Nonprescription Drugs Advisory Committee Meeting September 18

FDA Briefing Document NDA 208-425 Nicotine Mouth Spray

Nonprescription Drugs Advisory Committee Meeting

September 18, 2019

The committee will discuss data submitted by GlaxoSmithKline to support new drug application (NDA) 208-425, for over-the-counter (OTC) marketing of nicotine mouth spray, 1 mg. The proposed OTC use is to reduce withdrawal symptoms, including nicotine craving, associated with quitting smoking. The applicant proposes to label the product for 18 years and older. The committee will be asked to consider whether data support an acceptable benefit-risk profile for the nonprescription use of nicotine mouth spray, 1 mg by OTC consumers.

i FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Disclaimer Statement

The attached package contains background information prepared by the Food and Drug Administration (FDA) for the panel members of the advisory committee. The FDA background package often contains assessments and/or conclusions and recommendations written by individual FDA reviewers. Such conclusions and recommendations do not necessarily represent the final position of the individual reviewers, nor do they necessarily represent the final position of the Review Division or Office. We have brought NDA 208-425 to this Advisory Committee in order to gain the Committee’s insights and opinions, and the background package may not include all issues relevant to the final regulatory recommendation and instead is intended to focus on issues identified by the Agency for discussion by the advisory committee. The FDA will not issue a final determination on the issues at hand until input from the advisory committee process has been considered and all reviews have been finalized. The final determination may be affected by issues not discussed at the advisory committee meeting.

ii FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Table of Contents

Table of Tables ...... v Table of Figures ...... vii Division Director Memorandum ...... 8 Draft Topics for Discussion ...... 12 1. Introduction ...... 13 2. Background ...... 13 3. Summary of Presubmission/Submission Regulatory Activity ...... 16 4. Drug Product Summary ...... 17 5. Labeling Summary ...... 17 6. Clinical Pharmacology Summary ...... 18 6.1. Results from Study NICTDP1065 ...... 20 6.2. Results from Study NICTDP1066 ...... 22 7. Summary of Clinical Trials ...... 25 7.1. Review of Efficacy ...... 25 7.1.1. Study A6431111: Efficacy and Safety following use of a Novel NRT. Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, 52-Week Study in Smokers Motivated to Quit (Study 11)...... 26 7.1.2. Study CO-140121222102-SCCT (formerly NICTDP3038): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study Using a Naturalistic Clinical Model to Measure the Efficacy and Safety of a Novel Nicotine Replacement Therapy in Smokers Motivated to Quit (Study 38) ...... 34 7.1.3. Efficacy Conclusion ...... 47 7.2. Review of Safety ...... 49 7.2.1. Sources of Data ...... 49 7.2.2. Review of Safety Database ...... 52 7.2.3. Safety Results ...... 53 7.2.4. Safety Conclusions ...... 63 8. Summary of Postmarketing Safety ...... 64 8.1. Applicant Global Safety Database ...... 65 8.2. FDA FAERS Search ...... 70 8.2.1. FAERS Search Strategy ...... 72 8.2.2. FAERS Cases...... 73 8.2.3. Additional FAERS ORAL NRT Adverse Event Search ...... 76 8.3. FDA World Health Organization VigiBase Search ...... 78 8.3.1. World Health Organization VigiBase Database Search Strategy ...... 79 8.3.2. World Health Organization VigiBase Cases ...... 79 8.4. Literature Search ...... 81

iii FDA Briefing Document NDA 208-425 Nicotine Mouth Spray 8.5. Conclusions ...... 84 9. Label Comprehension Study #181093 ...... 84 9.1. Background and Executive Summary ...... 84 9.1.1. General Background on Label Comprehension Studies ...... 84 9.1.2. Executive Summary ...... 86 9.1.3. Regulatory History of LCS #18109 ...... 87 9.2. Study Design and Conduct ...... 87 9.3. Study Results ...... 90 9.3.1. Visibility of Directions for Use ...... 90 9.3.2. Primary Endpoint Analysis ...... 92 9.3.3. Secondary Endpoint Analysis ...... 95 9.3.4. Additional Analyses ...... 99 9.3.5. Conclusions...... 100 10. Human Factors Validation Study ...... 101 11. Appendix ...... 103 11.1. Summary of Presubmission Activities ...... 103 11.2. Drug Facts Label and Directions for Use ...... 108 12. Glossary ...... 114 13. References ...... 115

iv FDA Briefing Document NDA 208-425 Nicotine Mouth Spray

Table of Tables

Table 1. Approved Smoking Cessation Aids ...... 14 Table 2. Timeline of Key Regulatory Activities ...... 16 Table 3. Nicotine Mouth Spray Treatments, Study NICTDP1065 ...... 20 Table 4. Nicotine Pharmacokinetic Parameters (Mean ± SD) After NMS, Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Single-Dose Treatments (Study NICTDP1065) ...... 21

Table 5. Nicotine Baseline Corrected Cmax and AUC∞ (cCmax and cAUC∞) From the NMS Single-Dose (Study NICTDP1065) ...... 22 Table 6. Nicotine Mouth Spray Treatments, Study NICTDP1066 ...... 22 Table 7. Steady-State Pharmacokinetic Parameters After NMS, Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Treatments (Study NICTDP1066) ...... 24 Table 8. Pharmacokinetic Parameters (Mean ± SD) and Ratios* Between Pharmacokinetic Parameters Between Self- vs. Staff-Administered NMS 2 mg/h (Geometric Mean (95% CI)) (Study NICTDP1066) ...... 25 Table 9. Schematic for Study A6431111 ...... 27 Table 10. Patient Disposition for Study A6431111 ...... 29 Table 11. Demographic and Baseline Characteristics for Study A6431111 ...... 30 Table 12. Efficacy Results for Study A6431111 ...... 31 Table 13. User Acceptability Questionnaire (Full Analysis Set) ...... 33 Table 14. Subject Disposition for Study NICTDP3038...... 41 Table 15. Demographic and Baseline Characteristics for Study NICTDP3038 ...... 42 Table 16. Efficacy Results From Study NICTDP3038 (Study 38) ...... 43 Table 17. Subjects’ Perceptions of Investigational Product ...... 44 Table 18. Subjects Perceptions of Investigational Product: Effectiveness of Spray in Dealing With Desire/Urge to Smoke ...... 45 Table 19. Comparison of Subgroups for Pivotal Efficacy Studies ...... 47 Table 20. Clinical Trials ...... 49 Table 21. Study 11 Adverse Events Leading to Subject Discontinuation From Study* ....55 Table 22. Study 38 Adverse Events Leading to Discontinuation* ...... 56 Table 23. Study 11 AEs ≥2% of Active Arm ...... 59 Table 24. Study 38 TEAEs ≥2% of Active Arm ...... 60 Table 25. Study 11 FMQ Burning Sensation ...... 61 Table 26. Study 38 Visual mouth inspection (VMI) examples ...... 61 Table 27. Study 38 ADAE Database ...... 62

v FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Table 28. GSD Distribution of MedDRA PTs for Serious Cases With Frequency ≥10 Cases ...... 66 Table 29. GSD Distribution of MedDRA PTs for Nonserious Cases With Frequency ≥100 Cases ...... 66 Table 30. Summary of Global Safety Database Adverse Event Demographics ...... 67 Table 31. Definitions and Examples of Drug Abuse, Misuse, and Dependence in FDA Guidances (January 2017; November 2017) ...... 72 Table 32. FAERS Search Strategy ...... 72 Table 33. Descriptive Characteristics of All Adverse Events with Nicotine Mouth Spray in this FAERS Case Series, Received by FDA through April 23, 2019...... 73 Table 34. Adverse Event and Other Event Reports for Oral Nicotine ...... 78 Table 35. WHO VigiBase Search Strategy ...... 79 Table 36. Case Characteristics of ICSRs Received by WHO VigiBase through April 28, 2019 (n=180) ...... 80 Table 37. Studies of Longer Duration...... 82 Table 38. Studies of Shorter Duration ...... 82 Table 39. Demographics of Study Population ...... 90 Table 40. Opened vs. Did not Open Drug Fact Label Flap ...... 91 Table 41. Demographics of Study Population by Opening of Flap ...... 91 Table 42. Primary Endpoints for Total Population ...... 93 Table 43. Primary Endpoints by Opening of Flap ...... 93 Table 44. Primary Endpoints by Literacy ...... 94 Table 45. Primary Endpoints by Opening of Flap and Literacy ...... 94 Table 46. Secondary Endpoints: Key Dosing Steps ...... 95 Table 47. Secondary Endpoints: Key Dosing Steps by Opening Flap ...... 95 Table 48. Secondary Endpoints: Key Dosing Steps by Literacy ...... 96 Table 49. Secondary Endpoints: Key Dosing Steps by Opening Flap and Literacy ...... 96 Table 50. Secondary Endpoints: General Use ...... 97 Table 51. Secondary Endpoints: General Use by Opening Flap ...... 98 Table 52. Secondary Endpoints: General Use by Literacy ...... 98 Table 53. Combined Comprehension of Dosing Step 1 ...... 99 Table 54. Combined Comprehension of Dosing Steps 1, 2, and 3 ...... 100

vi FDA Briefing Document NDA 208-425 Nicotine Mouth Spray

Table of Figures

Figure 1. Mean Plasma Concentration vs. Time Profiles Over 12 hours After NMS (or ONS), Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Single-Dose Treatments (Study NICTDP1065) ...... 20 Figure 2. Mean Plasma Concentration vs. Time Profiles Over the First Hour After NMS (or ONS), Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Single-Dose Treatments (Study NICTDP1065) ...... 21 Figure 3. Mean Nicotine Plasma Concentration vs. Time Profiles After NMS (or ONS), Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Multiple-Dose Treatments Over 12 Hours After Start of First Administration (Study NICTDP1066) ...... 23 Figure 4. Mean Nicotine Plasma Concentration vs. Time Profiles After NMS (or ONS), Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Multiple-Dose Treatments After the Last One or Two Doses (11 to 12 Hours After Start of First Administration) (Study NICTDP1066)...... 24 Figure 5. Desire/Urge to Smoke (Subjects With Verified Abstinence During the Prior Week) ...... 32 Figure 6. Desire/Urge to Smoke (Mean ±2 SEM) Subjects With CO-Verified Abstinence Since Last Visit ...... 44 Figure 7. Adverse Events: Study 11 E-Diary...... 58 Figure 8. Leukoplakia at Baseline and 6 Weeks in Study 38 ...... 63 Figure 9. Global Safety Database Nonserious Cases ...... 69 Figure 10. Global Safety Database Serious Cases ...... 70 Figure 11. Rx Nicorette Gum 2mg, 1984-1989 ...... 77 Figure 12. OTC Nicorette Gum 2 and 4 mg, 1996-2001 ...... 77 Figure 13. OTC Nicorette Lozenge 2 and 4 mg, 2002-2007 ...... 77 Figure 14. LCS DFL ...... 89 Figure 15. DFL Tested in the LCS...... 108 Figure 16. DFL Submitted in the NDA ...... 109 Figure 17. DFL Used in Naturalistic Study ...... 111 Figure 18. Directions for Use in Clinical Trial ...... 112 Figure 19. Example of Nicotine Gum DFL ...... 113

vii FDA Briefing Document NDA 208-425 Nicotine Mouth Spray

Division Director Memorandum

Date: August 9, 2019

From: Theresa M. Michele, MD Director, Division of Nonprescription Drug Products (DNDP) CDER, FDA

To: Members, Nonprescription Drugs Advisory Committee

Subject: New Drug Application (NDA) 208-425, nicotine mouth spray 1 mg for the over the counter use as a smoking cessation aid

Background

Thank you for your participation in the Nonprescription Drugs Advisory Committee (NDAC) meeting to be held on September 18, 2019. As members of the Advisory Committee (AC) you provide important expert scientific advice and recommendations to the US Food and Drug Administration (the Agency) on the regulatory decision-making process related to the approval of a drug for over-the-counter (OTC) marketing in the United States. The upcoming meeting is to discuss the New Drug Application (NDA) from GlaxoSmithKline (GSK), seeking approval for direct to OTC marketing of nicotine mouth spray (NMS), 1 mg. The proposed OTC use is to reduce withdrawal symptoms, including nicotine craving, associated with quitting smoking in adults 18 years of age and older. Nicotine replacement products are currently available in the OTC setting as a smoking cessation aid in patch, gum, and lozenge form. In addition, nicotine replacement products are available as a nasal spray and as an oral inhaler on a prescription basis. NMS would offer an alternative dosage form as an aqueous nicotine solution, which is delivered by spraying directly into the oral cavity. NMS is approved in many countries worldwide, including the United Kingdom, Australia, and Canada, with variable behind-the-counter or OTC status, under the trade name Nicorette QuickMist.

As a nicotine replacement therapy with a novel dosage form, the clinical development program of NMS included studies of efficacy and safety as well as consumer studies, with a focus on OTC use. Unlike prescription products, nonprescription drug products can be adequately labeled such that the consumer can self-diagnose, self-treat, and self-manage the condition being treated without the intervention or input of a health care professional. In addition, nonprescription drugs are generally expected to have a low potential for misuse and abuse. Because there is no health care professional available to assist the consumer in determining how to use the product, ensuring easily understandable labeling is critically important to the safety and efficacy of the product. The clinical study program for NMS included two pivotal efficacy trials, four pharmacokinetic studies, one label comprehension study, and one human factors study. In addition, two supportive phase 2 studies and one phase 3 study that was terminated early due to a randomization error were included.

8 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Efficacy

As described in the review of efficacy found in Section 7 of this document, both of the Phase 3 clinical trials were multicenter, randomized, double-blind, and placebo controlled. Study 11, which was consistent with a prescription use setting, was conducted outside the U.S., with training and smoking cessation counseling provided by study personnel. Compliance with dosing was recorded in a subject e-diary and reviewed at each visit. In contrast, Study 38, which was designed to be consistent with typical OTC use, was conducted at U.S. sites without specific training of label contents or behavioral support provided by study personnel. The only information subjects were provided regarding the use of the investigational product was what was on the Drug Facts Label on the outer carton and the User’s Guide contained within the carton. The frequency of investigational product use was at the discretion of the subject and determined by each subject’s review and understanding of the Drug Facts Label and User’s Guide. There was minimal intervention and no behavioral support provided by the study staff. For questions related to investigational product use, the study site staff directed the subject back to the Drug Facts Label and User’s Guide. The study staff provided information on how to operate the dispenser (spray pump as referred to in the Drug Facts Label and User’s Guide) only if questions were initiated by the subject.

Both studies demonstrated a statistically significant difference from placebo for the primary endpoint, the continuous abstinence rate for weeks 2 through 6; however, the results of the two studies were discrepant. Study 11 demonstrated a between group treatment difference of 10%, giving a number needed to treat (NNT) of 10. In study 38, which was planned to resemble the actual OTC use scenario, the treatment difference was only 2%, with a corresponding number needed to treat of 40. Lower than expected quit rates were observed in both the active and placebo groups. Based on these results, 40 smokers would need to be treated with NMS 1 mg instead of placebo in the OTC setting in order to expect one additional person to be continuously abstinent for weeks 2 through 6. Of note, in order to enroll an adequate number of subjects for safety, this study was overpowered to meet the primary efficacy endpoint. Whether this treatment difference represents a clinically meaningful benefit we leave to your discussion.

FDA reviewers examined a number of different exploratory analyses to evaluate potential explanations for this discrepancy, including smoking history, literacy level, level of nicotine dependence, age, gender, and race, none of which explained the difference. Alternative explanations include inadequate OTC labeling, insufficient or incorrect use, differences in populations between the U.S. and Europe, or other factors.

The label comprehension study included 504 participants; of these, 130 (25.8%) were of limited literacy. The four primary comprehension objectives evaluated communication objectives on the Drug Facts label thought most likely to pose a safety risk if consumers did not understand. These included: do not inhale while spraying, rinse immediately with water if you spray in eyes as irritation will occur, maximum number of sprays per hour during Step 1 therapy, and maximum number of sprays per day during Step 1 therapy. Three of these 4 objectives met the prespecified lower bound target of 80%. The primary objective of “Rinse immediately with water if you spray in eyes as irritation will occur” did not meet the prespecified lower bound (LB) target threshold of 80%, with a LB of 74%. While participants did relatively well on the overall safety

9 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray objectives, secondary endpoints evaluating the dosing regimen were less well understood, with only 69% of normal literacy and 62% of low literacy understanding Step 3 dosing. Participants’ comprehension of the three steps combined was even lower, with only 48% of the total population (35% low literacy) correctly answering all three steps. Dosing instructions, which are much more permissive than for other smoking cessation products, may not have been adequately tested since the focus of the study was on safety objectives.

A human factors validation study evaluated 39 subjects’ ability to correctly perform the critical tasks for self-administration of the proposed nicotine mouth spray as described in the labeling (e.g., unlock, prime, align, administer simulated sprays, and lock), and subjects’ ability to comprehend a key message related to priming (when to prime). In the human factors study, there were a number of use failures for the critical tasks of priming, unlocking, and locking the device. While these failures may be associated with failure to obtain a correct first dose, the user would be expected to self-correct and become more facile manipulating the device over time.

Based on the studies described in this briefing package, a key question regarding the efficacy of NMS is whether the treatment difference observed in the OTC setting would translate to a clinically meaningful benefit for smokers using the NMS for a quit attempt without the intervention of a healthcare professional. Whether these studies provide substantial evidence of efficacy for NMS in the OTC setting is a primary focus of discussion for this meeting.

Safety

The safety of NMS primarily relies on data from the two pivotal trials, Study 11 and 38, as well as analysis of postmarketing data from the GSK database, FAERS, the World Health Organization Vigibase and published literature. Safety in clinical trials is described in Section 7 and postmarketing safety is described in Section 8 of this document. In clinical trials, serious adverse events were generally balanced between treatment groups and did not appear to have a causal relationship with NMS. The most frequently occurring adverse events in the phase 3 clinical trials included hiccups, headache, nausea, throat irritation, dyspepsia, and dizziness. Adverse events that affect the gastrointestinal system and nervous system, such as: nausea, vomiting, headaches, and dizziness were common in the active arms of both studies, which are typical adverse events in smoking cessation product studies. Adverse events that are more specific to NMS, such as hiccups, mouth/throat irritation, alteration in taste, dry mouth, mouth irritation, stomatitis, etc., are more likely a function of the delivery system. In the postmarketing setting, dependence was the most frequently reported serious adverse event, and hiccups was the most frequently reported nonserious adverse event, with a reported marketing distribution of approximately 1.4 million canisters of 150 sprays per canister in the fourth quarter of 2018. Overall, pharmacovigilance database and literature searches show a safety profile of NMS similar to existing formulations of oral nicotine products marketed as NRTs.

Because the pharmacokinetic profile of NMS demonstrates a much faster absorption of nicotine than other approved NRTs, a question raised during review of the application is whether NMS is more likely to result in misuse or abuse, particularly by nonsmokers (including adolescents and children) and persons not trying to quit smoking. While a few clear-cut cases of recreational use by adolescents resulting in adverse events were described, substantial numbers of cases were not.

10 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray However, it is of interest that in Study 38, 79% of subjects in the active treatment group continued to use the product after the treatment period ended at Week 26, even though only 3.4% had quit smoking, suggesting dual use. Whether data demonstrate substantial evidence of safety sufficient for marketing in the OTC setting is the second key discussion point for the meeting.

Topics for Discussion

The materials to be discussed at this AC meeting and the opinions we are seeking are primarily related to the overall benefit to risk ratio of NMS as an aid to smoking cessation in the OTC setting. Factors to consider for this discussion include the difference between the two phase three efficacy trials, whether consumers will be able to adequately use the product in the OTC setting based on the product label, labeling differences between this product and other nonprescription nicotine replacement products, human absorption data, and safety, including misuse and abuse. In the regulatory decision-making process to determine approvability of a product, FDA takes into consideration various other factors in addition to clinical and labeling issues, including chemistry, manufacturing and controls of a product. These will not be the focus of this AC meeting. We look forward to the discussion of this application.

11 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Draft Topics for Discussion

1. Discuss the efficacy of nicotine mouth spray (1 mg per spray) as an over-the-counter (OTC) smoking cessation aid. Consider the differences between the efficacy data from studies A6431111 and NICTDP3038.

