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

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2.3.5 FDA Draft Guidance ...... 38 3 Product Description and Patch Properties...... 40 3.1 Proposed Indication and Dosing Administration ...... 40 3.2 Agile Patch Product Overview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

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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 ...... 67 6.3.4.4 Previous Hormonal Contraceptive Use ...... 68 6.3.4.5 Age ...... 69 6.3.5 Life Table Analysis ...... 69 6.3.6 Sensitivity Analysis ...... 69 6.4 Interpretation of Study 23 Pearl Index Results ...... 70 6.5 Efficacy Conclusions...... 73 6.6 Additional Phase 3 Studies – Studies 12 and 13 ...... 74 6.6.1 Study Design ...... 74 6.6.2 Patient Population ...... 75 6.6.3 Primary Efficacy Endpoints (Pearl Index) for Studies 12 and 13 ...... 75 7 Clinical Safety ...... 76 7.1 Introduction to Combination Hormonal Contraceptive Safety ...... 76 7.2 Safety Population and Exposure ...... 76 7.3 Overview of Adverse Events...... 77 7.4 Common Adverse Events ...... 78 7.5 Adverse Events Leading to Study Discontinuation...... 79 7.6 Serious Adverse Events ...... 80 7.6.1 Venous Thromboembolism Events ...... 81 7.7 Hormone-Related Adverse Events ...... 84 7.8 Application Site Disorders ...... 85 7.9 Bleeding Profile...... 86 7.10 Pregnancy Outcomes ...... 88

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7.11 Safety Conclusions ...... 88 8 Risk Management ...... 90 8.1 Proposed Labeling ...... 90 8.2 Human Factors Study ...... 92 8.3 Patch Replacement ...... 93 8.4 Risk Management Plan...... 93 9 Benefit-Risk ...... 95 10 References ...... 98 11 Appendices ...... 102 11.1 CHC Trial Study Populations ...... 102 11.2 Pharmacokinetic Studies...... 103 11.3 Patch Adhesion Scale – Studies 16, 25, and 23 ...... 104 11.4 Study 23 eDiary Design ...... 105 11.4.1 Patch On Diary - Cycle Day 1 ...... 105 11.4.2 Daily Diary...... 106 11.4.3 Patch Change Diary - Cycle Days 8 and 15 ...... 110 11.5 Study 23 Schedule of Events ...... 113 11.6 Study 23 Inclusion and Exclusion Criteria ...... 114 11.6.1 Inclusion Criteria ...... 114 11.6.2 Exclusion Criteria ...... 115 11.7 Additional Key Secondary Endpoints in Study 23 ...... 118 11.8 Study 23 Screen Failures ...... 119 11.9 Comparison of Patient Demographics and Baseline Characteristics of Completers and Non-Completers in Study 23 ...... 120 11.10 Patient Disposition and Baseline Characteristics in Studies 12 and 13 ...... 122 11.11 Safety Findings in Studies 12 and 13 ...... 123 11.11.1 Overview of AEs ...... 123 11.11.2 Common Adverse Events ...... 124 11.11.3 Serious Adverse Events ...... 126 11.11.3.1 Study 12 and Study 13 ...... 126 11.11.4 Adverse Events Leading to Study Drug Discontinuation ...... 126 11.12 Serious Adverse Event Narratives ...... 129

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11.12.1 DVT/PE Event Narratives ...... 129 11.12.1.1 Patient A ...... 129 11.12.1.2 Patient B ...... 129 11.12.1.3 Patient C ...... 130 11.12.1.4 Patient D ...... 130 11.12.1.5 Patient E ...... 131 11.12.1.6 Patient F...... 131 11.12.2 Other Serious Adverse Events – Occurring in ≥ 2 Women ...... 132 11.12.2.1 Cholelithiasis (4) ...... 132 11.12.2.2 Gastroenteritis (3) ...... 136 11.12.2.3 Major Depression (3) ...... 138 11.12.2.4 Appendicitis (2) ...... 140 11.12.2.5 Cholecystitis (2) ...... 141 11.12.2.6 Ectopic Pregnancy (2) ...... 143 11.12.2.7 Pneumonia (2) ...... 145 11.12.2.8 Suicidal Ideation (2) ...... 146

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List of Tables Table 1: Summary of Patient Demographics and Baseline Characteristics – Study 23 ...... 23 Table 2: Summary of Weight and Body Mass Index Distribution – Study 23 ...... 24 Table 3: Primary Efficacy Analysis (Women ≤ 35 years) – Study 23 Contraceptive Efficacy Population – ITT Dataset ...... 24 Table 4: Summary of Adverse Events – Phase 3 Studies (Safety Population) ...... 27 Table 5: Comparison of Hormone-Related Adverse Events Between the Agile Patch and Recently Approved CHCs ...... 27 Table 6: European and US Pearl Indices in Contraceptive Clinical Trials ...... 37 Table 7: Summary of Agile Patch Pharmacokinetic Properties ...... 43 Table 8: Comparative Evaluation of EE PK Parameters: Agile Patch vs Ortho-Cyclen (Study 14 Primary PK Population) ...... 44 Table 9: Summary of Agile Patch Phase 3 Clinical Studies ...... 48 Table 10: Primary Adhesion Endpoint – Study 25 ...... 52 Table 11: Comparison of Study Discontinuation Rates in Study 23 (the Agile Patch) with Recently Approved CHCs ...... 60 Table 12: Reasons for Study Discontinuation – Study 23 Safety Population ...... 61 Table 13: Overview of Efficacy Populations – Study 23 ...... 61 Table 14: Patient Demographics and Baseline Characteristics – Study 23 ...... 63 Table 15: Summary of Patient Weight and Body Mass Index – Study 23 ...... 64 Table 16: Classification of Pregnancies – Study 23 Contraceptive Efficacy Population ...... 65 Table 17: Primary Efficacy Analysis (Women ≤ 35 years) – Study 23 Contraceptive Efficacy Population – ITT Dataset ...... 65 Table 18: Study Design Factors in Recent Contraceptive Trials ...... 71 Table 19: Primary Endpoint Pearl Index – Studies 12 and 13 ...... 75 Table 20: Demographics of Agile Patch Phase 3 Safety Population ...... 77 Table 21: Overall Summary of Adverse Events – Phase 3 Studies...... 78 Table 22: Most Common Adverse Events (≥ 2%) by Preferred Term – Phase 3 Studies ...... 78 Table 23: Adverse Events Leading to Study Discontinuation (≥ 0.2%) – Phase 3 studies ...... 80 Table 24: Serious Adverse Events in > 1 Patient – Phase 3 Studies ...... 81 Table 25: Summary of Venous Thromboembolism Events – Phase 3 Studies ...... 82

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Table 26: Comparison of Venous Thromboembolism Event Rates Between the Agile Patch and Recently Approved CHCs ...... 83 Table 27: Potentially Hormone-Related Adverse Events Occurring in ≥ 2% of Women – Phase 3 Studies ...... 84 Table 28: Potentially Hormone-Related Adverse Events Occurring in ≥ 2% of Women by BMI Category– Phase 3 Studies ...... 84 Table 29: Comparison of Hormone-Related Adverse Events Between the Agile Patch and Recently Approved CHCs ...... 85 Table 30: Application Site Disorder Adverse Events – Phase 3 Studies ...... 86 Table 31: Bleeding or Spotting Adverse Events Leading to Discontinuation – Phase 3 Studies .87 Table 32: Pearl Index by Body Mass Index category in Women ≤ 35 Years ...... 90 Table 33: Study Population of Select CHCs Evaluated Over Time ...... 102 Table 34: Summary of Key Agile Patch Phase 1 and 2 Clinical Studies ...... 103 Table 35: Study 23 Visit Schedule ...... 113 Table 36: Reasons for Patient Screen Failure in Study 23 ...... 119 Table 37: Demographic and Baseline Characteristics by Study Treatment Completion Status and Overall Safety Population ...... 120 Table 38: Patient disposition in Studies 12 and 13 ...... 122 Table 39: Patient Demographics and Baseline Characteristics Studies 12 and 13 ...... 123 Table 40: Adverse Events Overall Summary – Studies 12 and 13 ...... 124 Table 41: Most Common Adverse Events (≥ 2% of Women in the All Cycle Agile Patch Population) - Studies 12 and 13 ...... 125 Table 42: Potentially Hormone Adverse Events (≥ 2% of Women in the All Cycle Agile Patch Population) – Studies 12 and 13...... 125 Table 43: Summary of All Serious Adverse Events for the Agile Patch – Studies 12 and 13 ....126 Table 44: Incidence of Bleeding or Spotting Adverse Events Leading to Study Drug Discontinuation In Cycles 1-6 – Studies 12 and 13 ...... 127 Table 45: Potentially Hormone-Related Adverse Events Leading to Study Drug Discontinuation In Cycles 1-6 – Studies 12 and 13 ...... 128

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List of Figures Figure 1: Changing Pearl Indices of Approved CHCs used Over Time...... 17 Figure 2: The Agile Patch ...... 18 Figure 3: Mean Serum Concentration-Time Profiles of Ethinyl Estradiol Following Once-Daily Oral or Weekly Agile Patch for Two Cycles in Healthy Female Volunteers – Study 14 ...... 19 Figure 4: Agile Patch Regulatory History Timeline ...... 20 Figure 5: Patient Disposition – Study 23 ...... 22 Figure 6: Forest Plot of Pearl Index of the Agile Patch by BMI Category – Study 23 ...... 25 Figure 7: Contraceptive Options by Effectiveness Tiers ...... 31 Figure 8: Non-Daily Combined Hormonal Contraceptive Use 2002–2017 ...... 33 Figure 9: Effect of Obesity (BMI 30 kg/m2) on Risk of Pregnancy: Adjusted Hazard Ratio for Hormonal Contraceptives...... 36 Figure 10: Changing Pearl Indices of Approved CHCs used Over Time...... 38 Figure 11: The Agile Patch ...... 41 Figure 12: Mean Serum Concentration-Time Profiles of Levonorgestrel of the Agile Patch for Two Cycles in Healthy Female Volunteers – Study 14 ...... 42 Figure 13: Mean Serum Concentration-Time Profiles of Ethinyl Estradiol Following Once-Daily Oral or Weekly Agile Patch for Two Cycles in Healthy Female Volunteers – Study 14 ...... 43 Figure 14: Agile Patch Dose Selection: Ovarian Activity at Cycles 2 and 3 in Study 11 ...... 44 Figure 15: LNG and EE Concentrations in Women With and Without Obesity – Study 11 ...... 45 Figure 16: Study 25 Study Design ...... 51 Figure 17: Primary Adhesion Endpoint – Study 25 ...... 52 Figure 18: Agile Patch Application Schedule ...... 56 Figure 19: Patient Disposition – Study 23 ...... 60 Figure 20: Forest Plot of the Efficacy Analyses in Women ≤ 35 years by BMI – Study 23 Contraceptive Efficacy Population – ITT Dataset ...... 66 Figure 21: Forest Plot of the Efficacy Analyses in Women ≤ 35 years by Weight– Study 23 Contraceptive Efficacy Population – ITT Dataset ...... 67 Figure 22: Forest Plot of the Efficacy Analysis in Women ≤ 35 years by Race and Ethnicity – Study 23 Contraceptive Efficacy Population – ITT Dataset ...... 68

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Figure 23: Forest Plot of the Efficacy Analysis in Women ≤ 35 years by Previous Contraceptive Use – Study 23 Contraceptive Efficacy Population – ITT Dataset ...... 68 Figure 24: Life Table Analysis: Cumulative Pregnancy Rate in Women ≤ 35 Years of Age – Study 23 ...... 69 Figure 25: Percent of Women who Reported Unscheduled or Breakthrough Bleeding and/or Spotting – Study 23 Cycle Control Population ...... 88 Figure 26: Percent of Patches with ≥ 75% Adherence by Application Site-by Cycle – Study 23 .91 Figure 27: Percent of Patches with ≥ 75% Adherence by Cycle – Study 23 ...... 92

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LIST OF ABBREVIATIONS

Abbreviation Definition ACOG American College of Obstetricians and Gynecologists AE Adverse event ß-hCG ß-human chorionic gonadotropin BMI Body mass index BRUDAC Bone, Reproductive and Urologic Drugs Advisory Committee CDC Centers for Disease Control and Prevention CHC Combined hormonal contraceptive CI Confidence interval CL Confidence limit CRL Complete response letter COC Combination oral contraceptive DVT Deep vein thrombosis EE Ethinyl estradiol FDA Food and Drug Administration GI Gastrointestinal HCP Healthcare provider HF Human factors IFU Instructions for Use ITT Intent-to-treat IUD Intrauterine device LNG Levonorgestrel NDA New Drug Application OC Oral contraceptive PE Pulmonary embolism PD Pharmacodynamic PK Pharmacokinetic SAE Serious adverse event US United States VTE Venous thromboembolism

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1 EXECUTIVE SUMMARY

1.1 Introduction Agile Therapeutics, Inc (Agile) is seeking approval of the Agile Patch (AG200-15), an innovative, once-weekly contraceptive patch designed to provide a low-dose combined hormonal contraceptive (CHC) option for women who are seeking a transdermal method for the prevention of pregnancy. The Agile Patch delivers daily exposure of 120 mcg of levonorgestrel (LNG) and 30 mcg of ethinyl estradiol (EE), similar to oral low-dose CHCs. Currently, only a single transdermal contraceptive method, the Xulane® patch, is available in the United States (US). Xulane, the generic of the Ortho Evra® patch, has a boxed warning regarding risk of venous thromboembolism (VTE) and its delivery of a high daily dose of EE. When initially approved by the US Food and Drug Administration (FDA), the Ortho Evra patch was believed to deliver a low daily dose of EE. Prescriptions for Ortho Evra comprised 11% of all CHC prescriptions in the US at its peak, but once its high EE dose was recognized and the boxed warnings added to its labeling, its use declined rapidly (IMS National Prescription Audit). Use of Xulane remains low despite current data that show that women remain interested in transdermal contraception. As such, there is a need for a CHC patch that delivers an EE dose consistent with current standards for low-dose estrogen exposure. The safety and efficacy of the Agile Patch have been assessed in a comprehensive clinical development program that included over 4,100 women, approximately 3,500 of whom were exposed to the Agile Patch. Agile conducted two randomized, open-label, Phase 3 trials in 2010 and 2011 (Studies 12 and 13), both of which utilized an LNG/EE oral contraceptive pill (OC) as a control arm; no formal statistical comparisons were performed. The Agile Patch showed similar efficacy to the OCs; however, study execution issues and wide 95% confidence intervals (CIs) around the efficacy estimates limited conclusions from the results. The FDA determined that a third Phase 3 efficacy trial would be needed to provide reliable data from a well-conducted clinical trial in a representative US study population. The FDA and Agile agreed that given the objectives of Study 23, a single-arm, open-label trial with no comparator would be enough. Study 23 was subsequently designed with the benefit of detailed feedback from the FDA that resulted in enrollment of a broadly representative study population (35% of whom were women with obesity), regular occurrence of sexual activity of enrolled women during the trial, rigorous testing for pregnancy including provision of home pregnancy tests, exclusion of cycles with lack of sexual activity, and other key design and analytical elements. The Advisory Committee for Reproductive Health Drugs (currently the Bone, Reproductive and Urologic Drugs Advisory Committee [BRUDAC]) recommended many of these study design elements in 2007, describing the need to modify hormonal contraceptive trial designs to “provide results that reflect actual effectiveness in the real world” (2007 Advisory Committee Minutes). In 2015, FDA’s published meta-analysis showing an association between obesity and reduced CHC efficacy further suggested that broad study inclusion criteria are needed in contraceptive clinical trials (Yamazaki et al 2015). In July of this year, FDA formalized the 2007 Advisory

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Committee’s recommendations regarding sexual activity and study populations in a draft guidance titled, “Establishing Effectiveness and Safety for Hormonal Products Intended to Prevent Pregnancy” (2019 Draft Guidance; (FDA 2019)). The 2007 Advisory Committee also recommended use of an active controlled trial in most circumstances; however, as stated above, the FDA advised Agile that Study 23 would be adequate without a comparator. This advice to Agile is consistent with FDA’s 2019 Draft Guidance, which states that “single-arm, open-label, historically controlled trials are generally sufficient to establish efficacy.” Historical trials for contraceptives typically enrolled demographically selective populations, had exclusion criteria based on weight and/or body mass index (BMI), did not generally require or measure sexual activity during the study, and may not have been sufficiently rigorous to capture all on-treatment pregnancies. Not surprisingly, the Pearl Indices (the accepted regulatory primary efficacy endpoint in contraceptive trials) from these historical trials were consistently low (~1 pregnancy per 100 women years). Efficacy results based on one-year contraceptive failure rates (which clinicians use when counseling patients) were also consistently low, with one-year failure rates of approximately 1% per year. These results were not generalizable to real-world use. Consequently, there was a wide gap between clinical trial efficacy and actual-use product effectiveness. As industry has slowly incorporated more and more of BRUDAC’s recommendations, Pearl Indices have steadily risen over time, a phenomenon described by Trussell as the “Creeping Pearl” (Trussell and Portman 2013). Similarly, the gap between clinical trial failure rates and actual use effectiveness has narrowed. When designing Study 23, Agile used information available at the time to power the study, which, given the imprecise results from Studies 12 and 13, necessarily meant using historical information from CHC trials. Study 23 was a well-conducted trial that produced reliable results as reflected in the substantially narrower CIs that were achieved compared to Studies 12 and 13. The efficacy results from Study 23 show that the combined effect of all the study design and population elements in a single trial have a substantially greater impact on Pearl Index and upper bound results than was anticipated. It is likely that consistent with the predictions of Trussell and Portman, as more trials like Study 23 are conducted, clinical trial Pearl Indices and failure rates will continue to more closely reflect actual use failure rates in US women. For women and their healthcare providers (HCPs), this is a welcome change, as studies in representative populations with contemporary design elements yield more data that can better inform contraceptive decision-making. It will also be an important step towards encouraging labeling that includes comprehensive information from generalizable studies for future contraceptive products. This briefing document summarizes data on the efficacy and safety of the Agile Patch in the context of this evolving landscape of contraceptive trial designs. As the first CHC trial to incorporate the recommended study population, design, and analytical elements now formalized in FDA’s 2019 Draft Guidance, Study 23 both establishes the efficacy of the Agile Patch and provides important insights on the substantial impact of these elements on efficacy outcomes and what can be expected from contemporary CHC trials. The clinical results from Study 23, along with appropriate informative labeling, demonstrate a positive benefit-risk profile of the Agile

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Patch. Approval of the Agile Patch will be an important step forward for women who desire transdermal contraception.

1.2 Contraceptive Treatment Landscape Selection of a contraception method is a complex, preference-sensitive decision in which a woman and her HCP consider many factors, including hormone type and dose, effectiveness, safety, mechanism of action, route of delivery, and frequency of administration (Chen et al 2019). Due to the individual nature of this decision, contraceptive choices vary not only from one woman to another, but also within a given woman’s reproductive lifetime (Mansour 2014). Thus, having a wide range of contraceptive options is important to ensure that a woman can select a method that best meets her needs at a given time. Currently available contraceptives are categorized by the FDA and the Centers for Disease Control and Prevention (CDC) into three tiers based on effectiveness (ie, pregnancy rates): permanent and semi-permanent methods with pregnancy rates < 1% per year (Tier 1), systemic hormonal methods with annual pregnancy rates between 4–7% (Tier 2), and non-hormonal barrier or planning methods with annual pregnancy rates > 13% (Tier 3). All of these methods are considered effective when compared with the expected 85% rate of pregnancy when no contraceptive method is used (Hatcher et al 2018). Oral CHCs, which are included in Tier 2, are highly effective and are among the most popular short-acting methods used. However, many women report that consistent daily pill taking can be challenging. Only three non-daily CHC options are available in the US: a weekly patch, Xulane (discussed below), and two monthly vaginal rings, NuvaRing® and AnnoveraTM. Vaginal rings are not appropriate for or preferred by some women because of their more invasive nature and insertion challenges (Egarter et al 2013). Transdermal drug delivery has advantages over oral delivery for some women. Transdermal delivery systems provide continuous administration of drug through the skin, which maintains constant plasma drug levels and avoids the peaks and troughs observed with oral administration. Moreover, transdermal delivery avoids reduced bioavailability because of first-pass hepatic metabolism and enzymatic degradation in the gastrointestinal (GI) tract that are seen with oral drug administration. Other advantages of transdermal patches include a non-oral route of administration for patients who are unable to take oral medications and the immediate cessation of drug administration with removal of the patch (Burkman 2007). A non-daily, non-oral option has the potential to improve convenience over OCs, while still providing a woman control over her treatment and the flexibility of not committing to a long-term method. Convenience is extremely important for all medications, but in particular for contraception, as healthy individuals who are using a preventive medication are more likely to be consistent with a regimen that fits their lifestyles and daily routines (Martinez-Astorquiza-Ortiz de Zarate et al 2013). Xulane, the generic formulation of Ortho Evra, is the only available transdermal contraceptive. Xulane is a high-dose patch that delivers a daily dose of EE that is approximately 60% higher

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than low-dose OCs and is associated with the potential for an increased risk of VTE compared with low-dose OCs. In the years since the first OCs were approved, accumulating evidence demonstrated a relationship between estrogen and VTE, the most serious adverse event (SAE) associated with CHCs. In addition to the serious risks associated with high EE exposure, hormone-related adverse events (AE) (eg, nausea, breast tenderness, headache) were found to be more common, and although not life-threatening, often led to inconsistent use and discontinuation of CHCs due to poor tolerability. Thus, over the years, doses of estrogen in CHC methods have steadily declined. The American College of Obstetricians and Gynecologists (ACOG) considers CHCs that deliver 35 mcg of EE or less to be low-dose (ACOG Practice Bulletin 2019). The overwhelming majority of CHCs that are currently in use in the US are low- dose methods, which are strongly preferred by women and HCPs because of their more favorable safety and tolerability profiles. The Agile Patch would add a currently unavailable low-dose transdermal CHC to women’s Tier 2 contraceptive options.

