Scientific Evidence for Evaluating Modified Risk Tobacco Products

Transcription

1 Scientific Evidence for Evaluating Modified Risk Tobacco Products Presented to the IOM Committee on Scientific Standards for Modified Risk Tobacco Products May 9 th 2011, Washington DC 1 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

2 Outline Introduction Biomarkers Biomarkers of Exposure Biomarkers of Potential Harm Examples of Clinical Study Designs Short Term Long Term Summary & Key Considerations 2 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

3 Prototype ALCS PREP* Evaluation Framework Pre-FDA Market Ready Product Reduced Exposure Product Reduced Risk Product Reduction in Population Harm Toxicological Evaluation Sensory Acceptability Non-clinical Human *PREP=Potential Reduced Exposure Product RCT=Randomized Clinical Trials 3 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

4 Prototype ALCS PREP* Evaluation Framework Pre-FDA Market Ready Product Reduced Exposure Product Reduced Risk Product Reduction in Population Harm Toxicological Evaluation Non-Clinical Testing Sensory Acceptability RCTs Exposure & Behavior Testing Non-clinical Human *PREP=Potential Reduced Exposure Product RCT=Randomized Clinical Trials 4 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

5 Prototype ALCS PREP* Evaluation Framework Pre-FDA Market Ready Product Reduced Exposure Product Reduced Risk Product Reduction in Population Harm Toxicological Evaluation Non-Clinical Testing Sensory Acceptability RCTs Exposure & Behavior Testing RCTs Disease Risk & Behavior Testing Non-clinical Human *PREP=Potential Reduced Exposure Product RCT=Randomized Clinical Trials 5 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

6 Prototype ALCS PREP* Evaluation Framework Pre-FDA Market Ready Product Reduced Exposure Product Reduced Risk Product Reduction in Population Harm Toxicological Evaluation Non-Clinical Testing Sensory Acceptability RCTs Exposure & Behavior Testing Long Term Health Effects / Population Effect Studies RCTs Disease Risk & Behavior Testing Non-clinical Human *PREP=Potential Reduced Exposure Product RCT=Randomized Clinical Trials 6 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

7 Prototype ALCS PREP* Evaluation Framework Pre-FDA Market Ready Product Reduced Exposure Product Reduced Risk Product Reduction in Population Harm Toxicological Evaluation Non-Clinical Testing Sensory Acceptability RCTs Exposure & Behavior Testing Long Term Health Effects / Population Effect Studies RCTs Disease Risk & Behavior Testing Market Surveillance Studies Non-clinical Human *PREP=Potential Reduced Exposure Product RCT=Randomized Clinical Trials 7 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

8 Outline Introduction Biomarkers Biomarkers of Exposure Biomarkers of Potential Harm Examples of Clinical Study Designs Short Term Long Term Summary & Key Considerations 8 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

9 Biomarkers of Exposure CHRONIC EXPOSURE DISEASE A tobacco constituent or metabolite that is measured in a biological fluid or tissue that has the potential to interact with a biological macromolecule; sometimes considered a measure of internal dose *Clearing the smoke: Assessing the science base for tobacco harm reduction. Stratton K, Shetty P, Wallace R and Bondurant S. Eds. (2001), Pg. 150 Institute of Medicine Publication, National Academy Press Washington DC 9 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

10 Some Biomarkers of Exposure Gas / Gas- Vapor Phase Particulate Phase Biomarker of Exposure Smoke Constituent Sample Matrix Carboxyhemoglobin Carbon monoxide Blood 3-hydroxypropylmercapturic acid (3-HPMA) Acrolein Urine Monohydroxybutenylmercapturic acid (MHBMA) and dihydroxybutylmercapturic acid (DHBMA) 1,3-Butadiene Urine S-phenylmercapturic acid Benzene Urine 3-hydroxy-1-methylpropylmercapturic acid 2-carboxy1-1-methylethylmercapturic acid Crotonaldehyde Urine 4-Aminobiphenyl adducts, 4-Aminobiphenyl Aminobiphenyl Blood / Urine o-toluidine, 2-aminonaphthalene Aromatic amines Urine Nicotine, cotinine, trans-3 -hydroxycotinine and Nicotine (T) Urine their glucuronide conjugates A Nicotine, Cotinine, trans-3 -hydroxycotinine Nicotine (T) Plasma Total NNAL B NNK C (T) Urine Total NNN D NNN (T) Urine Total 1-hydroxypyrene Pyrene Urine 3-hydroxy-benzo[a]pyrene Benzo[a]pyrene Urine (T) Tobacco specific A The molar sum of nicotine and its five major metabolites were expressed as nicotine equivalents (NE) B 4- (methylnitrosamino)-1-(3-pyridyl)-1-butanol; C 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone ; D N -nitrosonornicotine 10 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