2. Discuss the results of the label comprehension study and the implications for efficacy in the OTC consumer setting.

3. Do the data provide substantial evidence of efficacy for the use of nicotine mouth spray (1 mg per spray) as a smoking cessation aid in the OTC setting? a. If no, what further data should be obtained?

4. Discuss the safety of nicotine mouth spray 1 mg per spray as a smoking cessation aid in the OTC setting.

5. Discuss the potential for abuse of nicotine mouth spray (1 mg per spray) by the adult and pediatric populations in the OTC setting. Consider its pharmacokinetic profile and other characteristics that are different from currently marketed OTC nicotine replacement therapy products.

6. Do the data provide substantial evidence of safety for OTC use of nicotine mouth spray (1 mg per spray)? a. If no, what further data should be obtained?

7. Is the benefit-risk profile of nicotine mouth spray (nicotine 1 mg per spray) supportive of OTC use as a smoking cessation aid? a. If yes, do you have additional comments or recommendations for labeling? b. If no, what further data should be obtained?

12 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray 1. Introduction

GlaxoSmithKline (GSK) has submitted a new drug application (NDA) for nicotine mouth spray (1 mg per spray) for use as a smoking cessation aid in the over-the-counter (OTC) setting. The proprietary name for the proposed drug product remains under FDA review at the time of this publishing, and therefore it will be referred to as nicotine mouth spray (NMS) throughout this document. The proposed formulation of nicotine in solution and administration using a device by directly spraying onto the oromucosal surfaces are unique aspects of a nicotine replacement therapy (NRT) product in both the OTC and prescription settings.

Nicotine mouth spray is currently approved as a smoking cessation aid in many countries outside the United States, with over 5 years postmarketing experience in several major markets, including the United Kingdom, Australia and Canada. To support the OTC marketing of this product in the United States, GSK submitted the results of two pivotal efficacy trials, four pharmacokinetic studies, and two consumer studies (label comprehension study and human factors study). In addition, two supportive phase 2 studies and one phase 3 study that was terminated early due to a randomization error were included. A review of safety data was also submitted including clinical trial data, postmarketing data, and published literature from the time of 2011 to 2019.

2. Background

Tobacco use is the leading preventable cause of death in the United States, and cigarette smoking causes about one of every five deaths each year (U.S. Department of Health and Human Services 2014). Although there has been a considerable decline in cigarette smoking among U.S. adults in the last 50 years, an estimated 14% of all adults (34.3 million people) were current cigarette smokers in the United States in 2017 (Wang et al. 2018). The benefits of smoking cessation are well established and include reductions in the incidence and prevalence of lung cancer, heart disease, stroke, and chronic obstructive pulmonary disease (U.S. Department of Health and Human Services 2014). The Agency is committed to increasing access to and use of therapies, including NRT drug products, to help more smokers quit smoking (February 2019).1

Currently, there are a variety of drug products available OTC and by prescription for smoking cessation (Table 1). NRT products are available in several different dosage forms: gum, lozenge, patch, nasal spray, and oral inhaler. The nicotine nasal spray and oral inhaler are the only NRT products available with a prescription. Bupropion and varenicline are approved for prescription use only.

1 When final, this guidance will represent the FDA’s current thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at https://www.fda.gov/RegulatoryInformation/Guidances/default.htm.

13 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Table 1. Approved Smoking Cessation Aids Drug Formulation (Dose) Route OTC Products Nicotine Gum Buccal polacrilex (2, 4 mg) Lozenge (2, 4 mg) Mini lozenge (2, 4 mg) Nicotine Patch Dermal (7, 14, 21 mg) Prescription Products Nicotine Inhalant Orally (10 mg cartridge; 4 mg inhaled delivered) Nasal Spray (50 µL/spray; Intranasal 0.5 mg delivered) Bupropion Tablet (150 mg) Oral Varenicline Tablet (0.5, 1 mg) Oral Abbreviations: OTC, over-the-counter

In the OTC setting, smoking cessation is a well-established indication. In 1984, the nicotine gum was the first NRT approved by FDA under an NDA as a prescription drug as a smoking cessation aid. The nicotine patch was subsequently approved as a prescription drug in 1991. In 1996, both the gum and patch formulations were approved for prescription to over-the-counter (Rx-to-OTC) switches. In 2002, nicotine lozenge was the first NRT approved for direct to OTC marketing. The nicotine nasal spray and nicotine oral inhaler were approved for prescription marketing in 1996 and 1997, respectively, and they both currently remain prescription products.

OTC NRTs are marketed for use by consumers without the intervention of a health care professional to obtain the product. OTC drugs generally have these characteristics: • Their benefits outweigh their risks • The potential for misuse and abuse is low • Consumers can use them for self-diagnosed conditions • They can be adequately labeled • Health care professionals are not needed for the safe and effective use of the product

Rx-to-OTC Switches of Smoking Cessation Products Shortly after the approval of the nicotine transdermal products and the 4 mg nicotine gum in the early 1990s, the Agency began to consider the requirements for Rx-to-OTC switch of these products. Much of the discussion, including FDA advisory committee involvement, concerned the fact that each nicotine replacement product had been tested in conjunction with behavioral support. The prescription labeling indicated that the products were intended to be used as part of a comprehensive behavioral program of smoking cessation treatment. There was concern that, in

14 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray the OTC environment, in the absence of the behavioral intervention called for in the labeling, the products would be ineffective.

At the same time, it was recognized that many physicians prescribed the products without providing comprehensive behavioral support. The concept of “real world” efficacy was identified, and it was noted that the quit rates observed in clinical trials were unlikely to be representative of the “real world” experience. It was felt that, in order to approve OTC marketing, each sponsor would have to develop a package of self-help materials which could be used with the product, and that the combination of drug plus self-help materials would need to demonstrate efficacy comparable to the “real world” efficacy seen with the prescription product. Various less-than-optimal methods were employed by four different sponsors pursuing simultaneous OTC switch development plans for five different products, but the results were strikingly consistent. Sponsors conducted “simulated OTC” trials of the product plus self-help package in which a broad population was given a chance to self-select the treatment and then offered the opportunity to purchase study drug supply. Some included a placebo or active comparator arm. Some studies were open label, with the “real world” quit rate determined through some other method (including surveys of individuals who had filled prescriptions for the marketed product at a retail pharmacy). By all methods (survey, parallel treatment arm), the “real world” rates of abstinence at six weeks, as well as the measured rates in the trials, fell consistently in a range of approximately 15% to 20% in smokers treated with active NRT.

Subsequently, the direct-to-OTC development program for the Commit (now Nicorette) Lozenge involved a randomized, double-blind, placebo-controlled efficacy trial in “OTC” conditions (minimal intervention, self-help package), although subjects were not required to pay for study drug. The 6-week quit rates in this trial were 46% in the active arm in the 2 mg group (lower dependence) versus 30% in the matched placebo arm, and 49% in the active arm in the 4 mg group (higher dependence) versus 21% in the matched placebo arm. This study illustrated that a placebo-controlled “simulated OTC” trial is feasible and that an effective package of product and self-help material can demonstrate efficacy convincingly in such a study.

We acknowledge there are pitfalls in making historical comparisons; however, the difference between historical efficacy for NRT studies and the efficacy shown by NMS in Study 38 is notable. In Study 38, which simulated OTC conditions, subjects given NMS and the self-help material in the labeling had a 5% quit rate, and subjects given placebo and the self-help material had a 2% quit rate (Table 16).

Indication All NRT products are approved for use as cigarette smoking cessation aids with the following indications in adults 18 years of age and older: • OTC: – To reduce withdrawal symptoms, including nicotine craving, associated with quitting smoking • Rx: – As an aid to smoking cessation for the relief of nicotine withdrawal symptoms

15 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray – Recommended for use as part of a comprehensive behavioral smoking cessation program.

3. Summary of Presubmission/Submission Regulatory Activity

This submission is supported by clinical studies conducted by McNeil Consumer Health Care, both under their own investigational new drug (IND) application and outside the IND process. Extensive interaction with McNeil took place during the course of the development program and advice was provided regarding the design and conduct of the trials.

Subsequently, an IND was submitted by the Applicant, GlaxoSmithKline Consumer Healthcare (GSKCH), referencing McNeil’s IND, and seeking advice on label comprehension and human factors studies.

A description of general advice from Division of Nonprescription Drug Products (DNDP) and Division of Anesthetic, Analgesic, and Addiction Products (DAAAP) for clinical program development, presubmission and submission activities is provided in Section 11.1. Table 2 below outlines the sequence of key regulatory activities. Details of these interactions are found in the appendix.

Table 2. Timeline of Key Regulatory Activities Date Key Presubmission Activity 6/18/2007 PIND meeting with McNeil Consumer Healthcare (original IND holder) 11/8/2007 IND 77479 submitted by McNeil, revised protocols for 2 PK studies and 1 pivotal efficacy trial (A6431111) 12/5/2007 All 3 studies placed on clinical hold, the 2 PK studies were allowed to proceed the following year. 9/22/2009 End-of-Phase 2 meeting: Trial A6431111 was initiated in Europe without Agency review of final protocol, the second efficacy study in naturalistic environment was proposed. 4/9/2010 SPA submitted for naturalistic trial 5/26/2010 SPA No Agreement letter sent by Agency 6/14/2010 Type A meeting package submitted to discuss SPA comments 2/16/2011 Final protocol submitted for naturalistic study A6431112 5/13/2011 A6431112 terminated 11/2/2011 Protocol NICTDP3038, new naturalistic trial sent as SPA 11/18/2011 SPA No Agreement letter sent by Agency 2/2/2012 Amended SPA submitted 3/15/2012 SPA No Agreement letter sent by Agency 4/27/2015 Amended Protocol NICTDP2028 submitted 6/29/2015 Sponsor changed to Johnson & Johnson Consumer Inc., McNeil Consumer Health Division 9/28/2016 Study report submitted for completed study CO-140121222102-SCCT (formerly NICTDP3038) 2/24/2017 Agency received Letter of Authorization granting GlaxoSmithKline Consumer Healthcare (GSKCH) permission to cross-reference IND 77479 3/21/2017 GSKCH met with Agency PIND 133467 regarding label comprehension and human factors studies. 3/2/2018 GSKCH requested another meeting to further discuss label comprehension and human factors studies

16 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Date Key Presubmission Activity 5/1/2018 Initial Pediatric Study Plan (iPSP) submitted by Sponsor, requested PREA waiver 5/24/2018 Agency provided written responses to Sponsor’s questions in lieu of meeting 10/8/2018 PREA waiver granted by Agency 12/20/2018 NDA 208425 submitted. No pre-NDA meeting to discuss format and content was requested or held. Source: Clinical Reviewer Synopsis of presubmission and submission activities Abbreviations: GSKCH, GlaxoSmithKline Consumer Healthcare; IND, investigational new drug; iPSP, initial pediatric study plan; NDA, new drug application; PIND, preinvestigational new drug; PK, pharmacokinetic; PREA, Pediatric Research Equity Act; SPA, Special Protocol Assessment

4. Drug Product Summary

The drug product is formulated as an aqueous buffered nicotine solution for oromucosal use. The finished product contains also cosolvents, flavors, sweeteners and buffers. The pKa of the active ingredient is such that it will be mostly protonated under the physiological pH of saliva. Therefore, to ensure that the drug is in its free base form for optimal absorption by the oral mucosa, the drug product solution is maintained at alkaline pH using a buffering system and controlled using tight release specifications. The pH of the solution is a critical quality attribute to ensure the drug is properly absorbed.

The container-closure system for the drug product solution is a spray dispenser nested inside a plastic shell. The spray dispenser is comprised of a spray pump crimped onto a vial, which is then filled with the drug product solution. The spray dispenser includes an actuator press fitted to the pump. After adequate priming, the pump delivers a metered quantity of 1 mg nicotine per spray and each dispenser will deliver at least 140 sprays. While the spray dispenser features a press-and-push locking mechanism that can be opened and used single-handedly, it is designed to be child-resistant (CR) and senior-friendly (SF), and the plastic shell is also tamper evident (TE).

The spray characteristics are adequately characterized. The percentage of droplets smaller than 10 microns, and thus potentially available for inhalation, is low, reducing the risk of lung deposition. The particle size distribution data has been evaluated at both the beginning and at the end of drug product shelf life, and the spray characteristics remain stable over the shelf-life of the product.

5. Labeling Summary

The proposed labeling for NMS includes the Drug Facts Label (DFL) displayed on the outer container of the package utilizing a flap, a 44-page Consumer Information Leaflet (CIL or User’s Guide), and a “Quick Start Guide”. See Figure 16 for the proposed DFL. Similar to currently approved oral NRT products (i.e., nicotine gum, nicotine lozenge), the proposed NMS uses a 12- week quit program. The first 17 pages of the CIL are specific to directions and warnings for the NMS product. The remaining pages of the CIL contain information on smoking cessation, which is consistent with other approved nicotine gum and lozenge products.

17 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray The 12-week program for all currently marketed nicotine gum and lozenge products is divided into 3 steps. For example, the nicotine gum product labeling directions state the following (Figure 19): • Step 1: 1 piece every 1 to 2 hours • Step 2: 1 piece every 2 to 4 hours • Step 3: 1 piece every 4 to 8 hours

In comparison, the proposed NMS directions are as follows: • Step 1: use 1 to 2 sprays whenever you would normally smoke a cigarette or have a craving to smoke • Step 2: start reducing the number of sprays per day, by week 9 you should be using half the number of sprays per day that you used in Step 1 • Step 3: continue reducing the number of sprays per day, so that you are not using more than 4 sprays per day during week 12

The currently marketed nicotine gum and lozenge product labeling includes directions for heavy and light smokers. Consumers who smoke their first cigarette within 30 minutes of waking are directed to use the 4 mg gum or lozenge products. Consumers who smoke their first cigarette more than 30 minutes after waking are directed to use the 2 mg gum or lozenge products. Compared to the currently marketed nicotine gum and lozenge products, the proposed NMS directions do not include guidelines for heavy smokers versus light smokers.

For currently approved nicotine gum and lozenge products, there is a statement under the directions that recommends consumers to use a minimum of 9 pieces of gum or lozenges per day during the first 6 weeks. This language is not present on the proposed NMS labeling. Instead, there is a statement that directs consumers to “use enough each day to reduce your urge to smoke.”

Nicotine gum and lozenge “club packs” with up to 200 count are available. However, for NMS, GSK is proposing a 2 count (140 sprays per immediate container/280 sprays total) product as the largest package size. In order to successfully complete the 12-week program, consumers, particularly heavy smokers, would need to purchase significantly more NMS packages compared to other nicotine replacement therapy products.

6. Clinical Pharmacology Summary

In addition to NMS designation, oromucosal nicotine spray (ONS) was also used interchangeably throughout the NMS drug development, so this terminology is shown in several figures provided by the Applicant.

The Applicant submitted four phase 1 pharmacokinetic (PK) studies: 1. Study A6431094: a single-dose, open-label, randomized, four-sequence, four-period, four-treatment, crossover study that compared nicotine PK after three different modes of administration of 2 mg of NMS (two sprays), with that of Nicorette Gum 2 mg chewed

18 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray for 30 minutes (gum was chewed once every 2 seconds for 30 minutes; saliva was swallowed once every minute). The sprays were directed either a) straight into the mouth, b) towards the buccal mucosa or c) sublingually.

2. Study A6431107: a single-dose, open-label, randomized, eight-sequence, six-period, six- treatment, crossover study that compared the nicotine single-dose PK after, 1, 2, 3, and 4 mg nicotine doses (one, two, three, and four sprays of 1 mg NMS, respectively). The 2 and 4-mg doses were administered with and without a 20-second delay in the sequence of sprays (the effect of a 20-second delay in the sequence of sprays on the PK parameters with the 2 and 4-mg doses was evaluated).

3. Study NICTDP1065: a single-dose, open-label, randomized, five-sequence, five-period, five-treatment, crossover study that compared the nicotine single-dose PK after 1, 2, and 4 mg nicotine doses (one, two or four sprays of NMS 1 mg, respectively; produced in >1/10 scale of manufacturing batches), with Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg.

4. Study NICTDP1066: a multiple-dose, open-label, randomized, four-sequence, five- period, five-treatment, crossover study that investigated the multiple-dose steady-state PK of nicotine after a 2 mg NMS dose (two consecutive sprays NMS 1 mg/spray) administered every 30 minutes and every hour (subject self-administration and administration by the study personnel), compared with Nicorette Gum 4 mg administered every hour and nicotine lozenge 4 mg administered every hour.

Studies A6431094 and A6431107 were identified as pilot or preliminary studies by the Applicant. The purpose of these studies was to identify the optimal route of nicotine delivery as well as preliminary nicotine exposure assessing 1 to 4 mg NMS and the effect of a 20-second delay in the sequence of sprays.

Based on the results of Study A6431094, the straight into mouth administration was judged as the easiest and most natural route for administration, and, became the basis for the development of NMS.

The results of Study A6431107 suggested that nicotine plasma exposure increased slightly less than proportionally in the 1 mg to 2 mg doses. No nicotine exposure differences were observed when NMS was administered with and without a 20 second delay between sprays, with 2 and 4 mg doses of NMS.

The two pertinent relative bioavailability (BA) studies, NICTDP1065 and NICTDP1066, used the final to-be-marketed product of NMS. These two studies provided adequate nicotine exposure information for the proposed product using the proposed dose of 1 mg. These two studies also provided relative bioavailability information comparing the proposed product to Nicorette gum and NiQuitin lozenge; which are both manufactured by the same Applicant.

19 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray 6.1. Results from Study NICTDP1065

Study NICTDP1065 was a single-dose, open-label, randomized, five-sequence, five-period, five- treatment, crossover study that compared the nicotine single-dose PK after 1, 2, and 4 mg nicotine doses (one, two or four sprays of NMS 1 mg, respectively; Table 3), with Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg.

Table 3. Nicotine Mouth Spray Treatments, Study NICTDP1065 Nicotine Treatment Drug Form Route Dose Regimen A NMS 1 mg Spray Oral 1 mg 1 spray B NMS 1 mg Spray Oral 2 mg 2 consecutive sprays C NMS 1 mg Spray Oral 4 mg 4 consecutive sprays D NiQuitin™ Lozenge Lozenge Oral 4 mg Single dose E Nicorette® Gum Gum Oral 4 mg 1 piece chewed for 30min. Source: Adapted from complete study report of Study NICTDP1065, available at m5\53-clin-stud-rep\535-rep-effic-safety-stud\stop- smoking-aid\5351-stud-rep-contr\nictdp1065\nictdp1065-a-hansson-2009; p. 2/542 Abbreviation: min, minute

The mean plasma concentration versus time profiles over 12 hours and 1 hour after NMS administration are shown in Figure 1 and Figure 2, respectively.

Figure 1. Mean Plasma Concentration vs. Time Profiles Over 12 hours After NMS (or ONS), Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Single-Dose Treatments (Study NICTDP1065)

Source: Complete study report of Study NICTDP1065 available at m5\53-clin-stud-rep\535-rep-effic-safety-stud\stop-smoking- aid\5351-stud-rep-contr\nictdp1065\nictdp1065-a-hansson-2009; p. 8/542 Abbreviations: NMS, nicotine mouth spray; ONS, oromucosal nicotine spray

20 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Figure 2. Mean Plasma Concentration vs. Time Profiles Over the First Hour After NMS (or ONS), Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Single-Dose Treatments (Study NICTDP1065)

The PK parameters after NMS single-dose administration are presented in Table 4.