1.3 Assessment of Efficacy in Contraceptive Trials – The Pearl Index When counseling patients about effectiveness of contraceptive options, clinicians rely on pregnancy rates from life table analyses (or contraceptive failure rates), which estimate the percentage of women who experience a pregnancy over one year of use of a method. As previously noted, the CDC has categorized contraceptive methods into three tiers based on pregnancy rates, Tier 1 being the most effective and Tier 3 having lower effectiveness. Such pregnancy rates are typically calculated via life table analyses as secondary endpoints in contraceptive clinical trials. The regulatory efficacy endpoint the FDA uses as the basis for approval decision-making, however, is the Pearl Index. The Pearl Index is an estimate of pregnancies per 100 “woman-years” of product use. The Pearl Index is calculated as follows: – × 13 = × 100 – 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 The FDA has acknowledged that Pearl𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 Indices𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 (and𝑜𝑜𝑜𝑜, collaterally,𝑡𝑡ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐 pregnancy𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 rates in clinical trials) are highly sensitive to study design and analytical factors, including study population demographics, pregnancy detection methods, and cycle exclusion rules. Changes in one or more of these factors has a direct impact on the Pearl Index, although the precise impact of each factor is not quantifiable because the factors are inter-related (eg, race and socioeconomic status). In an effort to consistently describe the advice the FDA has delivered to sponsors, like Agile, the FDA recommends incorporation of all of these factors in CHC trials in its new 2019 Draft Guidance. As these factors become combined into a single study, as they were with Study 23, the impact on Pearl Index results is expected to be much larger than the effect of each factor alone.

1.4 Evolution of Contraceptive Trials and the Creeping Pearl The design of hormonal contraceptive studies has evolved over time. Historically, contraceptive clinical trials enrolled highly selective populations and yielded very low pregnancy rates (1–2%)

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that were not generalizable to intended users, especially as the US population has become more diverse and rates of obesity have increased dramatically. As a result, contraceptive failure rates with actual use of products following FDA approval were many times higher than those observed in the clinical trials. This created a wide gap between the efficacy observed in clinical trials and effectiveness observed in the real world, a phenomenon widely accepted and understood by prescribers of birth control, who typically use the failure rates described in the contraceptive tiers rather than product labeling when counseling women about contraception. Recognizing the need for more clinically relevant information, the FDA has for years encouraged sponsors to enroll less selective study populations and incorporate more rigorous design factors into contraceptive studies. In addition, the 2007 Advisory Committee meeting convened by FDA discussed, among other things, contraceptive trial design, assessment of the acceptability of risks and benefits, and the role and impact of labeling. Important recommendations provided during the meeting included:

• Modifying trial designs to provide results that reflect effectiveness in the real world; • Changing entry criteria to reflect real-world prescribing; and • Ensuring that all relevant information be provided to the prescriber, including data on subgroups. To effectuate these changes, the 2007 Advisory Committee recommended that FDA avoid arbitrary limits for the Pearl Index point estimate and upper bound of the 95% CI in order to bring the widest range of new contraceptives to market. The Committee recognized that establishing regulatory mandates for Pearl Indices might also encourage trials that exclude women with higher BMIs or avoid enrolling a demographically diverse US population (2007 Advisory Committee Minutes). As sponsors have incrementally adopted this advice from the FDA and 2007 Advisory Committee, Pearl Indices have been slowly and steadily rising (the Creeping Pearl) (Trussell and Portman 2013). Cycles included in the denominator of the Pearl Index calculation, sexual activity, BMI, and study site location have been identified as key factors that can affect the Pearl Index. These factors are described in further detail in Section 2.3.3. As the Pearl Indices and their accompanying failure rates in clinical trials have risen, the failure rates with actual use have remained relatively steady over time; thus, the gap between study efficacy results and actual use effectiveness has narrowed over time. That the Creeping Pearl phenomenon is due to changes in study design and population rather than to the approval of less effective products over time is evident when comparing the Pearl Indices of individual hormonal contraceptives across studies conducted over a several year period. Figure 1 shows the Pearl Indices and upper bounds of the 95% CI (where available) of three products, Loestrin Fe®, Levlite®, and Nordette®, when they were approved and when used as comparators in later contraceptive clinical trials. These three products were selected because data are available from multiple studies over time. The Pearl Indices and, importantly, the associated upper bounds of the 95% CIs are notably higher in the later trials despite no change in

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the underlying product. Additional information about age, sample size, and weight/BMI for the studies included in Figure 1 can be found in Appendix 11.1. Although it is not possible to ascertain the specific contribution of each of these elements or of the difference in the study design to the higher Pearl Index, these data provide further evidence that study design and population can have a significant impact.

Figure 1: Changing Pearl Indices of Approved CHCs used Over Time

CHC = combined hormonal contraceptive; CI = confidence interval; EU = European Union; NR = not reported; PI = Pearl Index Note: Upper 95% CI not reported for all studies. Source: Adapted from Edelman et al 2018 The recommendations from the 2007 Advisory Committee and the factors identified by Trussell et al as producing the observed increases in Pearl Indices have been newly suggested in the 2019 Draft Guidance as the standard for contraceptive clinical trials (FDA 2019). As a result, the unique combination of design, population, and analytical factors incorporated into Study 23 is consistent with what the FDA now considers the standard approach to establishing efficacy and safety in clinical trials for contraceptives and is the first clinical trial to be conducted consistent with this standard. While not establishing a cutoff for approval, the 2019 Draft Guidance observes that CHCs approved in the past typically have Pearl Indices with an upper bound of the 95% CI below 5 at approval. An upper bound of 5 is not surprising given that these Pearl Indices and the upper bounds of their 95% CIs were derived from trials that did not incorporate the full set of design, population, and analytical factors favored by the FDA in the 2019 Draft Guidance. As more studies follow the example set by Study 23 and are conducted in accordance with the FDA’s recommendations, the results observed in clinical trials can be expected to be closer approximations to effectiveness observed in the real world.

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1.5 Product Description The Agile Patch is a low-dose, weekly transdermal CHC. The proposed Indication Statement, including a Limitation of Use are as follows: The Agile Patch is a weekly low-dose progestin/estrogen CHC transdermal patch indicated for use by females of reproductive potential to prevent pregnancy. Limitation of Use: The Agile Patch has demonstrated reduced effectiveness in women who weigh 202 lbs (92 kg) or more and/or have a BMI of 30 kg/m2 or more. The first part of the proposed Indication Statement is standard language for contraceptive products, while the Limitation of Use highlights the reduced effectiveness observed in women with obesity. The Agile Patch (Figure 2) contains 2.60 mg LNG and 2.30 mg EE in an active drug matrix, and delivers daily doses of 120 mcg LNG and 30 mcg EE, similar to low-dose OCs. The patch comprises six layers of active and inactive ingredients with an adhesive component integrated into the patch. Unlike most other transdermal systems, the Agile Patch was designed so that the active drug portion would not extend to the edges of the patch. The use of a peripheral laminate around the active drug core preserves the ability of the patch to deliver the drug in the event of a partial lift of the patch. The total area and thickness of the patch are 28 cm2 and < 1 mm, respectively.

Figure 2: The Agile Patch

The Agile Patch is applied once per week (worn for 7 days) for a 3-week period, followed by a 1-week hormone-free period, when no patch is worn. Patches can be applied to the abdomen, buttock, or upper torso (excluding the breasts). Like other CHCs, the Agile Patch prevents pregnancy primarily by suppressing ovulation. However, unlike OCs that are characterized by daily hormonal peaks and troughs, the Agile Patch delivers a steady concentration of hormones during the week of wear (Figure 3). Furthermore, owing to the transdermal delivery route, EE and LNG avoid first-pass metabolism by the liver, which enables lower dosing with continuous

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release, sustained levels of medication, and avoidance of GI drug-drug interactions. The Agile Patch provides serum levels of EE and LNG consistent with levels reported for combination oral contraceptives containing EE and LNG and steady-state EE concentrations are about half the levels previously reported for Ortho Evra (see Section 3.2.3).

Figure 3: Mean Serum Concentration-Time Profiles of Ethinyl Estradiol Following Once-Daily Oral or Weekly Agile Patch for Two Cycles in Healthy Female Volunteers – Study 14

EE = ethinyl estradiol; NGM = norgestimate Note 1: mean plasma concentration vs time curve for EE of the Agile Patch during Cycles 2 and 3 Note 2: Ortho Evra data are from labeling and not from a head-to-head study against the Agile Patch and error bars not available

1.6 Clinical and Regulatory Development 1.6.1 Regulatory History The regulatory history of the Agile Patch is summarized in Figure 4.

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Figure 4: Agile Patch Regulatory History Timeline

CRL = Complete Response Letter; FDA = Food and Drug Administration; NDA = New Drug Application Agile first submitted a New Drug Application (NDA) for approval of the Agile Patch in April 2012 based on Studies 12 and 13, which demonstrated similar efficacy between the Agile Patch and OCs. FDA issued a Complete Response Letter (CRL) concluding that sufficient evidence of efficacy was not provided by the two Phase 3 studies. Specifically, study execution issues related to loss to follow-up and missing data, in addition to wide CIs and higher than expected Pearl Index point estimates, limited conclusions from the efficacy results. The FDA determined that a third Phase 3 efficacy trial would be needed to provide reliable data from a well-conducted study. FDA and Agile agreed that a single-arm, open-label trial would be sufficient for evaluating efficacy of the Agile Patch. In consultation with the FDA, Agile designed and conducted Study 23 and resubmitted the NDA in June 2017. FDA issued a second CRL which raised questions about the in vivo adhesion data in Study 23 and about the Pearl Index in light of these adhesion concerns. After a Type A End-of-Review meeting with Agile, the FDA recommended that Agile reformulate the Agile Patch if concerns regarding adhesion could not be resolved. Agile sought further clarification on the decision regarding in vivo adhesion through FDA’s formal dispute resolution process, a standard process FDA makes available for resolving sponsor differences with the FDA. At the conclusion of the process, FDA advised Agile that reformulation was not needed. Rather, FDA determined that a head-to-head demonstration of non-inferior in vivo adhesion to that of Xulane, a marketed patch with adequate adhesion, would support that the Agile Patch had adequate in vivo adhesion. FDA also advised that, if in vivo adhesion questions were adequately resolved, the benefit-risk profile of the patch would be discussed at an Advisory Committee meeting. After Agile and the FDA agreed upon a study design, including a statistical measurement of non-inferiority, Agile conducted a head-to-head adhesion study. The Agile Patch demonstrated non-inferiority compared to Xulane since the upper 95% 1-sided confidence limit (CL) was below the prespecified non-interiority criterion (p < 0.0001; see Section 5.2). Agile resubmitted the NDA with these data in May 2019.

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1.6.2 Clinical Development Program Agile conducted a comprehensive clinical program to evaluate the Agile Patch, which included seven Phase 1, one Phase 2, and three Phase 3 trials. Overall, more than 4,100 women were enrolled in the studies, approximately 3,500 of whom were exposed to the Agile Patch. As agreed with the FDA, the assessment of efficacy of the Agile Patch is based on Study 23, which FDA concluded was a well-executed study. The safety assessment is based on the integrated safety database from the three Phase 3 studies: Study 12, Study 13, and Study 23. Study 23 included a US-only study population, placed no enrollment restrictions on BMI or weight, and required study participants to anticipate sexual activity at least once per cycle for the entire treatment period. Study 23 also included electronic diaries (eDiaries) for weekly tracking of sexual activity and daily patch use, provision of home pregnancy tests and encouragement to test when risk of pregnancy increased, and serum pregnancy testing of all women at study completion or discontinuation. The Pearl Index analysis excluded not only cycles in which back- up contraception was used, but also cycles in which the participant reported no sexual activity. To Agile’s knowledge, exclusion of cycles with no sexual activity has only been done for two other CHCs (Yaz® NDA Review; Lybrel® NDA Review).

1.7 Efficacy Findings 1.7.1 Study Design Study 23 was a single-arm, open-label, 13-cycle, multicenter Phase 3 clinical trial of the contraceptive efficacy, safety, and tolerability of the Agile Patch. Sexually active women ≥ 18 years old were enrolled for a treatment period of one year (thirteen 28-day cycles) after successfully completing the initial Screening visit and demonstrating the ability to use and comply with a daily eDiary. There were no enrollment restrictions for BMI or weight, and all enrolled women lived in the US. All women anticipated being sexually active each cycle during the study, ensuring a study population at actual risk for pregnancy during the trial. Participants completed 8 scheduled in-person clinic visits and 6 telephone visits; urine pregnancy testing was performed during each clinic visit, and home pregnancy tests were provided for use in the event of increased pregnancy risk. eDiaries were used throughout the study to track daily information on patch properties (wear, adhesion, exposure to water, skin irritation or itching) and vaginal bleeding or spotting and weekly details on patch replacement, application site, sexual activity, and use of back-up contraception methods. During each 28-day cycle, an Agile Patch was applied to the abdomen, buttock, or upper torso (excluding the breasts) each week for 3 weeks (21 total days), followed by 1 patch-free week (Day 21–28). The day following Day 28 was denoted as Day 1 of the next cycle. Efficacy Endpoints The primary efficacy endpoint was the Pearl Index for women in the intent-to-treat (ITT) dataset of the Contraceptive Efficacy Population ≤ 35 years, as recommended by the FDA during development and described in the 2019 Draft Guidance. A key secondary efficacy endpoint was

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the Pearl Index in women aged ≤ 35 years, with BMI < 30 kg/m2, utilizing the ITT efficacy cycle dataset (unless the woman became pregnant during the cycle). Statistical Analysis Methods Evaluation of contraceptive efficacy was based on on-treatment pregnancies, ie, pregnancies with an estimated date of conception between the first study patch application and 7 days after removal of the last Agile Patch in the study. The primary efficacy analysis was based on the calculation of pregnancy rates using the Pearl Index in women aged 18 to 35 years, irrespective of BMI. The point estimates were calculated, and 2-sided 95% CIs for the Pearl Indices were reported. The ITT Efficacy Dataset included all complete or incomplete on-therapy cycles in which intercourse occurred and no back-up contraception was used. Additional details are included in Section 6.1.4.

1.7.2 Results 1.7.2.1 Disposition A total of 2,032 women were enrolled in Study 23, and 989 women completed the study (Figure 5). The most common reasons for premature study discontinuation were patient decision (15.3%), loss to follow up (11.3%), and AE (10.9%). Information regarding reasons for screen failures can be found in Appendix 11.8.

Figure 5: Patient Disposition – Study 23

ITT = intent-to-treat

1.7.2.2 Demographics Demographics of the enrolled population are shown in Table 1 and Table 2. The majority (90.1%) of the women enrolled were ≤ 35 years of age, and the study population was generally

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An emerging body of research, including a large meta-analysis of CHC trial data conducted by the FDA discussed further in Section 2.3.3, is yielding accumulating evidence that obesity affects CHC efficacy. Study 23 provides important data that further support this relationship. A key learning from the study was that inclusion of women with obesity had a substantial effect on the overall efficacy outcome in women using the Agile Patch. The Pearl Index in Study 23 increased as the BMI increased (Figure 6). The Pearl Index ranged from 3.46 (95% CI: 1.77, 5.16) in women with normal BMI (< 25 kg/m2) to 10.51 (95% CI: 3.67, 17.35) in women with BMI > 40 kg/m2. While there was an expectation that a relationship would exist between weight/BMI and efficacy, a key learning from Study 23 was that inclusion of women with obesity had a strong effect on the overall efficacy outcome in women using the Agile Patch.

Figure 6: Forest Plot of Pearl Index of the Agile Patch by BMI Category – Study 23

BMI = body mass index; CI = confidence interval; ITT = intent-to-treat Reduced CHC efficacy in women with obesity is not unique to the Agile Patch. What is unique is the design and conduct of a study that captures the effect in a meaningful way and that can be communicated to prescribers and patients. Agile has proposed that the Agile Patch package insert include a table showing the Pearl Index for each BMI category to facilitate informed decision- making. Because this sort of information is typically displayed in Section 14 (Clinical Studies) of the prescribing information, Agile also sought to identify additional labeling elements that could highlight the BMI effect toward the beginning of the package insert. In our estimation, a Contraindication or Warning for women with obesity could unduly restrict prescriber choice and potentially expose those women to the even greater VTE risks associated with pregnancy. Agile instead chose to highlight the reduced effectiveness in women with obesity in the Indication Statement via a Limitation of Use.

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The proposed Limitation of Use in the Indication Statement states: Limitation of Use: The Agile Patch has demonstrated reduced effectiveness in women who weigh 202 lbs (92 kg) or more and/or have a BMI of 30 kg/m2 or more. Agile is open to other tools for communicating the important information for the population of women with obesity to women and to prescribers. Agile has not yet had an opportunity to discuss the Limitation of Use or other labeling elements with the FDA and looks forward to gaining the benefit of FDA’s experience in this area. The efficacy results of Study 23 establish clinically meaningful rates of prevention of pregnancy that are acceptable to women and their prescribers. The results, including the reduced efficacy in women with obesity, reflect the effects of the trial design and study population. Study 23 was designed to screen out women who were not consistently sexually active and to enroll women who were representative of the US population, including a substantial proportion of women with obesity. As a result, the efficacy results reflect a study population that entered the trial at a greater risk for pregnancy and included a larger proportion of women with obesity than previous trials. The Study 23 results, therefore, provide valuable information on the role of sexual activity and weight/BMI on contraceptive efficacy. Contemporary contraceptive trials conducted in the manner that the 2007 Advisory Committee and the FDA have recommended will result in Pearl Indices, and accompanying upper bounds of the 95% CI, higher than historically observed. Given the results of Study 23, sensitivity analyses performed on the Pearl Indices of some historical trials, and the CIs derived for older products used as comparators in more recent trials, upper bounds above 5 are expected to become the standard in future contraceptive studies.

1.8 Safety Findings Based on the well-established safety profiles of LNG and EE and the safety data from 3,481 women with 29,900 cycles of exposure to the Agile Patch in the Phase 3 studies, the overall safety profile is acceptable and consistent with approved low-dose CHCs. The most common AEs were expected, occurred at low overall rates, and led to discontinuation at rates similar to approved products. 1.8.1 Overview of Adverse Events An overview of AEs that occurred in the Phase 3 Studies 12, 13 and 23 is shown in Table 4. Approximately half of the women experienced an AE; however, few SAEs were reported (1.6%). Adverse events led to discontinuation in 10.8% of women. No deaths occurred in women who used the Agile Patch.

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discontinuation were metrorrhagia (0.7%), menorrhagia (0.4%), and vaginal hemorrhage (0.4%), none of which was serious. In the Phase 3 studies, the most common SAE was VTE. Six women experienced either a deep vein thrombosis (DVT) or pulmonary embolism (PE), and 5 of the 6 women were women with obesity, with a baseline BMI over 30 kg/m2. All events except one were considered related to study drug. All women were discontinued from the study and recovered. Additional details on the VTE events in the Phase 3 studies are provided in Section 7.6.1. Each VTE case was reviewed by two experts in hormone-related thromboembolism who concluded the rates were within those expected for a CHC study population with the demographic profile of Study 23. Other SAEs included cholelithiasis (reported in 4 women [0.1%]), gastroenteritis, and major depression (each of which was reported in 3 women [0.1%]). Overall, the safety findings of the Agile Patch are in line with the well-understood and acceptable safety profile of CHCs.

1.9 Benefit-Risk Summary Despite the numerous contraceptives available today, women need more options to fit their unique lifestyles and information about those options that is generalizable to the diverse US population. When considering hormonal contraception, many women and their HCPs prefer low- dose products because of their reduced AE profile – including SAEs. But most of these low-dose products are pills that require daily use. Many women who wish to avoid daily use prefer a weekly transdermal contraceptive, however, the only currently available patch delivers a high dose of EE that may increase the risk of VTE events (Bloemenkamp et al 1995). Other low-dose, patient-controlled alternatives require vaginal insertion, which may not be appropriate for or preferred by some women. The Agile Patch fills the treatment gap for a low-dose, once-weekly contraceptive that offers women freedom from taking a daily pill or inserting a vaginal ring without committing to a longer-acting method, such as an intrauterine device or an implant. These considerations in contraceptive selection are pertinent for all women, regardless of race, age, socioeconomic status, or BMI. As demonstrated in the registrational Phase 3 study, Study 23, the Agile Patch is effective in the prevention of pregnancy with a Pearl Index of 5.83 (95% C1: 4.45, 7.21). The efficacy results of the Agile Patch in Study 23 reflect the trial’s design, broadly representative US population, and analytical methods, and provide important information on the role of sexual activity and weight/BMI in efficacy outcomes. The evolution of Pearl Indices of hormonal contraceptives over time provide additional supportive evidence of the effect trial design and populations can have on efficacy outcomes. The Agile Patch demonstrates reduced efficacy in women with BMI ≥ 30 kg/m2. While this effect may be true for other CHCs, it has not been uniformly studied in a prospective manner in clinical trials leaving women with obesity and their HCPs to make decisions based on the Pearl Index in the overall population – a number that may be minimally relevant to their situation. The

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magnitude of the reduction in efficacy seen in women with obesity in Study 23 warrants informative labeling. The safety profile of the Agile Patch is acceptable and in line with the well-understood profile of approved CHCs. The most common AEs were expected, occurred at low overall rates, and led to discontinuation at rates similar to approved CHCs. As recognized by the FDA, the serious risks for the Agile Patch, including VTEs, were similar to those seen for other CHCs. The overall observed rate of VTE events was within the expected range for the study population. Like any SAE, VTEs are rare events, and Phase 3 clinical trials are too small to allow conclusions about absolute risk. The demonstrated differences in efficacy and potential risks of the Agile Patch between women without obesity (BMI < 30 kg/m2) and women with obesity (BMI ≥ 30 kg/m2) support a different benefit-risk calculus for the two populations. In women without obesity (65% of the women in Study 23), the Pearl Index for the Agile Patch was 4.34 (95% CI: 2.86, 5.82), and there was a single report of a VTE in the safety database. This benefit-risk profile is squarely in line with prior approvals. In women with obesity, the efficacy of the Agile Patch was reduced with a Pearl Index of 8.64 (95% CI: 5.79, 11.50). Five women with obesity experienced VTEs in the Safety Population. While the preventative effect is lower than that in women without obesity, it remains acceptable and likely in line with what might be expected with other CHCs had they been studied in this population. The Agile Patch data allow, for the first time, that effectiveness to be quantified in labeling. Although the observed rate of VTE in women with BMI ≥ 30 kg/m2 is a potential risk, the even higher risk of VTE during pregnancy, in addition to other potential complications, such as hypertension and pre-eclampsia, gestational diabetes, pre-term delivery, and caesarian section, is important to the prescribing decision. In addition, women with obesity reported a low rate of hormone-related AEs that can cause many women to discontinue hormonal contraception. CHCs are prescribed to women with obesity, despite a general understanding that their effectiveness is reduced, because even that reduced effectiveness is more protective than that seen with Tier 3 methods, such as barrier methods. The benefit-risk calculus for the population with obesity is different than that for the women without obesity and supports approval with a Limitation of Use, as Agile proposed, or other labeling tools. Such labeling tools would communicate important information to women and their HCPs to permit them to participate in a shared decision-making process to weigh the benefits and risks to determine whether the Agile Patch is the right option. For some women with obesity who seek hormonal contraception but wish to avoid a daily pill and do not desire intravaginal methods, the Agile Patch may be an acceptable choice. For other women with obesity, it may not. Overall, the Agile Patch has a favorable benefit-risk profile for use as a contraceptive in reproductive-aged women, and its approval will meaningfully expand the options for women who are seeking a low-dose CHC.