11 Nicotine Equivalents is a reasonable surrogate of smoke exposure 1 Relationship between Nicotine Equivalents and biomarkers of exposure Pearson correlation coefficients (r) Cigarette Type 2 Total NNAL Particulate Phase Total 1-OHP Gas-Vapor Phase Plasma Cotinine 3 3-HPMA S-PMA MHBMA COHb 3 CC CC CC Different cigarette types reflect different products with varying machine measured tar yields, CC6= 6 mg tar; CC11=11 mg tar and CC15 = 15 mg tar as measured by the Cambridge Filter Method. 3 Collected at 19:00 daily. p <.0001 for all the correlation significance testing. 1 Wang J, Liang Q, Mendes P, Sarkar M. Biomarkers. 16:144-54, l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

12 Outline Introduction Biomarkers Biomarkers of Exposure Biomarkers of Potential Harm Examples of Clinical Study Designs Short Term Long Term Summary & Key Considerations 12 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

13 Understanding disease mechanisms Genetic Susceptibility CHRONIC EXPOSURE Underlying Mechanisms e.g. INFLAMMATION & OXIDATIVE STRESS SUBCLINICAL CHANGES ALTERED STRUCTURE / FUNCTION DISEASE Adapted from: National Research Council Biological markers in environmental health research. Environmental Health Perspectives 74: l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

14 Biomarkers of Potential Harm CHRONIC EXPOSURE Underlying Mechanisms e.g. INFLAMMATION & OXIDATIVE STRESS SUBCLINICAL CHANGES ALTERED STRUCTURE / FUNCTION DISEASE A measurement of an effect due to exposure; these include early biological effects, alterations in morphology, structure or function and clinical symptoms consistent with harm; also includes preclinical changes *Clearing the smoke: Assessing the science base for tobacco harm reduction. Stratton K, Shetty P, Wallace R and Bondurant S. Eds. (2001), Pg. 150 Institute of Medicine Publication, National Academy Press Washington DC 14 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

15 RELEVANCE Surrogate Biomarkers along the disease pathway e.g. MI, Invasive Carcinoma Disease Event e.g. Endothelial Function, Exercise Tolerance Test e.g. IMT, Dysplasia, Lung Function Functional Biomarkers Morphologic Biomarkers Molecular Biomarkers e.g. DNA adducts, Proteomics Biochemical / Hematological Biomarkers e.g. 8-Epiprostaglandin F2 Cholesterol Days Weeks Months Years 15 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

16 Some Biomarkers of Potential Harm a Biomarker of Potential Harm Matrix Oxidative Stress 8-epi-prostaglandin F2 Urine Inflammation White Blood Cells Blood hs C-Reactive Protein Blood Fibrinogen Blood Platelet Activation 11-dehydrothromboxane B 2 Urine Endothelial Function Lipid Metabolism von Willebrand Factor Blood Microalbumin Urine Total Cholesterol Blood HDL Cholesterol LDL Cholesterol Lung Function Triglycerides FEV1 FVC Air Volume a Examples of some of the BOPHs, other biomarkers not listed include Hematological measures as well as markers of Metabolism, Cardiovascular, Renal and Hepatic function and enzymes 16 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