Table 4. Nicotine Pharmacokinetic Parameters (Mean ± SD) After NMS, Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Single-Dose Treatments (Study NICTDP1065) NMS NMS NMS NiQuitin™ Nicorette® Parameter 1 mg 2 mg 4 mg Lozenge 4 mg Gum 4 mg N 40 40 39 42 41 * Tmax (min) 10 12.5 10 45 30 # cCmax (ng/mL) 3.3±1.5 5.3±2.1 9.1±3.0 7.0±2.1 7.8±2.7 cAUCt# (h*ng/mL) 6.6±3.7 12.2±4.0 23.7±9.0 24.3±11.1 21.1±8.0 # cAUC∞ (h*ng/mL) 8.2±4.1 14.0±4.2 25.9±9.4 26.7±11.9 23.0±8.4 T1/2 (h) 2.89±1.19 2.63±0.92 2.56±0.72 2.87±0.75 2.45±0.75 Source: Adapted from complete study report of Study NICTDP1065 available at m5\53-clin-stud-rep\535-rep-effic-safety-stud\stop- smoking-aid\5351-stud-rep-contr\nictdp1065\nictdp1065-a-hansson-2009; p. 9/542 * Median; # base-line corrected Abbreviations: cAUC, baseline corrected area under the concentration-time curve; cCmax, baseline corrected maximum concentration; NMS, nicotine mouth spray

The results from Study NICTDP1065 showed that baseline corrected maximum nicotine concentration (Cmax) and area under the concentration-time curve (AUC∞; cCmax and cAUC∞) of the NMS 4 mg single-dose were slightly higher (approximately 34 and 7%, respectively) than that of NiQuitin™ lozenge 4 mg. Baseline corrected nicotine Cmax and AUC∞ (cCmax and cAUC∞) of the NMS 4 mg single-dose were slightly higher (approximately 20 and 15%,

21 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray respectively) than that of Nicorette® gum 4 mg. The results suggest that nicotine exposure, according to baseline corrected Cmax and AUC∞ (cCmax and cAUC∞), from the NMS single-dose increased less than proportionally (Table 5).

Table 5. Nicotine Baseline Corrected Cmax and AUC∞ (cCmax and cAUC∞) From the NMS Single-Dose (Study NICTDP1065) Spray Dose Dose Nicotine cCmax Nicotine cAUCinf (mg) X-Fold Increase (ng/mL) X-Fold Increase (ng.h/mL) X-Fold Increase 1 1 3.3 1 8.2 1 2 2 5.3 1.61 14 1.71 4 4 9.1 2.76 25.9 3.16 Source: Reviewer’s assessment Abbreviations: cAUC, baseline corrected area under the concentration-time curve; cCmax, baseline corrected maximum concentration; NMS, nicotine mouth spray

6.2. Results from Study NICTDP1066

Study NICTDP1066 was a multiple-dose, open-label, randomized, four-sequence, five-period, five-treatment, crossover study that investigated the multiple-dose steady-state PK of nicotine after 2 mg nicotine dose (two consecutive sprays NMS 1 mg/spray) administered every 30 minutes and every hour (subject self-administration and administration by the study personnel), compared with Nicorette Gum 4 mg administered every hour and nicotine lozenge 4 mg administered every hour (Table 6).

Table 6. Nicotine Mouth Spray Treatments, Study NICTDP1066 Nicotine Treatment Drug Form Route Regimen Dose 2 sprays by self- administration A NMS 1 mg Spray Oral 24 mg once every hour 2 sprays administered by study B NMS 1 mg Spray Oral 24 mg personnel once every hour 2 sprays administered by study C NMS 1 mg Spray Oral 48 mg personnel once every 30 minutes 1 lozenge administered by study D NiQuitin™ lozenge, 4 mg Lozenge Oral 48 mg personnel once every hour 1 piece chewed for 30 minutes E Nicorette® Gum, 4 mg Gum Oral 48 mg once every hour Source: Adapted from complete study report of Study NICTDP1066 available at m5\53-clin-stud-rep\535-rep-effic-safety-stud\stop- smoking-aid\5351-stud-rep-contr\nictdp1066\nictdp1066-a-hansson-2009; p. 4/469 Abbreviation: NMS, nicotine mouth spray

The average plasma concentration profiles for the study treatments over 12 hours after start of first administration are shown in Figure 3.

The average plasma concentration profiles for the study treatments after the last one or two doses (11 to 12 hours after start of first administration) are shown in Figure 4.

22 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Figure 3. Mean Nicotine Plasma Concentration vs. Time Profiles After NMS (or ONS), Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Multiple-Dose Treatments Over 12 Hours After Start of First Administration (Study NICTDP1066)

Source: Complete study report of Study NICTDP1066 available at m5\53-clin-stud-rep\535-rep-effic-safety-stud\stop-smoking- aid\5351-stud-rep-contr\nictdp1066\nictdp1066-a-hansson-2009; p. 8/469 Abbreviations: NMS, nicotine mouth spray; ONS, oromucosal nicotine spray

23 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Figure 4. Mean Nicotine Plasma Concentration vs. Time Profiles After NMS (or ONS), Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Multiple-Dose Treatments After the Last One or Two Doses (11 to 12 Hours After Start of First Administration) (Study NICTDP1066)

Source: Complete study report of Study NICTDP1066 available at m5\53-clin-stud-rep\535-rep-effic-safety-stud\stop-smoking- aid\5351-stud-rep-contr\nictdp1066\nictdp1066-a-hansson-2009; p. 9/469 Abbreviations: NMS, nicotine mouth spray; ONS, oromucosal nicotine spray

The PK parameters after NMS, Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg steady-state pharmacokinetic parameters are presented in Table 7.

Table 7. Steady-State Pharmacokinetic Parameters After NMS, Nicorette Gum 4 mg and NiQuitin Lozenge 4 mg Treatments (Study NICTDP1066) NMS NMS NiQuitin™ lozenge Nicorette® gum 4 Parameter 2 mg/h 2 mg/30 min 4 mg/h mg/h * Tmax (min) 10 10 25 30 Cmax (ng/mL) 17.1±5.0 31.4±9.8 29.0±11.0 27.3±8.6 Cmin (ng/mL) 11.7±4.0 25.3±8.4 22.1±9.7 19.0±7.0 ** Cav (ng/mL) 14.6±4.5 28.8±9.2 25.5±9.9 23.3±7.5 AUC (ng/mLxh) 14.6±4.5 14.4±4.6 25.5±9.9 23.3±7.5 Source: Adapted from complete study report of Study NICTDP1066 available at m5\53-clin-stud-rep\535-rep-effic-safety-stud\stop- smoking-aid\5351-stud-rep-contr\nictdp1066\nictdp1066-a-hansson-2009; p. 9/469 * median ** Cav: AUCτ/τ; τ=0.5 or 1 h Abbreviations: AUC, area under the concentration-time curve; Cmax/min/av, maximum/minimum/average concentration; NMS, nicotine mouth spray

Table 8 shows averages and standard deviations (SDs) for the pharmacokinetic parameters as well as estimated mean ratios and corresponding 95% confidence intervals for ratios between the self- and staff-administered ONS 2 mg/h treatments.

24 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Table 8. Pharmacokinetic Parameters (Mean ± SD) and Ratios* Between Pharmacokinetic Parameters Between Self- vs. Staff-Administered NMS 2 mg/h (Geometric Mean (95% CI)) (Study NICTDP1066) NMS 2 mg/h NMS 2 mg/h Ratio Self- vs. Staff- Parameter Self- Administration Staff- Administration Administration* C1h (ng/mL) 91.8% 4.7±1.6 5.0±1.5 (84.7-99.5) Cmax (ng/mL) 92.3% 16.5±6.1 17.1±5.0 (85.6-99.5) # Cav (ng/mL) 93.8% 14.3±5.6 14.6±4.5 (86.9-101.3) Tmax** (min) 15 10 5** (range: 5 – 45) (range: 5 – 42) Cmin (ng/mL) 98.0% 11.5±4.7 11.7±4.0 (88.9-107.0) Source: Adapted from complete study report of Study NICTDP1066 available at m5\53-clin-stud-rep\535-rep-effic-safety-stud\stop- smoking-aid\5351-stud-rep-contr\nictdp1066\nictdp1066-a-hansson-2009; p. 11/469 * Estimated ratios based on models for log-transformed values for C1h, Cmax and AUCτ, estimated ratios based on subjects’ untransformed individual ratios for Cmin ** Median observed difference and range # Cav: AUCτ/τ; τ=1 h Abbreviations: CI, confidence interval; Cmax/min/av, maximum/minimum/average concentration; SD, standard deviation

The results from Study NICTDP1066 showed steady state Cmax, Cav and AUCτ parameters of the NMS 2 mg administered every hour are lower than those for NiQuitin™ lozenge 4 mg administered every hour and Nicorette® gum 4 mg every hour. The results suggest that Cmax and Cav of the NMS 2 mg administered every 30 minutes are slightly higher than those for NiQuitin™ lozenge 4 mg administered every hour (10 to 15%) and Nicorette® gum 4 mg administered every hour (14 to 22%). No differences in nicotine exposure were observed between self- and study staff-administration of NMS.

In summary, pharmacokinetics of the proposed product, NMS, were evaluated after single and multiple doses. The results suggest that nicotine baseline corrected Cmax and AUCinf (cCmax and cAUCinf) of the NMS single-dose (1, 2, and 4 mg) increased less than proportionally. No differences in nicotine exposure were observed between self- and study staff-administration of NMS.

7. Summary of Clinical Trials

7.1. Review of Efficacy

This application includes the results from two efficacy studies. Study A6431111 (hereafter referred to as, “Study 11”) was conducted in a manner like studies submitted for prescription drugs, in which study personnel provide behavioral support and directions for product use. Study CO-140121222102-SCCT (hereafter referred to as, “Study 38”) was designed to resemble the OTC environment, with no behavioral support from study staff, and no specific explanation of the label contents. These studies were analyzed separately, and the differences were scrutinized to seek explanations for the divergent results.

25 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray 7.1.1. Study A6431111: Efficacy and Safety following use of a Novel NRT. Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group, 52-Week Study in Smokers Motivated to Quit (Study 11) 7.1.1.1. Overview and Objective This was a randomized, multicenter, double-blind, placebo-controlled, 52-week parallel group study to measure the efficacy of NMS for the treatment of tobacco dependence by relieving nicotine craving and withdrawal symptoms, to facilitate smoking cessation in smokers motivated to quit.

The primary objective was to evaluate the efficacy of NMS versus placebo in smokers to achieve continuous abstinence from smoking from the Week 2 visit until and including the Week 6, Week 24, and Week 52 visits, respectively.

Secondary objectives were: • To evaluate the efficacy of NMS versus placebo in smokers to achieve continuous abstinence from smoking from the Week 2 visit through all other time points throughout the study (i.e., until and including the Weeks 4, 8, 12, 16, and 20 visits, respectively) • To evaluate the efficacy of NMS versus placebo in smokers on 7-day point prevalence abstinence from smoking at Week 4 and all remaining visits • To assess the efficacy of NMS versus placebo in smokers on craving and withdrawal symptoms during the initial 4 weeks on study (daily ratings), as well as point ratings at Weeks 4, 6, 8, 12, 16, 20, and 24 • To document the compliance of NMS • To assess the level of nicotine substitution by measuring saliva cotinine levels • To document smoking status throughout the study • To evaluate the safety and adverse event (AE) profile of NMS, including vital sign measurements • To evaluate the product acceptability of NMS

7.1.1.2. Trial Design This was a phase 3, randomized, multicenter, double blind, placebo-controlled, 52-week parallel group study to measure the efficacy of NMS for the treatment of tobacco dependence by relieving nicotine craving and withdrawal symptoms, thereby facilitating smoking cessation in smokers who were motivated to quit. Subject participation in the study included a 6-week period of full study drug treatment, a 6-week period of tapering study drug treatment, a 12-week period of occasional use, a 30-day safety follow-up period, and a 24-week follow-up period with no study drug treatment. At all visits after the baseline visit, up to and including the Week 24 visit, study personnel discussed smoking cessation advice very briefly (<3 minutes) with all subjects. The study design is shown in the Table 9.

26 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Table 9. Schematic for Study A6431111

Source: Applicant’s Clinical Study Report

The investigational product was NMS for administration into the oral cavity, which delivered a metered dose of 1 mg of nicotine per spray, or the corresponding placebo spray. The spray solution (73.5 μL/dose) contained nicotine (13.6 mg/mL), flavoring, pH regulators, solubilizers, sweeteners, and surface-active agents. The placebo spray was identical in appearance and formulation, except it did not contain nicotine. The placebo spray contained capsaicin (0.0125 mg/mL) to mimic the taste of nicotine. All study products were manufactured and supplied by McNeil AB, Helsingborg, Sweden. The product was distributed in neutral packages with an attached label for clinical research. Each subject was given only the study drug assigned to him or her at the designated visit. At the first visit, all subjects were given 5 dispensers each. At the following visits, the amount of study drug dispensed was based on the treatment stage of the subject (full or tapering), the amount of study drug used since the last visit, and the number of full and partially full dispensers in use. The subjects were asked to return all spray dispensers (full, partially full, and empty) at every visit, and had the full and partially full dispensers returned to them for continued use. A dispenser contained 150 doses (1 mg/spray) and the maximum recommended dose was 64 sprays per day.

Eligibility for the study was first determined during a telephone screening; potentially eligible subjects were instructed to come to the study center for a baseline visit, during which they were enrolled in the study after satisfying the inclusion and exclusion criteria including giving written informed consent. Baseline measurements were recorded, and the subjects were then randomly assigned to receive either active or placebo treatment in a 2:1 ratio. The sample size of 465 subjects (307 active, 154 placebo) was determined using an estimate of 40% continuous abstinence rate at Week 6 for active treatment, an odds ratio of at least 2 to be detected, using a Pearson Chi-square test, with α=0.05, and 90% power.

Key Inclusion Criteria: • Males and females ≥18 years old • Daily cigarette smoker for the last 3 years or more • Carbon monoxide (CO) level of ≥10 parts per million (ppm) after at least 15 smoke-free minutes • Females of childbearing potential must have used medically acceptable means of birth control for at least 1 month before baseline visit and continued to use birth control during study period and 1 month after last dose of study drug

27 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray

Key Exclusion Criteria Subjects were not included in the study for the following reasons: • Current use of tobacco-containing products, other than cigarettes, or smoking of other substances • Use of NRT, bupropion, or varenicline, or had undergone any treatments for tobacco dependence during the previous 6 months • Unstable cardiovascular disease during the previous 3 months • Pregnancy, lactation, or intended pregnancy • Alcohol or drug abuse • Acute or chronic medical or psychiatric condition or previously diagnosed clinically important renal or hepatic disease, that may have increased the risk associated with study participation or may have interfered with the interpretation of study results and, in the judgment of the investigator, would have made the subject inappropriate for entry into the study • Subjects with presence of an oral lesion requiring further study, such as a biopsy

Study personnel provided general smoking cessation advice in writing and a brief discussion (<10 minutes) of this advice to eligible subjects. Subjects were then instructed to quit smoking on the next day and to start using NMS. All subjects were instructed to follow the NMS dispenser directions for use that were provided to them (Figure 18). Subjects were instructed to prime the dispenser by pressing the actuator several times until a fine spray appears, before the first dose is administered. To administer the NMS, they had to point the spray nozzle toward the open mouth; hold the dispenser as close to the mouth as possible and press the actuator to release one spray into the mouth, in order to receive a metered dose of 1 mg nicotine. They were also instructed to refrain from swallowing for a few seconds after spraying for best results.

Compliance with use of the study drug was recorded by the subject using an e-diary to collect data during the first 12 weeks of treatment. During the period from Week 12 to Week 24, compliance was assessed at visits during Weeks 16, 20, and 24. Smoking cessation was verified by self-reporting of abstinence and objective CO testing (CO <10 ppm in exhaled air) at all visits after the baseline visit. Saliva cotinine was measured in all subjects at Baseline and the Week 2, 6, 12, and 24 visits, to estimate the level of nicotine substitution with NMS compared with cigarette smoking. This gave an additional indication of the compliance with NMS usage.

Subjects could withdraw from the study at any time at their own request or they could have been withdrawn at any time at the discretion of the investigator or Applicant for safety, behavioral, or administrative reasons. If a subject did not return for a scheduled visit, every effort was made to contact the subject. In any circumstance, every effort was made to document subject outcome, if possible. The investigator inquired about the reason for withdrawal, requested the subjects to return all unused study drug and the e-diary, requested the subjects to return for a final visit, if applicable, and followed up with the subject regarding any unresolved AEs.

28 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray 7.1.1.3. Study Endpoints The primary efficacy variable was defined as the self-reported continuous abstinence from smoking rate (CAR) from the Week 2 visit until and including the Week 6 visit. Secondary endpoints were the CAR from Weeks 2 to 24, and Weeks 2 to 52. Abstinence was verified by an exhaled CO level of less than 10 ppm at all clinic visits from Week 2 through Week 52.

7.1.1.4. Statistical Analysis Plan The Full Analysis Set (FAS) was defined as all subjects who received study treatment. This was designated as the primary analysis population for efficacy endpoints.

The statistical analysis planned in the protocol was a Pearson’s Chi-square to compare the two treatment arms. The Applicant planned to report treatment differences in CAR rates and 95% confidence intervals. In the clinical study report the Applicant reported odds ratios for the treatment comparisons rather than the difference in CAR rates.

To be considered a responder, a subject had to report no cigarette use since Week 2, and no use of other tobacco, NRT, or smoking cessation products. Exhaled CO was recorded at each clinic visit to verify self-reported abstinence. Subjects who discontinued or did not have CO <10 ppm at required timepoints were classified as nonresponders, on the assumption that they had resumed smoking. The Applicant planned a hierarchical testing order, starting with the CAR Week 2 to 6 endpoint, followed by CAR Week 2 to 24 and then CAR Week 2 to 52, if applicable.

7.1.1.5. Study Results

Patient Disposition and Baseline Characteristics Of the 1016 subjects who were screened by telephone, 621 were found to be possibly eligible, and of these, 495 attended screening visits at the study sites. Of these, 479 were randomized (161 received placebo and 318 received active treatment). A total of 242 subjects completed double- blind treatment and 237 subjects discontinued from double-blind treatment. Although the overall completion was low, this is not uncommon in smoking cessation studies with prolonged post- treatment follow-up phases. Notably, the rate of dropout during the full-dose treatment period (Weeks 1-6) was lower: 18% in the NMS arm and 28% in the placebo arm.

In all analyses, dropouts were adjudicated as continuing smokers.

The disposition of these subjects is shown in Table 10.

Table 10. Patient Disposition for Study A6431111 NMS 1 mg Placebo Disposition Category N=318 (%)* N=161 (%)* Randomized (ITT) 318 (100%) 161 (100%) Received study treatment (FAS) 318 (100%) 161 (100%) Completed study 167 (53%) 75 (47%) Discontinued from study 151 (47%) 86 (53%)

29 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray NMS 1 mg Placebo Disposition Category N=318 (%)* N=161 (%)* Discontinued prior to Week 24 (end of treatment) 131 (41%) 81 (50%) Adverse event 29 (9%) 12 (7%) Death 1 (<1%) 0 Lost to follow-up 23 (7%) 9 (6%) Protocol violation 2 (1%) 3 (2%) Withdrew consent 72 (23%) 56 (35%) Other 4 (1%) 1 (1%) Discontinued after Week 24 through Week 52 (post-treatment) 20 (6%) 5 (3%) Adverse event 0 0 Death 0 0 Lost to follow-up 11 (3%) 2 (1%) Protocol violation 1 (<1%) 0 Withdrew consent 8 (3%) 3 (2%) Other 0 0 * All percentages are calculated based on Randomized N per group as denominator. Source: FDA Reviewer Abbreviations: FAS, Full Analysis Set; ITT, intent-to-treat; NMS, nicotine mouth spray

This study was conducted at three sites, two in Germany and one in Denmark. The two treatment groups were well balanced with respect to relevant demographic and baseline characteristics as shown in Table 11.

Table 11. Demographic and Baseline Characteristics for Study A6431111 NMS Placebo All Treated (FAS) N=318 N=161 Age (years) Mean (SD) 47 (10.9) 46 (11.3) Range 18 - 75 19 - 68 Gender Female 137 (43%) 73 (45%) Male 181 (57%) 88 (55%) Race White 313 (98%) 161 (100%) Black 1 (<1%) 0 Asian 1 (<1%) 0 Other 3 (1%) 0 Baseline # cigarettes smoked Mean (SD) 23 (8.8) 23 (8.7) Range 6 – 65 4 – 60

<20 92 (29%) 48 (30%)  20 226 (71%) 113 (70%) Baseline Fagerstrӧm Mean (SD) 5.3 (2.3) 5.4 (2.2) Range 0 - 10 0 - 10

<6 163 (51%) 80 (50%)  6 155 (49%) 81 (50%)

30 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray NMS Placebo All Treated (FAS) N=318 N=161 Time to first cigarette ≤30 minutes 233 (73%) 125 (78%) >30 minutes 85 (27%) 36 (22%) Source: FDA Statistical Reviewer Abbreviations: FAS, Full Analysis Set; NMS, nicotine mouth spray; SD, standard deviation

Compliance with Study Drug Treatment compliance was analyzed by the Applicant for those subjects who provided reports on their product use for at least four days in a given week. Based on mean values, study subjects did not adhere to the recommended dose of 1-2 sprays every 30-60 minutes during Weeks 1 through 6, generally using less spray than recommended. However, a wide range of use was reported. Per Applicant’s Table 14.2.1.5, even successful quitters were likely to use less of the product than recommended.

