Presentation toCommittee on Scientific Standards

for Studies on Modified Risk Tobacco Products

Peter G. Shields, MDLombardi Cancer CenterGeorgetown University

(soon to be of Ohio State University)

Smoke Chemistries

Short-term Human Switching Study(one week on product)Urine Mutagenicity

Skin Painting Animal Study

4 Week RJR Switching trial (n=11/12 subjects in 2 trials) (1997)

5http://legacy.library.ucsf.edu/tid/qgx12d00

RJR Eclipse Biomarker Studies Internal Studies

Bates 701751866

UsualBrand

UsualBrand Eclipse

9/28 6

(Acrolein)

http://legacy.library.ucsf.edu/tid/ymd87h00

Post-Market ActivitiesSurveillance and consumer use

Claims and messaging evaluationEpidemiology and intervention trials linked to clinical outcomes

Pre-Market EvaluationComparison with Conventional Products and Reference Cigarettes

Product design analysisChemical analysis (tobacco and smoke)

In Vitro cell culture and in vivo animal testingHuman Testing – perception, use, exposure and biomarkers

Pre-Claims Scientific Evaluation (Pre or Post-Market)Comparison with Conventional Products and Other PREPs

Human trials and/or epidemiology (e.g., cross-sectional, cohort) Consumer use and perception studies

Biomarkers for different disease outcomesAssess population and individual heterogeneity

Weight of scientific evidence and risk assessment

Tobacco Product Assessment Framework (N01-PC-64402)If

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Monitoring and Re-evaluationAssess product design changes

Re-evaluate evaluation based upon post-market activitiesRepeat laboratory and human studies

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Smoking machine puff profiles do not mimic human smoking behavior

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Extrapolating Laboratory Data

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Extrapolating Human Data to Individual Smoker and Population Risk

• Clinical Trial’s Questions – Generalizability• Goals, e.g., product performance, behavior,

exposure, etc.• Study design, controls, study duration,

recruitment methods, exclusion/inclusion criteria, retention, compliance, etc.

• Outcomes• Disease endpoints• Intermediate markers

• Biomarkers of exposure and effect• Chemically specific and complex exposures

• Weight of Evidence – qualitative assessment

– Evaluation of all Pre-Market and Pre-Claims data that is evidence-based, using causation-type criteria

– Quantitative weighting

• Risk Assessment - quantitative estimate

– Makes linkage of exposure to disease and exposure-reduction to disease reduction

– Considers the current tobacco users and the general population (including new tobacco users, delayed quitters and relapsed former users)

– Assesses specific disease outcomes, competing risks and overall morbidity and mortality

Weight of Evidence Review and Risk Assessment

• Changes in toxicants that we do not know to

measure, or do not have methods to measure

• Variability and shape of the dose-response

relationships for disease outcomes

• Variability in the shape of the decreasing dose-

response relationship(shape and slope)

• Relationship of biomarkers to disease

outcomes

• Population heterogeneity

• Population effects on initiation, delayed quitting

and sustained cessation

Some PREP Risk Assessment Uncertainties

• 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., CEBP2009 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.

The Risk Continuum and Risk Reduction

Complete Cessation

Smoking Reduction

• The only known way to reduce risk is to stop smoking• Risk reduction depends on smoking history and time since quitting

• Risk reduction estimates for smoking reduction are hypothetical, and may not be measurable in smokers

Never Smoker

Smoker

(Arbitrary Value)

Thank You