. Assumption: For Perception illustration and purposes acceptance only, the slope of the dose-response curve is linear. Nicotine dependence Personality traits Gender Dual use: same smoking and MRTP Cancer Risk in Users MRTP use begins Same smoking; No MRTP Dual use: Lesser smoking and MRTP MRTP only Complete cessation Duration of Use 8
Theoretical Outcome of MRTP Use in the Population Hypothesis: Cancer incidence depends on the determinants of the slope. Determinants of slope Assumption: MRTP meaningfully reduces smoke exposure and affects population use. Delayed cessation Increased initiation Reuptake in former smokers MRTP type Perception and acceptance Change in cancer incidence MRTP use becomes widespread in population Time Dual Use: Same smoking and MRTP Same smoking; No MRTP Lesser smoking and MRTP Lesser smoking without MRTP Complete cessation 9
Risk Reduction: How much is enough How much risk is acceptable? 2x 5x 10x Smoker Disease Risk Never Smoker How much risk reduction Complete Cessation is measurable, and acceptable? Complete Cessation Lifetime Exposure The only known way to reduce risk for tobacco products is complete cessation 10
The Risk Continuum and Risk Reduction Smoker Disease Risk Never Smoker MRTP Measurable NOT Risk Measurable Reduction Risk Reduction Age Complete Cessation The only known way to reduce risk for tobacco products is complete cessation 11
Tobacco and Lung Cancer Mortality Dose Response Models in Humans: Literature Summary Relative Risk Cigarettes/Day Puntoni, et. al., Carcinogenesis 16:1465, 1995 12
Tobacco and Lung Cancer Mortality Dose Response Models in Humans: Literature Summary Relative Risk Cigarettes/Day Puntoni, et. al., Carcinogenesis 16:1465, 1995 13
Effect of Smoking Reduction on Lung Cancer Risk HR=0.73 (0.54-0.98) HR=Hazard Ratio HR=0.50 HR=0.44 (0.36-0.69) (0.35-0.56)) HR=0.17 (0.13-0.23) HR=0.09 (0.06-0.13) 31 year follow-up for 3 prospective cohorts in Copenhagen (N=19714) Godtfredsen, et al. Jama 294: 1505, 2005 14
All Cause Mortality 15
Tools Available to Assess Tobacco Products Laboratory Smoking Machine Methods Smoke chemistry analysis In vitro assays In vivo experimental animal studies Human studies Clinical trials, e.g., switching studies Cross-sectional studies Cohort studies Interventional trials for disease outcomes 16
Extrapolating Laboratory Data???? 17
Smoking Machine Profiles: What about inhalation? Dixon and Derrick, BAT, 1986; Bates: 400746159 18
FTC rescinds 1966 FTC Guidance for measuring tar and nicotine yields for advertising -- 2008 Today, there are no accepted smoking machine puff profiles Optimizing machine puffing regimens Yield per mg nicotine Cross-regimen comparisons: match puffing regimens to human smoking behavior Puff topography matched to a particular product, modeling a variety of smokers Adjust machine parameters to match a nicotine yield, e.g., lower FTC nicotine yield cigarettes are smoked more intensely (Kozlowski & O Connor, 2000; Hammond, et al 2007) Measuring tar and nicotine yields is misleading as not all tars are the same 19
Challenges and questions for clinical trials: Experimental designs Primary goals, study design, duration, control group Subject recruitment Methods and inclusion/exclusion criteria Subject characteristics Generalizability to smokers Subject retention Methods, characteristics of drop-outs and retainers Compliance Outcomes: Use and biomarkers 20
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The Spectrum of Biomarkers External Exposure Exposure Biomarkers Biologically Effective Dose Biomarkers of Harm Outcome Surrogate marker in target tissue External Exposure Assessment Target tissue Internal Dose Target tissue Biologically Effective Dose Target tissue Early biological And genetic effects Target tissue Changes in morphology, structure and function Disease Marker in surrogate tissue Effect modification by host factors 24
Hecht biomarkers and lung cancer 25
Tobacco Product Assessment Framework Pre-Market Evaluation Comparison with Conventional Products and Reference Cigarettes Product design analysis Chemical analysis (tobacco and smoke) In Vitro cell culture and in vivo animal testing Human Testing perception, use, exposure and biomarkers If no claims are ever made If claims are anticipated Pre-Claims Scientific Evaluation (Pre or Post-Market) Comparison with Conventional Products and Other MRTPs Human trials and/or epidemiology (e.g., cross-sectional, cohort) Consumer use and perception studies Biomarkers for different disease outcomes Assess population and individual heterogeneity Weight of scientific evidence and risk assessment Post-Market Activities Surveillance and consumer use Claims and messaging evaluation Epidemiology and intervention trials linked to clinical outcomes Monitoring and Re-evaluation Assess product design changes Re-evaluate evaluation based upon post-market activities Repeat laboratory and human studies 26
Pre-Market Evaluation Product evaluation goal: How does the tobacco product compare with similar conventional and reference products, and does it result in more, less or different toxicant exposure than those products? Design Feature Analysis Design features (tobacco, filter, vent, draw) Reverse engineering unique features Consider additives and delivery mechanism and Chemical/Toxicological Analysis Tobacco constituent analysis Smoke Chemistry Emissions Testing In Vitro and In Vivo Testing (>2 smoking machine conditions, e.g., HC and human puff profiles) Substantial increase - Yes Substantial increase - Yes Stop Stop and Limited Human Testing Consumer Use and Beliefs Human Exposure Testing (Sensory perception, topography, biomarkers) Substantial increase - Yes Stop 27
Pre-Claims Scientific Evaluation Product evaluation goal: Does the product substantially reduce exposure in human studies relating to different disease outcomes that link to individual risk and population harm reduction when compared with conventional products and/or other MRTPs? Human Clinical Trials Long-term randomized switching studies, accounting for compensation Consumer use, perception and abuse liability measures Claims evaluation Biomarkers and Topography Adverse Events and Epidemiology For Products Already On the Market Cross-Sectional, and/or Cohort Studies Consumer use and perception measures Impact of product on cessation, initiation and re-uptake Biomarkers and Topography Assess Population and Individual Heterogeneity and Weight of Scientific Evidence Review and Risk Assessment Substantial decrease - No Substantial decrease - No Substantial decrease - No Substantial decrease - No Stop Stop Stop Stop and Health Claims and Product Messaging Evaluation Focus groups, clinical trials, test marketing Substantial decrease - No Stop 28 28
Post-Market Activities Product evaluation goal: Does the product adversely affect consumer use (e.g., initiation, intensity or cessation),, biomarkers and health outcomes on an individual and population basis? Population-wide Surveillance Consumer use and perceptions Impact of product on use, cessation, initiation and re-uptake Health claims and product messaging evaluation Assess population heterogeneity and Epidemiology Cross-Sectional and Cohort Studies Impact of product on use, cessation, initiation and re-uptake Health claims and product messaging evaluation Biomarkers and topography Assess disease outcomes Assess heterogeneity and Intervention Studies For Disease Outcomes If claims are made about disease outcomes Substantial decrease - No Substantial decrease - No Substantial decrease - No Stop Stop Stop 29
Pitfalls for implementing a Conceptual Framework that is not validated or correctly validated: Worsening public health False sense of security Widespread use of a product that is no different or worse, and/or maintains per capita tobacco use Consumer misperception Create disincentives for real change because of testing and minimal acceptable change guidelines Misdirected innovation for change evaluatiosn Appearance of government or academia endorsement of tobacco use Appearance of a tobacco industry partnership with government or academia 30
Thank you 31