Efficacy Results For the primary efficacy endpoint, the NMS 1 mg treatment group was statistically significantly better than the placebo treatment group (see Table 12). The treatment difference of 10% between the groups can be converted to the number needed to treat (NNT) of 10. In this case, for every 10 smokers who received NMS 1 mg instead of placebo, one additional success (continuous abstinence for weeks 2 through 6) was observed. The second comparison of interest, CAR Weeks 2 to 24, also showed evidence of a treatment difference as did the third comparison for CAR Weeks 2 to 52.

Table 12. Efficacy Results for Study A6431111 NMS 1 mg Placebo FAS Patient Population N=318 N=161 Primary: Responders, n (%) 83 (26%) 26 (16%) Continuous abstinence rate Diff. from placebo 10% Weeks 2 to 6 (95% CI) (2%, 17%) p-value 0.014 Secondary: Responders, n (%) 50 (16%) 11 (7%) Continuous abstinence rate Diff. from placebo 9% Weeks 2 to 24 (95% CI) (3%, 14%) (End of treatment) p-value 0.006 Secondary: Responders, n (%) 44 (14%) 9 (6%) Continuous abstinence rate Diff. from placebo 8% Weeks 2 to 52 (95% CI) (3%, 13%) (End of study) p-value 0.007 Source: FDA Statistical Reviewer Abbreviations: CI, confidence interval; NMS, nicotine mouth spray

“Craving” and other withdrawal symptoms were reported daily in the e-diary from Week 1 through Week 4 and then in the case report form (CRF) at each visit from Week 4 through Week 24.

31 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray “Craving” for cigarettes was measured by asking subjects to rate their “desire/urge to smoke” during the last 24 hours on a 5-point scale of 0 (not at all) to 4 (extremely so). The results are summarized in the Applicant’s figure below for subjects who were verified to be abstinent during the week for Weeks 1 through 4 and subjects who had verified 7-day “point prevalence”2 abstinence at the Weeks 4 through 24 visits.

For the first 4 weeks subjects registered craving, as well as withdrawal, scores daily in an e- diary, whereas during weeks 4 through 24 they were only reporting it at the respective visits.

Figure 5. Desire/Urge to Smoke (Subjects With Verified Abstinence During the Prior Week)

Source: Clinical Study Report, Figure 4, Supportive Table 14.2.6.1

At Weeks 1, 6, and 12, subjects were asked a variety of question about the acceptability of the NMS and their impressions of its taste, effectiveness, and convenience. The table below

2 “Point prevalence” abstinence refers to abstinence in a specific look-back window at a particular point in time. In this study, it is defined as patients reporting abstinence in the prior week.

32 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray illustrates the patient impressions of effectiveness in “dealing with cravings,” speed of action, and overall acceptability. Notably, there were no differences between the active and placebo spray in overall acceptability. Although statistically significant differences in effectiveness and speed were reported, it is notable that both the placebo and active sprays were rated as moderately effective and moderately fast.

Table 13. User Acceptability Questionnaire (Full Analysis Set) Week 1 Week 6 Week 12 Placebo Active Placebo Active Placebo Active Questionnaire Item N=161 N=318 N=161 N=318 N=161 N=318 Considering everything about this product, on a scale of 1 (very poor) to 10 (excellent), how would you rate the spray? N 133 276 83 199 73 190 Mean (SD) 6.5 (2.6) 6.8 (2.4) 6.9 (2.4) 7.1 (2.3) 6.8 (2.5) 7.2 (2.2) Median 7 8 8 8 7 8 P value 0.35 0.63 0.38 How effective is this spray in dealing with your cravings? (1 = not at all effective to 5 = extremely effective) N 136 279 87 206 75 193 Mean (SD) 2.9 (1.2) 3.5 (1.0) 2.9 (1.2) 3.7 (0.9) 2.9 (1.2) 3.7 (0.9) Median 3 4 3 4 3 4 P value 0.001 0.001 0.001 How would you rate the speed of action? (1 = extremely slow to 9 = extremely fast) N 135 277 86 207 75 192 Mean (SD) 5.9 (2.3) 7.2 (1.5) 6.0 (2.2) 7.2 (1.5) 5.8 (2.5) 7.2 (1.5) Median 7 8 7 8 7 8 P value 0.001 0.001 0.001 Source: Clinical Study Report Table 13

Duration of Use: Study drug was provided at visits through the Week 20 visit. Although the dosing directions included a recommendation to taper to discontinuation after Week 6, a significant number of patients on NMS reported ongoing use of the study drug during Week 24. The Applicant’s Table 14.2.1.8 shows that, among abstinent subjects using active NMS, 40% reported ongoing product use, while 60% of those not meeting abstinence criteria reported ongoing use. Use on a daily basis was reported by about half who reported ongoing use.

33 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray 7.1.2. Study CO-140121222102-SCCT (formerly NICTDP3038): A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study Using a Naturalistic Clinical Model to Measure the Efficacy and Safety of a Novel Nicotine Replacement Therapy in Smokers Motivated to Quit (Study 38) 7.1.2.1. Overview and Objective The current study was designed to assess the efficacy of NMS versus placebo in a naturalistic OTC-like setting at eight clinical sites in the United States; there was low intervention and no behavioral support provided by study staff.

The primary objective was to evaluate the efficacy of NMS versus placebo in smokers as measured by continuous abstinence from smoking from the Week 2 visit until and including the Week 6 visit.

Secondary objectives were: • To evaluate the efficacy of NMS versus placebo in smokers as measured by continuous abstinence from smoking from the Week 2 visit until and including the Week 12 visit and Week 26 visit • To evaluate the efficacy of NMS versus placebo in smokers as measured by continuous abstinence from smoking from the Week 2 visit through all other assessment timepoints throughout the study, (including the Week 4, 8, 16, and 20 visits) • To assess the efficacy of NMS versus placebo in abstinent smokers on craving and withdrawal symptoms at Week 1, 2, 4, and 6 visits • To document the use of NMS throughout the study • To document the number of cigarettes still smoked for non-abstinent subjects throughout the study • To evaluate subject perception of NMS at Week 1, 6, and 12 visits • To evaluate the safety and AE profile of NMS, including assessment of vital signs throughout the study and visual mouth inspection (VMI) at Baseline and Week 6 • To compare study treatments with respect to weight changes from Baseline to Week 6, 12, and 26 visits

7.1.2.2. Trial Design This was a multicenter, randomized, double-blind, placebo-controlled, parallel group, 26-week study (12-week treatment period and an additional 14-week Post Study Treatment Follow-up Period—note that treatment was allowed during this 14-week period when requested) in at least 1200 smokers motivated to quit smoking. Subjects were randomized to treatment in a 1:1 ratio (active versus placebo). Subject recruitment was designed to ensure that at least half of the subjects enrolled self-reported an average cigarette consumption of 20 or more cigarettes smoked per day at Baseline.

The study was performed at eight clinical sites across the United States and was designed to resemble the OTC environment under which the product will be marketed. Unlike a typical controlled clinical study design, where various forms of intensive intervention and measures are

34 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray taken to create a tightly controlled environment, the study included limited intervention or controlling procedures. The study had limited inclusion/exclusion criteria, no behavioral procedures, and no specific explanation of the label contents. The only information subjects were provided regarding the use of the investigational product was what was on the Drug Facts Label (DFL) on the outer carton and the User’s Guide contained within the carton.

The frequency of investigational product use was at the discretion of the subject and determined by their review and understanding of the Drug Facts Label and User’s Guide. There was minimal intervention and no behavioral support provided by the study staff. For questions related to investigational product use, the study site staff directed the subject back to the Drug Facts Label and User’s Guide.

The study staff provided information on how to operate the dispenser (spray pump as referred to in the Drug Facts Label and User’s Guide) only if questions were initiated by the subject. No additional information about the use of the investigational product was given. Subjects were informed that the investigational product was for personal use only. The assessment of the safety of NMS was performed by measurements of vital signs, VMI, and collection of subject-reported AEs.

Key Inclusion Criteria: • Males and females age 18 to 85 inclusive (age 19 to 85, if specified as the legal smoking age in their state). • Daily smoker, motivated to quit with aid of nicotine replacement, with exhaled CO measurement of ≥10 ppm at baseline. • Negative urine drug screen at baseline visit, unless positive for prescribed opioids, benzodiazepines, or stimulant medication (must present proof of prescription). • Females of child-bearing potential, must not be pregnant or lactating and must agree to practice medically acceptable form of birth control3 during the study or for 30 days following last dose of study drug, whichever was later. These females must also have used such birth control for at least 3 months prior to baseline visit. • Agreed to use only the study product as a smoking cessation aid.

Key Exclusion Criteria: Subjects with any of the following were not included in the study: • History of cardiovascular disease, (heart attack or stroke within the last 3 months, unstable or worsening angina pectoris, irregular heartbeat, or uncontrolled hypertension), and/or stomach ulcer, and/or diabetes

3 Hormonal methods (oral, injected, implanted, transdermal patch, or vaginal ring), barrier methods with spermicide, intrauterine device, surgical sterilization in self or partner, and abstinence (periodic abstinence or withdrawal were not acceptable).

35 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray • If subjects had any of the conditions listed above, they required a physician’s written approval for participation or would be excluded • Use of other forms of tobacco/nicotine-containing products other than cigarettes such as nicotine-containing e-cigarettes, pipes, cigars, snuff, or smokeless tobacco within 30 days before the Baseline visit • Use of any of the following within 30 days before Baseline visit: – NRTs (nicotine gum, patch, inhaler, microtab, lozenge/tablet, mouth spray, or nasal spray) – Smoking cessation products such as bupropion or varenicline – Non-drug smoking cessation therapies/procedures, such as counseling, acupuncture, or hypnosis • Female subjects who are pregnant or nursing or intend to be pregnant within the 6 months following the study, or males planning to impregnate partner during the study period or within the 30 days following study completion • Male subjects with a pregnant partner or partner who is currently trying to conceive • Sensitivity to nicotine products or components of study drug • Suspected alcohol or substance abuse (amphetamines, benzodiazepines, cocaine, marijuana, opiates) or history of significant psychiatric illness (including subjects taking prescription doses of medication for depression that may need adjustment) within the previous 12 months, which in the judgment of the investigator, would make the subject inappropriate for the study • Any other medical condition (severe acute, chronic condition or laboratory abnormality) that increased the risk associated with study participation • Presence of an oral lesion (suspected malignant lesion and/or erosive lesion) found at the Baseline VMI, requiring further investigation such as biopsy.

The active spray solution contained nicotine, flavoring, pH regulators, solubilizers (including ethanol 10%), sweeteners, and surface-acting agents. One spray of the active investigational product delivered 1 mg nicotine/dose to the oral cavity. The spray dispenser contained 140 doses. The placebo spray was identical in appearance and formulation, except it did not contain nicotine. The placebo, however, did contain a small amount of capsaicin (0.0125 mg/mL) to mimic the taste and produce a sensation in the oral cavity, similar to that of nicotine. The frequency of investigational product use during the 12-week treatment phase was at the discretion of the subject and determined by their review and understanding of the Drug Facts Label and User’s Guide. No one associated with the study conduct at the Applicant, Contract Research Organization (CRO), or study sites, was aware of the treatment assigned.

The study site took necessary measures to maintain the study treatment blind and prevent any unintended or premature unblinding. If unblinding was performed, the occurrence was reported by the PI to the CRO and the Applicant as soon as possible and was entered into the subject’s record, but the group assignment was not divulged. The subject whose treatment blind was broken was immediately discontinued from the study and followed-up by the study staff until the event or its sequelae resolved or stabilized at a level acceptable to the investigator.

36 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray After recruitment and initial screening, the following procedures were conducted at the first study visit: • Subjects were assigned an eight-digit ID number, first four digits represented the study site number and the last four digits represented the site unique subject number. • Subjects were asked to read the Drug Facts Label to self-assess whether or not the product was appropriate to help them stop smoking. Site staff did not provide more information than contained in the Drug Facts Label. The study staff documented the response, including the reason for those subjects who decided that the study drug was not appropriate for them to use as an aid to help them stop smoking. • All subjects were then asked to read the appropriate Institutional Review Board (IRB)- approved informed consent, asked questions if necessary, and were asked to sign/date the appropriate informed consent after having had the study activities explained. – Subjects who decided they were appropriate candidates to use the study product as a stop smoking aid were asked to sign/date the full IRB-approved consent, including risk of being randomized to placebo treatment. – Subjects who decided they were not appropriate candidates for the study product were asked to sign/date the abbreviated IRB-approved informed consent (allowing collection of minimal study data). The abbreviated consent related to the Drug Facts Label review aspects of the study. • All subjects then completed the following assessments at the Baseline visit regardless of their response: – Demographics including age, sex, race, and ethnicity – Highest level of education – Medical history – Rapid Estimate of Adult Literacy in Medicine (REALM) test of health literacy – Previous medications used within the 30-day period before the Baseline visit – Previous nondrug therapies/procedures within 30 days before the Baseline visit – Adverse events (if applicable, occurring after full informed consent was signed) – Subjects who self-selected out of the study, responding that they were not appropriate candidates for the study product also completed the subject disposition, and were not enrolled in the study • Subjects who self-selected into the study were informed by the site staff about the possibility of receiving either active treatment or placebo and completed the following assessments within 14 days after the initial visit: – Body weight and height, vital signs – Smoking and cessation history – Fagerstrӧm Test for Nicotine Dependence – Urine pregnancy test for females of child-bearing potential – Urine Drug Screen – Exhaled CO measurement, minimum of ≥10 ppm required for inclusion – VMI at the site or local dental office by a licensed dentist or an examiner such as a dental hygienist who had training in oral clinical exams. If subject failed to meet eligibility prior to the VMI being performed, then VMI was not required

37 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray • Subjects who responded that the product was appropriate for them, but who did not fulfill all the inclusion/exclusion criteria were not randomized into the study. • Subjects who self-selected for admission into the study, fulfilled inclusion/exclusion criteria and were still willing to participate, were randomized4 to receive either the active or placebo mouth spray (1:1 ratio). The assigned therapy the subject received was the same therapy throughout the study. – Subjects were encouraged to stop smoking and start using the study product the day after the product was dispensed. All smokers were instructed to follow the directions for use. • Study staff dispensed three kits of the assigned product to each randomized subject. Each kit consisted of a carton with the Drug Facts Label printed on the outer panel containing one labeled dispenser from the assigned treatment group and a User’s Guide. There was minimal intervention and no behavioral support provided by the study staff. The study site staff directed the subject back to the Drug Facts Label and User’s Guide when asked questions. The study staff provided information on how to operate the dispenser only if questions were initiated by the subject. • Investigational product was available to the subjects for use during the 12-week treatment period. Subjects could have requested resupply at any time during the 12-week period. Additional kits were dispensed as needed with a maximum of three kits given at any one time. Subjects were instructed to return empty dispensers, along with the cartons and User’s Guides at each visit to the study site. • At the Week 12 visit, those subjects who requested to continue on treatment at the end of the treatment period (Week 12) were dispensed new investigational product at that time. Additional investigational product was available up to Week 26 to those subjects who specifically requested it at any time beyond the 12-week treatment period (even with interrupted use). Every effort was made to retrieve all kits at study completion. • Those subjects who specifically requested additional kits of investigational product beyond Week 12 were reminded that information would continue to be collected. • Subjects received investigational product use reporting instructions at their Baseline visit that instructed the subjects to report their total number of sprays used and the maximum number of sprays used within any given hour each day via the telephone (i.e., Interactive Voice Response System). Subjects were reminded of investigational product use reporting throughout the study. • The study staff informed the subjects that information was collected via the telephone for tracking investigational product use on a daily basis while using the product. They were also given a handheld counter and were encouraged to use it to keep track of the number of sprays they used each day. They were reminded to report the maximum number of sprays used within any given hour each day. • The subjects received a wallet alert card with pertinent study reminders and study site contact information. • Subjects were given a Medical Problems Log for recording any new or worsened health issues that occurred during the 26 weeks of study participation.

4 The subject randomization list was stratified by study site and by number of cigarettes smoked (<20 cigarettes per day versus ≥20 cigarettes per day).

38 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray – Subjects were instructed that the log would be collected and reviewed, and a new log dispensed at each study visit through and including the Week 20 visit. – All new or worsened health issues captured in the Log during their study participation since their last visit was transferred to the AE case report form (CRF) page and additional information was collected. • During the treatment period, subjects reported to the clinical study site at Weeks 1, 2, 4, 6, 8, and 12. • Participating subjects were required to report to the clinical study site at visit Weeks 16 and 20 during the Post Study Treatment Follow-up Period for follow-up assessments. • Concomitant medications were reviewed and any changes or additions in concomitant medications were transferred to the Previous and Concomitant Medications CRF. • Participating subjects were required to report to the clinical study site at visit Week 26 (or early termination) for End-of-Study assessments. All End-of-Study procedures were completed at the 26-week End-of-Study visit or when the subject prematurely withdrew from the study before Week 26. • Any AEs unresolved upon completion of the 26-week End-of-Study visit were followed for up to 30 calendar days by the study staff until the event or its sequelae resolved or stabilized at a level acceptable to the investigator and recorded on the Adverse Event Follow-Up Disposition CRF.

Medications and non-drug therapies/procedures taken within 30 days before the Baseline visit were considered previous use. Medications and nondrug therapies/procedures taken after the completion of the Baseline visit (i.e., randomization) were considered concomitant use.

Subjects who started using any of the smoking cessation therapies listed in the exclusion criteria to quit smoking during the study (after Baseline visit) were not discontinued from the study. However, if any of these were used at any time from the Week 2 visit, those subjects were regarded as treatment failures in the analysis of continuous smoking abstinence from Week 2 from the day they started using the other therapy.

Use of all other concomitant medications during study participation was permitted. Any use of other investigational products was prohibited during the study. Information about concomitant medication use was captured at all study visits. Medications and nondrug therapies/procedures used during the study (after the Baseline visit) were recorded in the source document and on the Previous and Concomitant Medications and/or Previous and Concomitant Non-Drug Therapies/Procedures CRF, respectively.

Subjects received investigational product use reporting instructions at their Baseline visit that instructed the subjects to report, via telephone, their total number of sprays used and the maximum number of sprays used within any given hour each day. Compliance with use of investigational product was assessed during the 12-week treatment period via subject reported investigational product use of the total number of sprays used per day and the maximum number of sprays used within any given hour each day. Subjects were not withdrawn from the study for lack of compliance. Subjects were given a handheld counter and were encouraged to use it to keep track of the number of sprays they used each day. They were reminded to report the maximum number of sprays used within any given hour each day. Additional investigational

39 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray product was available up to Week 26 to those subjects who specifically requested it at any time beyond the 12-week treatment period.

Subjects had the right to withdraw from the study at any time for any reason without compromising their rights to receive further treatment. The investigator and/or the Applicant may have terminated a subject from investigational treatment and/or study follow-up in the event of any of the following: • Medical reasons considered significant by the subject, investigator and/or the Applicant, which included an AE, intercurrent illness, or medical reasons unrelated to the study; • Nonmedical reasons (subject request) • Pregnancy • Serious eligibility or on-study violation of the protocol • Administrative reasons

If a subject decided to withdraw from the study at any point, all efforts were made to complete all End-of-Study assessments (if subject could not come to study site, a telephone call to collect information was performed). The investigator requested the subject return all kits, i.e., full, partially full, and empty dispensers, along with the cartons and User’s Guides and followed-up with the subject regarding any unresolved AEs.

