1 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Clinical Exposure Evaluation Hans J. Roethig, MD, PhD, FCP, FFPM Director Clinical Evaluation Philip Morris USA, Inc.

2 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Exposure Exposure Nicotine equivalents concept Nicotine equivalents concept Smoking topography Smoking topography Study design Study design Case studies Case studies

3 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Exposure Exposure Nicotine equivalents concept Nicotine equivalents concept Smoking topography Smoking topography Study design Study design Case studies Case studies

4 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only 4 Definitions of Exposure Exposure is the contact over time and space between a person and one or more biological, chemical or physical agents (US NRC, 1991) Exposure is the contact over time and space between a person and one or more biological, chemical or physical agents (US NRC, 1991) Exposure is the concentration of a substance in the human body over time, (c x t) Exposure is the concentration of a substance in the human body over time, (c x t) Exposure can be measured as the area under the concentration-time-curve, (AUC) Exposure can be measured as the area under the concentration-time-curve, (AUC)

5 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Where Can We Determine Exposure? Respiratory tract Respiratory tract Central compartment Central compartment Tissues Tissues

6 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Exposure Exposure Nicotine equivalents concept Nicotine equivalents concept Smoking topography Smoking topography Study design Study design Case studies Case studies

7 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Nicotine Equivalents = Molar Sum of Nicotine and its 5 Major Metabolites

8 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Daily Nicotine Equivalents Excretion

9 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Daily Nicotine Equivalent Excretion Per Cigarette

10 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only

11 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Exposure Exposure Nicotine equivalents concept Nicotine equivalents concept Smoking topography Smoking topography Study design Study design Case studies Case studies

12 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Clinical Research Support Systems (CReSS) Plowshares Technologies, Inc. Lab-based CReSS

13 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Topography Measurement CReSS Puffing Parameters Puff Volume Puff Volume Puff Duration Puff Duration Inter-Puff Interval Inter-Puff Interval Peak Flow Peak Flow Time of Peak Flow Time of Peak Flow Puffs per Cigarette Puffs per Cigarette Time to First Puff Time to First Puff Time to Removal Time to Removal Date and Time Date and Time

14 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Flow (ml/sec) » Threshold » Total recorded puff volume Puff volume not recorded Device detects start of puff >> Device detects end << of puff Puff Duration CReSSmicro® Threshold

15 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Source of Data Data from 3 clinical short term exposure studies and 1 long term study; n=363 subjects and n>7260 observations of puffing parameters Data from 3 clinical short term exposure studies and 1 long term study; n=363 subjects and n>7260 observations of puffing parameters

16 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only

17 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only

18 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Relationship between Exposure and Puffing Profile Total puff volume (TPV), total inter- puff interval (TPI) and number of cigarettes smoked were significantly correlated (r 2 =0.57, p<0.001) with nicotine equivalents per cigarette (NE) Total puff volume (TPV), total inter- puff interval (TPI) and number of cigarettes smoked were significantly correlated (r 2 =0.57, p<0.001) with nicotine equivalents per cigarette (NE) nicotine equivalents nicotine equivalents TPI= ∑ Inter-puff interval / Number of cigarettes

19 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Exposure Exposure Nicotine equivalents concept Nicotine equivalents concept Smoking topography Smoking topography Study design Study design Case studies Case studies

20 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only 20 Reduced Exposure Claims IOM, 2001: “.. For most such products the scientific evidence supporting exposure reduction claims will come from in-vitro studies, animal studies, and pharmacokinetic studies in humans.” (emphasis added)

21 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only CC 1 Baseline R a n d o m i z a t i o n CC 1 CC 2 EHCSS No-Smoking Clinical Study Design: Randomized Forced-Switching Forced-switching Day - 2 Day -1 Day EHCSS uncontrolled CC 1 Acclima tion

22 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Exposure Assessment Exposure Assessment Exposure = f {cigarette design/brand} f {cigarette design/brand} x f {smoking behavior} x f {smoking behavior} x number of cigarettes x f {ADME of the individual} ADME = absorption, distribution, metabolism, elimination

23 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Controlled Smoking Day –2 (before randomization): Acclimation day Acclimation day  Subjects smoking the same conventional cigarette only  Subjects allowed to smoke as many cigarettes as reported in their smoking history plus 20%  Subjects are monitored for actual cigarette consumption to determine their daily allotment for the remainder of the study (days -1 to 8). This determines the maximum daily allowance ( cigarettes per day)  Smoking allowed only at predetermined smoking times from 7 AM to 11 PM (every 32 minutes, maximally 30 smoking times)  Cigarettes to be smoked evenly over the day

24 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Daily Nicotine Equivalents Excretion

25 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Carboxyhemoglobin (AUC)

26 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Minimum Detectable Difference Between Study Groups In Biomarkers of Exposure* (% Change from Baseline) BiomarkerVariability Detectable Difference [%] Nicotine equivalents COHb *Assuming 80% power, 5 % type I error rate, two-sided test, n=20 per group

27 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Exposure Assessment Exposure Assessment Exposure = f {cigarette design/brand} x f {smoking behavior} f {cigarette design/brand} x f {smoking behavior} x number of cigarettes x f {ADME of the individual} ADME = absorption, distribution, metabolism, elimination

28 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Long Term Exposure Study Design  Continuation of Short Term Study  Unrestricted smoking, free cigarettes  Biomarkers of Exposure to be reported after 3 and 6 months

29 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Exposure Exposure Nicotine equivalents concept Nicotine equivalents concept Smoking topography Smoking topography Study design Study design Case studies Case studies

30 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Case Study 1 Comparison of 2 cigarettes: 1. Reference cigarette identified 2. Reference cigarette unidentified Same FTC tar delivery, same taste

31 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Mean + SD

32 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Mean + SD

33 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Case Study 2 Comparison of 2 cigarettes: 1. Reference cigarette 2. Test cigarette Same FTC tar delivery, different taste

34 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Mean + SD

35 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Mean + SD

36 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Mean + SD

37 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Case Study 3 Comparison of 3 cigarettes: 1. 2 Reference cigarettes 2. Test cigarette Different FTC tar delivery, different taste

38 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Smoking Topography

39 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Smoking Topography

40 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Puffing profiles are altered immediately when switching to a different cigarette type but remain constant for the rest of the study Puffing profiles are altered immediately when switching to a different cigarette type but remain constant for the rest of the studyswitching

41 Hans J Roethig, Philip Morris USA, LSRO Presentation, 11, 6, 03; for discussion only Conclusions We have validated a clinical study design for the evaluation of cigarettes concerning smoking behavior and exposure. We have validated a clinical study design for the evaluation of cigarettes concerning smoking behavior and exposure. Cigarettes with different FTC tar delivery and different taste exhibited different smoking behavior and exposure. Cigarettes with different FTC tar delivery and different taste exhibited different smoking behavior and exposure. Based on our studies taste of cigarettes seems to have no influence on smoking behavior and exposure for cigarettes with the same FTC tar delivery. Based on our studies taste of cigarettes seems to have no influence on smoking behavior and exposure for cigarettes with the same FTC tar delivery.