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not limited, to effectiveness, safety, mechanism of action (hormonal or non-hormonal), regimen, delivery route, and frequency of administration. No single factor drives contraceptive decision- making. Therefore, no single method is right for all women, and women change methods throughout their lifetimes depending on their needs and priorities (Mansour 2014). Studies have shown that over the course of one year, between 24% and 61% of women switch contraceptive methods (Frost et al 2007; Grady et al 2002). In addition, a woman stays with a method for longer and is more likely to be consistent with its use if it is a method of her choosing that fits her lifestyle (Frost and Darroch 2008). Thus, having a range of safe and effective contraceptive options is important for women. Currently available contraceptives range from permanent sterilization to methods that require use during each episode of sexual activity. The FDA and the CDC categorize the effectiveness of contraceptive methods into 3 tiers of effectiveness based on life table analyses from real-world actual (or typical) use data (Hatcher et al 2018), as shown in Figure 7. Although the annual pregnancy rates vary, all methods are considered effective when compared with the expected 85% rate of pregnancy when no contraceptive method is used (Hatcher et al 2018). The most effective options (Tier 1) have annual pregnancy rates < 1% per year and include permanent and semi-permanent invasive methods such as sterilization and intrauterine devices (IUDs). Tier 2 options (annual pregnancy rates between 4–7%) include systemic hormonal methods, most of which rely heavily on proper use. Tier 3 methods require use during each episode of sexual activity and are also highly reliant on correct and consistent use; annual pregnancy rates of Tier 3 options are > 13%. HCPs commonly use these tiers in contraceptive counseling as they reflect the expected effectiveness in actual users rather than results from controlled clinical trials in product labeling.

Figure 7: Contraceptive Options by Effectiveness Tiers

Source: Adapted from Hatcher et al 2018

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The most commonly used reversible contraceptive option is the combination oral contraceptive (COC), which must be taken daily (United Nations 2019). Other CHC products like the monthly intravaginal ring are also popular and do not require daily dosing. COCs and CHCs more generally contain an estrogen and progestin component. With the exception of the currently available transdermal patch, these products typically contain a low dose of estrogen, less than 35 mcg. Low-dose CHCs have become the standard because of their lower rates of hormone- related AEs, including SAEs like VTEs (ACOG Practice Bulletin 2019).

2.2 Need for A Low-Dose Transdermal CHC When used consistently and correctly, oral CHCs are highly effective; however, inconsistent use is an ongoing challenge. Studies have shown that 30% to 50% of women miss 1 or more pills per month, and 20% miss 2 or more (Trussell 2011), which could lead to unplanned pregnancies. A non-daily option, such as a weekly transdermal method (ie, a patch) offers greater convenience over daily pills and thus has the potential for improved consistency and long-term adherence than daily pills. According to the FDA, “…a patch that is changed once a week… decreases the chance associated with typical birth control pills that a woman might miss one or more daily doses” (2005 FDA Ortho Evra Labeling Update press release). Other advantages of a transdermal patch include controlled release over time offering the potential to reduce the incidence and/or severity of side effects, and the elimination of first pass metabolism and avoidance of GI drug-drug interactions. Furthermore, the transdermal route can be more appealing for some women than taking a daily OC or using an intravaginal contraceptive. Despite these advantages, only one contraceptive patch is currently available in the US, Xulane (the generic equivalent of Ortho Evra). The Ortho Evra patch was approved in 2001; however, in subsequent years, it was found that Ortho Evra’s daily delivery of EE was approximately 60% greater than an OC containing 35 mcg of EE. The suspected association of EE dose with risk for certain cardiovascular side effects such as VTEs as well as post-marketing AE data resulted in the post-approval expansion of a boxed warning in the Ortho Evra labeling in 2005. The expanded boxed warning also appears in the labeling of Xulane, the generic equivalent of Ortho Evra. It describes an increased risk of VTE among women who use the Ortho Evra/Xulane patch and includes details on the pharmacokinetic profile of EE for Ortho Evra/Xulane. The Dosage Forms and Strengths section of the currently approved Xulane labeling describes its EE dose as 35 mcg/day. The current boxed warning for Xulane provides that the exposure levels of EE in women using the product is approximately 60% higher than in women using an oral contraceptive containing 35 mcg of EE. After its approval, Ortho Evra was a popular contraceptive option among women. At its peak, prescriptions for Ortho Evra represented 11% of prescriptions (IMS National Prescription Audit). As shown in Figure 8, after Ortho Evra’s initially high use, it fell dramatically in 2005 following concerns around the higher level of estrogen dosing than originally thought and associated VTE risks. Use remained low yet consistent for Ortho Evra through 2014 when the generic version, Xulane, was launched. Use of Xulane remains low.

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Figure 8: Non-Daily Combined Hormonal Contraceptive Use 2002–2017

Source: Data extracted from the IMS National Prescription Audit With the drop in Ortho Evra prescriptions, NuvaRing (a non-daily, non-oral, once monthly vaginal contraceptive ring also approved in 2001) prescriptions increased, suggesting that prescribers may have recommended NuvaRing to women requesting a non-daily method. However, NuvaRing’s uptake has never approached that of Ortho Evra at its peak, indicating that many former Ortho Evra users were left without a non-daily, low-dose method that fit their preferences for a transdermal rather than a method that required insertion. A contraceptive patch that delivers an EE dose consistent with current standards for low estrogen exposure, while providing the convenience of a non-daily and non-invasive route of administration, may help fill this need.

2.3 The Evolution of Contraceptive Clinical Trials 2.3.1 Measures of Clinical Efficacy In contraceptive clinical trials, the Pearl Index is the most common regulatory endpoint for contraceptive efficacy. This efficacy measure, which provides an estimate of the number of pregnancies per 100 woman-years of product use, is highly sensitive to study design. Although the Pearl Index is used as the overall primary endpoint in registrational trials, most clinicians refer to life table analyses when evaluating contraceptive methods and counseling their patients regarding expected contraceptive effectiveness over a year of use (Hatcher et al 2018). Therefore, life table analyses are also generated as important secondary outcomes in clinical trials, as they depict the patient’s month-by-month (one-year) risk of pregnancy.

2.3.2 Evolution of Clinical Trial Designs The design of hormonal contraceptive studies has evolved over time. Historically, contraceptive clinical trials enrolled highly selective populations, including women with low BMI, non-racially diverse populations, and European women. In addition, historical contraceptive trials did not

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have an inclusion criterion for anticipation of sexual activity each cycle, generally did not track sexual activity or exclude cycles without sexual activity and included less sensitive pregnancy testing. Accordingly, these studies resulted in low Pearl Indices and contraceptive failure rates that were not generalizable to the broader population. Consequently, contraceptive failure rates with actual use of products following FDA approval were many times higher than those observed in the clinical trials. Thus, a wide gap existed between the efficacy observed in clinical trials and effectiveness observed in the real world, a phenomenon widely accepted and understood by prescribers of birth control, who either extrapolate clinical trial results to account for this gap, or more typically use the more clinically relevant failure rates described in the contraceptive tiers rather than product labeling when counseling women about contraception. Recognizing the need for more clinically relevant information for women and their HCPs, the FDA has for years encouraged sponsors to enroll less selective study populations and incorporate more rigorous design factors into contraceptive studies. In addition, the 2007 Advisory Committee meeting discussed among other things, contraceptive trial design, assessment of the acceptability of risks and benefits, and the role and impact of labeling. Important recommendations provided during the meeting included:

• Modifying trial designs to provide results that reflect effectiveness in the real world; • Changing entry criteria to reflect real-world prescribing; and • Ensuring that all relevant information be provided to the prescriber, including data on subgroups. To effectuate these changes, the 2007 Advisory Committee recommended that FDA avoid arbitrary limits for the Pearl Index point estimate and upper bound of the 95% CI in order to bring the widest range of new contraceptives to market. The Committee recognized that establishing regulatory mandates for Pearl Indices might also encourage trials that exclude women with higher BMIs or avoid enrolling a demographically diverse US population (2007 Advisory Committee Transcript).

2.3.3 Creeping Pearl: Rising Pearl Indices and the Factors that Influence the Pearl Index Not surprisingly, as sponsors have incrementally adopted advice from the FDA and the 2007 Advisory Committee, Pearl Indices have been slowly and steadily rising – a trend referred to as the Creeping Pearl (Trussell and Portman 2013). No single factor appears to be driving changes in the Pearl Index. Rather, a combination of multiple factors, including study design, population, and analytical methods, are contributing to this evolution in results (Gerlinger et al 2014; Trussell and Portman 2013). As the Pearl Indices and their accompanying 95% CIs from clinical trials have risen, failure rates with actual use in the general population of contraceptive users have remained relatively steady over time; thus, the gap between study efficacy results and actual use effectiveness has narrowed. This was predicted by Trussell and Portman who stated, “because study populations appear to be increasingly representative of the likely actual users once the product is marketed, we can expect to see even higher failure rates in ongoing and future studies” (Trussell and Portman 2013).

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Important factors that influence the Pearl Index include, but are not limited to, the frequency of sexual activity, number of cycles included in the denominator of the Pearl Index, BMI, and study site location. Each is discussed below. Sexual Activity/Calculation of Pearl Index Denominator A highly sexually active population is one of the most important factors contributing to pregnancy risk (Hatcher et al 2018; Steiner et al 1999). Therefore, the manner in which sexual activity is monitored and analyzed throughout a clinical trial can greatly impact Pearl Index results. For instance, if a study includes a less sexually active population, and cycles without sexual activity or in which back-up methods were used are included in the denominator of the Pearl Index calculation, the Pearl Index would be reduced since the study would not account for the role of sexual activity on efficacy. Consequently, the overall efficacy result would overestimate the effectiveness of the contraceptive in a more sexually active population, where women are at a greater risk for pregnancy. Nevertheless, enrollment based on expectation of sexual activity, monitoring of sexual activity, and cycle exclusion parameters vary throughout clinical trials. Many trials specify only that participants should be “sexually active” or “at risk of pregnancy,” without specifying a) that participants must be sexually active during the study or b) that they engage in sexual activity with any regularity or specific frequency during the treatment period. For example, the FDA’s review of Yasmin® observed that in registrational trials for that drug “there was no requirement (for study enrollment) that subjects be at risk for pregnancy.” As more stringent studies are conducted that prioritize regular sexual activity, monitor that activity, and exclude cycles without sexual activity, as is now recommended in the 2019 Draft Guidance, Pearl Indices can be expected to continue to rise. Such studies may report Pearl Indices that more closely reflect real-world use of the contraceptive by a sexually active population. Body Mass Index BMI of study participants can greatly impact contraceptive efficacy (Edelman et al 2018). For almost as long as CHCs have been available, clinicians have noted a tendency for women with obesity to have higher rates of pregnancy than women without obesity during CHC use (Boden 1980). As a result, some contraceptive trials, especially historical trials forming the basis of approval for many contraceptives currently available, have excluded women with obesity to obtain lower Pearl Indices, and the reported efficacy of those products is likely not generalizable to the current US population of women seeking contraception. While prior studies have not rigorously enrolled women with obesity, several recent studies have analyzed their efficacy data by BMI or weight. Agile’s review of NDAs for Phase 3 trials of approved products that have assessed differences in Pearl Index by BMI and/or weight has shown a clear relationship between BMI and Pearl Index.

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The FDA’s own research supports the effect of obesity on the Pearl Index. A meta-analysis of individual patient data from seven Phase 3 COC trials and the Ortho Evra patch showed that the risk of pregnancy was higher in women with obesity compared to women without obesity (Yamazaki et al 2015). Figure 9 shows the adjusted hazard ratios of 8 hormonal contraceptives using women without obesity (BMI < 30 kg/m2) as the reference group. Overall, after adjusting for age and race, women with obesity had a 44% higher rate of pregnancy compared to women without obesity in COC trials. This overall increased rate jumped to a 65% higher rate of pregnancy when the analysis included the Ortho Evra patch. These findings led the FDA to specifically recommend inclusion of women with obesity in contraceptive trials and analyses by BMI subgroups.

Figure 9: Effect of Obesity (BMI 30 kg/m2) on Risk of Pregnancy: Adjusted Hazard Ratio for Hormonal Contraceptives

BMI = body mass index; CI = confidence interval; COC = combination oral contraceptive; EE = ethinyl estradiol *Adjusted for age and race Source: Adapted from Yamazaki, 2015 As the prevalence of obesity in the US continues to rise and clinical trials include more women with obesity to reflect the broadly representative population of women who use contraceptives, elevated overall Pearl Indices and CI results can be expected. Regional Differences: United States versus European Study Participants Inclusion of European participants has also been shown to have a sizable impact on the Pearl Index. Historically, contraceptive products approved in the US were approved on the basis of a substantial amount of data from women in Europe, in whom failure rates in clinical trials are uniformly lower than in women in the US. The FDA has recognized this difference, stating that “[e]fficacy results can differ considerably between countries” (FDA 2019) and that FDA is “well aware that Pearl Indices obtained in European populations . . . are not representative of those obtained in US women” (Type C Preliminary Comments Feb 2014). Table 6 displays some key examples of the difference in efficacy results between the US and Europe. This effect, while

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2.3.4 Examples of the Creeping Pearl Review of approved CHCs used as comparators in trials suggests that the rise in Pearl Indices is due to changes in study design and population rather than to the approval of less effective products over time. As illustrated in Figure 10, the Pearl Indices of Loestrin Fe, Levlite, and Nordette were substantially higher when they were used in subsequent studies conducted in demographically broader study populations compared to their Pearl Indices reported at their approval (Edelman et al 2018). For example, the mean BMI in the registrational Levlite study in 1998 was 25.6 kg/m2 compared to the study conducted with Levlite as a comparator in the Seasonale® registrational study in 2003 in which the mean BMI was 27.3 kg/m2. These comparisons support that Pearl Indices increase as effective products are studied in more broadly representative populations and in a more stringent manner over time. Additional information about age, sample size, and weight/BMI for the studies included in Figure 10 can be found in Appendix 11.1. Notably, it is not possible to ascertain the specific contribution of each of these elements or of the difference in the study design to the higher Pearl Index. But it provides further evidence that study design and population can have a significant impact.

Figure 10: Changing Pearl Indices of Approved CHCs used Over Time

CHC = combined hormonal contraceptives; CI = confidence interval; EU = European Union; NR = not reported; PI = Pearl Index Note: Upper 95% CI not reported for all studies. Source: Edelman et al 2018 The FDA acknowledges this trend, stating that “Pearl Indices for clinical trials vary considerably, even for the same formulation, depending on the studies from which data are obtained” (Lo Loestrin Fe® Medical Review). These results also highlight the challenge of comparing Pearl Index point estimates and upper bounds across CHC studies rather than assessing them on their own merits.

2.3.5 FDA Draft Guidance Recognizing the effect that design, population, and analytical factors can have on the Pearl Index, the FDA through its 2019 Draft Guidance now recommends that all clinical trials for

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CHCs incorporate the factors in Study 23. The 2019 Draft Guidance observes that approved CHCs typically have Pearl Indices with an upper bound of the 95% CI below 5 at approval. This is not surprising given that these Pearl Indices and the upper bounds of their 95% CI were derived from trials that did not incorporate the full set of design, population, and analytical factors favored by the FDA in the 2019 Draft Guidance. Notably, the 2019 Draft Guidance is careful not to identify the upper bound of the 95% CI of 5 as a limit for approval, and, in fact, provides an example of when an upper bound of the 95% CI higher than that typically observed may be acceptable (eg, a hormonal contraceptive with fewer risks, such as a progestin-only product). Agile believes another example in which an upper bound higher than 5 could be acceptable is a study with a design like Study 23 that was conducted in the US, in a population of women that represents the US population in terms of BMI, weight, race, and ethnicity who were also engaged in regular sexual activity at actual risk for pregnancy. As more trials are conducted in accordance with FDA’s recommendations, the Pearl Indices and upper bounds of the 95% CIs higher than 5 will likely become the standard.

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association with contraceptives and their well-established pharmacokinetic and pharmacodynamic (PK/PD) profiles. The Agile Patch contains 2.60 mg LNG and 2.30 mg EE within an active drug matrix core. It delivers daily doses similar to daily oral doses of 120 mcg of LNG and 30 mcg of EE, which are within ranges reported for currently available low-dose oral CHC products. Unlike most other transdermal systems, the Agile Patch was designed so that the active drug portion would not extend to the edges of the patch. The use of a peripheral laminate around the active drug core preserves the ability of the patch to deliver the drug in the event of a partial lift of the patch. The active drug matrix core is 15 cm2 and the peripheral laminate extends beyond the perimeter of the active matrix for a complete area of 28 cm2. The patch is less than 1 mm in total thickness.

Figure 11: The Agile Patch

3.2.2 Mechanism of Action As with other CHCs, the Agile Patch prevents pregnancy through a number of mechanisms, including suppression of ovulation and changes in cervical mucus. Selection of the specific formation of the Agile Patch (ie, 2.60 mg LNG and 2.30 mg EE in a 15 cm2 active matrix) was based on Phase 2 Study 11 to provide optimal suppression of ovulation, described in Section 3.2.3. Because the Agile Patch NDA is a 505(b)(2) application, Agile is relying, in part, on the vast public literature that supports the safety and efficacy of LNG and EE as combination therapy in preventing pregnancy.

3.2.3 Pharmacokinetics Overview The Agile Patch delivers LNG and EE continuously over a 7-day period, which provides relatively constant hormone levels over time, as shown in Figure 12 and Figure 13. Figure 13

Page 41 of 147 Agile Therapeutics, Inc The Agile Patch Bone, Reproductive and Urologic Drugs Advisory Committee also illustrates that the Agile Patch avoids the plasma concentration peaks and troughs observed with a daily OC and highlights the EE exposure difference between Ortho Evra and the Agile Patch; the EE exposure with the Agile Patch is approximately half that of the EE exposure with Ortho Evra. As described in the Ortho Evra labeling, the product exposes women to approximately 60% higher levels of EE than 35 mcg of EE described in the Dosage Forms and Strengths section of the currently approved Xulane labeling (ie, approximately 56 mcg of EE per day). Additional PK parameters measured in the definitive PK study, Study 14, are summarized in Table 7.

Figure 12: Mean Serum Concentration-Time Profiles of Levonorgestrel of the Agile Patch for Two Cycles in Healthy Female Volunteers – Study 14

LNG = levonorgestrel; SE = standard error

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are within the range of contraceptive levels seen with other approved CHCs for women of all weight and BMI categories. As shown in Figure 15, a similar pattern of LNG delivery was observed in women with BMI < 30 kg/m2 and ≥ 30 kg/m2, and the mean LNG concentration delivered by the Agile Patch was above the threshold of 300–400 pg/mL necessary to suppress ovulation.

Figure 15: LNG and EE Concentrations in Women With and Without Obesity – Study 11

BMI = body mass index; EE = ethinyl estradiol; LNG = levonorgestrel Source: Foegh et al 2013; *Adapted from Edelman 2016 3.2.4 Adhesion Overview

For the Agile Patch to deliver efficacious levels of LNG and EE, adequate adhesion across the 7-day wear period is vital. The adhesion profile of the Agile Patch is adequate for approval and supported by a robust body of data (see Section 5), including a non-inferiority wear trial against Xulane (Study 25), the generic of Ortho Evra and the only CHC patch available to women. These studies support acceptable adhesion in the real-world setting.

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women in the US without BMI or restrictions. FDA advised Agile that Study 23 would be adequate without a comparator arm. Agile resubmitted the NDA in June 2017 with Study 23 results. On 21 December 2017, the FDA issued a second CRL (2017 CRL) citing, for the first time, concerns about adhesion of the patch, as well as the efficacy observed in Study 23. The CRL deficiency regarding the adequacy of in vivo adhesion was the subject of numerous discussions between Agile and FDA, including those occurring during a two-stage formal dispute resolution process. At the conclusion of the formal dispute resolution request process, the FDA concluded that completion of a successful head-to-head comparative wear study with the Xulane patch would demonstrate adequate in vivo adhesion of the Agile Patch. Specifically, the Office of New Drugs stated that “if [the Agile Patch] can demonstrate generally similar adhesion performance to Xulane, this would support the conclusion of adequate adhesion of [the Agile Patch] and suggest that the results of [Study 23] are those that might be seen with an adequately performing patch in the context of a clinical trial.” Agile completed Study 25 to comply with the FDA's recommendations; the study successfully demonstrated noninferiority compared to Xulane since the upper 95% 1-sided CL was below the prespecified non-interiority criterion (p < 0.0001) as described in Section 5.2. In May 2019, Agile resubmitted the NDA for the Agile Patch in response to the 2017 CRL. The resubmitted NDA included the favorable results from Study 25 and addressed the other issues identified in the 2017 CRL.

4.2 Clinical Development Program Agile has conducted a comprehensive clinical program enrolling over 4,100 women, approximately 3,500 of whom have used the Agile Patch. The clinical program was designed to incorporate key recommendations regarding clinical trial design from the 2007 Advisory Committee Meeting, further described in Section 6.1. The clinical program involved 21 clinical studies, including:

• Three Phase 3 studies • Four Phase 1 and Phase 2 PK/PD studies • Two patch adhesion studies As is typical for a 505(b)(2) application and as agreed with the FDA, non-clinical safety studies were not conducted. Non-clinical safety of LNG and EE was based on the wealth of existing non-clinical safety information establishing the safety of LNG and EE. The efficacy and safety of the Agile Patch were assessed in three Phase 3 studies (Studies 12, 13, and 23) and 1 Phase 2 study (Study 11). Primary efficacy is derived from the registrational Phase 3 study, Study 23; safety data are derived from all 3 Phase 3 studies. Key study design features and results of the Phase 3 studies are outlined in Table 9.

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Pharmacokinetic comparisons were performed between the Agile Patch and several commercially available oral contraceptives in two Phase 1 trials (Study 14 and Study 10), one Phase 2 trial (Study 11), and two larger Phase 3 trials (Studies 12 and 13). Additional PK studies were performed to evaluate the PK profile at different anatomical sites (Study 15) and under different external conditions of heat, cold, and humidity (Study 16). An overview of the PK studies is provided in Appendix 11.2. The in vivo adhesion of the Agile Patch was assessed in several studies that are discussed in Section 5. A human factors (HF) study was also conducted to evaluate the labeling and increase the likelihood of proper patch use (Section 8.2). In communication with the Agency, the FDA expressed interest in ways to accelerate the learning curve observed in Study 23. Accordingly, though not required, Agile proactively conducted a HF study to support our efforts to improve the learning curve by optimizing the patient labeling.