If a subject withdrew prior to Week 6, every attempt was made to perform the VMI at the final study visit. For women of child-bearing potential, a pregnancy test was performed at the final study visit regardless of whether the subject self-reported a pregnancy and regardless of whether the subject continued using investigational product up to Week 26. If a subject discontinued the study at Baseline, then the pregnancy test was not repeated.

7.1.2.3. Study Endpoints The primary efficacy endpoint was self-reported continuous abstinence from smoking from the Week 2 visit until and including the Week 6 visit, verified by an exhaled CO level of less than 10 ppm at the Week 2, 4, and 6 visits.

Two key secondary efficacy endpoints were: (1) self-reported continuous abstinence from smoking from the Week 2 visit until and including the Week 12 visit, and (2) self-reported continuous abstinence from smoking from the Week 2 visit until and including the Week 26 visit. Both endpoints were verified by an exhaled CO level of less than 10 ppm at all clinic visits from the Week 2 visit until and including the Week 12 and 26 visits, respectively.

7.1.2.4. Statistical Analysis Plan The statistical analysis planned to use similar methodology as in Study A6431111, with the addition of strata as a controlling variable for the between-group comparisons of CAR rates. The treatment duration and length of study were shorter for study 38, so the secondary efficacy endpoints were defined with timeframes to match the study design. The hierarchical testing order

40 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray was similar, starting with CAR Weeks 2 to 6, followed by CAR Weeks 2 to 12, then CAR Weeks 2 to 26, as appropriate.

7.1.2.5. Study Results

Patient Disposition Overall, 1198 subjects were randomized to double-blind study treatment, 597 were assigned to active treatment and 601 were assigned to placebo. Four hundred eighty-one (481, 40.2%) subjects withdrew from the study and 717 (59.8%) subjects completed the study. Although the overall completion was low, this is not uncommon in smoking cessation studies with prolonged follow-up phases. Notably, the rate of dropout during the full-dose treatment period (Weeks 1-6) was lower: 13% in the NMS arm and 14% in the placebo arm.

In all analyses, dropouts were adjudicated as continuing smokers.

These discontinuation rates are lower than the rates presented for Study 11. This is likely due to the length of the non-treatment follow-up period for Study 11, in which medications were last dispensed at week 20, and follow-up continued to week 52. Historically, discontinuation rates for smoking cessation studies are 40-50%. Reasons for withdrawal were similar for both treatment groups. Subject disposition is displayed in Table 14.

Table 14. Subject Disposition for Study NICTDP3038 NMS 1 mg Placebo Disposition Category N=597 N=601 Randomized (ITT) 597 (100%) 601 (100%) Received study treatment (FAS) 597 (100%) 601 (100%) Completed study 365 (61%) 352 (59%) Discontinued from study 232 (39%) 249 (41%) Discontinued prior to Week 12 (end of treatment) 182 (30%) 208 (35%) Adverse event 23 (4%) 16 (3%) Death 2 (<1%) 3 (<1%) Lost to follow-Up 86 (14%) 113 (19%) Protocol violation 0 2 (<1%) Withdrew consent 68 (11%) 68 (11%) Other 3 (<1%) 6 (1%) Discontinued after Week 12 through Week 26 50 (8%) 41 (7%) (post-treatment) Adverse event 1 (<1%) 0 Death 0 1 (<1%) Lost to follow-up 17 (3%) 18 (3%) Protocol violation 0 0 Withdrew consent 32 (5%) 22 (4%) Other 0 0 Source: FDA Reviewer All percentages are calculated based on Randomized N per group as denominator.

41 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Demographic and baseline characteristics were similar for both treatment groups and are provided in Table 15 below. Overall, the mean age of the study population was 51 years, 60% of subjects were white, 92% of subjects were not of Hispanic or Latino ethnicity, and 54% of subjects were women. The highest level of education was some college or technical school for 46.2% of subjects; high school graduate, GED, or certificate for 22.5% of subjects; college graduate for 19.0% of subjects, and some high school or less for 7.8% of subjects. The mean REALM score was 62.9, with 14.7% of subjects (16.6% for the active treatment group and 12.8% for the placebo treatment group) with a REALM score ≤60 (low literacy).

Table 15. Demographic and Baseline Characteristics for Study NICTDP3038 NMS Placebo All Treated (FAS) N=597 N=601 Age (years) Mean (SD) 51 (11.7) 51 (11.7) Range 18 - 79 19 - 81 Gender Female 332 (56%) 319 (53%) Male 265 (44%) 282 (47%) Race White 345 (58%) 373 (62%) Black 228 (38%) 209 (35%) Asian 6 (1%) 5 (1%) Other 18 (3%) 14 (2%) Baseline # cigarettes smoked Mean (SD) 18 (8.5) 18 (7.7) Range 3 – 70 2 – 60

<20 297 (50%) 295 (49%)  20 300 (50%) 306 (51%) Baseline Fagerstrӧm Mean (SD) 5.2 (2.0) 5.4 (2.2) Range 0 - 10 0 - 10

<6 318 (53%) 329 (55%)  6 278 (47%) 272 (45%) Time to first cigarette ≤30 minutes 510 (86%) 489 (81%) >30 minutes 86 (14%) 112 (19%) Source: FDA Statistical Reviewer

Compliance with Study Drug: Treatment compliance was analyzed by the Applicant for those subjects who provided reports on their product use for at least four days in a given week. Based on mean values, study subjects did not adhere to the recommended dose of 1-2 sprays every 30-60 minutes during Weeks 1 through 6, generally using fewer sprays than recommended. According to Applicant’s Table 64, subjects who were successful quitters on active NMS were even more likely than unsuccessful quitters to use the spray less than recommended and were more likely than non-quitters to report using no doses in a given week.

42 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Efficacy Results Table 16 presents the results for the efficacy endpoints. Although the p-values indicate statistical significance between the groups, the size of the treatment differences is much smaller than in study A6431111, as well as smaller than the assumptions stated in the sample size determination based on a prior study. While these results are statistically significant, the continuous abstinence rates are very low, and are of questionable clinical benefit. The number needed to treat for this study is 40, meaning in the actual use setting, 40 smokers would need to be treated with NMS 1 mg instead of placebo to expect one additional success for continuous abstinence for weeks 2 through 6.

Table 16. Efficacy Results From Study NICTDP3038 (Study 38) NMS 1 mg Placebo FAS Subjects N=597 N=601 Primary: Responders, n (%) 30 (5.0%) 15 (2.5%) Continuous abstinence Diff. from placebo 2.5% rate (95% CI) (0.4%, 4.7%) Weeks 2 to 6 p-value 0.022 Secondary: Responders, n (%) 24 (4.0%) 8 (1.3%) Continuous abstinence Diff. from placebo 2.6% rate (95% CI) (0.9%, 4.5%) Weeks 2 to 12 (EOT) p-value 0.004 (end of treatment) Secondary: Responders, n (%) 20 (3.4%) 7 (1.2%) Continuous abstinence Diff. from placebo 2.2% rate (95% CI) (0.5%, 3.9%) Weeks 2 to 26 (EOS) p-value 0.011 (end of study) Abbreviations: EOS, end of study; EOT, end of treatment Source: FDA Statistical Reviewer

Subjects were also asked to report desire or urge to smoke on a 0 to 4 scale at Weeks 1, 2, 4, and 6. At Weeks 1, 6, and 12, they were asked to provide an overall impression of the product on a scale of 1 (very poor) to 10 (excellent) and a rating of the effectiveness of spray in dealing with the desire/urge to smoke on a scale of 1 (not at all effective) to 5 (extremely effective). The tables and figures below, from the Applicant’s study report, show that there was no difference in the effect of active and placebo study drugs.

At Week 1, in subjects with verified abstinence since the last visit, the mean desire or urge smoke was 1.7 for the active treatment group and 1.8 for the placebo treatment group. At Week 2, the mean desire or urge smoke was 1.5 for the active treatment group and 1.6 for the placebo treatment group. At Week 4, the mean desire or urge smoke was 0.9 for the active treatment group and 1.1 for the placebo treatment group. At Week 6, the mean desire or urge smoke was 1.1 for the active treatment group and 1.0 for the placebo treatment group. There were no statistically significant differences between treatment groups for the desire or urge to smoke at Weeks 1, 2, 4, and 6.

43 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Figure 6. Desire/Urge to Smoke (Mean ±2 SEM) Subjects With CO-Verified Abstinence Since Last Visit

Source: Clinical Study Report Figure 3

Table 17. Subjects’ Perceptions of Investigational Product Overall Product Visit Rating Score Placebo (N=601) Active (N=597) Week 1 1 (Very poor) 18 (3.2%) 10 (1.8%) 2 17 (3.1%) 14 (2.6%) 3 15 (2.7%) 21 (3.9%) 4 33 (6.0%) 28 (5.2%) 5 103 (18.6%) 87 (16.0%) 6 51 (9.2%) 46 (8.5%) 7 103 (18.6%) 102 (18.8%) 8 111 (20.0%) 115 (21.2%) 9 37 (6.7%) 43 (7.9%) 10 (Excellent) 66 (11.9%) 77 (14.2%) Total 554 (100%) 543 (100%) Summary Statistics Mean (SD) 6.5 (2.35) 6.8 (2.21) Median (min, 7.0 (1, 10) 7.0 (1, 10) max)

44 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Overall Product Visit Rating Score Placebo (N=601) Active (N=597) Week 6 1 (Very poor) 25 (5.3%) 11 (2.4%) 2 10 (2.1%) 14 (3.0%) 3 21 (4.5%) 16 (3.4%) 4 24 (5.1%) 15 (3.2%) 5 70 (14.9%) 59 (12.6%) 6 42 (8.9%) 48 (10.3%) 7 88 (18.7%) 83 (17.8%) 8 105 (22.3%) 100 (21.4%) 9 39 (8.3%) 48 (10.3%) 10 46 (9.8%) 73 (15.6%) Total 470 (100%) 467 (100%) Summary Statistics Mean (SD) 6.5 (2.35) 7.0 (2.26) Median (min, 7.0 (1, 10) 7.0 (1, 10) max) Week 12 1 (Very poor) 22 (5.5%) 15 (3.5%) 2 14 (3.5%) 10 (2.3%) 3 15 (3.7%) 14 (3.3%) 4 15 (3.7%) 9 (2.1%) 5 46 (11.4%) 53 (12.4%) 6 40 (10%) 29 (6.8%) 7 67 (16.7%) 60 (14.0%) 8 82 (20.4%) 101 (23.6%) 9 44 (10.9%) 47 (11.0%) 10 57 (14.2%) 90 (21.0%) Total 402 (100%) 428 (100%) Summary Statistics Mean (SD) 6.8 (2.49) 7.3 (2.37) Median (min, 7.0 (1, 10) 8.0 (1, 10) max) Source: Study Report Table 31

Table 18. Subjects Perceptions of Investigational Product: Effectiveness of Spray in Dealing With Desire/Urge to Smoke

Visit At Rating of Effectiveness Placebo (N=601) Active (N=597) Week 1 Not at all effective (1) 48 (8.7%) 23 (4.2%) Somewhat effective (2) 154 (27.8%) 113 (20.8%) Moderately effective (3) 191 (23.3%) 176 (32.4%) Very effective (4) 129 (23.3%) 162 (29.8%) Extremely effective (5) 32 (5.8%) 69 (12.7%) Summary Statistics N 554 543 Mean (SD) 2.9 (1.04) 3.3 (1.06) Median (min, max) 3.0 (1, 5) 3.0 (1, 5)

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Visit At Rating of Effectiveness Placebo (N=601) Active (N=597) Week 6 Not at all effective (1) 55 (11.7%) 25 (5.4%) Somewhat effective (2) 126 (26.8%) 91 (19.5%) Moderately effective (3) 149 (31.7%) 152 (32.5%) Very effective (4) 108 (23.0%) 145 (31.0%) Extremely effective (5) 32 (6.8%) 54 (11.5%) Summary Statistics N 470 467 Mean (SD) 2.9 (1.11) 3.2 (1.06) Median (min, max) 3.0 (1, 5) 3.0 (1, 5) Week 12 Not at all effective (1) 51 (12.7%) 29 (6.8%) Somewhat effective (2) 81 (20.1%) 73 (17.1%) Moderately effective (3) 129 (32.1%) 127 (29.7%) Very effective (4) 103 (25.6%) 123 (28.7%) Extremely effective (5) 38 (9.5%) 76 (17.8%) Summary Statistics N 402 428 Mean (SD) 3.0 (1.16) 3.3 (1.15) Median (min, max) 3.0 (1, 5) 3.0 (1, 5) Source: Study Report Table 32

Duration of Use The dosing directions included a recommendation to taper to discontinuation between Week 6 and Week 12, but subjects were permitted to request supplies of study medication beyond the labeled 12-week treatment/taper period. For many subjects, use of product spray was longer than recommended according to the label.

The Applicant’s study report notes, “Use of product spray was longer than recommended according to the label. At Week 13, 92.0% (231/251) of subjects assigned to active treatment that reported use data on 4 or more days during Week 13 were continuing to use the product. At Week 26, 78.8% (108/137) of subjects assigned to active treatment that reported use data on 4 or more days during Week 26 were continuing to use the product.”

It should be noted that 108 subjects (the total number reporting continuing use at Week 26) represents 18% of the intent-to-treat (ITT) population (compare to the abstinence rate at 26 Weeks, 3.4%). The overwhelming majority of these 108 subjects did not meet criteria for abstinence and were likely dual users of product and cigarettes.

The Applicant’s study report (Table 64), displays the use of study drug (no use, less than recommended, as recommended, or more than recommended) among subjects in the active NMS arm who provided use data on four or more days in a given week. At Week 26, 14 of 28 abstinent subjects (50%) reported no use of study drug. Among those using study drug, 12 reported using less than the recommended dose and 2 reported using more. Among non-abstinent subjects, 15 of 109 (14%) reported no use of product. The remaining 94 people reported ongoing use, suggesting dual use of NMS and cigarettes. These numbers differ slightly from the text

46 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray quoted above, but yield the same conclusion. The likelihood of persistent use without quitting is clearly higher than the likelihood of quitting. These data are not available for the placebo group.

7.1.3. Efficacy Conclusion The Applicant presents the efficacy results in terms of odds ratios (OR). This is an alternative mathematical formula for presenting the same data that is presented here in the efficacy tables (Table 12 and Table 16). We prefer to present the differences in rates, and the corresponding number needed to treat interpretation. The odds ratio statistic is useful in case-control studies where the number of exposed/unexposed subjects is unknown prior to conducting the study. These studies are prospectively planned, well-controlled, randomized clinical studies, so the use of odds ratios is not necessary.

Both studies demonstrated statistical significance for the continuous abstinence rate for weeks 2 through 6. However, in study 38, which was planned to resemble actual OTC use scenario, the treatment difference was only 2%, with a corresponding number needed to treat of 40. Forty smokers would need to be treated with NMS 1 mg instead of placebo in order to expect one additional person to be continuously abstinent for weeks 2 through 6.

The discrepant results between the two studies were explored in depth to attempt to identify potential explanations. The table below illustrates a variety of exploratory analyses conducted to examine the role of smoking history, literacy level, level of dependence, and other factors. No specific justification for the discrepant results could be identified.

Table 19. Comparison of Subgroups for Pivotal Efficacy Studies Study 38 CAR Weeks 2-6 Study 11 “OTC Setting” % Responders “Typical” Clinical Study Study Total NMS Placebo NMS Placebo N=318 N=161 N=597 N=601 Overall responder 83/318 (26%) 26/161 (16%) 30/597 (5%) 15/601 (2%) rate Age 18-39 yrs 17/72 (24%) 4/40 (10%) 2/90 (2%) 3/102 (3%) 40-54 yrs 44/169 (26%) 15/85 (18%) 14/255 (5%) 6/245 (2%) 55+ yrs 22/77 (29%) 7/36 (19%) 14/252 (6%) 6/254 (2%) Gender Female 25/137 (18%) 5/73 (7%) 15/332 (5%) 7/319 (2%) Male 58/181 (32%) 21/88 (25%) 15/265 (6%) 8/282 (3%) Race White 82/313 (26%) 26/161 (16%) 21/345 (6%) 10/373 (3%) POC 1/5 (20%) 0/0 9/252 (4%) 5/228 (2%) Baseline # cigs. <20 27/92 (29%) 9/48 (19%) 15/297 (5%) 7/295 (2%) smoked ≥20 56/226 (25%) 17/113 (15%) 15/300 (5%) 8/306 (3%) Baseline <6 48/163 (29%) 14/80 (18%) 16/318 (5%) 6/329 (2%) Fagerstrӧm ≥6 35/155 (29%) 12/81 (15%) 14/278 (5%) 9/272 (3%) nic. dep. score Time to first ≤30 mins 56/233 (24%) 18/125 (14%) 25/510 (5%) 11/489 (2%) cigarette >30 mins 27/85 (32%) 8/36 (22%) 5/86 (6%) 4/112 (4%) REALM code Low literacy 5/99 (5%) 2/77 (3%) High literacy 25/498 (5%) 13/524 (2%) Abbreviations: CAR, continuous abstinence rate; NMS, nicotine mouth spray; REALM, Rapid Estimate of Adult Literacy in Medicine; POC, persons of color

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Notable differences between the studies included: 1. Location: Study 11 was conducted in Europe and Study 38 was conducted in the United States. The population envisioned for marketing in the United States is the U.S. consumer population. 2. Drug supply: In Study 11, patients were given 5 units at the first visit and in Study 38 they were given 3 units. The likely number of units purchased by an OTC consumer would be one package at a time. 3. Instructions and support: In Study 11, patients were provided instructions on how to use the product and brief smoking cessation counseling at visits. In Study 38, patients were provided only the written instructions included in the package. The scenario envisioned for marketing would be the latter condition. 4. Patient characteristics: Study 38 had a higher average age (51 versus 47 years), a higher percentage of females (54% versus 44%), a higher percentage of patients of color (40% versus 1%), and a higher percentage of patients whose first cigarette was within 30 minutes of waking (83% versus 75%). None of these dissimilarities in the enrolled patients justified the disparity in efficacy results. 5. Discontinuation rate: In Study 11, 18% of subjects on active drug and 28% of subjects on placebo discontinued prior to the primary efficacy ascertainment visit (Week 6), as compared to 13% vs 14% in the active and placebo arms in Study 38. Because non- completers are adjudicated as continuing smokers, the higher rate of discontinuations in Study 11 would tend to lower the quit rate and does not explain the differences in the two studies.

Compliance with the recommended treatment regimen was low and similar in both studies and does not explain the differences in results.

