THE AGILE PATCH: A LOW-DOSE LEVONORGESTREL/ETHINYL ESTRADIOL TRANSDERMAL CONTRACEPTIVE DELIVERY SYSTEM SPONSOR BRIEFING DOCUMENT BONE, REPRODUCTIVE AND UROLOGIC DRUGS ADVISORY COMMITTEE MEETING DATE: OCTOBER 30, 2019 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Agile Therapeutics, Inc The Agile Patch Bone, Reproductive and Urologic Drugs Advisory Committee TABLE OF CONTENTS Table of Contents ............................................................................................................................ 2 List of Tables .............................................................................................................................. 7 List of Figures ............................................................................................................................. 9 List of Abbreviations .................................................................................................................... 11 1 Executive Summary .............................................................................................................. 12 1.1 Introduction .................................................................................................................... 12 1.2 Contraceptive Treatment Landscape .............................................................................. 14 1.3 Assessment of Efficacy in Contraceptive Trials – The Pearl Index ............................... 15 1.4 Evolution of Contraceptive Trials and the Creeping Pearl ............................................ 15 1.5 Product Description ........................................................................................................ 18 1.6 Clinical and Regulatory Development ........................................................................... 19 1.6.1 Regulatory History .................................................................................................. 19 1.6.2 Clinical Development Program ............................................................................... 21 1.7 Efficacy Findings ........................................................................................................... 21 1.7.1 Study Design ........................................................................................................... 21 1.7.2 Results ..................................................................................................................... 22 1.7.2.1 Disposition ..................................................................................................... 22 1.7.2.2 Demographics................................................................................................. 22 1.7.2.3 Efficacy Endpoint Results .............................................................................. 24 1.8 Safety Findings ............................................................................................................... 26 1.8.1 Overview of Adverse Events .................................................................................. 26 1.9 Benefit-Risk Summary ................................................................................................... 28 2 Background on Contraception Options and Clinical Trials .................................................. 30 2.1 Overview of Contraception ............................................................................................ 30 2.2 Need for A Low-Dose Transdermal CHC...................................................................... 32 2.3 The Evolution of Contraceptive Clinical Trials ............................................................. 33 2.3.1 Measures of Clinical Efficacy ................................................................................. 33 2.3.2 Evolution of Clinical Trial Designs ........................................................................ 33 2.3.3 Creeping Pearl: Rising Pearl Indices and the Factors that Influence the Pearl Index . ................................................................................................................................. 34 2.3.4 Examples of the Creeping Pearl .............................................................................. 38 Page 2 of 147 Agile Therapeutics, Inc The Agile Patch Bone, Reproductive and Urologic Drugs Advisory Committee 2.3.5 FDA Draft Guidance ............................................................................................... 38 3 Product Description and Patch Properties............................................................................. 40 3.1 Proposed Indication and Dosing Administration ........................................................... 40 3.2 Agile Patch Product Overview ....................................................................................... 40 3.2.1 Patch Design ........................................................................................................... 40 3.2.2 Mechanism of Action .............................................................................................. 41 3.2.3 Pharmacokinetics Overview ................................................................................... 41 3.2.4 Adhesion Overview ................................................................................................ 45 4 Regulatory and Development History .................................................................................. 46 4.1 Regulatory Milestones.................................................................................................... 46 4.2 Clinical Development Program ...................................................................................... 47 5 Patch Adhesion ..................................................................................................................... 50 5.1 Extreme Environmental Conditions Study – Study 16 .................................................. 50 5.2 Comparative Wear Study – Study 25 ............................................................................. 50 5.2.1 Study Design ........................................................................................................... 50 5.2.2 Results ..................................................................................................................... 51 5.3 Phase 3 Study – Study 23 ............................................................................................... 52 5.4 Patch Adhesion Conclusions .......................................................................................... 53 6 Clinical Efficacy ................................................................................................................... 54 6.1 Phase 3 Study Design – Study 23................................................................................... 54 6.1.1 Treatment Regimen ................................................................................................. 56 6.1.2 Enrollment Criteria ................................................................................................. 56 6.1.2.1 Key Inclusion Criteria .................................................................................... 56 6.1.2.2 Key Exclusion Criteria ................................................................................... 57 6.1.3 Endpoints ................................................................................................................ 57 6.1.4 Statistical Methods .................................................................................................. 57 6.1.4.1 Sample Size .................................................................................................... 57 6.1.4.2 Analysis Populations ...................................................................................... 58 6.1.4.3 Endpoint Analyses.......................................................................................... 58 6.1.4.4 Subgroup Analyses ......................................................................................... 59 6.1.4.5 Sensitivity Analyses ....................................................................................... 59 6.2 Study Population – Study 23 .......................................................................................... 59 Page 3 of 147 Agile Therapeutics, Inc The Agile Patch Bone, Reproductive and Urologic Drugs Advisory Committee 6.2.1 Patient Disposition .................................................................................................. 59 6.2.2 Demographics and Baseline Characteristics ........................................................... 61 6.3 Phase 3 Efficacy Results – Study 23 .............................................................................. 64 6.3.1 Confirmed Pregnancies ........................................................................................... 64 6.3.2 Primary Endpoint – Pearl Index .............................................................................. 65 6.3.3 Secondary Endpoints .............................................................................................. 65 6.3.4 Subgroup Analyses ................................................................................................. 66 6.3.4.1 Body Mass Index ............................................................................................ 66 6.3.4.2 Weight ............................................................................................................ 66 6.3.4.3 Race and Ethnicity ........................................................................................