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Topical Delivery Systems for ANDAs (ANDA Guidance) and the specific feedback from the Division after receipt of the 2017 CRL as described in Section 4. Study 25 was a randomized, open-label, single-dose, 2-treatment comparative crossover adhesion study of the Agile Patch and Xulane contraceptive patches in healthy female volunteers aged 18–35 years with BMI < 35 kg/m2 and weight < 90 kg (198.4 lbs). A sample size of approximately 80 women provided approximately 90% power to demonstrate non-inferiority of the Agile Patch compared to Xulane. Participants were randomized to wear either Xulane followed by the Agile Patch or the Agile Patch followed by Xulane (Figure 16). Women wore the patch for 7 days (168 hours). Immediately following removal of the first patch, the second patch was placed on the contralateral side and was worn for an additional 7 days (168 hours). All patches were applied to the lower abdomen by trained study site personnel and removed by study site personnel at the end of the treatment period.

Figure 16: Study 25 Study Design

The primary endpoint for the trial was the mean difference in adhesion scores between the Agile Patch and Xulane. Mean adhesion scores were derived from each patch’s individual adhesion score at each assessment timepoint, averaged across all the timepoints (except baseline). To calculate the mean adhesion score for each patch, the highest observed adhesion score for each patch was carried forward to each time point for subsequent time points until a higher score was assessed. To demonstrate adequate product adhesion, the Agile Patch would be considered statistically non-inferior to Xulane if a non-inferiority margin less than 0.15 (δ < 0.15) was satisfied (ie, the upper bound of the mean difference of the 1-sided 95% CL was below +0.15).

5.2.2 Results Eighty-three (83) women were enrolled, and 79 women completed the study. All 4 of the women who did not complete the study discontinued during the first treatment period (2 in each treatment group), and all discontinued due to personal reasons unrelated to study drug. The mean adhesion score of 0.39 for Xulane was higher (ie, worse) than the mean score of 0.14 for the Agile Patch, producing a negative mean difference and an upper bound of the 1-sided 95% CL of -0.16. The test for non-inferiority demonstrated a p value < 0.0001, consistent with in vivo adhesion of the Agile Patch being non-inferior to Xulane (Table 10).

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5.4 Patch Adhesion Conclusions The results of the controlled comparative wear study (Study 25), combined with results from Studies 16 and 23, support that the adhesion of Agile Patch is acceptable. Given that the Agile Patch has directly demonstrated non-inferiority to Xulane, it can be concluded that the data from Study 23 are those that might be seen with an adequately performing patch in a Phase 3 clinical trial setting.

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the US 18 years of age or older seeking hormonal contraception for at least one year and sexually active and at risk for pregnancy. In order to ensure that Study 23’s population closely represented that of women in the US who use contraception, the study specified the following population enrollment specifications:

• Inclusion of a US-only study population; • No enrollment restriction on weight or BMI; and • Study participants confirmed to be at-risk for pregnancy via enrollment criterion requiring that potential participants anticipate sexual activity at least once per cycle for the entire treatment period. In addition, Study 23 incorporated the following design aspects:

• Ongoing monitoring of sexual activity during the study through the use of eDiaries for accurate reporting of sexual activity and patch use; • Provision of home pregnancy tests and encouragement of participants to test for pregnancy in the event of increased pregnancy risk (eg, delayed patch application during a cycle without use of back-up contraception); • Pregnancy testing of all women at study completion or discontinuation; and • Exclusion of cycles in which sexual activity did not occur (in addition to exclusion of cycles in which an alternate (back-up) method of contraception was reported). The study consisted of an initial Screening Visit followed by a Run-In Visit and a subsequent Run-In Period during which women were required to demonstrate ability to use and comply with an eDiary and other requirements for communication with the investigative site. Women who successfully completed the Run-In Period were enrolled for a treatment period of one year (thirteen 28-day cycles). Throughout the study, each participant was to complete a total of 8 scheduled in-person clinic visits and 6 telephone visits (visit schedule provided in Appendix 11.5). Urine pregnancy testing was performed during each clinic visit. Home pregnancy tests were provided for use in the event of increased pregnancy risk (eg, delayed patch application without the use of back-up contraception). Participants utilized eDiaries in which they entered daily information on patch wear, patch adhesion (using a numbered patch adhesion scale, provided in Appendix 11.3), exposure of the patch to water, patch-related skin irritation/itching, and vaginal bleeding/spotting. Weekly patch use information, including patch change and removal day and anatomic site of patch application, were also reported in the eDiary. Participants reported sexual activity and use of back-up methods of contraception (including reasons for back-up contraception if applicable) weekly in their eDiaries. To confirm sexual activity, participants were asked once a week “Have you had sexual intercourse during this

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cycle?" If the woman answered “yes” at any time during the cycle, she was not asked again until the following cycle. As a result of these features, the Study 23 population was at greater risk for pregnancy than historical trials and was able to account for the role of sexual activity in efficacy outcomes. Additional details on the eDiary questions, along with screenshots, are provided in Appendix 11.4.

6.1.1 Treatment Regimen During each 28-day cycle, an Agile Patch was applied to the abdomen, buttock, or upper torso (excluding the breasts) and changed weekly for three consecutive weeks (21 total days), followed by 1 patch-free week (Day 21–28), as shown in Figure 18.

Figure 18: Agile Patch Application Schedule

6.1.2 Enrollment Criteria Following the Division’s recommendations, Agile designed a trial that would yield generalizable data in a demographically representative study population approximating the current US population of women using CHCs. Key inclusion and exclusion criteria are described below. The intent was to enroll a population with regular sexual activity during the trial and thus at actual risk for pregnancy. A full list of inclusion and exclusion criteria is provided in Appendix 11.6.

6.1.2.1 Key Inclusion Criteria Key inclusion criteria for Study 23 included the following:

• Was a sexually active woman in good health with an intact uterus, both ovaries and fallopian tubes, at least 18 years and 0 days of age at Screening, at risk for pregnancy, and seeking to use hormonal contraception for at least one year • Willing to discontinue her current method of contraception and agree to use the Agile Patch as her sole method of contraception throughout the study, except when an alternate

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method was required for prevention of sexually transmitted infection or back-up contraception in the setting of patch detachment/patch scheduling issues • Anticipated being sexually active during each cycle throughout the study • Regular menses, at least 3 menses post-lactation, at least 10 months since last injectable contraceptive with at least 2 spontaneous menses • Able to forego steroidal hormonal therapy other than topical or inhaled corticosteroids for duration of study • At least 90% compliant with eDiary entry and returned 2 check-in phone calls during the 2-week Run-In Period 6.1.2.2 Key Exclusion Criteria Key exclusion criteria for Study 23 included the following:

• Known or suspected pregnancy or currently lactating • Desired pregnancy within the next 12 months • Anticipated or planned use any form of back-up contraception during the study • Current use of a contraceptive implant or IUD • Recent surgical or medically induced abortion, spontaneous abortion, or ectopic pregnancy, unless the woman had 3 consecutive, spontaneous menses or withdrawal bleeding episodes prior to the date of consent • Recent vaginal or cesarean delivery, unless the women had 3 consecutive, spontaneous menses or withdrawal bleeding episodes prior to the date of consent • Women with various risk factors for VTE were excluded • History of dermal hypersensitivity to medicated patches or topical applications 6.1.3 Endpoints The primary efficacy analysis was the Pearl Index for women in the ITT dataset of the Contraceptive Efficacy Population who were ≤ 35 years of age, as recommended by the FDA for all contraceptive clinical trials. The most relevant prespecified secondary endpoint was the Pearl Index in women aged ≤ 35 years, with BMI < 30 kg/m2, utilizing the ITT efficacy cycle dataset (unless the woman became pregnant during the cycle). Additional secondary endpoints are described in Appendix 11.7.

6.1.4 Statistical Methods 6.1.4.1 Sample Size The study sample size was calculated to provide 90% power to establish that an underlying Pearl Index no larger than 3.5 would have an upper limit of a 2-sided 95% CI no larger than 5 to be

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consistent with Agile’s understanding of the FDA’s expectation regarding the upper bound of the 95% CI. In addition, the study sample size was calculated under the assumption that each of 1,900 enrolled women would on average provide 8.5 cycles on treatment, so that the study would generate approximately 16,000 cycles of exposure to the Agile Patch in women aged 18 to ≤ 35 years. The calculations also assumed that close to 21% of these cycles would not be included in the primary evaluation of efficacy because of use of back-up contraception or absence of sexual activity. Thus, the power calculations used a total of approximately 12,675 cycles.

6.1.4.2 Analysis Populations Contraceptive Efficacy Population and Efficacy Analysis Datasets The Contraceptive Efficacy Population included all women who wore at least 1 patch and were documented to have a negative enrollment serum ß-human chorionic gonadotropin (ß-hCG). The primary Pearl Index was calculated in the ITT population based on criteria for inclusion and exclusion of cycles for all complete or incomplete on-therapy cycles in which intercourse occurred and no back-up contraception was used. A cycle was defined as a 28-day period consisting of 21 days on treatment followed by 7 days off treatment.

6.1.4.3 Endpoint Analyses Contraceptive efficacy was evaluated by on-treatment pregnancy rates, which were estimated for the ITT contraceptive efficacy datasets, described previously in Section 6.1.4.2.

6.1.4.3.1 Classification of Pregnancies Based on the determined estimated date of conception in relation to the date of first patch application and/or date of last patch removal, each confirmed pregnancy was classified as:

• Pre-treatment: estimated date of conception prior to the date of the first study patch application; • On-treatment: estimated date of conception from the date of the first study patch application through Day 7 following removal of the last study patch (agreed to with the FDA); • Post-treatment: estimated date of conception after Day 7 following removal of the last study patch. 6.1.4.3.2 Pearl Index The Pearl Index served as the primary contraceptive efficacy endpoint for evaluation of pregnancy rates for this study. The Pearl Index was calculated as follows: – × 13 = × 100 – 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑜𝑜𝑜𝑜 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐 𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃𝑃 𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼𝐼 𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛𝑛 𝑜𝑜𝑜𝑜 𝑜𝑜𝑜𝑜 𝑡𝑡ℎ𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐

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In addition to the point estimates, 2-sided 95% CIs for the Pearl Indices were reported. The CI was calculated for the number of on-treatment pregnancies divided by the number of on-therapy cycles (ie, binomial CI using the normal approximation), and the result multiplied by 1,300.

6.1.4.3.3 Life Table Analysis A life table analysis was used to estimate pregnancy rates over time for all women who were in the Contraceptive Efficacy Population, as recommended in the 2019 Draft Guidance. Life table analysis was conducted as a supportive efficacy analysis to estimate pregnancy rates. From the clinical perspective, life table analyses are generally considered more clinically relevant than Pearl Indices as they provide information on pregnancy risk, or failure rates. This analysis utilized the Contraceptive Efficacy Population, ie the ITT population, and included all cycles for women who applied at least one patch and were documented to have a negative enrollment serum ß-hCG. The cumulative probability of pregnancy and 2-sided 95% CIs were calculated by the Kaplan-Meier method for Cycles 1–13; the endpoint of primary interest was the cumulative probability of pregnancy at the end of cycle 13. Non-pregnant women were censored in the cycle in which the patch was last worn.

6.1.4.4 Subgroup Analyses The primary endpoint was analyzed by subgroup, including BMI, weight, race, ethnicity, age, and previous hormonal contraceptive use in prespecified analyses. 6.1.4.5 Sensitivity Analyses A sensitivity analysis was performed to evaluate the effects of three key design/population factors (BMI and exclusion of cycles for lack of sexual activity and use of back-up contraception) that can affect Pearl Index point estimates and CIs. The analysis was performed by:

• Removing women with BMI > 30 kg/m2; • Assuming no exclusion of cycles with lack of sexual activity (ie, 5.4% of cycles added back to the Pearl Index calculation denominator); • Assuming no exclusion of cycles with use of back up contraception.

6.2 Study Population – Study 23 6.2.1 Patient Disposition Patient disposition in Study 23 is summarized in Figure 19. A total of 4,033 women were screened and 2,032 women were enrolled. Reasons for screen failure are summarized in Appendix 11.8. One woman enrolled in the trial discontinued prior to application of the first patch, leading to 2,031 women in the Safety Population. Of the enrolled women, 989 (48.7%) completed the study, which is in line with other contraceptive clinical (Table 11).

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Of the women enrolled in Study 23, 34.7% were current hormonal contraceptive users, 43.1% were former users of hormonal contraceptives (ie, not used in the 6 months prior to enrollment), 12.9% were recent users (ie, not currently using a hormonal contraceptive, but have used a hormonal contraceptive within 6 months prior to enrollment), and 9.4% were naïve to previous hormonal contraception. Overall, 82.7% of women were naïve to contraceptive patches.

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A key secondary efficacy analyses was the evaluation of the Pearl Index in women aged ≤ 35 years with BMI < 30 kg/m2 (ie, “non-obese”) utilizing the ITT dataset, which excluded cycles for lack of sexual activity or use of back-up contraception (unless the woman became pregnant during the cycle). Among these women, the Pearl Index was 4.34 with a 95% CI of 2.86 to 5.82. This population accounts for approximately 65% of the women in Study 23 and represents the majority of women in the US seeking contraception (Vahratian et al 2009, Daniels and Abma 2018).

6.3.4 Subgroup Analyses 6.3.4.1 Body Mass Index As shown in the forest plot in Figure 20, the Pearl Index by BMI rose with each increasing BMI category. Among women ≤ 35 years of age, the normal BMI subgroup included the greatest number of cycles evaluated and had the lowest Pearl Index at 3.46 with a 95% CI of 1.77 to 5.16. As stated above, the Pearl Index in women without obesity (BMI < 30 kg/m2) was 4.34 with a 95% CI of 2.86 to 5.82. The Agile Patch demonstrated reduced efficacy in women with obesity (BMI ≥ 30 kg/m2) with a Pearl Index of 8.64. Notably, the 95% CI in this subgroup was 5.79 to 11.50, demonstrating minimal overlap with the Pearl Index for women without obesity and no overlap with the Pearl Index for women of normal BMI. On the other hand, the 95% CIs for the normal and non-obese subgroups showed substantial overlap, suggesting minimal difference between these groups.

Figure 20: Forest Plot of the Efficacy Analyses in Women ≤ 35 years by BMI – Study 23 Contraceptive Efficacy Population – ITT Dataset

BMI = body mass index; CI = confidence interval; ITT = intent-to-treat Note: BMI could not be calculated from one woman. 6.3.4.2 Weight Figure 21 shows a forest plot of Pearl Indices by median weight and weight quartile for the ITT dataset. As with BMI, among women ≤ 35 years of age, there was a strong trend toward rising

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Pearl Indices with increasing weight. The Pearl Index was 4.50 (95% CI: 2.80, 6.19) in women with baseline weight less than the median weight compared with 7.26 (95% CI: 5.04, 9.47) in women with baseline weight equal to or greater than the median weight. A similar strong trend was apparent when the Pearl Index was analyzed by weight quartile. Figure 21: Forest Plot of the Efficacy Analyses in Women ≤ 35 years by Weight– Study 23 Contraceptive Efficacy Population – ITT Dataset

CI = confidence interval; ITT = intent-to-treat 6.3.4.3 Race and Ethnicity A forest plot of the Pearl Index by race and ethnicity for the ITT dataset is provided in Figure 22. Among women ≤ 35 years of age, the Pearl Index point estimate was slightly lower in White women as compared to Black or African American women (5.82 [95%: CI 4.14, 7.49] vs 6.40 [95% CI: 3.36, 9.43], respectively). Among women ≤ 35 years of age, the Pearl Index was 5.47 (95% CI: 2.38, 8.56) among Hispanic or Latina women and 5.91 (95%: CI 4.37, 7.46) in non- Hispanic or Latina women.

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Figure 22: Forest Plot of the Efficacy Analysis in Women ≤ 35 years by Race and Ethnicity – Study 23 Contraceptive Efficacy Population – ITT Dataset

CI = confidence interval; ITT = intent-to-treat 6.3.4.4 Previous Hormonal Contraceptive Use Among women ≤ 35 years of age, the Pearl Indices were 3.16 (95% CI: 1.51, 4.82) for current users of hormonal contraception, 4.59 (95% CI: 0.57, 8.61) for naïve users, 7.45 (95% CI: 4.99, 9.91) for former users (ie, those who had not used hormonal contraceptives within the 6 months prior to enrollment), and 9.64 (95% CI: 4.61, 14.67) for recent users (those who used hormonal contraceptives within 6 months prior to enrollment). The CIs for naïve and recent users were wider than for current and former users, reflecting the small proportion of overall cycles in each subgroup (Figure 23).

Figure 23: Forest Plot of the Efficacy Analysis in Women ≤ 35 years by Previous Contraceptive Use – Study 23 Contraceptive Efficacy Population – ITT Dataset

CI = confidence interval; ITT = intent-to-treat

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6.3.4.5 Age The Pearl Index among women ≤ 35 years of age was 5.83 (95% CI: 4.45, 7.21) compared with 3.98 (95% CI: 0.80, 7.16) among women > 35 years of age. The 95% CI of the Pearl Index was wider for women > 35 years of age since fewer cycles were included in the analysis. The Pearl Index for all women regardless of age was similar to that of women ≤ 35 years of age, reflecting the fact that the majority of enrolled women was 35 years of age or younger.

6.3.5 Life Table Analysis A life table analysis was conducted as a supportive efficacy analysis to estimate pregnancy rates. Life table analyses are generally considered more clinically relevant than Pearl Indices as they provide information on pregnancy risk, or failure rates, by each cycle and are used more frequently by HCPs in contraceptive counseling. The life table analysis, shown in Figure 24, utilized the Contraceptive Efficacy Population, ie ITT population, and included all cycles for women who applied at least one patch and were documented to have a negative enrollment serum ß-hCG. The estimated life table cumulative pregnancy rate through Cycle 13 in all women ≤ 35 years of age was 5.29% (95% CI: 4.17, 6.70), which, due to the design of Study 23, is likely a close approximation of actual use efficacy. This percentage falls within the 4% to 7% range of Tier 2 CHCs (Hatcher et al 2018).

Figure 24: Life Table Analysis: Cumulative Pregnancy Rate in Women ≤ 35 Years of Age – Study 23

Note: Cumulative probability of pregnancy calculated by the Kaplan-Meier method for Cycles 1–13.

6.3.6 Sensitivity Analysis Accurately assessing the impact of individual factors on the Pearl Index is fraught with difficulty and does not account for the interplay between various factors, such as race/ethnicity and BMI for example. Nevertheless, in an effort to quantify and thereby illustrate the effects of BMI and

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exclusion of cycles for lack of sexual activity and back-up contraception, Agile conducted a sensitivity analysis. This analysis was conducted in a number of sequential steps, as described below:

• First, we assumed that Study 23 excluded women with BMI > 30 kg/m2 (ie, removing women with BMI > 30 kg/m2) • Second, we assumed that cycles with no reported sexual activity were not excluded for the Pearl Index calculation (ie, 5.4% of cycles were added back to the Pearl Index denominator). Notably, Study 23 prescreened for women who anticipated regular sexual activity at least once per cycle, likely resulting in a low number of cycles without sexual activity. • Third, we assumed no exclusion of cycles in which back-up contraception was used. The Agile Patch Pearl Index was re-calculated with the assumption (both separately and together) using the actual sample size of women ≤ 35 years of age in Study 23 (N = 1,823). When women with BMI > 30 kg/m2 were removed from the analysis, the resulting Pearl Index is 4.34, with a 95% CI of 2.86 to 5.82. When the 5.4% of cycles were added back in to account for the exclusion of cycles without sexual activity, the Pearl Index is 5.51 (95% CI: 4.20, 6.82). Re- estimating the Pearl Index to adjust for both of these factors yielded a Pearl Index of 4.10, with a 95% CI of 2.71 to 5.50. With addition of the third step described above (no exclusion of cycles with use of back-up contraception), the Pearl Index is further adjusted to 3.96, with a 95% CI of 2.61 to 5.31. This sensitivity analysis provides support for the conclusion that under similar conditions as other CHC studies, the Agile Patch efficacy results do not differ from those of approved CHCs. We note the impact on Pearl Index of just three of the factors that we have described as having substantial effects on study results over time. Other factors that also affect efficacy results, such as race/ethnicity, inclusion of European participants, differences in pregnancy testing, were not accounted for in this limited analysis.

6.4 Interpretation of Study 23 Pearl Index Results As shown in Table 18, Study 23 was the first trial to include this particular combination of population, design, and analytical factors for a CHC trial. Inclusion of these factors is now the standard set forth in the 2019 Draft Guidance. While no single factor can account for the Pearl Index observed in Study 23, when taken together, several factors had a substantial impact on the Pearl Index.

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in a category of very obese, and 7.5% were in a category of extremely obese. Consistent with the 2019 Draft Guidance, which notes the potential effect of obesity on CHC efficacy, Study 23 showed evidence of a correlation between BMI and efficacy, with reduced efficacy observed in women with obesity. Agile chose to highlight the reduced efficacy in women with obesity in the Indication Statement via a Limitation of Use. The proposed Limitation of Use in the Indication Statement states: Limitation of Use: The Agile Patch has demonstrated reduced effectiveness in women who weigh 202 lbs (92 kg) or more and/or have a BMI of 30 kg/m2 or more.

Agile is open to other tools for communicating the important information for the population of women with obesity to women and to prescribers. Agile has not yet had an opportunity to discuss the Limitation of Use or other labeling elements with the FDA and looks forward to gaining the benefit of FDA’s experience in this area. While the independent effect of BMI on the Pearl Index cannot be precisely quantified, the data strongly support that obesity accounts for much of the difference between the Agile Patch results and historical CHC studies. For additional context from other CHC studies:

• Annovera (2018; overall Pearl Index of 2.98) excluded patients with a BMI > 29 kg/m2 midway through registrational trial enrollment, discontinuing those with higher BMI who had been enrolled; • Lo Loestrin (2010; overall Pearl Index of 2.92) excluded patients with a BMI > 35 kg/m2; and • Natazia (2010; overall Pearl Index of 1.64) excluded patients with BMI > 30 kg/m2

To Agile’s knowledge, the mean BMI enrolled in Study 23 of 28.3 kg/m2 is not matched or exceeded by any prior approved CHC therapy. Regional Differences: United States versus European Study Participants Study 23 enrolled only US women, which, as described in Section 2.3.3, likely contributed to a more generalizable Pearl Index than other products approved in the US that included a substantial amount of data from European women. Several approved contraceptives, including more recently approved products, enrolled substantial proportions of non-US women in their registrational trials. These studies showed differences in the Pearl Index results for the US and non-US women (Table 6). Other Factors Racial and ethnic diversity of contraceptive trial populations have been described as important factors that affect contraceptive trial efficacy outcomes (Gerlinger et al 2014; Trussell and Portman 2013). The Study 23 population was one of the most diverse with respect to race and ethnicity. Nearly 25% of the enrolled women were Black, and 19.7% were Hispanic. To Agile’s knowledge, previous CHC studies have not enrolled a population as racially diverse as those in Study 23.