17 Relationship between Biomarkers of Exposure and Potential Harm* % Difference dehydroxythrombane B2 8-epi-prostaglandin F2a White Blood Cells NS Q1 Q2 Q3 Q4 Nicotine Equivalents Nicotine Equivalents = 24 hr urinary excretion of nicotine and five of its metabolites expressed as molar equivalents of nicotine Q1 < 8.2; Q2 >8.2, < 13.2; Q3 >13.2, < 19.0; Q4 >19.0 mg/24h Some BOPHs are relatively more sensitive to differences in exposure *Adapted from Liu et al (revised manuscript under review at Cancer Epidem. Biomark. Prev. ) 17 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

18 How long does it take to observe changes in clinical findings? Reductions in WBC count and HDL Cholesterol in Long Term Studies* Own cigarette Test Product Test Product Own cigarette The collective weight of evidence may give an indication of anticipated reduction in morbidity and mortality *Roethig et al J Clin. Pharmacol. 48: (2008) 18 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

19 Outline Introduction Biomarkers Biomarkers of Exposure Biomarkers of Potential Harm Examples of Clinical Study Designs Short Term Long Term Summary & Key Considerations 19 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

20 A Clinical Model to Assess Exposure Switching Studies Short Term Randomized Parallel Group Confined to the Clinic Appropriate Comparators Daily Investigations Biomarkers of exposure 24 hour urine and precisely timed blood measurements Behavioral Measurements Primary Objective of Short Term Studies To assess changes in exposure due to the product 20 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

21 A Clinical Model to Assess Exposure & Changes in Disease Risk Switching Studies Long Term Randomized Parallel Group Ambulatory Ad Libitum Product use Appropriate Comparators Monthly Investigations Biomarkers of exposure Biomarkers of potential harm (BOPH) 24 hour urine and blood measurements Behavioral Measurements Primary Objective of Long Term Studies To assess exposure and changes in BOPH under ad libitum product use 21 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

22 Standards of Quality In accordance with GCP and the principles of the Declaration of Helsinki Laboratory measurements conducted in accordance with GLP and CLIA Studies adequately powered for statistical inferences QC checks before database lock Appropriate Data Management and Statistical Analysis Plans Studies monitored to ensure quality 22 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

23 Challenges in assessing the evidence Number of Cigarettes Test Control SCoR 6 Marlboro UL Short Term Long Term Study Day Week Data shown as Mean + SD 3-HPMA (ug/mg Cr) (% change from baseline) 120 SCoR Test 100 Marlboro UL Control Day Week Data shown as Mean + SE 3-HPMA=3-hydroxypropyl mercapturic acid (metabolite of acrolein) Product use behavior is complex and multi-faceted Adapted from Sarkar et al Nic. Tob. Res. 10: (2008) 23 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

24 Challenges in assessing the evidence Multiple stepwise Regression Model for BOPHs* Biomarker R 2 Most important factor in Model 8-epi-prostaglandin F 2 (ng/24hr) 0.23 BMI White Blood Cells (x 10 3 / l) 0.14 NE hs-crp (mg/l) 0.21 BMI 11-dehydrothromboxane B 2 (ng/24hr) 0.13 NE HDL Cholesterol (mg/dl) 0.21 BMI Factors included in the Multiple stepwise regression model were age, gender, race, Body Mass Index (BMI,) smoking duration and nicotine equivalents (mg/24hr, NE) Response is confounded by many internal and external factors *Frost-Pineda et al Nicotine and Tob. Res. 13: (2011) 24 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

25 Outline Introduction Biomarkers Biomarkers of Exposure Biomarkers of Potential Harm Examples of Clinical Study Designs Short Term Long Term Summary & Key Considerations 25 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

26 Summary Based on the product being evaluated nicotine equivalents can provide a reasonable estimate of overall smoke exposure Systemic exposure might also provide an integrated measure of overall product use behavior by adult smokers Assessment of biomarkers of potential harm has revealed that biomarkers of chronic inflammation, oxidative stress and platelet activation are the most sensitive to changes in exposure Switching study designs of short term and long term duration are useful models for developing the scientific evidence 26 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l

27 Key Considerations Consumer acceptability is critical The level of evidence needed should depend on the claim and product being evaluated Existing knowledge on similar products should be considered Information should be assessed using a weight of evidence approach 27 l Altria Client Services l Mohamadi Sarkar - Presentation to the IOM Committee on Standards for MRTP l l