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7.2. Review of Safety

7.2.1. Sources of Data Table 20. Clinical Trials Regimen/ Treatment No. of Number of schedule/ Study Duration/ patients Study Centers and Trial Identity Trial Design route Endpoints Follow Up enrolled Population Countries Controlled Studies to Support Efficacy and Safety (Pivotal Studies to be Reviewed) A6431111 Randomized, 1-2 sprays Continuous 52 weeks 479 Smokers 3 centers, 2 (“Study 11”) double-blind, per 30 min, abstinence with countries placebo- max daily Week 2-6, exhaled controlled, dose 64 24, & 52 CO ≥10 parallel sprays visits ppm group study CO- Randomized, Same as Continuous 26 weeks 1198 Smokers 8 centers in 140121222102- double-blind, above abstinence with United States SCCT placebo- Week 2-6 exhaled only (“Study 38”) controlled, visits CO ≥10 parallel ppm group study in a naturalistic environment

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Regimen/ Treatment No. of Number of schedule/ Study Duration/ patients Study Centers and Trial Identity Trial Design route Endpoints Follow Up enrolled Population Countries Other Efficacy Studies NICTDP2010 Open-label, 1 mg/spray, 3 weeks 258 Healthy 2 placebo- 1-2 sprays smokers controlled, in a fixed- randomized dose study for 3 regimen weeks to (every 30- evaluate 60 min) or usage in a flexible patterns, regimen (ad continuous libitum) abstinence, and safety of NMS with fixed or flexible use directions A6431112 Randomized, NMS 1 Continuous 12 weeks 257 Healthy Terminated double-blind, mg/spray, abstinence smokers early due to placebo- ad libitum week 2-6, error in controlled, (max 4 12 randomization parallel- mg/hr, 64 group study mg/day) to evaluate efficacy and safety of NMS vs. placebo in a naturalistic setting (pharmacies)

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Regimen/ Treatment No. of Number of schedule/ Study Duration/ patients Study Centers and Trial Identity Trial Design route Endpoints Follow Up enrolled Population Countries Pharmacokinetic Studies NICTDP1066 Randomized, 2 sprays of PK study 5 visits 40 Healthy 1 multiple- NMS 1 smokers dose, active- mg/spray, controlled, 4- every 30-60 way minutes; crossover to nicotine assess PK gum 4 mg, and safety 1 gum/hr; between nicotine NMS and lozenge, 4 reference mg, 1 products lozenge/hr NICTDP2011 Randomized, NMS 2 PD study Single- 200 Healthy 1 2 single sprays, 1 doses, 3 smokers doses, open, mg/spray, visits active- twice with 5 controlled, 3- hrs between way doses; crossover to nicotine assess urges lozenge 2 to smoke and mg, twice safety of with 5 hrs NMS (2 between sprays) vs. doses; nicotine nicotine lozenge 2 mg lozenge 4 or 4 mg mg, twice with 5 hrs between doses A6431094 Randomized, NMS 2 PK study Single- 31 Healthy 1 single-dose, sprays, doses, 4 smokers active- mg/spray visits controlled, 4- straight into way mouth, crossover to sublingually, assess PK and and safety of buccally, NMS vs nicotine reference gum 2 mg product

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Regimen/ Treatment No. of Number of schedule/ Study Duration/ patients Study Centers and Trial Identity Trial Design route Endpoints Follow Up enrolled Population Countries A64331107 Randomized, 1, 2, 4 PK study Single- 24 Healthy 1 single-dose, consecutive dose 6 smokers active- sprays of visits controlled, 5- NMS 1 way mg/spray crossover to straight into assess PK, mouth; (for safety, and 2 and 4 mg dose sprays with relationship and without of NMS vs. delay) reference products NICTDP1065 Randomized, 1, 2, 4 PK study Single- 45 Healthy 1 single-dose, consecutive dose, 5 smokers active- sprays of visits controlled, 5- NMS 1 way mg/spray crossover straight into study to mouth; assess PK, nicotine safety, and gum 4 mg; dose nicotine relationship lozenge of NMS vs. 4 mg reference products Source: Applicant Submission Module 2: Synopses of Individual Studies Abbreviations: NMS, nicotine mouth spray; PD, pharmacodynamic; PK, pharmacokinetic

The safety evaluation of this application was based on the two efficacy studies (Studies 11 and 38) and 7 additional phase 1 and 2 studies.

7.2.2. Review of Safety Database Nine clinical studies of NMS, all conducted in healthy smokers, have been completed. These studies comprise four phase 1 pharmacokinetic (PK) studies, one phase 2 pharmacodynamic (PD) study which investigated the craving relief properties of the spray, one phase 2 pilot low intervention use study, and two phase 3 placebo-controlled efficacy and safety studies, and one phase 3 terminated study. As noted above, this review focuses on the two pivotal efficacy studies. The phase 1 and 2 studies were included only in review of deaths and serious adverse events (SAEs).

Study 11, conducted in Europe, investigated and evaluated the efficacy and safety of NMS 1 mg compared to placebo over a 24-week period of investigational product use, a 30-day safety follow-up period, and a 26-week follow-up period with no investigational product use. This study included smoking cessation counseling and training on product use. A total of 242 subjects

52 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray completed the 24-week treatment period and 28-week extended follow-up period: 75 subjects in the placebo group and 167 subjects in the active treatment group.

Study 38, conducted in the United States, investigated and evaluated the efficacy and safety of flexible use of NMS 1 mg compared to placebo over a 26-week period. This study did not include counseling or training on product use because of the requirement to mimic the nonprescription product environment in which patients may only rely on the materials included with the product. A total of 1198 subjects were randomized, 601 subjects in the placebo group, and 597 in the active treatment group. All subjects were assumed to have used at least 1 dose of study medication.

Demographics and baseline characteristics were presented in section 6 for each pivotal study. The safety population for each study was an adequate representation of the target treatment population of smokers. The total number of subjects exposed to NMS including PK studies was approximately 1526.

7.2.3. Safety Results The safety evaluation of this application was based primarily on pivotal efficacy studies 11 and 38. Safety data were not pooled for this review, because the studies were conducted differently.

For Study 11, an e-diary included prompts to report specific adverse events as well as an opportunity to specify “other” AEs. Several treatment-emergent adverse events (TEAEs; 20 (6%) in NMS arm and 4 (2%)) were coded as “adverse event” with no additional information given, presumably due to subjects not providing the information on the e-diary prompt screen. Otherwise, preferred terms were congruent with subject verbatim terms.

For Study 38, a medical problems log was kept by subjects to assist them in reporting health problems they experienced during the 26 weeks of study participation. No checklist of events was provided. The log also collected information on any medications or treatment taken in conjunction with the AEs reported. The subjects recorded spray usage and smoking status within the two hours prior to the event.

The visual mouth inspection (VMI) data from Study 11 were collected separately on a form and not recorded as AEs. For Study 38, the VMI data were recorded on a separate form and then transferred onto the AE form. Moreover, the VMI time points were different for the 2 studies. For Study 11, the VMI was performed at baseline, and Weeks 2, 12, and 24. For Study 38, VMI was performed at baseline and Week 6 (or end of study if subject withdrawal was before Week 6).

Deaths A total of eight deaths occurred in both pivotal studies, and the terminated study, A6431112 (five subjects who received placebo and three subjects who received NMS 1 mg). There were no deaths reported in the phase 1 and phase 2 studies. Summarized narratives are as follows:

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Study 11: NMS Subject: 47-year-old male, smoked for 33 years [10 cigarettes per day (cpd)], randomized to study on 3/31/09, found dead at his home with blood on his nose and mouth. Autopsy showed cavitation of lung tissue in both upper lobes of lungs, patient was treated for pneumonia 3 months prior. Nicotine level was 7 ng/mL, last dose of study drug was 4/10/09, avg 11.4 doses (1 mg of nicotine/spray) per day, which didn’t exceed max dose. Death was most likely due to chronic lung disease and not study drug.

Study 38: NMS Subject: 46-year-old female, history of (h/o) bilateral tubal ligation, hypertension (HTN), rheumatoid arthritis, systemic lupus erythematosus, left ventricular hypertrophy, smoked for 31 years 30 cpd randomized to NMS on 4/20/15. Subject died of cardiac arrest in her sleep. No autopsy was performed. Last recorded use was 7/14/15. The death certificate listed the immediate cause of death as cardiac arrest due to cardiac arrhythmia, essential hypertension, and lupus erythematosus, with a contributing condition of left ventricular hypertrophy. It is unlikely that death was caused by study product.

NMS Subject: 44-year-old female, h/o constipation smoked for 31 years, 12 cpd was randomized to NMS on 4/2/15. The subject’s sister reported subject died of combined toxic effects of alcohol, cocaine, and fentanyl, according to the death certificate. Last use of product was 5/9/15. It is unlikely that death was caused by study product.

Placebo Subject: 69-year-old male, h/o HTN, diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), gastroesophageal reflux disease (GERD), smoked for 52 years, 11 cpd, randomized to placebo 5/16/15. Subject was admitted to hospital with perforated bowel, died of sepsis.

Placebo Subject: 57-year-old male, h/o DM, erectile dysfunction, smoked for 40 years, 20 cpd, randomized to placebo on 2/18/15. Subject called study site on 6/2/15, reported that he was diagnosed with pancreatic cancer. Patient last used study product 6/17/15, died of cancer.

Placebo Subject: 79-year-old male, h/o GERD, lumbar fusion of L3-L4, multiple myeloma, smoked for 49 years, 20 cpd, was randomized to placebo 3/16/15. Subject died of multiple myeloma, pneumonia, and sepsis. His last use of product was 7/23/15.

Placebo Subject: 63-year-old female, h/o myocardial infarction, HTN, GERD, generalized anxiety disorder, smoked 42 years, 20 cpd randomized to placebo 4/30/15. Subject died in sleep. No autopsy was performed.

Study A6431112 (terminated P3 study): Placebo Subject: 60-year-old white female with a smoking history of 20 years (average cigarettes per day of 20 at screening), rheumatoid arthritis, kidney disease, and known carotid endovascular disease, was randomized to placebo mouth spray on 7/3/11, and died at home. The most likely cause was a coronary or cerebrovascular event, not likely related to the study drug.

54 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray 7.2.3.1. Serious Adverse Events In the phase 1 studies, there were two SAEs, abdominal pain and toothache, neither of which were related to the study drug. For the phase 2 studies, five SAEs were reported; one due to Crohn’s disease exacerbation, one due to chronic obstructive pulmonary disease exacerbation, one due to severe tonsillitis, and one had kidney stones and kidney infection. These studies had no placebo arm; therefore, all were exposed to active product. Extensive subject narrative review revealed no relation to the study drug.

For the terminated phase 3 study, three nonfatal SAEs were reported in the placebo subjects, and one in the NMS subjects. Extensive subject narrative review revealed no relation to study drug.

For the pivotal phase 3 studies, a total of 19 (2.5%) of 762 placebo subjects experienced nonfatal SAEs compared with 33 (3.6%) of 915 NMS 1 mg subjects. The sources reviewed were CRFs and Applicant’s narrative summaries.

Almost all SAEs were single events. The only SAEs reported in more than one subject were as follows: appendicitis and breast cancer, each in one subject in the placebo group and one subject in the NMS 1 mg group; peripheral arterial occlusive disease in two subjects in the placebo group; and postprocedural infection, lung neoplasm malignant, and acute kidney injury, each reported in subjects in the NMS 1 mg group.

Thorough review of narratives and CRFs for SAEs in both pivotal studies revealed no causal relationship between study drug and SAEs.

7.2.3.2. Dropouts and/or Discontinuations Due to Adverse Events The following tables display adverse events leading to discontinuation by preferred term. Similar terms were combined (i.e., depression/depressed mood).

In study 11, 41 subjects discontinued from treatment because of AEs, 12 (7%) in the placebo group (3 subjects had more than one AE leading to discontinuation) and 29 (9%) in the active treatment group (3 subjects had more than one AE leading to discontinuation).

Table 21. Study 11 Adverse Events Leading to Subject Discontinuation From Study* NMS (N=318) Placebo (N=161) AE Preferred Term n (%) n (%) Dyspepsia 1 (0.3) 4 (2.5) Nausea 10 (3.1) 3 (1.9) Vomiting 4 (1.3) 3 (1.9) Diarrhea 0 1 (0.6) Constipation 0 1 (0.6) Abdominal distention 0 1 (0.6) Abdominal pain 1 (0.3) 0 Flatulence 0 1 (0.6) Stomatitis 3 (0.9) 1 (0.6) Dry Mouth 2 (0.6) 0

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NMS (N=318) Placebo (N=161) AE Preferred Term n (%) n (%) Salivary hypersecretion 2 (0.6) 0 Dysgeusia 2 (0.6) 1 (0.6) Product taste abnormal 1 (0.3) 0 Throat irritation 6 (1.9) 1 (0.6) Throat tightness 2 (0.6) 0 Bronchospasm 1 (0.3) 0 Hiccups 1 (0.3) 0 Nasopharyngitis 0 1 (0.6) Hypersensitivity 0 1 (0.6) Hyperhidrosis 0 1 (0.6) Cerebrovascular accident 0 1 (0.6) Headache 2 (0.6) 0 Cervical root pain 1 (0.3) 0 Dizziness 2 (0.6) 2 (1.2) Depression 4 (1.3) 1 (0.6) Aversion 1 (0.3) 0 Somnolence 0 1 (0.6) Breast cancer 1 (0.3) 0 Breast pain 1 (0.3) 0 Burning sensation 2 (0.6) 0 * Several subjects discontinued study due to more than one AE Abbreviations: AE, adverse event; NMS, nicotine mouth spray

In study 38, 40 subjects withdrew from the study due to an AE, 16 (2.7%) in the placebo group, and 24 (4%) in the active treatment group.

Table 22. Study 38 Adverse Events Leading to Discontinuation* NMS (N=597) Placebo (N=601) AE Preferred Term n (%) n (%) Nausea 5(0.8) 2 (0.3) Oral discomfort 5 (0.8) 0 Diarrhea 2 (0.3) 2 (0.3) Dyspepsia 1 (0.2) 2 (0.3) GERD 2 (0.3) 0 Vomiting 1 (0.2) 1 (0.2) Abdominal discomfort 1 (0.2) 0 Abdominal pain upper 0 0 Constipation 1 (0.2) 0 Dry mouth 1 (0.2) 0 Lip blister 1 (0.2) 0 Noninfective gingivitis 1 (0.2) 0 Oral mucosal blistering 1 (0.2) 0 Oral mucosal erythema 1 (0.2) 0 Stomatitis 1 (0.2) 0 Hiccups 9 (1.5) 0 Throat irritation 1 (0.2) 2 (0.3) Cough 2 (0.3) 0 Oropharyngeal pain 2 (0.3) 0 Choking/choking sensation 2 (0.3) 0

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NMS (N=597) Placebo (N=601) AE Preferred Term n (%) n (%) Pleural effusion 1 (0.2) 0 Productive cough 1 (0.2) 0 Pulmonary mass 1 (0.2) 0 Sinus congestion 1 (0.2) 0 Tooth abscess 0 3 (0.5) Upper resp tract infection 1 (0.2) 1 (0.2) Angular cheilitis 1 (0.2) 0 Cellulitis 1 (0.2) 0 Fungal infection 1 (0.2) 0 Gingivitis 0 1 (0.2) Influenza 1 (0.2) 0 Otitis media 1 (0.2) 0 Periodontitis 1 (0.2) 0 Pharyngitis 1 (0.2) 0 Sepsis 1 (0.2) 0 Urinary tract infection 1 (0.2) 0 Headaches 3 (0.5) 2 (0.3) Dizziness 3 (0.5) 0 Dysgeusia 2 (0.3) 0 Bite 1 (0.2) 1 (0.2) Head injury 0 1 (0.2) Laceration 0 1 (0.2) Ligament rupture 0 1 (0.2) Muscle strain 1 (0.2) 0 Postoperative ileus 1 (0.2) 0 Scratch 0 1 (0.2) Hypertension 2 (0.3) 1 (0.2) Uncontrolled HTN 0 1 (0.2) Anxiety 1 (0.2) 0 Bipolar disorder 0 1 (0.2) Delirium 1 (0.2) 0 Dysphoria 1 (0.2) 0 Emotional disorder 0 1 (0.2) Insomnia 1 (0.2) 0 Dermatitis 0 1 (0.2) Pruritis 1 (0.2) 0 Rash 1 (0.2) 0 Eye inflammation 0 1 (0.2) Vision blurred 1 (0.2) 0 Chest pain 0 1 (0.2) Taste abnormal 0 1 (0.2) Back pain 0 1 (0.2) Osteoarthritis 1 (0.2) 0 Lung neoplasm malignancy 1 (0.2) 0 Renal cell carcinoma 1 (0.2) 0 Acute kidney injury 1 (0.2) 0 Urinary retention 1 (0.2) 0 Leukocytosis 1 (0.2) 0 Ear pain 1 (0.2) 0 Blood pressure increased 0 1 (0.2)

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NMS (N=597) Placebo (N=601) AE Preferred Term n (%) n (%) Hypernatremia 1 (0.2) 0 Hyperkalemia 1 (0.2) 0 * Several Subjects discontinued due to more than 1 AE Abbreviations: AE, adverse event; GERD, gastroesophageal reflux disease; HTN, hypertension; NMS, nicotine mouth spray

7.2.3.3. Treatment-Emergent Adverse Events and Adverse Reactions The following tables illustrate AE’s reported ≥2% in the active arm and at a higher rate than in the placebo arm for each of the pivotal efficacy studies.

AEs that affect the gastrointestinal system and nervous system, such as: nausea, vomiting, headaches, and dizziness were common in the active arms of both studies, which are typical adverse events in smoking cessation product studies. AEs that are more specific to NMS, such as hiccups, mouth/throat irritation, alteration in taste, dry mouth, mouth irritation, stomatitis, etc., are more likely a function of the delivery system.

The following items were solicited in the e-diary in Study 11, which likely increased the reporting rate for these specific terms. The term “adverse event” in the figure below appears to reflect subjects selecting the term “other.” The Study 11 AE data sets did not flag AEs specifically as “treatment emergent.” Therefore, the Study 11 AE table represents all adverse events collected during the study.

Figure 7. Adverse Events: Study 11 E-Diary

Source: Applicant Submission

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Table 23. Study 11 AEs ≥2% of Active Arm

Source: Clinical Reviewer, Data set ADAE Abbreviations: SOC, system organ class; HLGT, high-level group term; NEC, not elsewhere classified; NMS, nicotine mouth spray; AE, adverse event

59 FDA Briefing Document NDA 208-425 Nicotine Mouth Spray Table 24. Study 38 TEAEs ≥2% of Active Arm SOC HLGT Preferred Term NMS NMS % Placebo Placebo % Gastrointestinal disorders Gastrointestinal motility and defaecation conditions Diarrhoea 16 3 13 2 Gastrointestinal disorders Gastrointestinal signs and symptoms Dyspepsia 22 4 19 3 Gastrointestinal disorders Gastrointestinal signs and symptoms Nausea 59 10 26 4 Gastrointestinal disorders Gastrointestinal signs and symptoms Vomiting 11 2 4 1 Gastrointestinal disorders Oral soft tissue conditions Oral discomfort 21 4 3 0 Infections and infestations Infections - pathogen unspecified Nasopharyngitis 35 6 22 4 Infections and infestations Infections - pathogen unspecified Upper respiratory tract infection35 6 23 4 Investigations Cardiac and vascular investigations (excl enzyme tests) Blood pressure increased 12 2 13 2 Musculoskeletal and connective tissueJoint disorders disorders Arthralgia 10 2 5 1 Musculoskeletal and connective tissueMusculoskeletal disorders and connective tissue disorders NEC Back pain 11 2 8 1 Nervous system disorders Headaches Headache 48 8 38 6 Nervous system disorders Neurological disorders NEC Dizziness 18 3 6 1 Psychiatric disorders Sleep disorders and disturbances Insomnia 12 2 8 1 Respiratory, thoracic and mediastinal Respiratorydisorders disorders NEC Cough 24 4 20 3 Respiratory, thoracic and mediastinal Respiratorydisorders disorders NEC Hiccups 252 42 47 8 Respiratory, thoracic and mediastinal Respiratorydisorders disorders NEC Oropharyngeal pain 21 4 21 3 Respiratory, thoracic and mediastinal Respiratorydisorders disorders NEC Throat irritation 26 4 14 2 Vascular disorders Vascular hypertensive disorders Hypertension 30 5 18 3 Source: Clinical Reviewer, Data set ADAE Abbreviations: SOC, system organ class; HLGT, high-level group term; NEC, not elsewhere classified; NMS, nicotine mouth spray; TEAE, treatment-emergent adverse event

7.2.3.4. Oral Mucosal Safety Nicotine is a known local irritant to the mouth and is implicated in many pathological conditions ranging from milder ones such as hyperkeratosis to serious ones, such as oral cancer. This includes exposure to nicotine through smoking cigarettes, cigars and pipes, as well as through the use of chewing tobacco. As part of the risk/benefit equation for approval of nicotine as an aid to smoking cessation, adverse events must be weighed against the benefits gained from cessation of smoking.

The VMI data, collected in the two long-term phase 3 Studies 11 and 38, were not pooled together because the data were collected differently in each study. The VMI data from Study 11 were collected separately on a form and not recorded as AEs. For Study 38 the VMI data were recorded on a separate form and then transferred onto the AE form. Moreover, the VMI time points were different for the 2 studies. For Study 11, the VMI was performed at baseline, and Weeks 2, 12, and 24. For Study 38, VMI was performed at baseline and Week 6 (or end of study if subject withdrawal was before Week 6).

The VMI data from Study 11 were collected separately on a form and not recorded as AEs. In the VMI Adverse Event Analysis (ADAE) Database from Study 11 “Burning sensation” is coded as oral discomfort or burning sensation. For consistency, all were recoded as FDA Medical Dictionary for Regulatory Activities Query (FMQ) “Burning sensation” (Table 25).