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The frequency, sensitivity, and accuracy of pregnancy testing has evolved over the years and was identified by Trussell and Portman as one of the key factors that has contributed to rising Pearl Indices (Trussell and Portman 2013). In Study 23, women were tested for pregnancy at every office visit (Cycles 2, 3, 5, 7, 9, and 13). To further increase the detection of early pregnancies, patients were also provided with home pregnancy tests (sensitive to serum ß-hCG of ≥ 20 mIU/mL) and encouraged to test for pregnancy in the event of increased pregnancy risk such as non-use of back-up contraception after missed or delayed patch application. Accordingly, Study 23 was designed to detect as many pregnancies as possible, including those that may have spontaneously miscarried prior to detection had Study 23’s methods for pregnancy testing mimicked those of some historical trials. For example, a review of the on-treatment pregnancies and pregnancy outcomes showed that, of the 68 on-treatment pregnancies in Study 23 in women ≤ 35 years, 5 pregnancies resulted in miscarriages early in the first trimester of pregnancy and could potentially have been missed in historical trials with less frequent and/or less sensitive pregnancy testing. Three of the 5 were detected with home pregnancy tests. All were included in the Pearl Index calculation for the Agile Patch.

6.5 Efficacy Conclusions The Agile Patch was studied in a contemporary, demographically representative population with stringent analyses that included sensitive pregnancy testing, monitoring of sexual activity, and exclusion of cycles without sexual activity in addition to traditional exclusion for use of back-up contraception. Incorporation of these factors fulfilled the FDA’s recommendations to Agile and the recommendations of the 2007 Advisory Committee. Agile’s trial design is now recommended in the 2019 Draft Guidance, which provides the standard for the evaluation of safety and efficacy for a hormonal contraceptive. Contraceptive trials conducted in this manner will result in Pearl Indices, and accompanying upper bounds of the 95% CI, higher than historically observed. Given the results of Study 23, sensitivity analyses performed on the Pearl Indices of some historical trials, and the CIs derived for older products used as comparators in more recent trials, it can be expected that higher upper bounds may become the standard. It can be expected, therefore, that the failure rate observed in Study 23 is a closer approximation of the rates that would be observed in a real-world setting. The traditional concept that clinical trial data “may not accurately predict contraceptive efficacy in everyday use” and that real-world failure rates would inevitably be much higher than in clinical studies was a relevant concern in the past. Fortunately, because FDA has recognized the need for generalizable, clinically relevant data for the current US population, newer studies, such as Study 23, represent actual use effectiveness more closely, and provide more generalizable information to users and HCPs to enable informed decision making. The results of the primary efficacy analysis of Study 23, in conjunction with key secondary and subgroup efficacy analyses, demonstrate that the Agile Patch is effective in preventing pregnancy in a diverse population of sexually active US women of reproductive age. Efficacy was reduced in women with BMI ≥ 30 kg/m2 and in women who weigh ≥ 202 lbs (92 kg), which is stated in the Indication Statement of the proposed labeling via a Limitation of Use. The

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proposed labeling would for the first time for a hormonal contraceptive, present efficacy results by BMI category. This unique subgroup information combined with a generalizable overall Pearl Index will help women and HCPs make informed contraceptive decisions.

6.6 Additional Phase 3 Studies – Studies 12 and 13 The original Phase 3 studies, Studies 12 and 13, were the subject of the FDA CRL in which the FDA stated there was limited confidence in the conclusions reached primarily due to missing data and loss to follow up. The FDA agreed that the efficacy of the Agile Patch will be based on the results of Study 23, and that pooling or integration of efficacy results from Study 23 with Studies 12 and/or 13 was not warranted. However, safety data from Study 12 and Study 13 were combined with Study 23 to assess the safety profile of the Agile Patch as further discussed in Section 7. Recognizing the limitations of the interpretability of Studies 12 and 13, the data are generally supportive of the comparative efficacy of the Agile Patch to the OC comparators used in each study because any limitations would have affected both arms equally.

6.6.1 Study Design Study 12, conducted in 2010, was an open-label, randomized, active-controlled, parallel group, multicenter study of the contraceptive efficacy and safety of the Agile Patch in comparison to a low-dose OC containing 20 mcg EE and 100 mcg LNG (OC20). Women in the US aged 17 to 40 years were enrolled and randomized 3:1 to the Agile Patch or OC. Women randomized into the Agile Patch group were treated for one year (13 cycles); women randomized into the OC/Agile Patch group were treated for 6 cycles of OC and then switched to the Agile Patch for an additional 7 cycles of treatment. Study 13, conducted in 2011, was an open-label, randomized, active-controlled, parallel group, multicenter study of the contraceptive efficacy and safety of the Agile Patch in comparison with an OC containing 30 mcg EE and 150 mcg LNG (OC30). Women in the US aged 18 to 40 years were enrolled and randomized 1:1 to the Agile Patch or OC. Women were treated for 6 cycles. The prespecified primary endpoint in Studies 12 and 13 was the contraceptive efficacy of the Agile Patch and the OCs for Cycles 1–6. Contraceptive efficacy was evaluated by the Pearl Index (and 95% CI) for all on-treatment pregnancies (date of conception between the first patch application or first active pill taken through Day 14 after the last patch removal or the last active pill taken) using the primary ITT efficacy cycle dataset. The efficacy datasets for each study were defined as follows:

• Study 12: all complete or incomplete on-therapy cycles, excluding cycles with no intercourse and cycles with no pregnancies where other birth control methods, in women aged 17 to 35 years with a BMI < 32 kg/m2 • Study 13: all complete or incomplete on-therapy cycles, excluding cycles with no intercourse and cycles with no pregnancies where other birth control methods, in women aged 18 to 35 years

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7.5 Adverse Events Leading to Study Discontinuation Across the Phase 3 studies, 10.8% of women who were exposed to the Agile Patch reported AEs resulting in study drug discontinuation (Table 23). Preferred terms within the system organ class of General Disorders and Administration Site Conditions were the most frequently reported AE resulting in study drug discontinuation (4.1%). Overall, the only preferred terms of AE resulting in study drug discontinuation reported in ≥ 1.0% of women were application site irritation (1.5%) and application site pruritus (1.1%). Of the other application site disorder AEs resulting in study drug discontinuation, each was reported in < 1.0% of women. Application Disorder AEs are further discussed in Section 7.8. AEs leading to study drug discontinuation that were related to bleeding or spotting were reported by 1.9% of women. None of these AEs was serious. Bleeding-related AEs are described in Section 7.9.

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Figure 25: Percent of Women who Reported Unscheduled or Breakthrough Bleeding and/or Spotting – Study 23 Cycle Control Population

Note: The Cycle Control Population included all women in the Contraceptive Efficacy Population who provided information on bleeding and patch application. According to eDiary data, scheduled (withdrawal) bleeding and/or spotting remained stable over time and the median duration of withdrawal bleeding was 3 to 4 days. The mean number of days of scheduled bleeding decreased from 3.7 days in Cycle 2 to 3.3 days in Cycle 13. The percentages of women with no bleeding and/or spotting days (amenorrhea) in a cycle ranged from 11.9% in Cycle 1 to 6.3% in Cycle 13.

7.10 Pregnancy Outcomes In Study 23, pregnancy outcomes were provided by the study sites for all except for 9 of the 74 on-treatment pregnancies that occurred in women of any age (68 in women ≤ years of age). Of the 65 outcomes available for the on-treatment pregnancies, 2 were ectopic pregnancies and 5 were spontaneous abortions; 12 women underwent elective pregnancy terminations. The remaining on-treatment pregnancies resulted in term or pre-term deliveries; no pre-term delivery was reported to have occurred prior to 34 weeks of gestation. One woman delivered an infant prematurely who was diagnosed with pulmonary stenosis; the Investigator considered this event to be unrelated to study drug. An infant with phenylketonuria was also delivered.

7.11 Safety Conclusions The overall safety profile of the Agile Patch is acceptable and in line with the well-understood and acceptable profile of CHCs. The most common AEs were expected, occurred at low overall rates, and led to discontinuation at rates similar to approved products. There were low rates of application site reactions, and few led to discontinuations from the studies. Frequently reported hormone-related AEs included nausea, headache, dysmenorrhea, and increased weight. As recognized by the FDA, the overall rate of SAEs, including the risk of VTE, was similar to that of approved CHCs. Those risks will be adequately addressed in the Sponsor's proposed labeling, including the CHC class labeling. In addition, the observed rate of VTEs is expected based on the enrolled study population that includes a high proportion of women with obesity.

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The Phase 3 program supports that women with obesity who might use the product may anticipate a similar risk of VTE as with currently approved low-dose CHCs, for which current labeling notes obesity as a known risk factor.

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In Study 23, women recorded daily patch adhesion details using a numbered patch adhesion scale (Appendix 11.3) in their eDiaries. The collection of these data yielded extensive information on adhesion performance of the Agile Patch. The Phase 3 by-cycle data demonstrate early and consistent learning by patch users, with adhesion scores improving over time as patients gained experience with the patch, regardless of application site. Learning curves, such as the one observed in Study 23, are not uncommon whenever a patient starts a new method of contraception/medication (Gomez-Panzani et al 2000). As shown in Figure 26 mean adhesion scores for patches worn on the abdomen were consistently better throughout the trial as compared to those for other anatomic sites and reached the threshold of 90% of patches with worst scores of 0 or 1 (≥ 75% adherent) before Cycle 3.

Figure 26: Percent of Patches with ≥ 75% Adherence by Application Site-by Cycle – Study 23

*Worst score of 0 or 1 ≥ 75% adhesion The horizontal lines represent 90% and 75% of patches with worst scores of 0 or 1, indicating no worse than 25% lift at any time during wear

Given these observations, Agile is proposing a recommendation to apply the patch to the abdomen during initial use of the patch: “When first using [the Agile Patch], patients should apply the patch to the lower abdomen. As patients get experience using the patch, they may try applying the patch to the buttock or upper torso (excluding the breasts) to see which anatomic location works best.” Further, Study 23 adhesion data also showed that women correctly and successfully re-applied patches after partial lifting as instructed to do as per the protocol. As shown in Figure 27, the percentage of patches with greater than or equal to 75% adhesion (ie, a worst score of 0 or 1) was well above 90% throughout the study when including patches that initially reported as < 75%

Page 91 of 147 Agile Therapeutics, Inc The Agile Patch Bone, Reproductive and Urologic Drugs Advisory Committee adhered were successfully re-adhered. This supports patient labeling that instructs patients to attempt to re-apply patches that have been partially or completely detached for less than one day.

Figure 27: Percent of Patches with ≥ 75% Adherence by Cycle – Study 23

Note: Based on Worst Score of 0 or 1 Combined with Patches with a Worst Score of 2, 3, or 4 that Re-Adhered to 0 or 1- *Worst score of 0 or 1 = ≥75% adhesion The horizontal lines represent 90% and 75% of patches with worst scores of 0 or 1, indicating no worse than 25% lift at any time during wear.

8.2 Human Factors Study Having observed a learning curve related to patch application, Agile conducted a focused human factors study to assess and improve the usability of the patient Instructions for Use (IFU), thereby increasing the safe and effective use of the patch. This was not required by FDA, but Agile determined it was important to do additional work to support appropriate patch use. The IFU was tested through a heuristic evaluation, which assessed the instructions with regard to human factors design principles, such as use of minimalist language and error prevention. Areas for improvement of usability were identified, including a redesign of the instructions to reflect a numbered, rather than bulleted, list of steps in the patch application process, to make the sequential order easier for users to follow and to help them identify their location within the process; redesigning images to consistently reflect all the important information in a readily digestible manner; reformatting images to increase the contrast between the different components within them; and rewording instructions to facilitate user comprehension. Following IFU modifications based on the heuristic evaluation, the modified IFU was then evaluated in a quantitative and qualitative study in 10 women to identify potential mistakes in patch application and assess effectiveness of the IFU in preventing any mistaken behaviors during patch application. The study identified areas for further improvement of the IFU based on

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observed mistakes in the patch application process (eg, failing to ensure full adherence of the patch following application) and feedback from the participants (eg, difficulty locating instructions). Recommendations to optimize and clarify the IFU included modification of images to be consistent with the language, further simplification and clarification of language, and reorganization of sections in the patient labeling to more clearly present the patch application instructions. The proposed IFU incorporated recommendations to improve proper use of the Agile Patch and reduce mistakes with applying the patch.

8.3 Patch Replacement To ensure women are able to replace a patch if needed, proposed packaging of the Agile Patch includes 3 patches per box for initial and refill prescriptions and as a package with one patch per box should a woman need a replacement. In addition, single patches will be available in pharmacies, should a woman need an extra patch.

8.4 Risk Management Plan Agile is developing a Risk Management Plan to support the ongoing assessment of the benefit- risk profile of the Agile Patch. The overall benefit-risk profile for the Agile Patch suggests that its risks can be sufficiently managed with FDA-approved Package Insert, Patient Labeling, and routine pharmacovigilance activities. While the risks of the Agile Patch will be primarily communicated through standard contraceptive labeling, Agile is considering a variety of tools and patient education resources to further improve patient and HCP knowledge, use of, and experience with the Agile Patch. The resources being considered are organized into three main categories: resources for use throughout treatment, resources for HCP use in patient counseling, and patient resources that could be widely accessible for women to use at their own convenience. Potential tools and resources being considered by Agile include the following:

• An HCP Information Letter to alert prescribers and other HCPs about important information in the product label including the limitation of use, the effects of BMI/weight on safety and efficacy, the importance of proper and consistent product use, and instructions for patients when the product is not used as directed. • A Patient Information Sheet to emphasize the role of the patient in observing SAEs such as VTE events and immediately reporting any changes or concerns to their HCP and/or Agile. • Non-medicated practice patches to be provided to HCPs for in-office demonstration to complement the techniques and instructions described in the patient labeling. • An in-depth, user friendly training video to demonstrate proper technique and describe potential mistakes to avoid during patch application. This video would be made available

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to HCPs and patients via HCP office technology, the product website, and mobile technologies. • A text message reminder program to aid in long-term adherence. The text message reminder program may include, but not be limited to (a) general patch education and instructions for proper use, (b) periodic reminders to check patch adhesion, (c) weekly reminders to replace the patch, and (d) refill reminders based on start-of-therapy date. • A mobile application (app) to provide similar resources as the product website and the text message reminder program. Agile is committed to ongoing evaluation of tool effectiveness via medication error reports that will allow for further modifications as appropriate based on data collected during post-marketing pharmacovigilance. Contraceptive studies in broader populations that reflect actual use are critical in that they can clarify the broader efficacy and safety profiles in populations that are often excluded from more tightly controlled registrational trials. Thus, Agile is interested in working with FDA and other hormonal contraceptive manufacturers to design and conduct an industry-wide study to address important questions about effects of obesity on contraceptive efficacy and safety.

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9 BENEFIT-RISK In order to make the best choice for themselves, women need more low-dose options and information about those options that is generalizable to the diverse US population. A weekly transdermal contraceptive is preferred by many women who wish to avoid the challenges of consistent daily use, yet the only currently available patch delivers a high dose of EE that may increase the risk of VTE events. Other low-dose alternatives either require insertion (vaginal or subdermal) or require a daily pill. The Agile Patch would provide a low-dose transdermal option not currently available to women. Importantly, the Agile Patch was studied in a broadly representative population of sexually active women in the US, including many women with obesity. Study 23 has provided substantial evidence of the efficacy of the Agile Patch. The observed overall Pearl Index point estimate of 5.83 (95% CI: 4.45, 7.21) for the study population aged ≤ 35 years demonstrates acceptable efficacy. While the Pearl Index is above the 95% CI upper bound of 5 identified in the FDA’s recent guidance as “typically” observed in other contraceptive trials, previous trials had more limited designs and enrolled more selective populations. Study 23 is the first clinical trial to be conducted with a trial design consistent with the 2019 Draft Guidance, which sets the standard for contraceptive trials going forward. As more sponsors design trials that follow the guidance, it will become more clear what typical Pearl Indices from contemporary contraceptive trials will be. The efficacy results from Study 23 show that the combined effect of the study design and population elements in a single trial have a substantial impact on Pearl Index and upper bound results. Moreover, Study 23 showed an effect of BMI, with the Pearl Indices in women with BMI < 25 kg/m2 (ie, normal BMI) and < 30 kg/m2 (ie, non-obese) well within the range of approved products, Study 23 also showed reduced efficacy in women with obesity. These results are consistent with FDA’s meta-analysis findings regarding the effect of BMI on CHC efficacy, but they suggest the effect may be greater than previously estimated. Agile proposed a Limitation of Use highlighted in the Indication Statement regarding lower efficacy in women with BMI ≥ 30 kg/m2 and weight ≥ 202 lbs (92 kg) and a tabular presentation of efficacy by BMI category to communicate important information necessary to enable informed decision making. Considering the enrollment of the largest proportions of women in BMI categories of obese and very obese in a Phase 3 CHC registrational trial, the impact of the efficacy results in these subgroups on the overall results of Study 23 is evident. While the independent effect of each of the factors that affect the Pearl Index cannot be quantified, the data strongly support that obesity accounts for much of the difference between the Study 23 results and historical CHC studies. In addition, the sensitivity analyses discussed in Section 6.3.6 provides directional support for the conclusion that under similar conditions as other CHC studies, the Agile Patch efficacy results are not different from those of approved CHCs.

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The overall safety profile of the Agile Patch is acceptable and in line with the well-understood and acceptable profile of CHCs. The most commonly observed AEs were similar to those observed with the use of other CHCs, occurred at low overall rates, and led to discontinuation at rates similar to approved CHC products. Local patch site reactions were generally low and led to few discontinuations from the studies. The rate of SAEs was consistent with approved CHCs, and the observed rate of VTEs is expected based on the enrolled study population, which included high proportions of women in the BMI categories of obese, very obese, and extremely obese. Notably, 5 out of 6 VTE events in the Phase 3 studies occurred in women with obesity, who are known to be at increased baseline risk of VTE. The demonstrated differences in efficacy and potential risks of the Agile Patch between women without obesity (BMI < 30 kg/m2) and women with obesity (BMI ≥ 30 kg/m2) support a different benefit-risk calculus for the two populations. In women without obesity (65% of the women in Study 23), the Pearl Index for the Agile Patch was 4.34 (95% CI: 2.86, 5.82), and there was a single report of a VTE in the safety database. This benefit-risk profile is squarely in line with prior approvals. In women with obesity, the efficacy of the Agile Patch was reduced with a Pearl Index of 8.64 (95% CI: 5.79, 11.50). Five women with obesity experienced VTEs in the Safety Population. While the preventative effect is lower than that in women without obesity, it remains acceptable and likely in line with what might be expected with other CHCs had they been studied in this population. The Agile Patch data allow, for the first time, that effectiveness to be quantified in labeling. Although the observed rate of VTE in women with BMI ≥ 30 kg/m2 is a potential risk, the even higher risk of VTE during pregnancy, in addition to other potential complications, such as hypertension and pre-eclampsia, gestational diabetes, pre-term delivery, and caesarian section, is important to the prescribing decision. In addition, women with obesity reported a low rate of hormone-related AEs that can cause many women to discontinue hormonal contraception. CHCs are prescribed to women with obesity, despite a general understanding that their effectiveness is reduced, because even that reduced effectiveness is more protective than that seen with Tier 3 methods, such as barrier methods. The benefit-risk calculus for the population with obesity is different than that for the women without obesity and supports approval with a Limitation of Use, as Agile proposed, or other labeling tools. Such labeling tools would communicate important information to women and their HCPs to permit them to participate in a shared decision-making process to weigh the benefits and risks to determine whether the Agile Patch is the right option. For some women with obesity who seek hormonal contraception but wish to avoid a daily pill and do not desire intravaginal methods, the Agile Patch may be an acceptable choice. For other women with obesity, it may not. The risks associated with the Agile Patch will be managed through standard contraceptive labeling and routine pharmacovigilance activities. A variety of tools and patient education resources may further improve patient and provider experience with the Agile Patch.

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Overall, the safety and efficacy data generated through the Agile Patch Phase 3 clinical program have demonstrated that the Agile Patch has an acceptable benefit-risk profile for use in the general population of reproductive-aged women in the US.

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10 REFERENCES ACOG Practice Bulletin No. 206: Use of Hormonal Contraception in Women With Coexisting Medical Conditions. Obstet Gynecol. 2019;133(2):e128-e50.

Annovera Medical Review, NDA 209627. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/209627Orig1s000MultidisciplineR.p df.

Bloemenkamp KW, Rosendaal FR, Helmerhorst FM, Buller HR, Vandenbroucke JP. Enhancement by factor V Leiden mutation of risk of deep-vein thrombosis associated with oral contraceptives containing a third-generation progestagen. Lancet. 1995;346(8990):1593-6.

Boden DC. Unplanned pregnancies and the pill. Med J Aust. 1980;1(8):391.

Burkman RT. Transdermal hormonal contraception: benefits and risks. Am J Obstet Gynecol. 2007;197(2):134 e1-6.

CDC National Survey of Family Growth 2011-2015.

Chen M, Lindley A, Kimport K, Dehlendorf C. An in-depth analysis of the use of shared decision making in contraceptive counseling. Contraception. 2019;99(3):187-91.

Daniels K, Abma JC. Current contraceptive status among women aged 15–49: United States, 2015–2017. NCHS Data Brief, no 327. Hyattsville, MD: National Center for Health Statistics. 2018.

Edelman A, Trussell J, Aiken ARA, Portman DJ, Chiodo JA, 3rd, Garner EIO. The emerging role of obesity in short-acting hormonal contraceptive effectiveness. Contraception. 2018;97(5):371-7.

Egarter C, Frey Tirri B, Bitzer J, Kaminskyy V, Oddens BJ, Prilepskaya V, et al. Women's perceptions and reasons for choosing the pill, patch, or ring in the CHOICE study: a cross- sectional survey of contraceptive method selection after counseling. BMC Womens Health. 2013;13:9.

