Temporary Compliance Waiver Notice The linked files may not be fully accessible to readers using assistive technology. We regret any inconvenience that this may cause our readers. In the event you are unable to read the documents or portions thereof, please email [email protected] or call 1-877-287-1373. Philip Morris Products S.A. THS Page 1 PMI Research & Development 2.7 Executive Summary MRTPA Section 2.7 Executive Summary Confidentiality Statement Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed without the written consent of Philip Morris International. Philip Morris Products S.A. THS Page 2 PMI Research & Development 2.7 Executive Summary TABLE OF CONTENTS 2.7.1 EXECUTIVE SUMMARY .....................................................................................9 2.7.2 PROPOSED MODIFIED RISK AND MODIFIED EXPOSURE CLAIMS ........15 2.7.3 MODIFIED RISK TOBACCO PRODUCTS AND HARM REDUCTION .........17 2.7.4 PRODUCT DESCRIPTION AND SCIENTIFIC RATIONALE ..........................19 Development Rationale and Product Description for THS ............................................19 Heating Instead of Burning Reduces Harmful Constituents ......................................19 Product Description ...................................................................................................20 Scientific Rationale and Assessment Framework for THS........................................24 Causal Linkages between HPHC Exposure and Disease ...........................................24 Smoking Cessation – the Gold Standard for Assessing Risk Reduction ...................25 2.7.5 PMI SCIENTIFIC PROGRAM FOR THE ASSESSMENT OF THS ..................28 2.7.6 THE SCIENTIFIC BASIS FOR APPROVAL ......................................................31 A Reduction in Harm and the Risk of Tobacco-Related Disease to Individual Tobacco Users ................................................................................................................31 Product Design and Control Principles (Step 1) ........................................................31 Aerosol Chemistry and Physics (Step 2) ...................................................................34 Standard Toxicology Assessment (Step 3) ................................................................45 Systems Toxicology Assessment (Step 4) .................................................................58 Overall Summary of Non-Clinical Assessment (Steps 3 and 4) ................................72 Clinical Studies (Step 5) ............................................................................................73 Overall Summary of Clinical Studies (Steps 5) .........................................................97 Conclusion Part A: Reduction in Individual Harm and Risk of Tobacco-Related Disease ....................................................................................................................110 B Benefit the Health of the Population as a Whole ..............................................112 Perception and Behavior Assessment (PBA) Framework (Step 6) .........................113 Population Health Impact Model (PHIM) ...............................................................174 Post-market studies and surveillance (Step 7) .........................................................182 Conclusion Part B: Benefit the Health of the Population as a Whole .....................187 2.7.7 OVERALL CONCLUSION ................................................................................190 2.7.8 REFERENCES ....................................................................................................194 Confidentiality Statement Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed without the written consent of Philip Morris International. Philip Morris Products S.A. THS Page 3 PMI Research & Development 2.7 Executive Summary LIST OF TABLES Table 1: PMI scientific program for the assessment of THS ............................................ 30 Table 2: PMI-58 list of analytes (excluding product-specific analytes) ........................... 36 Table 3: In vitro assessment of THS aerosol .................................................................... 47 Table 4: Sub-chronic 90-day inhalation studies - selected endpoints and results ........... 52 Table 5: THS clinical assessment ..................................................................................... 74 Table 6: Overview of the measured HPHCs and BoExp .................................................. 77 Table 7: Summary of 5-Day Reduced Exposure Study Results: BoExp [100-(THS:CC) ratio and 100-(SA:CC) ratio in %] in studies ZRHR-REXC-03-EU and ZRHR-REXC-04- JP at Day 5 ........................................................................................................................ 80 Table 8: Summary of 90-Day Reduced Exposure Studies: Reduction of the Primary BoExp at Day 5 and Day 90 [100-(THS:CC) ratio and 100-(SA:CC) ratio in %] ........... 82 Table 9: Adjusted Geometric Least Square Means of THS to CC ratios of the Primary BoExp, NNN and total NNK at Day 5 in two studies conducted in Japan. ...................... 88 Table 10: 8-epi-PGF2α Measured at the Day 90 Visit in the Reduced Exposure - Ambulatory Studies .......................................................................................................... 91 Table 11: 11-DTX-B2 Measured at the Day 90 Visit in the Reduced Exposure - Ambulatory Studies .......................................................................................................... 92 Table 12: FEV1 Measured at the Day 90 Visit in the Reduced Exposure - Ambulatory Studies ............................................................................................................................... 94 Table 13: HDL-Cholesterol Measured at the Day 90 Visit in the Reduced Exposure - Ambulatory Studies .......................................................................................................... 95 Table 14: WBC Counts at the Day 90 Visit in the Reduced Exposure - Ambulatory Studies ............................................................................................................................... 96 Table 15: sICAM-1 Measured at the Day 90 Visit in the Reduced Exposure - Ambulatory Studies ............................................................................................................................... 97 Table 16: PBA Program Structure and WOT Studies .................................................... 116 Table 17: Assessment of consumer responses to product messages............................... 121 Table 18: Modified risk claim and messages for Claim #1 ............................................ 123 Table 19: Modified risk claim and messages for Claim #2 ............................................ 124 Table 20: Modified risk claim and messages for Claim #3 ............................................ 124 Table 21: THS Communication Materials, Warning Type and Study Arms in THS-PBA- 05-US Studies ................................................................................................................. 126 Table 22: Overview of studies conducted on product use .............................................. 131 Confidentiality Statement Confidentiality Statement: Data and information contained in this document are considered to constitute trade secrets and confidential commercial information, and the legal protections provided to such trade secrets and confidential information are hereby claimed under the applicable provisions of United States law. No part of this document may be publicly disclosed without the written consent of Philip Morris International. Philip Morris Products S.A. THS Page 4 PMI Research & Development 2.7 Executive Summary Table 23: Proportion of Subjects with Positive Intention to Try and Intention to Use THS- Adult Smokers with No Intention to Quit in THS-PBA-03-US ..................................... 133 Table 24: Proportion of Adult Smokers with No Intention to Quit CC with Positive Intention to Try THS and Positive Intention to Use THS in THS-PBA-05 Studies ....... 134 Table 25: Proportion of Subjects with Positive Intention to Try and Intention to Use THS Adult Smokers With the Intention to Quit Smoking in THS-PBA-03-US ..................... 135 Table 26: Proportion of Adult Smokers With the Intention to Quit Smoking with Positive Intention to Try THS and Positive Intention to Use THS in THS-PBA-05-US Studies 136 Table 27: Proportion of Adult Smokers with Intention to Quit Smoking Who Stated a Change in Intention to Quit Smoking or All Tobacco in THS-PBA-05-US Studies...... 139 Table 28: THS Product Messages and Intent to Use in Study THS-PBA-02-US .......... 162 Table 29: Proportion of Adult Nonsmokers with Positive Intention to Try and Positive Intention to Use THS in THS-PBA-05-RRC-US, THS-PBA-05-RRC2-US and THS- PBA-05-REC-US