Table 25. Study 11 FMQ Burning Sensation Adverse Event Term AEDECOD FMQ Burning feeling in the mouth Oral discomfort Burning sensation Burning in the mouth Oral discomfort Burning sensation Burning inside the mouth Oral discomfort Burning sensation Burning lips Burning sensation Burning sensation Burning of mouth Oral discomfort Burning sensation Burning on the tongue Glossodynia Burning sensation Burning sensation Burning sensation Burning sensation Burning sensation in mouth Oral discomfort Burning sensation

The VMI Database from Study 38 did not use standard Medical Dictionary for Regulatory Activities (MedDRA) terms for the classification of local AEs (Table 26). The location and condition are recorded, but the “abnormality descriptions” are not standardized. For example, “white patch,” “white patches,” and “hyperkeratosis” are clinically consistent with leukoplakia but are recorded as unique events. To address this data coding, all AEs with a similar clinical presentation were recoded as FMQ “leukoplakia.”

Table 26. Study 38 Visual mouth inspection (VMI) examples Parameter Condition ABNDESC FMQ Tongue Abnormal Coated Coated tongue Tongue Abnormal Coated tongue Coated tongue Mucobuccal fold Abnormal Hyperkeratosis Leukoplakia Gingiva Abnormal Inflammation Gingivitis Buccal mucosa Abnormal Hyperkeratosis Leukoplakia

Parameter Condition ABNDESC FMQ Tongue Abnormal Coating on tongue Coated tongue Gingiva Abnormal Hyperkeratosis Leukoplakia Gingiva Abnormal White patches Leukoplakia Buccal mucosa Abnormal Cheek biting Linea alba Buccal mucosa Abnormal Cheek bite Linea alba Gingiva Abnormal White patch Leukoplakia Lips/labial mucosa Abnormal Nodule Nodule Tongue Abnormal Fissured Fissured tongue Buccal mucosa Abnormal White patch Leukoplakia Buccal mucosa Abnormal White patches Leukoplakia Hard/soft palate Abnormal Erythema Erythema Tongue Abnormal Geographic tongue Geographic tongue Uvula/oropharynx Abnormal Inflammation Inflammation Hard/soft palate Abnormal Hyperkeratosis Leukoplakia Buccal mucosa Abnormal Biting Linea alba Gingiva Abnormal Nodule Nodule Hard/soft palate Abnormal Inflammation Inflammation Hard/soft palate Abnormal White patch Leukoplakia Abbreviation: FMQ, FDA Medical Dictionary for Regulatory Activities Query; ABNDESC, Abnormality Description

Similar coding issues exist in the ADAE database, where “White patch in the lower right retromolar pad” is coded as “oral mucosal discoloration”, but clinically is consistent with “leukoplakia” (Table 27).

Table 27. Study 38 ADAE Database Adverse Event Term AEDECOD Adverse Event FMQ White patch L buccal mucosa Leukoplakia oral Leukoplakia oral Buccal mucosa (buccal surface bilateral white Oral mucosal discoloration Leukoplakia oral patch small (NCS) Lower R white patch (retromolar pad) Oral mucosal discoloration Leukoplakia oral Mild leukoplakia left buccal Leukoplakia oral Leukoplakia oral Right buccal mucosa leukoplakia (no other Leukoplakia oral Leukoplakia oral information) Slight leukoplakic change left buccal Leukoplakia oral Leukoplakia oral Small white spot on right outer edge of tongue Tongue discoloration Leukoplakia oral White area palatal upper molars (gingiva) Gingival discoloration Leukoplakia oral White patch buccal mucosa Pigmentation buccal Leukoplakia oral White patch left lateral border on tongue Tongue discoloration Leukoplakia oral White patch lower right retromolar pad Mucosal discoloration Leukoplakia oral White patches on right cheek buccal mucosa Oral mucosal discoloration Leukoplakia oral Worsening of white patches on mucobuccal fold Oral mucosal discoloration Leukoplakia oral Abbreviations: AEDECOD, AE Dictionary-Derived Term; FMQ, FDA MedDRA Query; NCS, not clinically significant

At baseline for study 11, eight patients had leukoplakia compared to 4 in the placebo group. Since this study was randomised 2:1 this is to be expected. One patient did not have leukoplakia at baseline (A6431111) but developed leukoplakia in week 2; the patient was in the active arm. The baseline prevalence for leukoplakia in this study is about 2.5%, compared to 8.9% in Study 38.

In Study 38, applying the leukoplakia FMQ coding, 8.9% of patients in the active arm had leukoplakia compared to 6.7% in the placebo arm at baseline (see Figure 8). Nine patients had no leukoplakia at baseline and developed leukoplakia at 6 weeks (5 in the NMS group and 4 in the placebo arm).

Figure 8. Leukoplakia at Baseline and 6 Weeks in Study 38

Abbreviation: NMS, nicotine mouth spray

Nicotine is a known local irritant to the mouth. Smokers have increased prevalence pathological conditions affecting their oral mucosa — ranging from milder ones such as hyperkeratosis, leukoplakia to serious ones, such as oral cancer. This is supported in the literature as well as in the clinical visual mouth inspections from Studies 11 and 38. As part of the benefit-risk equation for approval of NMS as an aid to smoking cessation, adverse events must be weighed against the benefits gained from the cessation of cigarette smoking.

7.2.4. Safety Conclusions The safety of NMS 1 mg used by healthy smokers was evaluated in data from two placebo- controlled phase 3 studies (A6431111 and NICTDP3038) as well as several phase 1 PK/PD studies and a phase 2 study.

Overall, the percentage of subjects experiencing TEAEs was greater in subjects receiving NMS 1 mg compared with those subjects receiving placebo. The most frequent TEAEs observed with NMS were related to respiratory, gastrointestinal, infection, and nervous system conditions. The most frequent TEAEs (by preferred term) in subjects receiving the NMS 1 mg flexible dose in the efficacy (A6431111 and NICTDP3038) studies were fairly similar, although Study 11 had more commonly-reported terms presumably due to the use of an AE checklist, and AEs were collected for the entire 52 weeks.

The most-commonly reported events in the active arm in study 11 and study 38 respectively, were hiccups (72%, 42%), headache (50%,8%), and nausea (41%, 10%). The occurrence of some of these events, such as throat irritation and hiccups are associated with NMS 1 mg delivering a dose of nicotine to the mucosa but did not appear to adversely affect toleration of the product. Dropouts due to AEs were fairly infrequent. The most common AEs leading to discontinuation in study 11 were nausea (3%) and throat irritation (2%), while in study 38, they were hiccups (1.5%), and nausea (0.8%).

The cumulative incidence by time to first onset of TEAEs showed that the onset of most TEAEs was within the first week of treatment, and thereafter the rate of AE onset declined.

A total of eight deaths (five subjects receiving placebo and three subjects receiving NMS 1 mg) were reported, of which 7 of the deaths occurred in the phase 3 Studies A6431111 and NICTDP3038, and one death occurred in terminated Study A6431112. On review of narratives, the causes were unlikely to be related to study treatment.

Non-fatal SAEs were experienced by 2% of subjects receiving placebo and 3% of subjects receiving NMS. Upon extensive review of CRFs and narratives, SAEs were determined to be unrelated to study drug.

In summary, the safety findings based on the clinical data analyzed for this Integrated Summary of Safety suggest that new exposure to NMS 1 mg triggers onset of AEs, particularly the more common ones (hiccups, nausea, salivary hypersecretion, headache, throat irritation, dizziness, and dyspepsia), but over time the occurrence of these AEs decline. The decrease in occurrence of AEs also follows the fall-off in use of NMS over time.

8. Summary of Postmarketing Safety

The proposed OTC NMS NRT, approved in the United Kingdom in 2010 for adults and children aged 12 years and over, is reported to be marketed in many countries in a behind-the-counter or front of the counter (OTC) status. This postmarketing safety summary of the proposed OTC NRT includes identification of AEs associated with NMS through searches of pharmacovigilance databases and published literature.

Sources of Postmarketing Data: • Applicant’s Global Medical Safety database search from March 2011 to September 2018 of NMS 1 mg (MedDRA version 21.0 preferred terms (PT)) and 120-Day Safety Update from October 2018 to December 2018 • FDA Adverse Events Reporting System (FAERS) database search conducted for reports through April 2019 (MedDRA version 22.0) • World Health Organization (WHO) VigiBase search conducted for reports through April 2019 • PubMed and Embase literature search through July 2019 for articles related to the use of NMS and other oral NRT products

The FDA defines an AE as any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related. Therefore, an AE can be any unfavorable and unintended sign, symptom or disease temporally associated with the use of a drug product.

When evaluating adverse events some events are more worrisome than others. These are categorized as serious adverse events (SAE) and defined by FDA as any adverse drug event (experience) occurring at any dose that results in any of the following outcomes: • Death • Life-threatening • Hospitalization • Disability or Permanent Damage • Congenital Anomaly or Birth Defect • Required Intervention to Prevent Permanent Impairment or Damage • Other Serious (Important Medical Events) – Blood dyscrasias – Seizures – Allergic bronchospasm – Development of drug dependence or drug abuse

Results of the postmarketing database searches are constrained by content typical of spontaneous reporting. For example, reports may be submitted by a variety of individuals including consumers and practitioners. Data in case reports are often incomplete, and over time events may be less frequently reported. Limitations to interpreting the spontaneous reports include: • Reports are submitted voluntarily, and the magnitude of underreporting is unknown. • Reporting systems yield reporting trends, and not incidences. • Clinical information is often limited in the reports, and causality cannot often be determined. • Duplicate cases are common, may not be removed, and may affect the impact of further analysis. • Reporting may be biased. A reporter’s intent may confound the interpretation of associations between use of a drug and AEs.

8.1. Applicant Global Safety Database

This section includes FDA’s review and summary of the Applicant’s global safety database (GSD) assessment of postmarketing data for NMS. The Applicant’s GSD is a pharmacovigilance system for managing adverse event data collection with safety data sourced from spontaneous reports and research activities.

The Applicant noted AE data specifically associated with internationally marketed NMS consists primarily of an adult population. Of 4596 cases from 2011 to 2018, 450 were serious reporting 1143 AEs. Table 28 lists the most common PTs in serious cases. There were 4146 nonserious cases reporting 8662 AEs. Table 29 lists the most common PTs in nonserious cases. Few pediatric or adolescent NMS events were reported, and no age or gender-related AE patterns were identified in subgroup demographics from nonclinical trial case reports.

Table 30 summarizes subgroup demographics. A discussion of serious and nonserious cases follows.

Table 28. GSD Distribution of MedDRA PTs for Serious Cases With Frequency ≥10 Cases

Source: Excerpted from Applicant submission Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term Table 29. GSD Distribution of MedDRA PTs for Nonserious Cases With Frequency ≥100 Cases

Source: Excerpted from Applicant submission Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term

Table 30. Summary of Global Safety Database Adverse Event Demographics

Source: Excerpted from Applicant submission

The Applicant’s GSD search reported deaths, serious and nonserious cases as described below.

Death One publication cited by the Applicant included deaths (Dollerup et al. 2017). None of the cases were reported as causally related to NMS.

Overdose The Applicant reported 134 cases of overdose. Nineteen of 25 serious cases were reported as overdose because they involved high dosage spray use, use of more than two forms of NRT and continued use of spray after cessation or continuation of smoking. In 105 nonserious cases reporting overdose, approximately half were associated with drug administration errors and the remainder related to systemic events such as nausea, malaise, dizziness and headache.

Dependence/Misuse/Abuse In 293 cases, the Applicant reported SAEs of drug dependence, nicotine dependence or dependence. Drug product misuse or abuse terminology was reported in 74 cases. Among these 74 cases, 15 serious cases reported development of dependence that may be associated with inability to wean off NRT as a transferred dependence. The Applicant explained that absence of information on smoking characteristics of the patients and insufficient information on the occurrence of withdrawal symptoms suggested behavioral dependence that may be associated with the patients’ inability to wean off NRT in order to quit smoking or maintain smoking cessation.

There were 60 nonserious reports; 25 involved use by nonsmokers, 23 for longer duration, and three at higher frequencies.

Respiratory The Applicant reported 63 serious respiratory cases which included 34 dyspnea, 9 asthma, 9 cough, 3 chronic obstructive pulmonary disease, 3 respiratory disorder, 2 asthmatic crisis, 2 obstructive airways disorder, and 1 bronchospasm. The Applicant notes insufficient smoking history characteristics to identify an association of these respiratory AEs with NMS use.

Cardiovascular The Applicant reported SAEs of cardiovascular and cerebrovascular disorders in 11 cases. Of these 11 cases, cerebrovascular accident was reported in five cases, angina pectoris was reported in three cases, myocardial infarction was reported in two cases, and cardiac flutter was reported in one case.

Anaphylaxis The Applicant reported PTs of five serious cases which included anaphylactic shock and/or anaphylactic reaction. The Applicant noted that limited report information and atypical descriptions precluded determination of a causal relationship to NMS.

Medication Error The Applicant reported medication errors in 792 cases. The majority of 152 serious cases reported incorrect drug administration with 137 cases characterized as product use longer than recommended duration. In 640 nonserious cases, 159 were associated with medication error, 130 wrong technique, 114 incorrect duration, and 113 accidental exposure. The distribution included one infant, four children, five adolescents, 237 adults, and 48 elderly. Age was not reported in 476 cases. It is notable that the spray dispenser features a press-and-push locking mechanism that is designed to be child-resistant (see Section 4).

Nonserious Cases According to the Applicant, hiccups, oral discomfort, and throat irritation comprised most local events and contributed to 26% of nonserious event reports (2275/8662). Hiccups represented 6.8% of reported events as the only AE. Fifteen percent (1315/8662) of the events were related to product handling including quality issues, device malfunction, and medication error. Nausea and vomiting were among 12.7% of systemic event reports.

Pediatric/Adolescent Use According to the Applicant, among the cases reporting an age, there were only 16 cases associated with the use of NMS in the pediatric subgroup. No serious cases were reported. Twelve cases reporting age included one infant, eight children, and seven adolescents with seven

females and six males. The AEs reported in these cases were burning sensation, dizziness, dyspnea, headache, malaise, nausea, pain, pallor, suffocation feeling, throat irritation, and vomiting. These AEs are known and consistent with nonserious AEs of the adult population (Bailey et al. 2012).

• Four cases involved patients ranging from 0 to 10 years of age. In one case the wrong patient received medication, in three cases accidental exposure to product was reported. • Six cases involved patients ranging from 12 to 17 years of age who were using NMS for the treatment for cessation of smoking or chewing tobacco. • United Kingdom newspaper article reporting that prescription nicotine spray for a 12- year-old girl was shared with a group of 20 classmates (11 to 13-year-old). The news release noted that students became nauseous, having symptoms of vomiting, dizziness, and headaches. One student needed hospital treatment that was not further evaluated (Alexander 2015).

Graphics summarizing GSD nonserious cases and highlighting SAEs are provided in Figures 9 and 10 below.

Figure 9. Global Safety Database Nonserious Cases Nonserious Case Events 2500

2000

1500

1000 NUMBER OF CASES OF NUMBER

500

0 Local effects Product Systemic handling effects

Source: Summary of Applicant submitted data

Figure 10. Global Safety Database Serious Cases

Serious Case Events 350 300 250 200 150 100

50 NUMBER OF CASES OF NUMBER 0

Source: Summary of Applicant submitted data

120-Day Safety Update The Global Safety Database was researched by the Applicant in the fourth quarter of 2018. A total of 216,977,000 units (1 unit =1 spray) were reported as distributed; equaling 1,446,513 canisters having 150 sprays per canister as currently marketed outside the U.S. Fifty-two percent of AEs were associated with three countries: Australia, Russia, and Germany. There were 249 cases with 23 SAEs and 226 AEs. Reporting included eight overdoses considered nonserious and related to concomitant use of more than one NRT; no misuse or abuse; no deaths; no case reports of AEs in subjects <18 years old; no significant gender related AEs; and no new literature related to NMS AEs described.

8.2. FDA FAERS Search

The FAERS database contains adverse event and medication error reports submitted to the FDA from a variety of sources. The database is designed to support FDA's postmarketing safety surveillance program for drug products marketed in the United States and adheres to international safety reporting guidance issued by the International Conference on Harmonisation (ICH E2B) (Food and Drug Administration 2019). Non-U.S. marketed drug product reports may appear in FAERS when directly reported by an international sponsor or in cases when an adverse event report contains multiple drugs, including a U.S. marketed product and in this instance, NMS as well.

FDA’s Division of Pharmacovigilance (DPV) searched FAERS for cases having events associated with the use of NMS.

Inclusion criterion: • Reported event occurred following the use of NMS

Exclusion criteria: • Different form of NRT (e.g., gum, lozenge, patch, nasal spray) • No adverse event reported • Alternate etiology provided (e.g., concomitant medication, underlying disease state) • Report from a clinical trial (not postmarketing reports)

Cases related to drug abuse, misuse, and/or dependence, were classified by inclusion criteria, as described in the Office of Surveillance and Epidemiology (OSE) Case Definition of Drug Abuse, Misuse, Dependence, Tolerance and Withdrawal (Patel et al. 2019).

1. Case reports with one or more of the following: The term(s) “drug abuse” or “drug misuse” or “drug dependence” is stated in the narrative with or without clinical manifestations associated with drug abuse or misuse of, or dependence on, the drug of interest.

2. Clinical assessment by the reviewer of drug abuse, misuse, or dependence using the definitions in Table 31.

Table 31. Definitions and Examples of Drug Abuse, Misuse, and Dependence in FDA Guidances (January 2017; November 2017) Definition Intentional, nontherapeutic use of a drug product or substance even once, to achieve a desired psychological or physiological effect

Drug abuse Examples: Additional doses to achieve euphoria Administration via an unapproved route Intentional therapeutic use of a drug product in an inappropriate way and specifically excludes the definition of abuse

Drug misuse Examples: Additional dose of pain medication to alleviate pain Additional dose of weight loss medication to achieve greater or faster weight loss Taking a sleeping pill for insomnia from a friend Physical dependence is a state that develops as a result of physiological adaptation in response to repeated drug use, manifested by withdrawal signs and symptoms after abrupt discontinuation or a significant dose reduction of a drug.

Examples: Caffeine Clonidine Drug Amphetamines dependence Psychological dependence is a state in which individuals have impaired control over drug use based on the rewarding properties of the drug (ability to produce positive sensations that increase the likelihood of drug use) or the psychological distress produced in the absence of the drug.

Example: Opioids

8.2.1. FAERS Search Strategy FDA searched the FAERS database with the strategy described in Table 32.

Table 32. FAERS Search Strategy Search #1: Broad Search Search #2: Narrow Search Date of Search April 24, 2019 Time Period of Search All reports through April 23, 2019 Search Type FBIS Quick Query

Search #1: Broad Search Search #2: Narrow Search Product Terms Product Active Ingredient: Verbatim terms: Nicotine Nicorette Bucomist Administration route: Nicorette (Nicotine) Spray Oral; Oropharyngeal; Buccal Nicorette quickmist Product formulation: Nicorette Quickmist Spray, oromucosal spray Nicorette Quick Mist Narrative text search: NICORETTE QUICK MIST Bucomist, mouthspray, mouth NICORETTE QUICKMIST spray, nicospray, nico-spray, Nicorette Quick Mist 1 Mg quickmist, quick mist, spray Nicorette Quick Mist 1mg Nicorette Quickmist 1mg Nicorette Quick Mist 1mg Nico Spray Nicorette Quickmist 1mg Nico Spray Nicorette Quickmist 1mg Nico-Spray Nicorette Quickmist Mouthspray Nicorette Quickmist Nico-Spray Nicorette Spray Nicotine Mouth Spray 1 Mg Nicotine Spray

8.2.2. FAERS Cases The FAERS search retrieved 166 reports. After applying the case definition and accounting for duplicate reports, 96 cases were included in the case series of all adverse events reported with NMS use. Table 33 summarizes these 96 FAERS cases.