FDA. Establishing Effectiveness and Safety for Hormonal Drug Products Intended to Prevent Pregnancy Guidance for Industry – Draft Guidance. 2019.

FDA. 2007 Advisory Committee for Reproductive Drugs, Transcript Vol 1, Jan. 23, 2007.

FDA. Labeling for Combined Hormonal Contraceptive Guidance for Industry – Draft Guidance. 2017.

FDA and Agile Therapeutics, Inc. Type C Preliminary Comments. Feb 2014.

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FDA Ortho Evra Labeling Update Press Release; 2005. Available from: https://wayback.archive- it.org/7993/20170112033254/http:/www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ 2005/ucm108517.htm. Foegh M, Archer DF, Stanczyk FZ, Rubin A, Mishell DR, Jr. Ovarian activity in obese and nonobese women treated with three transdermal contraceptive patches delivering three different doses of ethinyl estradiol and levonorgestrel. Contraception. 2013;87(2):201-11. Flegal KM, Kruszon-Moran D, Carroll MD, Fryar CD, Ogden CL. Trends in Obesity Among Adults in the United States, 2005 to 2014. JAMA. 2016;315(21):2284-91.

Frost JJ, Darroch JE. Factors associated with contraceptive choice and inconsistent method use, United States, 2004. Perspect Sex Reprod Health. 2008;40(2):94-104.

Frost JJ, Singh S, Finer LB. U.S. women's one-year contraceptive use patterns, 2004. Perspect Sex Reprod Health. 2007;39(1):48-55.

Generess. Medical Review, NDA 22-573. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022573Orig1s000SumR.pdf

Gerlinger C, Trussell J, Mellinger U, Merz M, Marr J, Bannemerschult R, et al. Different Pearl Indices in studies of hormonal contraceptives in the United States: impact of study population. Contraception. 2014;90(2):142-6.

Gomez-Panzani E, Williams MB, Kuznicki JT, Myers WR, Zoller SA, Bixler CA, et al. Application and maintenance habits do make a difference in adhesion of Alora transdermal systems. Maturitas. 2000;35(1):57-64.

Grady WR, Billy JO, Klepinger DH. Contraceptive method switching in the United States. Perspect Sex Reprod Health. 2002;34(3):135-45.

Hatcher RT, J, Nelson, AL, Cates W, Kowal D, Policar M. Contraceptive Technology. 21st ed: Bridging the Gap Communications; 2018.

Horton LG, Simmons KB, Curtis KM. Combined hormonal contraceptive use among obese women and risk for cardiovascular events: A systematic review. Contraception. 2016;94(6):590- 604.

Hofmann B, Reinecke I, Schuet B, Merz M, Zurth C. Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive. International Journal of Clinical Pharmacology and Therapeutics 2014;52:1059-70.

IMS National Prescription Audit - April 2017

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Joint Meeting of Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management Advisory Committee; December 8, 2011. Available at http://wayback.archive- it.org/7993/20170113093209/http://www.fda.gov/downloads/AdvisoryCommittees/Committees MeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/UCM282462.pdf

Levlite Medical Review, NDA 20-860. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20860_medr_chemr_pharmr.pdf

Lidegaard O, Lokkegaard E, Svendsen AL, Agger C. Hormonal contraception and risk of venous thromboembolism: national follow-up study. BMJ 2009;339:b2890.

Lo Loestrin Fe Medical Review. NDA 22-501. Available at https://www.accessdata.fda.gov/drugsatfda docs/nda/2010/022501Orig1s000MedR.pdf

Lo Seasonique Medical Review. NDA 022262. Available at https://www.accessdata.fda.gov/drugsatfda docs/nda/2008/022262 loseasonique toc.cfm

Lucke JC. Enhancing shared decision-making in contraceptive consultations. J Fam Plann Reprod Health Care. 2017;43(2):126-7.

Lybrel Medical Review, NDA 21-864. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2007/021864s000_MedR_P1.pdf Mansour D. International survey to assess women's attitudes regarding choice of daily versus nondaily female hormonal contraception. Int J Womens Health. 2014;6:367-75.

Martinez-Astorquiza-Ortiz de Zarate T, Diaz-Martin T, Martinez-Astorquiza-Corral T, MIAS Investigators. Evaluation of factors associated with noncompliance in users of combined hormonal contraceptive methods: a cross-sectional study: results from the MIA study. BMC Womens Health. 2013;13:38. Natazia NDA Medical review, NDA 022252. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022252_Orig-1_SumR.pdf Ortho Evra NDA Medical Review, NDA 21180. Available at https://www.accessdata.fda.gov/drugsatfda docs/nda/2001/021- 180 Ortho%20EVRA medr P1.pdf Quartette Clinical Pharmacology Review. NDA 204061. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204061Orig1s000ClinPharmR.pdf

Quartette Medical Review. NDA 204061. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/204061Orig1s000MedR.pdf

Quartette (levonorgestrel/ethinyl estradiol and ethinyl estradiol) [prescribing information]. Sellersville, PA: Teva Pharmaceuticals USA, Inc.; 2013.

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Rabe T, Luxembourg B, Ludwig M, Dinger J, Bauersachs R, Rott H, et al. Contraception and thrombophilia – a statement from the German Society for Gynecological Endocrinology and Reproductive Medicine (DGGEF e.V.) and the Professional Association of German Gynaecologists (BVF e.V.). J Reproduktionsmed Endokrinol. 2011;8(Special Issue 1):178-218.

Reif S, Snelder N, Blode H. Characterisation of the pharmacokinetics of ethinyloestradiol and drosperione in extended-cycle regimens: population pharmacokinetic analysis from a randomized Phase II study. Journal of Family Planning and Reproductive Health Care. 2013;39:e1.

Steiner MJ, Hertz-Picciotto I, Raymond E, Trussell J, Wheeless A, Schoenbach V. Influence of cycle variability and coital frequency on the risk of pregnancy. Contraception. 1999;60(3):137- 43.

Trussell J. Contraceptive failure in the United States. Contraception. 2011;83(5):397-404.

Trussell J, Portman D. The creeping Pearl: Why has the rate of contraceptive failure increased in clinical trials of combined hormonal contraceptive pills? Contraception. 2013;88(5):604-10.

United Nations. World Contraceptive Use c2019 [cited 2019 Sept 26]. Available from: https:// www.un.org/en/development/desa/population/publications/dataset/contraception/wcu2019.asp

Vahratian A, Barber JS, Lawrence JM, Kim C. Family-planning practices among women with diabetes and overweight and obese women in the 2002 National Survey for Family Growth. Diabetes Care. 2009; 32: 1026–31.

Villavicencio J, Allen RH. Unscheduled bleeding and contraceptive choice: increasing satisfaction and continuation rates. Open Access J Contracept. 2016;7:43-52.

Westhoff CL, Torgal AT, Mayeda ER, Shimoni N, Stanczyk FZ, Pike MC. Predictors of noncompliance in an oral contraceptive clinical trial. Contraception. 2012;85(5):465-9.

Xulane (norelgestromin and ethinyl estradiol transdermal system) [prescribing information]. Morgantown, WV: Mylan Pharmaceuticals Inc.; 2017.

Yamazaki M, Dwyer K, Sobhan M, Davis D, Kim MJ, Soule L, et al. Effect of obesity on the effectiveness of hormonal contraceptives: an individual participant data meta-analysis. Contraception. 2015;92(5):445-52.

Yasmin NDA Medical Review, NDA 21098, 2000.

Yaz NDA Medical Review, NDA 21-873. Available at https://www.accessdata.fda.gov/drugsatfda docs/nda/2006/021873s000 MedR P1.pdf

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11.3 Patch Adhesion Scale – Studies 16, 25, and 23 In Studies 16, 25, and 23, the Investigator or Sub-investigator rated patch adhesion using the following five-point adhesion scale during each study visit. If the participant was seen during her patch-free week, a “non-applicable” entry was utilized. 0: ≥ 90% adhered (none to minimal lift) 1: ≥ 75% adhered but < 90% (some edges showing lift) 2: ≥ 50% adhered but < 75% (at least half of system lifts off) 3: < 50% (more than half of the patch lifts off, but the patch remains attached) 4: Patch completely detached. Participants recorded patch adhesion in their eDiaries on all days excluding the patch-free week, using this simplified scale: 0: No lifting or small amount of lifting at the edges of the patch 1: More than a small amount of lifting at the edges up to one-quarter of the patch lifting off 2: More than one quarter of the patch lifting off up to half of the patch lifting off 3: More than half of the patch is lifting off, but the patch is still on 4: Patch has completely come off.

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11.4 Study 23 eDiary Design The following sections describe the Study 23 eDiary questions. Subjects used the eDiary to record patch use, sexual activity, back-up contraception use, in addition to patch site reactions. Women were trained how to use the Patch-On Diary at their study site, and the first entry was made while at the site following initial patch application. In user acceptability testing, it took fewer than 5 minutes to complete all daily eDiary entries. The screenshots provided below are the screens presented to study subjects. “Behind the scenes” programming was aimed at making the eDiary simple and straightforward to complete, with automatic presentations of appropriate screens for the relevant days of the cycle.

11.4.1 Patch On Diary - Cycle Day 1 On Day 1 of each cycle, women completed the Patch On Diary. This diary contained questions regarding the date, time, and anatomic location of patch application.

If the subject did not complete the Patch On Diary on the expected Cycle Day 1 date, the screen below appeared, and the subjects was asked to apply a patch and complete the Patch On Diary.

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If the patch application date then entered was greater than 24 hours after the expected date, the subject was prompted to start a new cycle and to use back-up contraception:

Once the Patch-On diary was completed, the entry was verified with a signature, and the Daily Diary was then presented to the subject for completion.

11.4.2 Daily Diary The Daily Diary contained the daily questions (in order of presentation) on patch wear (yes/no), skin irritation, itching, water exposure, patch adhesion and bleeding. Sexual activity and use of back-up contraception questions were also included in the Daily Diary, but were presented weekly. Cycle Days 1-21 On Cycle Days 1-21, the patch wear question was asked first to determine whether the participant was wearing a patch.

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If the subject answered no to this question and did not complete the diary on the previous day (if the patch was expected), she was asked if her patch was on the day prior.

If another “No” response occurred on days the subject was expected to be wearing a patch, she was instructed to place a patch to start a new cycle, and directed to the daily questions, starting with skin irritation:

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The Patch On Diary was then presented for completion at the end of the Daily Diary questions. In response to a request from the Division, a water exposure question was added to the eDiary and is presented below in the sequence in which it appeared in the Daily Diary:

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Sexual Intercourse and Back-Up Contraceptive Use Sexual intercourse and back-up contraceptive use questions were presented weekly and at the end of each cycle. If the subject answered yes to either question during the cycle, that question was not asked again until the next cycle. If yes was answered for back-up contraception, the subject was prompted for reason for use.

Entries were verified by the signature page. Cycle Day 22 – Start of Patch-Free Week The screen below was presented at the beginning of the Daily Diary on Cycle Day 22 (and subsequent days until a patch removal date was entered).

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The subject was then directed to the daily questions, starting with skin irritation shown previously. The water exposure and patch adhesion questions were not presented during the patch-free week.

11.4.3 Patch Change Diary - Cycle Days 8 and 15 The Patch Change Diary was always available for when any patch change occurred. The following screens were presented for both scheduled (Cycle Days 8 and 15) and unscheduled patch changes.

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Unscheduled Patch Change The eDiary was programmed such that if the patch change date was:

• Outside the 48-hour window for Cycle Day 8 or 15, • Inside the 48-hour window for Cycle Day 8 or 15 but a Scheduled Patch Change was already recorded for that window, • Inside the 48-hour window for Cycle Day 15, but a Patch Change for Cycle Day 8 was never recorded, the subject was routed to the screen below to enter the reason for an unscheduled patch change.

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If the subject was late for a scheduled patch change, she was notified to apply a patch:

If the patch change date entered was greater than 48 hours after the expected day of change, the participant was prompted to start a new cycle and to use back-up contraception: as show below.

Otherwise, the participant proceeded directly to the signature screen.

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11.6 Study 23 Inclusion and Exclusion Criteria 11.6.1 Inclusion Criteria 1. To participate in the study, a subject must have met all of the following inclusion criteria: 2. Was a sexually active woman at least 18 years and 0 days of age at Screening, at risk for pregnancy, and seeking to use hormonal contraception for at least 1 year 3. Willing to discontinue her current method of contraception and agree to use [the Agile Patch] as her sole method of contraception throughout the study, except when an alternate method was required for prevention of sexually transmitted infection (STI) or back-up contraception in the setting of patch detachment/patch scheduling issues 4. Did not anticipate or plan using alternate contraceptive methods for STI prevention and/or emergency contraception 5. Anticipated being sexually active during each cycle throughout the study, eg did not anticipate partner deployment or other separations 6. Must have regular menses every 21-38 days (based on combination of FIGO recommendations of 24-38 days and ACOG recommendations of 21-35 days) 7. If subject had recently used hormonal contraception, historical data prior to use was used to determine qualification and must also have met this criterion. 8. If recently discontinued breastfeeding, must have demonstrated return to regular cycling and have had at least 3 menses post-lactation 9. If subject received prior administration of injectable contraceptives (eg, depot medroxyprogesterone acetate), then must have been at least 10 months since last injection and subject must have had at least two spontaneous menses 10. In good general health, confirmed by medical history, physical (including gynecologic) examination and screening laboratory values 11. Had an intact uterus and both ovaries and fallopian tubes 12. Medically able and willing to forgo the use of other steroid hormonal therapy (other than topical or inhaled corticosteroids) for the duration of the study 13. Demonstrated at least 90% compliance with electronic Diary entry and returned 2 check-in phone calls from the Investigator site during the two-week Run-In Period 14. In the Investigator’s assessment, subject demonstrated ability and willingness to participate and adhere to study protocol for the full study, including at least one transvaginal ultrasound if subject had a positive urine ß-hCG at any point during the study 15. Willing and able to sign the informed consent form.

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11.6.2 Exclusion Criteria To participate in the study, a subject must not have met any of the following exclusion criteria: 1. Known or suspected pregnancy 2. Desired pregnancy within the next 12 months 3. Currently lactating 4. Anticipated or planned use of condoms or emergency contraception or any other form of back- up contraception during the study 5. Current use of a contraceptive implant; if an implant was recently removed, subject must have had at least three consecutive, spontaneous menses prior to the date of consent

6. Current use of an intrauterine device (IUD); if an IUD was recently removed, subject must have had at least one spontaneous menses following removal and prior to the date of consent 7. Recent surgical or medically induced abortion, spontaneous abortion, or ectopic pregnancy, unless the subject had three consecutive, spontaneous menses or withdrawal bleeding episodes prior to the date of consent 8. Recent vaginal or cesarean delivery, unless the subject had three consecutive, spontaneous menses or withdrawal bleeding episodes prior to the date of consent. 9. Unexplained vaginal bleeding 10. Known hypersensitivity to, or intolerance of, progestins or estrogens (leading to discontinuation), including hormonal contraception; or history of serious or severe AE related to progestins or estrogens, including hormonal contraception (eg, worsening of a disease or condition while on hormonal contraception) 11. History of dermal hypersensitivity in response to medicated patches (eg, nicotine patch) or topical applications (bandages, surgical tape, etc) or known hypersensitivity to any components of the [Agile Patch] product 12. Had a contraindication to combined estrogen-progestin contraceptive use (as defined by a category 3 or 4 CDC US Medical Eligibility Criteria for Contraceptive Use condition), including: a. Personal history of or existing deep venous thrombosis (DVT) or venous thromboembolism b. History of stroke, vascular or cerebral vascular disease including transient ischemic attacks or coronary artery disease c. Known inherited or acquired hypercoagulopathy, including thrombogenic mutations (eg, factor V Leiden; prothrombin mutation; protein S, protein C, or antithrombin deficiency) d. Systemic Lupus Erythematosus with positive or unknown antiphospholipid antibodies

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e. Known or suspected carcinoma of the breast, including past personal history of breast cancer f. Jaundice with prior combination hormonal contraceptive use g. Hepatocellular adenoma or carcinoma h. Severe cirrhosis i. Symptomatic current or medically treated gallbladder disease j. Smoker who was 35 years old or over, or smoker who turned 35 years old during the course of the trial (Smoking included cigarettes, cigars, smokeless tobacco, ecigarettes, hookah, etc) k. Headaches with focal neurological symptoms (ie, migraines with auras) l. Migraines of any type in women over 35 years of age m. Diabetes mellitus with nephropathy, neuropathy, retinopathy, or other vascular disease; diabetes mellitus of ˃ 20 year’s duration n. Plans for major surgery with anticipated prolonged immobilization during the study o. Elevated blood pressure (BP), defined as screening sitting BP ≥ 140 mm Hg systolic or ≥ 90 mm Hg diastolic; or hypertension with known vascular disease p. History of peripartum cardiomyopathy. 13. Known thrombophilia, including antiphospholipid antibody syndrome 14. History of any other condition that in the Investigator’s opinion suggested an elevated risk of arterial or venous thromboembolic disease 15. Carcinoma of the endometrium, ovary, fallopian tubes, or other known or suspected estrogen- dependent malignant or pre-malignant neoplasia 16. Other active malignancy, excluding non-melanoma skin cancer 17. Acute or chronic hepatocellular disease with significantly abnormal liver function as measured by liver function tests ≥ 2 x normal 18. Triglycerides ≥ 350 mg/dL 19. Thrombogenic valvular or thrombogenic rhythm diseases of the heart (eg, subacute bacterial endocarditis with valvular disease or atrial fibrillation) 20. Uncontrolled diabetes mellitus; subjects with a history of gestational diabetes were eligible for the study if they were currently euglyemic

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21. Abnormal central laboratory fasting glucose ≥ 126 mg/dL and/or HbA1C value (≥ 6.5%); glucose could be repeated if last caloric intake was not at least 8 hours prior to blood draw 22. Uncontrolled thyroid disorder 23. Known human immunodeficiency virus (HIV) and/or hepatitis B or C infection, or positive test at Screening Visit 24. Positive screen for chlamydia or gonorrhea (subjects who screened fail due to positive results could be re-screened and enrolled in the study after standard medical treatment) 25. Significantly abnormal Papanicolaou (Pap) test Pap test results [and human papilloma virus (HPV) testing, if applicable] from within the previous 3 months prior to consent were acceptable if the report was available for inclusion in the subject's source file. 26. Current chronic use of any medication that might interfere with the efficacy of hormonal contraceptives, or be affected by the hormonal contraceptive (including barbiturates, primidone, bosentan, carbamazepine, felbamate, griseofulvin, oxcarbazepine, phenytoin, rifampin, rifabutin, St. John’s Wort, topiramate, lamotrigine, and ritonavir-boosted HIV protease inhibitors) 27. History of suicidal ideation or attempt, or history of severe depression requiring hospitalization within the past year 28. Recent history (within prior 12 months) of drug or alcohol abuse or at Investigator discretion, history greater than 12 months prior and at risk for noncompliance 29. Positive urine drug screen for Cocaine, Methamphetamine, Opiates, Phencyclidine unless there was a documented prescription with supporting medical history and diagnosis 30. Administration of any investigational drug and/or experimental device within 30 days prior to the date of consent or planned administration of such drug or device during the duration of the study; or current participation in any investigational studies 31. Previously enrolled in this protocol or prior Agile Protocols CL12 or CL 13 and dispensed study patch Note that the exclusion of subjects previously enrolled in Protocols CL12 or CL13 was added by Protocol Amendment 2. 32. Deemed per the Investigator’s discretion to have limited ability to comply with the protocol and to provide accurate information (eg, subject reports a history of difficulty in keeping up with regular daily tasks or behaviors; subject previously on OCs and reports repeatedly missing pills and/or becoming pregnant while on OCs) 33. Subject was a dependent of (eg, relative or family member) and/or was a member of the Investigator’s staff.

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11.7 Additional Key Secondary Endpoints in Study 23 The second and third key secondary endpoints in Study 23 included:

• The Pearl Index in women aged ≤ 35 years, with BMI < 30 kg/m2 utilizing the Per Protocol Instructions efficacy cycle dataset (unless the woman became pregnant during the cycle) • The Pearl Index in women aged ≤ 35 years, irrespective of BMI, utilizing the Per Protocol Instructions efficacy cycle dataset These secondary endpoints were calculated using the Per-Protocol-Instructions Efficacy Dataset, which utilized all complete or incomplete on-therapy cycles in which intercourse occurred, excluding two cohorts of cycles:

• Cohort 1: cycles in which a back-up method of contraception was used for reasons other than the protocol-specified procedures for missed days of patch use, unless pregnancy occurred • Cohort 2: cycles in which the woman missed ≥ 1 day of patch use and did not adhere to the recommended procedures for missed days of patch use The Pearl Index in women aged ≤ 35 years, with BMI < 30 kg/m2, utilizing the Per-Protocol- Instructions dataset was 3.94 with a 95% CI of 2.48 to 5.40. The lower Pearl Index in this population supports the improved efficacy of the Agile Patch when it is used as instructed. The Pearl Index in women aged ≤ 35 years, irrespective of BMI, utilizing the Per-Protocol- Instructions dataset was 5.25 with a 95% CI of 3.89 to 6.61. The increased Pearl Index illustrates the impact of the high BMI population on the Pearl Index, even when used as instructed.

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11.12 Serious Adverse Event Narratives 11.12.1 DVT/PE Event Narratives 11.12.1.1 Patient A A 35-year-old white, non-Hispanic, non-smoker: At Screening for Study 23 the subject weighed 93.4 kg (205.9 lbs) with a BMI of 37.1 kg/m2 (Her BMI during hospitalization was noted to have increased to 39 kg/m2). Screening laboratory assessments were within normal limits. The subject reported a medical history of headaches, dysmenorrhea, seasonal allergies, acid reflux, sinusitis, and Bartholin cysts. She reported being on oral hormonal contraceptives recently and hormonal patch contraception in the past. Concomitant medications reported included Motrin for (b) (6) headaches, Zyrtec for seasonal allergies, and a multivitamin. On , the subject was enrolled in the study and her first patch was applied. Her vitals at Enrollment were within (b) (6) normal limits. The subject reported taking a flight on (Study Day 126) and (b) (6) started having pain in her right leg after the flight. On she took a return flight home and experienced extreme right leg pain and shortness of breath. The subject called the site on (b) (6) and informed site staff she went to the ER for shortness of breath and right leg pain and was admitted for a right leg DVT and bilateral pulmonary emboli (SAEs of DVT and PE, respectively). A Computed Tomography (CT) of the chest showed multiple emboli bilaterally, and a peripheral venous exam revealed non-occlusive right femoral and posterior tibial DVT, as well as occlusive right popliteal and peroneal DVT. The subject reported a family history of coronary artery disease and diabetes but no history of clotting issues, emboli, or thrombi. The subject was treated with hydrocodone and acetaminophen 5/325 mg PO, enoxaparin 100 mg subcutaneous (SC), and warfarin 5 g PO. The subject was discharged on (b) (6) (b) (6) in stable condition. The subject removed the patch on (Study Day 134) and was permanently discontinued from the study on February 1, 2016. The Investigator and Sponsor considered the AEs of DVT and PE probably related to AG200-15.

