U.S. Food & Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 www.fda.gov PMTA Scientific Review: Technical Project Lead (TPL) SUBMISSION INFORMATION Applicant 22nd Century Group, Inc. Product Manufacturer NASCO Products, LLC Submission Date December 4, 2018 FDA Receipt Date December 4, 2018 Cross-referenced Cross-referenced STN Primary STN(s) Submission1 (b)(4) Applies to all STNs NEW TOBACCO PRODUCTS PM0000491: Moonlight ®2 Product Category Cigarettes Product Sub-Category Combusted, Filtered Package Type Hard pack Package Quantity 20 per pack Characterizing Flavor None Length 83 mm Diameter 7.9 mm Ventilation 13% PM0000492: Moonlight ® Menthol2 Product Category Cigarettes Product Sub-Category Combusted, Filtered Package Type Hard pack Package Quantity 20 per pack Characterizing Flavor Menthol Length 83 mm Diameter 7.9 mm Ventilation 13% 1 The application contains a valid and active cross-reference, which contains appropriate authorization for the applicant to reference the entire file or certain sections thereof. 2 On December 4, 2018, FDA received original PMTAs for VLN™ King and VLN™ Menthol. On October 2, 2019, the applicant submitted a proposed name change for the products to Moonlight and Moonlight Menthol, respectively. The scientific reviews reflect the proposed names (VLN™ and VLN™ Menthol) in the original PMTA submissions. STN PM0000491 – PM0000492 Page 2 of 89 DISCIPLINES REVIEWED Primary Reviewer(s) DATE OF REVIEW Behavioral and Clinical Pharmacology Kia Jackson October 29, 2019 Chemistry An Vu October 29, 2019 Environmental Science Rudaina Alrefai-Kirkpatrick October 29, 2019 Engineering Robert Meyer October 30, 2019 Epidemiology Joanne Chang October 29, 2019 Medical Anna-Sophie Weidner October 30, 2019 Microbiology Prashanthi Mulinti October 30, 2019 OCE – BIMO Tara Singh October 30, 2019 OCE – Manufacturing/Lab Eugene Chang October 30, 2019 OCE – DPAL Matthew Rohit October 30, 2019 Social Science Katherine Margolis October 29, 2019 Statistics Chunfeng Ren October 30, 2019 Toxicology Jonathan Fallica October 31, 2019 Recommendation Issue marketing order letters Issue denial letters Technical Project Lead (TPL): Iilun C. Murphy -S 2019.11.20 15:52:43 -05'00' Iilun Murphy, M.D. Director Division of Individual Health Science, Office of Science Signatory Decision: ☒ Concur with TPL recommendation and basis of recommendation ☐ Concur with TPL recommendation with additional comments (see separate memo) ☐ Do not concur with TPL recommendation (see separate memo) Digitally signed by Matthew R. Holman - S Date: 2019.11.22 16:13:51 -05'00' Matthew R. Holman, Ph.D. Director Office of Science STN PM0000491 – PM0000492 Page 3 of 89 TABLE OF CONTENTS 1. EXECUTIVE SUMMARY ......................................................................................... 6 2. REVIEW OF PMTAS ............................................................................................. 11 2.1. Regulatory History .......................................................................................................................... 11 2.2. Product Composition, Design, and Manufacturing ......................................................................... 13 2.2.1. Tobacco Ingredients ................................................................................................................................... 14 2.2.2. Non-tobacco Ingredients ............................................................................................................................ 16 2.2.3. Product Design ........................................................................................................................................... 19 2.2.4. Manufacturing, Process, and Controls ....................................................................................................... 21 2.2.5. FDA Sample Testing .................................................................................................................................... 21 2.2.6. Product Stability ......................................................................................................................................... 22 2.2.7. Inspections of Manufacturing Facilities ...................................................................................................... 24 2.2.8. Summary of Composition, Design, and Manufacturing Findings ...............................................................24 2.3. Toxicological Risk Assessment ........................................................................................................ 25 2.3.1. Harmful and Potentially Harmful Constituents (HPHCs) ............................................................................ 25 2.3.1.1. General Overview ......................................................................................................................... 25 2.3.1.2. ISO Regimen HPHC Data ............................................................................................................... 26 2.3.1.3. CI Regimen HPHC Data ................................................................................................................. 27 2.3.1.4. Comparison Between VLN™ Cigarettes and SPECTRUM Research Cigarettes .............................29 2.3.2. Nonclinical Studies and Literature Search .................................................................................................. 31 2.3.3. Quantitative Risk Assessment (QRA) .......................................................................................................... 31 2.3.4. Summary of Toxicological Findings ............................................................................................................ 32 2.4. Individual Health Impact ................................................................................................................ 34 2.4.1. Overview of Behavioral and Clinical Pharmacology (BCP) Studies .............................................................34 2.4.2. Nicotine Pharmacokinetics ......................................................................................................................... 36 2.4.3. Behavioral Pharmacology ........................................................................................................................... 37 2.4.3.1. Abuse Liability ............................................................................................................................... 37 2.4.3.2. Use Behavior and Topography...................................................................................................... 39 2.4.3.3. Product Use/Consumption ........................................................................................................... 40 2.4.3.4. Craving, Withdrawal, and Dependence ........................................................................................42 2.4.3.5. Cessation ...................................................................................................................................... 45 2.4.4. Summary of Overall Behavioral and Clinical Pharmacology Findings.........................................................46 2.4.5. Biomarkers of Exposure (BOE).................................................................................................................... 47 2.4.5.1. Effect of Switching to VLNC Cigarettes on BOE ............................................................................47 2.4.5.2. Dual Use and Non-compliance ..................................................................................................... 48 2.4.5.3. Summary of BOE Findings ............................................................................................................. 49 2.4.6. Biomarkers of Potential Harm (BOPH) ....................................................................................................... 50 2.4.7. Adverse Health Effects ............................................................................................................................... 51 2.4.7.1. Health Risks to Non-Users ............................................................................................................ 52 STN PM0000491 – PM0000492 Page 4 of 89 2.4.7.2. Consumer Use and Potential Misuse ............................................................................................52 2.4.7.3. Health Risks Associated with Polyuse ........................................................................................... 52 2.4.7.4. Health Risks Associated with Switching to this Product Compared to Continued Smoking .........53 2.4.7.5. Health Risks Associated with Switching to this Product Compared to Tobacco Cessation ..........53 2.4.7.6. Health Risks Associated with Switching to Product Compared to Cessation Medication ............54 2.4.7.7. Summary of Adverse Health Effects .............................................................................................54 2.4.8. Likelihood of Product Misuse or Malfunction ............................................................................................ 54 2.4.9. Bioresearch Monitoring (BIMO) Inspection ............................................................................................... 55 2.4.10. Summary of Individual Health Findings ...................................................................................................... 55 2.5. Population Health .........................................................................................................................