11.12.1.2 Patient B A 25-year-old white, non-Hispanic, non-smoker: At Screening for Study 23, the subject weighted 92.1 kg (203.0 lbs) with a BMI of 31.8 kg/m2. The subject reported a medical history of migraines, asthma, and stress. She reported previous use of hormonal contraceptives which were discontinued due to non-coverage by her insurance company and the use of emergency contraception. No CMEDS were reported. Additional history not reported to the Investigator at screening was obtained from the hospitalization medical records and included a family history of (b) (6) clotting disorder. On the subject was enrolled in the study and her first patch was applied. Her vitals at Enrollment were within normal limits. The subject applied her most recent patch on November 18, 2015. On (b) (6) (Study Day 178), the subject informed the Investigator that she was admitted to the hospital with chest pain and found to have a blood clot (b) (6) in her lung (SAE of PE). The subject was discharged on on a Coumadin regimen. The subject was discontinued from the study due to the PE. The subject was no longer on anticoagulant therapy and considered recovered on April 25, 2016. The Investigator and Sponsor considered the PE to be probably related to AG200-15.

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11.12.1.3 Patient C A 26-year-old white, non-Hispanic, former smoker: At Screening for Study 23, the subject weighed 91.9 kg (202.6 lbs) and had a BMI of 34.3 kg/m2. Abnormal screening laboratory assessments included monocytes 0.14 x 109/L, cholesterol 5.66 mmol/L, and triglycerides 2.5 mmol/L. The subject reported a medical history of thrush, acne, headaches, fatigue, eczema, constipation, urinary tract infections, yeast infection, uterine fibroids with myomectomy, dysmenorrhea, endometriosis, dyspareunia, bladder incontinence, appendectomy, mild depression, sulfa allergy, laparoscopy and hysteroscopy, spastic colon, menorrhagia, and seasonal allergies. The subject reported a family history of stroke in maternal and paternal grandmothers who were reportedly in their sixties at the time of the events. Prior hormonal contraceptives included Depo-Provera, Yaz, and NuvaRing. Concomitant medications reported at Screening included prenatal vitamins and nitrofurantoin for intermittent yeast infections. On (b) (6) the subject was enrolled in the study and her first patch was applied. Her (b) (6) vitals at Enrollment were within normal limits. On (Study Day 125), the subject began experiencing chest pressure primarily below the sternum and shortness of breath. A CT Scan revealed a small left lower lobe pulmonary embolus with small infarction (SAE of PE). The subject was admitted to the hospital, treated with Xarelto 15 mg PO, and the study patch discontinued. While hospitalized the subject was newly diagnosed with hyperthyroidism. (b) (6) The subject was discharged on The subject was discontinued from the study because of the AE on February 11, 2016. The Investigator and Sponsor considered the PE probably related to AG200-15.

11.12.1.4 Patient D A 33-year-old black, non-Hispanic: At Screening for Study 23, the subject weighed 93 kg (205.0 lbs) and had a BMI of 36.3 kg/m2. Abnormal screening laboratory assessments included eosinophils 0.03 x 109/L, hematocrit 0.33 (ratio), hemoglobin 108 g/L and monocytes 0.16 x 109/L. The subject reported a medical history of urge incontinence, genital herpes, gastric sleeve, obesity, and spasmodic dysphonia. She reported switching from the Ortho Evra patch directly to the [the Agile Patch]. She had a prior use history of OCs, the vaginal ring, and a progestin IUD. No CMEDS were reported at screening. She had 8 prior pregnancies with 3 full-term deliveries (b) (6) and 5 elective abortions. On the subject was enrolled in the study and her first patch was applied. Her vitals at Enrollment were within normal limits. The subject was discontinued from the study on April 27, 2016 due to pregnancy and last wore the patch on April (b) (6) 26, 2016. On (Study Day 351), the subject visited her OB/GYN and complained of left leg pain and was sent to the ER for evaluation. On the same day, she called the Investigative site to report she was admitted to the hospital for a left leg DVT (SAE). An ultrasound revealed acute, non-occlusive DVT in the left gastrocnemius veins. The subject was also slightly hypotensive. The subject was started on IV heparin and then transitioned to Lovenox SC. The (b) (6) subject was discharged on on Lovenox SC 100 mg/mL, prenatal vitamins, and Tylenol with codeine. The subject fully recovered. The Investigator considered the DVT unrelated to AG200-15. The Sponsor disagreed with this assessment and considered the DVT probably related to study drug, given the early gestational age at which the clot event occurred.

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11.12.1.5 Patient E A 26 year old, White, non - Hispanic female with a BMI of 19.9 was screened for Study 12 on September 20, 2010: The subject was using condom and spermicidal agent as a current method of birth control prior to study entry. Seasonal allergies, tonsillitis, viral meningitis, breast augmentation and Chlamydia were noted in the subject‘s medical history. Her concomitant medication included Z pack for Chlamydia, multivitamins, and Claritin. The subject also began taking Spirolactone for acne on December 3, 2010. The subject‘s laboratory evaluations, physical exam and vital signs were within normal limits. The subject met all of the inclusion and exclusion criteria and was randomized to [the Agile Patch] treatment group on September 24, (b) (6) 2010. The subject applied the patch on October 7, 2010. On the subject presented to the ER with dull pain in her left arm for 6 days. The subject reported discontinuing the patch one week prior due to increased acne. The subject‘s platelet count at the time of the ER admission was 222 and her BUN was slightly elevated at 33.3; all other labs were within normal limits. A venous Doppler revealed a deep vein thrombosis with partial occlusion in the left subclavian vein proximally. The subject was admitted to the hospital and Heparin drip was (b) (6) started. On the subject was discharged on Coumadin and told to follow up with ultrasound in 2 weeks and with primary care doctor for PT/INR checks every two weeks. The subject was active and noted she lifted weights and participated in kick boxing. Her workouts involved multiple repetitions with the use of weights that are 8-10 pounds. The sponsor requested the subject be evaluated for possible Paget-Schroetter syndrome, effort-related or exercise-induced upper-extremity thrombotic event. It was noted that the subject‘s great aunt also had a similar clot. No other significant family history was noted. Study medication was permanently discontinued.

11.12.1.6 Patient F A 24-year-old Hispanic subject who reported race as “Other.” At Screening for Study 23, the subject weighed 93.7 kg (206.6 lbs) with a BMI of 35.7 kg/m2. Her Screening erythrocyte results was abnormal at 5.3 x109/L. The subject reported a medical history of fibroids and obesity, and no concomitant medications. The subject’s contraceptive history included the use of oral contraceptive pills within the six months prior to Screening as well as emergency contraception (b) (6) use greater than six months prior to Screening. On , the subject was enrolled in the study and her first patch was applied. Vital signs at Enrollment were within normal limits with (b) (6) the exception of her pulse which was elevated at 99 bpm. On (Study Day 3), the subject presented to the ER with complaints of pain and fainting, and was admitted. Blood work indicated an increased bilirubin. An ultrasound revealed cholelithiasis and ascites. A CT of the abdomen and pelvis was done on the same day that showed severe acute pancreatitis (SAE – necrotizing pancreatitis), known cholelithiasis, moderate ascites and a large pedunculated uterine fibroid. Her condition later decompensated and ARDS (reported as SAE) developed shortly after (b) (6) arriving at the ER. She was transferred to the Intensive Care Unit. On the subject required intubation for ARDS. During the early course of hospitalization, the subject had decreased hematocrit which required treatment with packed red blood cells. She also experienced oliguria (SAE) with an elevated creatinine which required hemodialysis treatment. On (b) (6)

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considered not clinically significant. The study patch was removed, and the subject was discontinued from the study on March 5, 2015. Clinical laboratory assessments performed on February 25, 2015, were within normal limits. The subject was scheduled to have laparoscopic surgery after a course of antibiotics; however, on February 27, 2015, the subject reported increasing abdominal pain without resolution. Clinical laboratory results revealed a lipase of 19 U/L (normal 22-51 U/L) and albumin at 3.4 g/dL (normal 3.5-4.8 g/dL). All other laboratory results, as well as the subject’s vital signs, were within normal limits. It was (b) (6) also noted that the subject’s weight at this time was 133 kg (293.2 lbs). On the subject underwent laparoscopic cholecystectomy with cholangiogram. The subject was anesthetized with Marcaine, and the gallbladder was removed. The cholangiogram was normal. The surgical pathology report revealed cholelithiasis and slight chronic cholecystitis. The subject had an unremarkable recovery and was discharged with Colace and oxycodone. The event was considered resolved. The subject’s last patch removal was on February 24, 2015, and she was discontinued from the study on March 5, 2015. The Investigator and Sponsor consider this SAE to be possibly related to AG200-15.

Serious Adverse Events: Acute/chronic cholecystitis without obstruction and cholelithiasis

The subject is a 28-year-old white, non-Hispanic female who signed informed consent for Study 23 on May 28, 2015. At screening, the subject had a BMI of 39 kg/m2 and weighed 103 kg (227.1 lbs). Screening laboratory assessments and vitals, with the exception of BMI, were within normal limits. Drug testing at screening was negative. The subject reported a medical history of kidney stones, benign skin growth on neck, and hirsutism. She reported prior use of oral hormonal contraception but not within the last 6 months. No concomitant medications were reported at screening. On July 15, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment, except BMI, were within normal limits.

(b) (6) On the subject reported going to ER with abdominal pain described as sharp and stabbing in the right upper quadrant, nausea, vomiting, blood in stool, and anorexia. A CT of the abdomen indicated mild enteritis and cholelithiasis. The subject also had an elevated WBC count (13 thou/uL) and elevated glucose (133 mg/dL). She was treated with Toradol, Zofran, and morphine in the ER and discharged. Additional medications given included Cipro, Flagyl, Norco, and IV hyoscyamine, and Levsin. Last patch removal date was April 22, 2016, and the subject discontinued the study on May 2, 2016. The subject symptoms persisted and cholecystectomy was recommended. The subject underwent (b) (6) laparoscopic cholecystectomy on The final microscopic diagnosis was cholelithiasis, acute and chronic cholecystitis with prominent mural fibrosis and myoid changes. The subject tolerated the procedure well and was discharged the same day. The Investigator and the Sponsor consider these events possibly related to AG200-15.

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Serious Adverse Event: Necrotizing Pancreatitis, cholelithiasis, acute respiratory distress syndrome, oliguria, multiorgan failure, bilateral deep vein thrombosis, Klebsiella bacteremia, gastrocutaneous fistula, stage II pressure ulcers The subject is a 25-year-old Hispanic female, reporting her race as “Other,” who signed informed consent for Study 23 on April 15, 2015. At screening, the subject weighed 97.3 kg (214.5 lbs) with a BMI of 35.7 kg/m2. Abnormal screening laboratory assessment was erythrocytes (5.3x1012/L). Vital signs were completed on April 15, 2015, and were within normal limits with the exception of BMI. Drug testing at screening was negative. The subject reported fibroids and obesity in the medical history. No concomitant medications were reported at screening. She reported being a non-smoker and consumes less than one drink per week. The subject’s contraceptive history includes the use of oral contraceptive pills within the six months prior to screening as well as emergency contraception use greater than six months prior to study inclusion. (b) (6) On the subject was enrolled in the study and her first patch was applied. Vital signs at enrollment were within normal limits with the exception of her pulse (elevated at 99 bpm).

(b) (6) On the subject presented to the ER with complaints of pain and fainting and was admitted. Her condition later decompensated and acute respiratory distress syndrome (ARDS) (b) (6) developed shortly after arriving at the ER. She was transferred to the ICU. On the subject required intubation for ARDS. During the early course of hospitalization, the subject had decreased hematocrit, which required treatment with packed RBCs. She also experienced oliguria with an elevated creatinine of 3.9 mg/dL, which required hemodialysis treatment through (b) (6)

(b) (6) On blood work indicated an increased bilirubin of 3.3 mg/dL. An ultrasound done (b) (6) on revealed cholelithiasis and ascites. A CT of the abdomen and pelvis was done on the same day that showed severe acute pancreatitis, known cholelithiasis, moderate ascites, and a large pedunculated uterine fibroid. (b) (6) On another CT of the abdomen and pelvis was performed, which showed small perihepatic ascites, cholelithiasis with contracted gallbladder, and a small right pleural effusion. (b) (6) On the subject had spiking fevers with suspected fungal infection. She was treated with vancomycin, micafungin, cefepime, and Flagyl.

(b) (6) On the subject underwent tracheostomy because she still required mechanical ventilatory assistance.

(b) (6) On , the subject became febrile requiring paracentesis for culture, which revealed (b) (6) Klebsiella. The subject’s WBC count was elevated to 19.4 thous/uL on and it was suspected she may have Klebsiella bacteremia; however, the blood cultures were negative on

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Serious Adverse Event: Cholelithiasis The subject is a 33-year-old, white, Hispanic female who signed informed consent for Study 23 on February 11, 2015. Her weight at screening was 96.3 kg (212.3 lbs) and her BMI was 38.8 kg/m2. The subject reports a medical history of myopia, fractures in the right leg and right wrist, as well as cholecystitis in October 2014. No concomitant medications were reported at screening. The subject reports prior use (greater than 6 months ago) of the contraception patch, vaginal ring, and emergency contraception. The screening physical and gynecological exams were within normal limits except scarring and deformity following surgery after a motor vehicle accident. Vital signs were within normal limits at screening with the exception of BMI. Screening laboratory assessments were within normal limits except platelets (431x109/L). The subject was enrolled in the study on March 12, 2015. (b) (6) On the subject went to the ER with complaint of right upper quadrant abdominal pain, nausea, and vomiting for the last 24-48 hours. (b) (6) The subject recovered without sequelae and was discharged on The subject did not discontinue study medication and continued in the study. Both the Investigator and the Sponsor feel that this event was possibly related to study drug given the expectedness and temporal association. The subject reported a 10/10 on the pain scale and was intolerant to taking anything by mouth. It was determined that the subject had cholelithiasis with elevated liver enzymes. The symptoms improved and the subject was initially discharged but she returned to the ER shortly after with returning symptoms and the subject was then admitted for a cholecystectomy and intraoperative cholangiogram. During the cholangiogram, the no contrast could be visualized in the duodenum. The subject then underwent an ERCP, and a stone was found in the cystic duct. No stones were found in the common bile duct. The subject had a sphincterotomy and a stent placed on the common bile duct. The subject was stable for discharge on (b) (6) , and was to follow up with her primary care physician in 1 week for liver function tests, with her general surgery in 1 week for post-operative checkup, and with her GI physician in 6-8 weeks for an endoscopic retrograde cholangiopancreatography and removal of stent. The subject was discharged with Norco for pain and ondansetron for nausea. Study drug was temporarily interrupted from October 9, 2015, to October 12, 2015, but was not discontinued. The Investigator considered the SAE of cholelithiasis unrelated to the study medication; however, the Sponsor considered the exacerbation of a pre-existing condition to be possibly related given the temporal association and side-effect profile of AG200-15. 11.12.2.2 Gastroenteritis (3) Serious Adverse Events: Gastroenteritis The subject is a 23 year old White, non-Hispanic female with a BMI of 35.0 screened for Study 12 on 9/07/10: Her gynecological history includes no prior pregnancy. The subject’s first menses was at 12 years old and subject has regular menses occurring approximately every 28-30 days and lasting 5 days. Her last menses prior to screening was 8/27/10.

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The subject was using condoms as a method of birth control prior to study entry. No significant medical or concomitant medication history is noted except for headaches for which she takes Excedrin prn and the subject’s laboratory evaluations, physical exam and vital signs were within normal limits. The subject met all of the inclusion and exclusion criteria and was randomized to the AG200-15 treatment group on 9/10/10. The subject applied the first patch on 10/02/10.

(b) (6) On subject developed abdominal pain and was admitted to the hospital for hydration (b) (6) and evaluation. A CT scan of the abdomen and pelvis with contrast performed on showed a questionable thickening/edema involving the mid small bowel loops raising a suspicion of infectious versus inflammatory enteritis. A CT scan performed the following day showed no bowel abnormality and a significant decrease in free fluid noticed in the previous exam. Laboratory tests showed signs of urinary tract infection. Blood tests showed leukocytosis, slight increase in RBC and hemoglobin/hematocrit and hyperglycemia as well as high CRP. Blood, urine and stool cultures were negative. The investigator deemed the event unrelated to study drug. Study medication was not discontinued and the subject continues in the study. Discharged (b) (6) event was considered resolved. Study Medication was not discontinued and subject continues in the study.

Serious Adverse Event: Gastroenteritis

The subject is a 22-year-old non-Hispanic, Native Hawaiian or other Pacific Islander female who signed informed consent for Study 23 on June 10, 2015. At screening, the subject had a BMI of 24 kg/m2 and weighed 53.9 kg (118.8 lbs). Screening laboratory assessments were within normal limits with the exception of monocytes (0.12x109/L). Screening vitals were within normal limits. Drug testing at screening was negative. The subject reported no significant medical history. She was a prior user of injectable contraceptive but otherwise reported no concomitant medications at screening. On July 22, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment were within normal limits.

(b) (6) On the subject reported to the ER with several hours of nausea, vomiting, and diarrhea. The subject had a fever, and her WBC was elevated to 16.2 K/uL. Urinalysis showed WBCs and bacteria. An abdominal CT showed minimal wall thickening of the appendix. She was diagnosed with gastroenteritis and possible urinary tract infection and was hospitalized. The subject was afebrile but tachycardic at 107 bpm upon admission. During hospitalization, she was (b) (6) treated with hydrocodone/acetaminophen, ondansetron, Levaquin, and cephalexin. On (b) (6) WBC count was reported at 3.6x109/L. Urinalysis and culture revealed mixed gram- (b) (6) positive bacteria. The subject was discharged on on a continued course of cephalexin. Last patch removal date was August 27, 2016. The subject completed the study on September 12, 2016.

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The Investigator and Sponsor consider this SAE unrelated to AG200-15.

Serious Adverse Event: Gastroenteritis

The subject is a 22-year-old black, non-Hispanic female who signed informed consent for Study 23 on September 11, 2015. At screening, the subject’s weight was 62.4 kg (137.6 lbs) and her BMI was 24.9 kg/m2. Screening laboratory assessments were within normal limits except monocytes (0.19x109/L), cholesterol (5.53 mmol/L), and LDL (3.47 mmol/L). Vital signs were within normal limits. At screening, the subject reported a medical history of LSIL. The subject was a prior user of injectable hormonal contraception. There were no concomitant medications reported before enrollment. On October 5, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment were within normal limits. On January 3, 2016, the subject developed fever, nausea, and diarrhea shortly after eating at (b) (6) Chipotle Mexican Grill. Later she developed vomiting and a rash and went the ER on (b) (6)

The subject was admitted and treated with IV fluids and medication for pain, nausea, and fever. The subject continued to wear the patch throughout her hospitalization. She was discharged on (b) (6) has since recovered, and has followed up with her primary care physician. Medical records have been requested. The Investigator and Sponsor consider this SAE to be unrelated to AG200-15.

11.12.2.3 Major Depression (3) Serious Adverse Event: Major depressive disorder

The subject is a 20-year-old, white, non-Hispanic female who signed informed consent for Study 23 on May 18, 2015. At screening, the subject weighed 69.9 kg (154.1 lbs), with a BMI of 22.1 kg/m2. Screening laboratory assessments within normal limits. Traces of protein were present in her urine at screening. Screening vitals were within normal limits. Drug testing at screening was negative. At the time of screening and enrollment, the subject reported a medical history of seasonal allergies; however, medical records indicate she also has a history of episodic anxiety and depression as well as cutting since age 14. Concomitant medications include cetirizine and recent use of NuvaRing. On June 29, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment were within normal limits.

(b) (6) The subject initially stated she was admitted to the hospital on , for a food (b) (6) allergy/reaction. However, medical records indicate the subject was admitted on for suicide attempt after she reported to the emergency room indicating she had ingested approximately 18 Tylenol tablets. The subject also reported a history of sexual, physical, and emotional abuse and described being distraught due to recent conflicts with her boyfriend. The subject was diagnosed with major depressive disorder and post-traumatic stress disorder, for which she was treated with a trial of sertraline 25 mg PO QD. The subject was discharged on

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(b) (6) when her suicidal ideations had resolved. The discharge plan was for her to attend outpatient counseling and continue monitoring the effectiveness of sertraline. The patch was (b) (6) initially only temporarily discontinued on , but due to suicidal ideation, the subject was no longer eligible to continue in the study. The subject was scheduled for a discontinuation visit on July 27, 2015 but did not attend the appointment. After contacting the subject, it was determined she removed the patch on August 2, 2015, and despite the subject refusing to come in for a termination visit she was discontinued from the study on September 2, 2015. The Investigator considered the SAE of major depressive disorder to be unrelated to AG200-15. However, due to the temporal association and expectedness of the event, the Sponsor considers this event possibly related to AG200-15.

Serious Adverse Event: Major depressive episode - recurrent

The subject is an 18-year-old Hispanic female of Chinese and Mexican descent who signed informed consent for Study 23 on October 2, 2015. At screening, the subject had a BMI of 30.3 kg/m2 and weighed 90.3 kg (199.1 lbs). Abnormal screening laboratory assessments were cholesterol (4.45 mmol/L), LDL (2.92 mmol/L), and alanine aminotransferase (51 U/L). Except slightly high BMI, vital signs were within normal limits. Drug testing at screening was negative. The subject reported a medical history of urinary tract infection, arm surgery, abnormal vaginal odor, dry throat, and minor scoliosis. In addition, the subject had a history of an eating disorder, self-harm, suicidal behavior, child abuse, and chronic marijuana use. A history of depression that started at age 12, resolved in 2014, then returned in August 2015 was reported to the Investigator on May 3, 2016. She reported recent use of oral hormonal contraception and prior use of emergency contraception. Concomitant medication reported at screening included the contraception norethindrone. On October 16, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment were within normal limits. (b) (6) On May 3, 2016, the subject reported being admitted to the hospital on for severe (b) (6) depression and suicidal ideations. The subject was admitted under section , which authorizes a qualified officer or clinician to involuntarily confine a person suspected to have a mental disorder that makes him or her a danger to him- or herself, a danger to others, and/or (b) (6) gravely disabled. She was subsequently discharged on because her psychiatric (b) (6) assessment did not meet the criteria for a hold. The subject reported she was under a lot of stress and feeling neglected in a polygamous relationship with her boyfriend. According to the subject’s electronic diary, she removed the last patch on March 26, 2016, and did not reapply. She received a primary diagnosis of major depressive episode - recurrent; a secondary diagnosis of self-reported monthly cannabis abuse was provided based on her negative drug test. Urine pregnancy test was negative. The subject was discontinued from the study on May 5, 2016. The Investigator and Sponsor consider this SAE possibly related to AG200-15.

Serious Adverse Event: Major depressive disorder, recurrent, severe without psychosis

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The subject is a 22-year-old white, Hispanic female who signed informed consent for Study 23 on June 16, 2015. At screening, the subject weighed 87.5 kg (192.9 lbs) with a BMI of 36.5 kg/m2. Screening laboratory assessments and vitals were within normal limits with the exception of BMI. Drug testing at screening was negative. The subject reported a medical history of asthma, headaches, depression, and left hand tendon surgery. Concomitant medications include a multivitamin and calcium supplement, recent use of oral hormonal contraceptive and emergency contraceptive, and prior use of injectable contraceptive. On July 31, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment were within normal limits except for a slightly high respiratory rate (21 breaths/min).

(b) (6) On the subject was admitted to the hospital for a suicide attempt after taking 100 propranolol pills. According to the subject, her boyfriend noticed she was acting strange and decided to call 911. The subject was transported to the hospital via ambulance. Upon admission, her vital signs were within normal limits. Laboratory values were also within normal limits with the exception of glucose which was elevated to 153 mg/dL. The subject’s glucose had normalized to 78 mg/dL later that day. The subject indicated she had a history of depression and was a cutter as a teenager, but denies prior hospitalization or suicide attempt. The subject also admits to smoking marijuana weekly but does not use any other drugs. The subject was cleared medically and admitted to the adult psychiatric unit. During her hospital stay, she was treated with IV fluids, magnesium hydroxide, ziprasidone, Tylenol, propranolol, and fluoxetine 20 mg. (b) (6) The patch was removed by the nursing staff on The subject also had an (b) (6) echocardiogram on which was normal. The subject had a repeat (b) (6) echocardiogram on which indicated sinus tachycardia, for which additional (b) (6) information has been requested. The subject was discharged on with a diagnosis of major depressive disorder, recurrent and severe without psychosis, and was advised to continue taking fluoxetine. She was referred for psychiatric counseling. The subject reapplied the patch on (b) (6) The removal date is unknown. She applied another patch on August 28, 2015, but the patch was removed later that same day at her discontinuation visit. The subject was discontinued permanently from the study on August 28, 2015. The Investigator considered this SAE to be unrelated to AG200-15; however, due to the temporal association, the Sponsor considers this SAE to be possibly related to AG200-15.

11.12.2.4 Appendicitis (2) Serious Adverse Event: Appendicitis The subject is a 28 year old White, non-Hispanic female with a BMI of 24.1 who was screened for Study 12 on 8/31/10. She has no history of prior pregnancies. The subject’s first menses was at 12 years old. Her menses is regular occurring approximately every 28 days and lasting 4 days. Her last menses prior to screening was 8/16/2010. The subject was using the oral contraceptive Yaz as a current method of birth control until 9/10/2010. Her medical history includes asthma and seasonal allergies since 1990, menstrual

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cramps since 1994, intermittent urinary tract infections since 2000 and anemia and intermittent headaches since 2001. At Screening, concomitant medications included Singulair 10 mg qd for asthma and ibuprofen 200 mg prn for menstrual cramps. The subject’s laboratory evaluations, physical exam and vital signs were within normal limits. The subject met all of the inclusion and exclusion criteria and the subject was randomized to the AG200-15 treatment group on 9/8/2010. The subject applied the first patch on 9/11/2010. (b) (6) On subject was admitted to the ER with a 3-day history of mid-abdominal pain. A CT scan showed an inflammatory mass in the right lower quadrant and a diagnosis was made for acute appendicitis with contained perforation. The subject was treated with IV antibiotics (b) (6) rather than surgery. Subject was discharged and subject had appendix removed (b) (6) on Subject continued in the study.

Serious Adverse Event: Acute appendicitis

The subject is a 22-year-old white, Hispanic female who signed informed consent for Study 23 on September 16, 2015. At screening, the subject’s weight was 95.8 kg (211.2 lbs), and her BMI was 32.1 kg/m2. Abnormal screening laboratory assessments included cholesterol (6.36 mmol/L) and LDL (4.16 mmol/L). Squamous epithelial cells, traces of protein, a high pH, erythrocytes, and leukocytes were present in urine. With the exception of high BMI, vitals were within normal limits at screening and enrollment. Drug testing at screening was negative. The subject reported a current medical history of depression, anxiety, mild chronic gastritis, seasonal allergies, positive chlamydia test, pneumonia, and an allergy to penicillin. Concomitant medications at screening included Xanax, Lexapro, loratadine, omeprazole, Zithromax, albuterol nasal spray, and Biaxin. On September 23, 2015, the subject was enrolled in the study and her first patch was applied. The subject reported being a current hormonal contraceptive user at enrollment

(b) (6) On the subject went to the ER for ongoing right lower quadrant pain with nausea and diarrhea for the previous 16 hours. She was subsequently admitted to the hospital with acute appendicitis. The subject’s WBC on admission was 17.48 K/uL. The subject underwent an appendectomy and was discharged the same day. During her hospital stay, the subject received IV hydration, SC heparin, IV Dilaudid, IV Reglan, IV Zofran, PO Norco, PO oxycodone, PO ibuprofen, IV cefotetan, and chlorhexidine. No other information was provided at the time this event was reported; medical records were also pending at that time. Last patch removal date was September 8, 2016. The subject was not discontinued from the study and has recovered. She completed the study on October 4, 2016. The Investigator and Sponsor consider this SAE to be unrelated to AG200-15.

11.12.2.5 Cholecystitis (2) Serious Adverse Event: Cholecystitis The subject is a 29-year-old white, non-Hispanic female who signed informed consent for Study 23 on October 2, 2014. At screening, the subject weighed 116.1 kg (255.0 lbs), and her BMI was 40 kg/m2. Her screening vitals, with the exception of BMI, were otherwise within normal limits.

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Some screening laboratory assessments were not within normal limits, including alkaline phosphatase (127 U/L), cholesterol (5.51 mmol/L), and triglycerides (2.55 mmol/L). She reported a history of pilonidal cyst in the umbilicus region, ankle fracture, elective abortion, and vaginal infection. Metronidazole and dietary supplement were the only reported concomitant medications. The subject was enrolled in the study and applied her first patch on November 1, 2014.

(b) (6) On (Cycle 5), the subject began experiencing sudden onset sharp stabbing pain that radiated to her back approximately two hours after eating tacos with beef and went to the emergency room. She was admitted for pain management and possible operative intervention. Laboratory tests revealed liver enzymes (ALT 111 U/L and AST 150 U/L). Abdominal ultrasound revealed multiple stones in the gallbladder with gallbladder wall thickening consistent with cholecystitis. The subject was treated with IV fluids, cefoxitin, famotidine, Reglan, ibuprofen, ketorolac, (b) (6) lorazepam, ondansetron, piperacillin/tazobactam, and narcotic pain management. On (b) (6) , the subject underwent a cholecystectomy. Operative findings included edema and inflammation of the gallbladder. Following the procedure, she was treated with acetaminophen, ketorolac, metoclopramide, cephalexin, Pyridium, and tamsulosin. The subject was discharged (b) (6) later the same day on No complications were noted, and the subject has since recovered without sequelae. The subject removed the patch on March 26, 2015, and was discontinued from the study on April 27, 2015. The Investigator and Sponsor consider this SAE to be possibly related to AG200-15. Serious Adverse Events: Cholecystitis and hepatitis This subject is a 32-year-old non-Hispanic, black female who signed informed consent for Study 23 on July 22, 2015, and re-screened on August 12, 2015. Her weight at screening was 128.4 kg (283.1 lbs) and her BMI was 44.4 kg/m2. Screening laboratory assessments were within normal limits with the exception of hematocrit (0.32) and hemoglobin (95 g/L). Vital signs were within normal limits with the exception of BMI. Bacteria, squamous epithelial cells, protein, erythrocytes, and leukocytes were present in the urine. The subject reports no significant medical history other than four cesarean sections; however, medical records received from the hospital indicate she has chronic anemia, constipation likely due to ferrous sulfate, as well as acid reflux approximately 2 times per week. Concomitant medications noted in the hospital medical records indicate the subject is taking ferrous sulfate. The subject reports having used oral hormonal contraception as well as a progestin IUD and injectable contraception in the past but not in the last 6 months. The screening physical and gynecological exams were within normal limits. The subject was enrolled in the study on September 16, 2015, and her first patch was applied. (b) (6) On the subject reported to the ER with severe abdominal pain and vomiting. The subject called the study site to inform them she was hospitalized for cholecystitis and will be having her gallbladder removed. The subject reports experiencing right upper quadrant pain,

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vomiting, diarrhea, and jaundice over the past month prior to reporting to ER. Results from the abdominal ultrasound indicated gallstones but no biliary dilatation. HIDA scan results showed retained hepatic parenchymal tracer which demonstrates liver dysfunction. The subject’s ALT (157 U/L) and AST (97 U/L) were also elevated. Alkaline phosphatase was 215 U/L, bilirubin was 0.7 mg/dL, and albumin was 2.8 g/dL. The subject’s hepatitis panel was negative. During her hospitalization, the subject was treated with famotidine, Phenergan, and Norco. Medical records received from the cholecystectomy and liver wedge biopsy show chronic cholecystitis with complete impaction and innumerable stones which distend the wall of the gallbladder. The lumen showed mucosal changes, suggesting cholesterolosis and mucosal ulceration. The liver wedge biopsy showed chronic hepatitis with minimal activity and stage 1 fibrosis possibly related to transient obstruction of the biliary tree and some background chronic changes secondary to a prior occurrence. Laboratory values including ALT, AST, and ALP were noted to be decreasing post-surgery. Follow-up liver enzyme laboratory assessments (ALT and AST) taken on January 17, 2016, were within normal limits. Additionally, in a follow-up visit with her primary care physician, the subject indicated she recovered but had some issues with constipation post-operatively due to pain medications. The subject also indicated she had loose stools when eating fried foods but is currently on a weight loss program and is avoiding fried foods. (b) (6) Last patch removal date was The subject attended her early termination visit on March 11, 2016, and treatment was permanently discontinued that day. The Investigator and Sponsor consider the SAEs of cholecystitis and hepatitis to be possibly related to AG200-15. 11.12.2.6 Ectopic Pregnancy (2) Serious Adverse Event: Ectopic pregnancy

The subject is a 22-year-old black, non-Hispanic female who signed informed consent for Study 23 on April 15, 2015. At screening, the subject’s weight was 115 kg (253.5 lbs), and her BMI was 47.9 kg/m2. Abnormal screening laboratory assessments were hematocrit (0.31), hemoglobin (97 g/L), monocytes (0.13x109/L), and platelets (464x109/L). At screening, temperature and blood pressure were within normal limits; however, BMI was high at 47.9 kg/m2, heart rate was 57 bpm, and respiratory rate was 22 breaths/min. The subject reported a history of mild depression, acid reflux, seasonal allergies, obesity, and back pain. The subject was a prior user of an injectable hormonal birth control. The subject has had one prior pregnancy with one full-term delivery. The subject was taking a prenatal vitamin at screening for general health and ibuprofen on an as needed basis for back pain. On May 28, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment were within normal limits.

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On June 13, 2016, during the end of study visit, the subject had a positive serum β-hCG of 23 mIU/mL. The subject’s last patch wear was noted to be on May 19, 2016. A repeat serum β-hCG on June 15, 2016, was also positive with a result of 43 mIU/mL. An ectopic pregnancy was suspected due to slowly rising β-hCG levels. No risk factors for ectopic pregnancy were evident. A transvaginal ultrasound done on (b) (6) showed a left adnexal mass measuring 1.7 x 1.3 x 1.3 cm with a fetal pole noted and a fetal heartbeat detected. The CRL estimate of gestation was 6 weeks and 1 day. The subject was diagnosed with an intact left ectopic pregnancy and was scheduled for surgery. The subject’s hemoglobin was 10.9 g/dL. No other laboratory (b) (6) abnormalities were noted. The subject had a laparoscopic, left partial salpingectomy on (b) (6) without complication and recovered well. The pregnancy is considered post-treatment. The Investigator and Sponsor consider this SAE to be unrelated to AG200-15.

Serious Adverse Event: Left tubal ectopic pregnancy

The subject is a 30-year-old white, non-Hispanic female who signed informed consent for Study 23 on August 28, 2015. At screening, the subject’s weight was 104.3 kg (229.9 lbs) and her BMI was 38.9 kg/m2. Screening laboratory assessments were within normal limits with the exception of HDL (0.78 mmol/L). Vital signs at screening were within normal limits except BMI. Traces of protein were present in her urine. The subject reported dermatologic urticaria, urethral and vaginal sling, allergy to latex and mold, mononucleosis, urinary incontinence, and heart murmur. The subject was a recent user of a progestin IUD, but was otherwise naïve to hormonal birth control. The subject has had two prior pregnancies that resulted in two full-term deliveries. She reported Mirena as a concomitant medication at screening. On October 8, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment were within normal limits. On January 28, 2016, the subject had a positive serum pregnancy test which was 962 mIU/L. Additional laboratory assessments were performed by a local laboratory on January 29, 2016, with the result of 610 mIU/L and on February 5, 2016, with a result of 2301 mIU/L. A transvaginal ultrasound was performed that showed no gestational sac and a left adnexal mass. An additional serum pregnancy test was performed by the clinical trial laboratory on February 8, 2016, which was 2206 mIU/L. The subject was subsequently diagnosed with a left tubal ectopic pregnancy. Treatment with methotrexate 50 mg IM once weekly until resolution was initiated on February 8, 2016. On February 12, 2016, a serum pregnancy test result at the local laboratory was 2399 mIU/L. At that time the subject was given a second methotrexate injection of 50 mg IM. A serum pregnancy test done on February 19, 2016, showed a decreasing value at 450.8 mIU/L, and no methotrexate was given. The last serum pregnancy test was performed on February 26, 2016, which was again decreased to 61 mIU/L. At that time, no methotrexate was given, the pregnancy was considered resolved, and the subject recovered. No further follow-up was planned. Last patch removal date was January 21, 2016, and the subject was discontinued on January 27, 2016. The Investigator and Sponsor consider this SAE to be possibly related to AG200-15.

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11.12.2.7 Pneumonia (2) Serious Adverse Event: Bilateral Pneumonia

The subject is a 34 year old, White, non-Hispanic female with a BMI of 26.2 who was screened for Study 12 on 8/17/10. She has a gynecological history of no prior pregnancies. The subject’s first menses was at 13 years old. Her menses is regular occurring approximately every 28-32 days and lasting 4 days. Her last menses prior to screening was 8/10/10. The subject was using male condoms as a current method of birth control prior to study entry. Subject informed she was a smoker from 1994 through 4/2010. Her medical history includes depression, fibromyalgia, migraines, irritable bowel syndrome, asthma, bilateral pneumonia (4/2010), C. dificile colitis (7/2010) allergic rhinitis and gastroesophageal reflux disease. Her surgery history included cholecystectomy (b) (6) ) and left foot surgery (1992). Concomitant medication history includes Zoloft and Klonopin for depression, Lyrica, Percocet and Excedrin for fibromyalgia, Nexium and Dexilant for GERD, and acidophilus and Bentyl for IBS. The subject’s laboratory evaluations, physical exam and vital signs were within normal limits. The subject met all of the inclusion and exclusion criteria and the subject was randomized to AG200- 15 on 8/31/10. The subject applied the patch on 9/10/10.

(b) (6) On the subject went to the emergency room with complaints of productive cough, shortness of breath and severe right scapular pain. Her physical examination revealed findings of bilateral wheezes and scattered bronchi. Her medications prior to admission included Symbicort, albuterol, astepro 0.15%, Lyrica, Dexilant, Potassium ER, Creon, Tramadol, Percocet, Fentanyl, Librax, Meclizine, Tigan, Klonopin, prednisone, Bentyl, and acidophilus. She was admitted with a suspicion of pneumonia and asthma exacerbation. She was treated with steroids, vancomycin (b) (6) initially and then Zosyn ((b) (6) through ).

(b) (6) During her hospital stay she developed antibiotic-induced diarrhea. Chest X-Ray on showed bilateral changes suggestive of congestive changes and/or infiltrates.

(b) (6) Blood culture on was negative. Labs have shown mild anemia and high white cell blood count through hospital stay. Stool culture was negative for C. difficile. Discharged (b) (6) ; event considered resolved. Study medication was not discontinued and subject continues in the study.

Serious Adverse Event: Pneumonia

The subject is a 26-year-old white, non-Hispanic female who signed informed consent for Study 23 on June 11, 2015. At screening, the subject weighed 112.4 kg (247.8 lbs), with a BMI of 46.9 kg/m2. Abnormal screening laboratory assessments were eosinophils (0.75x109/L), eosinophils/leukocytes (11.4%), monocytes (0.19x109/L), cholesterol (5.28 mmol/L), and LDL (3.49 mmol/L). Vital signs at screening were within normal limits except for BMI. Drug testing at screening was negative. The subject reported a current medical history of depression. The

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subject reports being a pack-a-day smoker since 2010. The subject reports no significant medical history and no concomitant medications. On July 10, 2015, the subject was enrolled in the study and her first patch was applied. Her vitals at enrollment were within normal limits.

(b) (6) On the subject informed the Investigator that she was admitted to the hospital with pneumonia. A CT scan of the chest indicates mild, patchy, diffuse bilateral pulmonary airspace consolidation indicative of infectious pneumonia or pulmonary edema. The subject had an elevated WBC count on admission of 15.2 which decreased to 12.1 at discharge. The subject was treated with albuterol, Bacid, Levaquin, and prednisone starting at 60 mg then (b) (6) tapered to 20 mg. The subject was discharged on Discharge medications included levofloxacin, guaifenesin, acidophilus, prednisone taper (60 mg x 2 days, 40 mg x 2 days, 20 mg x 2 days), and albuterol. The discharge diagnosis was pneumonia and acute bronchitis. The subject was seen by the Investigator on September 8, 2015, and was symptom- free. The event is considered resolved. Last patch removal date was November 13, 2015. The subject was discontinued from the study on January 15, 2016. The Investigator and Sponsor consider this SAE to be unrelated to AG200-15.

11.12.2.8 Suicidal Ideation (2) Serious Adverse Event: Suicidal ideation The subject is a 38 year old, White, Hispanic female with a BMI of 40.5 who was screened for Study 12 on 9/02/10. She has a gynecological history of 3 prior pregnancies with 2 live births and one abortion in 1990. The subject’s first menses was at 13 years old. Her menses is regular occurring approximately every 28-30 days and lasting 3 days. Her last menses prior to screening was 8/30/10. The subject was not using any method of birth control prior to study entry. Her medical history (b) (6) includes Thoracic Outlet Syndrome for which she underwent corrective surgery in (b) (6) (b) (6) and surgical removal of the left first rib in and a MVA in Subject was not taking any medication at the time she was screened for the study. The subject’s laboratory evaluations, physical exam and vital signs were within normal limits. The subject met all of the inclusion and exclusion criteria and the subject was randomized to (b) (6) AG200-15 on 9/16/10. The subject applied the patch on 9/25/10. On subject experienced severe depression and thoughts of suicide and was admitted to the hospital. Subject and Principal Investigator attributed both events to the recent passing of subject’s father. Several attempts have been made to obtain subject’s hospital records but subject could not be reached and did not respond to several phone calls/voicemail messages and 2 certified letters. Site and Principal Investigator were concerned with subject’s well-being and contacted subject’s emergency contact who informed that subject was doing well. Emergency contact was asked to have subject contact site but site has not heard from subject. Subject was discharged from the

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(b) (6) hospital on ; suicidal ideation considered resolved. Depression ongoing for which she was prescribed Celexa. Subject is Lost to Follow-Up.

Serious Adverse Events: Bipolar disorder, currently depressed without psychotic features, and suicidal ideation

The subject is a 24-year-old white, non-Hispanic female who signed informed consent for Study 23 on July 21, 2015. At screening, the subject had a BMI of 30.7 kg/m2 and weighed 98.4 kg (216.9 lbs). Abnormal screening laboratory assessment was triglycerides (3.58 mmol/L). Vital signs, with the exception of slightly high BMI, were within normal limits. Drug testing at screening was negative. The subject reported a medical history of mild depression since 2007, seasonal allergies, tonsillectomy, adenoidectomy, food poisoning, and gallbladder removal. Medical records indicate a history of bipolar disorder and attention deficit hyperactivity disorder, although this was not reported to the Investigator prior to study entry. After prior use of vaginal ring, she reported switching from oral hormonal contraception directly to the Agile Patch. Concomitant medications reported at screening included Camila, Lo Loestrin Fe, Pepto-Bismol tablets, and Prozac. On August 19, 2015, the subject was enrolled in the study and her first patch was applied. Her vital signs at enrollment were within normal limits, though her BMI was slightly high at 30.7 kg/m2 and temperature was slightly high at 99.3⁰F. The subject was brought to the emergency room by her grandmother after the subject stated she is waiting to kill herself and reported having a plan for committing suicide. The subject also reported being very depressed for the last couple of months, with an inability to eat or sleep regularly, often crying, having severe mood swings, and having very low energy. The subject denies hallucinations. She reported discontinuing her medications for about two weeks. The subject denied drug or alcohol abuse but reported having a pending case for driving under the influence. She was admitted for bipolar disorder with suicidal ideations on (b) (6) . She was treated with dextroamphetamine-amphetamine ER 20 mg QD, lithium carbonate 300 mg QD, BuSpar 15 mg BID, fluoxetine 20 mg QD, hydroxine pamoate 50 mg QD, trazadone 50 mg at bedtime for sleep, and Adderall. Adderall was discontinued prior to discharge. The subject continued wearing the patch and stated she wished to continue in the study. The subject was (b) (6) discharged on and was referred for intensive outpatient counseling on March 29, 2016. At discharge, the subject had a depressed mood but denied suicidal ideations. The subject’s last patch was removed and she was permanently discontinued from the study on April 14, 2016. The Investigator considers these events unrelated to AG200-15. The Sponsor considers these events possibly related to AG200-15.

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