Table 33. Descriptive Characteristics of All Adverse Events with Nicotine Mouth Spray in this FAERS Case Series, Received by FDA through April 23, 2019 Characteristics (N=96) Age (years), n=49 Mean 49 Median 49 Range 24-75 Sex Female 47 Male 42 Not reported 7 Region Europe 65 Australia/New Zealand 19 Canada 11 Southeast Asia 1 Year received by FDA 2011 15 2012 13 2013 43 2014 15 2015 4 2016 1 2017 3 2018 2

Characteristics (N=96) Reporter Consumer 48 Health care professional 48 MedDRA PTs reported with n ≥5 (not mutually exclusive) Nicotine dependence 15 Asthma 10 Dyspnea 10 Intentional product use issue 10 Overdose 10 Drug dependence 8 Incorrect product administration duration 8 Malaise 7 Palpitations 7 Dizziness 6 Product quality issue 6 Drug ineffective 5 Nausea 5 Oral discomfort 5 Reported reason for use Smoking cessation 65 Intentional misuse+ 1 Not reported 30 Classified as abuse/misuse/dependence (n=26), not mutually exclusive Abuse 3 Misuse 18 Dependence 24 * For the purposes of this review, the following outcomes qualify as serious: death, life-threatening, hospitalization (initial or prolonged), disability, congenital anomaly, required intervention and other serious important medical events. A case may have more than one serious outcome. + Case 8961318 reported a pharmacy assistant who intentionally misused the NMS to “have a little fun” and experienced an asthma attack. She recovered in 45 minutes. We classified this case as abuse rather than misuse based on the OSE case definition. Abbreviations: CA, congenital anomaly; DE, death; DS, disability; FAERS, FDA Adverse Event Reporting System; HO, hospitalization; LT, life-threatening; MedDRA, Medical Dictionary for Regulatory Activities; NRT, nicotine replacement therapy; OT, other medically significant; PT, preferred term

Dependence/Misuse/Abuse5 24/96 (25%) cases met the OSE case definition criteria for drug dependence, 18/96 (19%) for drug misuse, and 3/96 (3%) for drug abuse (not mutually exclusive).

In the dependence cases, 24 cases described nicotine dependence. One case reported a recovering alcoholic who felt he may have become addicted to the product due to its alcohol content.

12 of 18 misuse cases described use of NMS for longer than labeled duration (reported range of 3 months to 5.5 years) and eight cases described use of NMS at higher doses than labeled. Note

5 Development of dependence is considered a serious event. The term “drug dependence” was introduced as a preferred term (PT) in Medical Dictionary for Regulatory Activities (MedDRA 2.1) in 1999, while “nicotine dependence” became a PT in the 2003 MedDRA, version 6.1 for more specificity. Detailed patient information about “dependence,” “nicotine dependence,” and “drug dependence” is not intrinsically included in the databases making it difficult to confirm the exact differences among PTs.

these cases are not mutually exclusive. Two cases reported a person liking the taste of the product.

In the abuse cases, one reported a pharmacy assistant who intentionally misused NMS to “have a little fun” and experienced an asthma attack. She recovered in 45 minutes. Based on the case definition described earlier, this case was classified as abuse. Another reported a 60-year-old female who was “using the NMS too often and she was abusing it (drug abuse).” And the third case reported a 35-year-old female who was awakening in the night to use the NMS to relieve her psychological distress of longing for more.

Oral Disorders 15/96 (16%) cases reported oral disorders. The cases of oral disorders reported (not mutually exclusive): oral blisters/ulcers (6), mouth/lip burning (5), tongue numbness (2), throat irritation/pharyngitis (2), ageusia (1), aphonia (1).

Anaphylaxis 14/96 (15%) cases met the OSE Case Definition criteria for anaphylaxis. Most of the cases appeared to be mild; 12 recovered and 2 outcomes were unknown.

The following modified Sampson Criteria (Simons et al. 2011; Simons et al. 2012; Simons et al. 2013) were used to evaluate cases for anaphylaxis. Anaphylaxis is highly likely when any one of the following three criteria is fulfilled:

1. Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or both (e.g., generalized urticaria, itching or flushing, swollen lips- tongue-uvula) And at least one of the following: A) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced peak expiratory flow (PEF), hypoxemia) B) Reduced blood pressure or associated symptoms of end-organ dysfunction (e.g., hypotonia [collapse], syncope, incontinence)

2. Two or more of the following that occur rapidly after exposure to a likely allergen6 for that patient (minutes to several hours) A) Involvement of the skin-mucosal tissue (e.g., generalized urticaria, itch-flush, swollen lips-tongue-uvula) B) Respiratory compromise (e.g., dyspnea, wheeze-bronchospasm, stridor, reduced PEF, hypoxemia) C) Reduced blood pressure or associated symptoms (e.g., hypotonia [collapse], syncope, incontinence)

6 Or other trigger, for example, immunologic but IgE-independent, or nonimmunologic (direct) mast cell activation.

D) Persistent gastrointestinal symptoms (e.g., crampy abdominal pain, vomiting)

3. Reduced blood pressure after exposure to known allergen7 for that patient (minutes to several hours)8 A) Infants and children: low systolic blood pressure (age-specific) or greater than 30% decrease in systolic blood pressure B) Adults: systolic blood pressure of less than 90 mm Hg or greater than 30% decrease from that person’s baseline

Asthma Eleven of 96 (11%) cases reported asthma/asthma exacerbation (PT asthma, n=10 and PT asthmatic crisis, N=1).

8.2.3. Additional FAERS ORAL NRT Adverse Event Search FDA conducted an additional search of FAERS for Nicorette Gum and Lozenge products from the date of first approval to five years after was conducted to evaluate reported adverse events in other oral nicotine products. A 5-year time frame was selected to account for reporting biases, such as a potential decline in reports over time after regulatory approval. A limitation of the search is potential for duplicate reporting. • Rx Gum – Nicorette 2 mg gum searched from 1/13/1984 (date of Rx approval) to 1/13/1989 • OTC Gum – Nicorette 2 mg and 4 mg gum searched from 2/9/1996 (date of Rx-to-OTC switch) through 2/9/2001 • OTC Lozenge – Nicorette 2 mg and 4mg lozenge searched from 10/31/2002 (date of direct to OTC approval) to 10/31/2007

In all three searches, either “Drug dependence” (RX Gum, OTC Gum) or “Nicotine dependence” (OTC Lozenge) ranked amongst the top three PTs reported for all adverse events. Search results are illustrated in Figure 11 to Figure 13 below.

7 For example, after an insect sting, reduced blood pressure might be the only manifestation of anaphylaxis; or, in a similar example, during allergen immunotherapy, after injection of a known allergen for that patient, generalized urticaria (only one body organ system affected) might be the only initial manifestation of anaphylaxis. 8 Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less than (70 mm Hg + [2x age]) from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years. Normal heart rate ranges from 80 to 140 beats/min at age 1 to 2 years; from 80 to 120 beats/min at age 3 years; and from 70 to 115 beats/min after age 3 years. Infants are more likely to have respiratory compromise than hypotension or shock, and in this age group, shock is more likely to be manifest initially by tachycardia than by hypotension.

Figure 11. Rx Nicorette Gum 2mg, 1984-1989

Top 5 PTs Reported 300 250 200 150 100 50 0 DRUG TOOTH DRUG NAUSEA STOMATITIS DEPENDENCE DISORDER INEFFECTIVE

Figure 12. OTC Nicorette Gum 2 and 4 mg, 1996-2001 Top 5 PTs Reported 700 600 500 400 300 200 100 0 DRUG NAUSEA VOMITING DYSPEPSIA STOMATITIS DEPENDENCE

Figure 13. OTC Nicorette Lozenge 2 and 4 mg, 2002-2007

Top 5 PTs Reported 400 350 300 250 200 150 100 50 0 NAUSEA INTENTIONAL NICOTINE DRUG ORAL PRODUCT DEPENDENCE ABUSER DISCOMFORT MISUSE

A 2018 publication provided an analysis of FAERS reports associated with smoking cessation treatments and electronic cigarettes from January 2004 to December 2016 (Motooka et al. 2018). The most frequent routes of administration included transdermal, buccal, and oral. Error! R eference source not found. summarizes AE reports for oral nicotine with reporting odds ratio of 95% confidence intervals used to detect adverse event signals. Dependence was the most frequently reported event representing in total, 88% of reported cases. The author noted that detailed patient information about “dependence,” “nicotine dependence,” and “drug dependence” is not intrinsically included in the FAERS database, making it difficult to confirm the exact differences among PTs. However, reporting of odds ratios for oral and buccal nicotine were higher than transdermal, and Motooka stated that the risk of nicotine dependency related to oral or buccal formulas should not be underestimated.

Table 34. Adverse Event and Other Event Reports for Oral Nicotine

Source: (Motooka et al. 2018) Table 4 Abbreviations: AE, adverse event; CI, confidence interval

8.3. FDA World Health Organization VigiBase Search

The World Health Organization VigiBase (VigiBase) is a global database of individual case safety reports (ICSRs) received by the Uppsala Monitoring Centre (UMC) in its role as the World Health Organization (WHO) Collaborating Centre for International Drug Monitoring. VigiBase includes ICSRs submitted by over 130 countries for allopathic medicines, traditional medicines (herbals), and biological medicines, including vaccines. The FDA does not have access to case narratives in VigiBase. The limitations and qualifications that apply to VigiBase information and its use are described below.

Tentative and Variable Nature of the Data Uncertainty: The reports submitted to UMC generally describe no more than suspicions which have arisen from observation of an unexpected or unwanted event. In most instances it cannot be proven that a specific medicinal product is the cause of an event, rather than, for example, underlying illness or other concomitant medication

Variability of source: Reports submitted to national centers come from both regulated and voluntary sources. Practice varies: some national centers accept reports only from medical practitioners; others from a broader range of reporters, including patients, some include reports from pharmaceutical companies.

Contingent influences: The volume of reports for a particular medicinal product may be influenced by the extent of use of the product, publicity, the nature of the adverse effects and other factors.

No prevalence data: No information is provided on the number of patients exposed to the product, and only a small part of the reactions occurring are reported.

Time to VigiBase: Some national centers make an assessment of the likelihood that a medicinal product caused the suspected reaction, while others do not. Time from receipt of an ICSR by a national center until submission to UMC varies from country to country. Information obtained from UMC may therefore differ from that obtained directly from national centers.

8.3.1. World Health Organization VigiBase Database Search Strategy FDA searched the VigiBase to identify cases outside the United States where NMS is marketed. The search strategy is described in Table 35.

Table 35. WHO VigiBase Search Strategy Date of Search April 30, 2019 Time period of search All reports through April 28, 2019 Product terms Nicorette spray (trade name), Nicorette QuickMist (trade name)

8.3.2. World Health Organization VigiBase Cases The VigiBase search retrieved 180 ICSRs. Some reports may be duplicates of the FAERS cases already identified. Narratives are not available for the cases identified in VigiBase, and therefore case definitions were not applied. Case characteristics of the ICSRs received by VigiBase through April 28, 2019, are described in Table 36.

Table 36. Case Characteristics of ICSRs Received by WHO VigiBase through April 28, 2019 (n=180) Characteristic Count Percent Entry year 2019 9 5.0 2018 12 6.7 2017 34 18.9 2016 30 16.7 2015 28 15.6 2014 21 11.7 2013 26 14.4 2012 13 7.2 2011 7 3.9 Country United Kingdom 121 67.2 Denmark 42 23.3 France 11 6.1 Australia 2 1.1 Germany 2 1.1 Switzerland 2 1.1 Reporter type* Consumer 105 58.3 Pharmacist 33 18.3 Other health professional 29 16.1 Physician 13 7.2 Patient sex Female 94 52.2 Male 75 41.7 Not reported 11 6.1 Patient age (years) Mean 48 Median 49 Range 1-73 Not reported 99 Patient age distribution 0-27 days 1 0.6 12-17 years 1 0.6 18-44 years 32 17.8 45-64 years 35 19.4 65-74 years 12 6.7 Not reported 99 55.0

Characteristic Count Percent MedDRA PT’s reported with n ≥5 (not mutually exclusive) Drug dependence 56 31.1 Incorrect product administration duration 32 17.8 Nicotine dependence 20 11.1 Dyspnea 12 6.7 Intentional product use issue 12 6.7 Drug ineffective 9 5.0 Malaise 9 5.0 Vomiting 9 5.0 Cough 8 4.4 Nausea 8 4.4 Oral discomfort 8 4.4 Accidental exposure to product 6 3.3 Overdose 6 3.3 Product complaint 6 3.3 Dizziness 5 2.8 Hiccups 5 2.8 Product quality issue 5 2.8 Product taste abnormal 5 2.8 Throat irritation 5 2.8 Reported reason for use Smoking cessation 49 27.2 Not reported 131 72.8 * Some cases described more than one reporter type. The counts are based on the primary reporter type in the listing. † For the purposes of this review, the following outcomes qualify as serious: death, life-threatening, hospitalization (initial or prolonged), disability, congenital anomaly, required intervention and other serious important medical events. A case may have more than one serious outcome. Abbreviations: MedDRA, Medical Dictionary for Regulatory Activities; PT, preferred term

8.4. Literature Search

The Applicant conducted a literature search and identified seven publications which were reviewed by the FDA and are summarized below. These articles describe randomized trials of NMS with comparison of NMS to placebo or another form of NRT (gum, lozenge or inhaler). The publications are listed by treatment duration in Table 37 and Table 38.

According to the Applicant, Table 37 outlines four studies conducted for 12 weeks or longer that involved 1,681 patients receiving NMS. Commonly reported AEs with NMS in these longer duration studies (excluding Caldwell 2014) included hiccups, nausea, throat irritation, dyspepsia, stomatitis, salivary hypersecretion, constipation, burning sensation in mouth and burning of the tongue/throat. In the shorter studies identified in Table 38, a total of 292 patients received NMS, nicotine lozenge, nicotine gum or a placebo as a single dose. Commonly reported AEs with NMS in short duration studies include hiccups, nausea, throat irritation, dyspepsia, mouth irritation, feeling sick, salivary hypersecretion, dizziness and headache. The Applicant noted a higher incidence of NMS AEs (most commonly hiccups) than other NRTs or placebo groups and postulated a plausible decline over time due to subject learning.

Table 37. Studies of Longer Duration

Source: Applicant submission, (Bolliger et al. 2007; Tonnesen et al. 2012; Caldwell et al. 2014; Nides et al. 2018) Abbreviation: NMS, nicotine mouth spray

Table 38. Studies of Shorter Duration

Source: Applicant submission, (McRobbie et al. 2010; Kraiczi et al. 2011; Hansson et al. 2012) Abbreviation: NMS, nicotine mouth spray

The publication by Nides details results of a naturalistic clinical study submitted as support for the NMS OTC application. Tonnesen’s published results of the European clinical study are also submitted in support of NMS. Discussion of these clinical study results are highlighted in the clinical study review (see Section 6).

Bollinger published the results of a pilot study to assess user preference, safety and efficacy of a new nicotine mouth spray (referred to as the Quit spray in South Africa) compared to gum and inhaler. Fifty-four of the hundred enrolled smokers preferred the spray. AEs were mostly drug- related local symptoms. Out of 106 drug-related AEs, 90 were due to the spray. The three most frequent AEs were almost exclusively caused by the spray: burning of the tongue/throat reported by 35, nausea by 18, and hiccups by 16 subjects. The author concluded that subjects preferred the mouth spray, but its use was associated with a high rate of local AEs (Bolliger et al. 2007).

Hansson published results of a randomized, cross-over trial investigating the effect of 2 mg nicotine mouth spray, 2 mg nicotine lozenge or 4 mg nicotine lozenge on urges to smoke. In 199 subjects with evaluable data for at least one endpoint and one treatment, the author noted 340 AEs with 183, 68 and 89 AEs possibly related to mouth spray 2 mg, lozenge 2 mg and lozenge 4

mg, respectively. Overall, the most common AEs for mouth spray 2 mg, lozenge 2 mg and lozenge 4 mg (number of subjects reporting) were hiccups (29, 2, 6), nausea (29, 4, 15), throat irritation (21, 11, 13), dyspepsia (18, 4, 9) and salivary hypersecretion (9, 1, 2). The author concluded that types of AEs reported with the mouth spray were similar to those reported with the lozenge, and no unexpected adverse events occurred with the spray (Hansson et al 2012).

In McRobbie’s publication of a cross-over trial to determine the effects on craving of two new NRTs, 47 participants were randomly assigned a new nicotine mouth spray (1 mg/spray), new nicotine lozenge (2.5 mg), gum (4 mg) and placebo lozenge on each of four study days. The new products were reported to exhibit a safety profile similar to that observed with the gum. Feeling sick (38% lozenges, 34% gum and 36% mouth spray) and mouth irritation (25% lozenges, 30% gum and 45% mouth spray) were the most commonly reported AEs. Mouth spray users reported a significantly higher frequency of hiccups (36%) than gum (13%) or lozenge (17%) users (p = 0.01). The author concluded AEs were of short duration, resolved spontaneously, and related to known nicotine effects (McRobbie et al 2010).

Kraiczi published results of a single-dose, randomized crossover study comparing the pharmacokinetics of nicotine following oral administration of NMS at three doses (1, 2, and 4 mg) versus nicotine gum 4 mg and nicotine lozenge 4 mg. In 39 subjects completing the study, 79 treatment-emergent AEs were reported including hiccups, nausea, and throat irritation. The author noted this small pharmacokinetic study was not designed to permit statistically valid inferences about comparisons of adverse events between the three products (Kraiczi et al 2011).

Additional Literature FDA conducted an additional search of the published literature to evaluate AEs associated with NRT products to compare with AEs reported for NMS. Summaries of several of the publications follow.

A Cochrane review of NRTs published in 2018 concluded that AEs from using NRTs were related to the type of product and often caused minor irritation of the site through which it was administered (Hartmann-Boyce et al. 2018). The authors state that synthesizing the incidence of various adverse effects were hindered by extensive variation in reporting the nature, timing and duration of symptoms. They commented that in the study of oral spray by Tonnesen (Tonnesen et al. 2012), hiccups and throat irritation were the most commonly reported AEs.

Bailey’s 2012 review of studies examining the efficacy and tolerability of pharmacotherapies for smoking cessation in adolescents included seven studies of patch, gum, and nasal spray NRTs that reported no severe or life-threatening AEs. Commonly reported AEs for the patch included local skin reactions, headache, nausea and vomiting, tiredness, sleep disturbances, joint and muscle ache, and lightheadedness and dizziness; AEs for gum included sore throat, hiccups and pruritus; and AEs for nasal spray included nasal irritation/burning and complaints of taste and smell. The author concluded that AEs reported by adolescents for NRT use were similar to those reported by adult smokers (Bailey et al. 2012).

A 2010 systematic review and meta-analysis by Mills aimed to identify all randomized clinical trials (RCTs) of NRT versus inert controls and all observational studies to determine the magnitude of reported adverse effects with NRT. Ninety-two RCTs involving 32,185 subjects and 28 observational studies involving 145,205 subjects were identified. The author’s pooled RCT evidence of varying NRT formulations found an increased risk of heart palpitations and chest pains (OR 2.06, 95% Confidence Interval [CI] 1.51 to 2.82, P<0.001); nausea and vomiting (OR 1.67, 95% CI 1.37 to 2.04, P<0.001); gastrointestinal complaints (OR 1.54, 95% CI, 1.25 to 1.89, P<0.001); and insomnia (OR 1.42, 95% CI, 1.21 to 1.66, P<0.001). Pooled evidence specific to the NRT patch found an increase in skin irritations (OR 2.80, 95% CI, 2.28 to 3.24, P<0.001). Orally administered NRT was associated with mouth and throat soreness (OR 1.87, 95% CI, 1.36 to 2.57, P<0.001); mouth ulcers (OR 1.49, 95% CI, 1.05 to 2.20, P<0.001); hiccups (OR 7.68, 95% CI, 4.59 to 12.85, P<0.001) and coughing (OR 2.89, 95% CI, 1.92 to 4.33, P<0.001) (Mills et al. 2010).

Limited publications specific to NMS identify common AEs of hiccups and sore throat and a general similarity to AE profiles of other oral NRTs.

8.5. Conclusions

GSD database AEs identified in the Applicant’s search were associated specifically with the proposed spray product. FAERS and WHO VigiBase searches conducted by FDA identified AEs for reports relevant to NMS. The most frequently reported postmarketing SAE was drug dependence, nicotine dependence or dependence across the three database searches. Because different types of events could be included in dependence terminology, the clinical significance of this is unclear. Hiccups represent the most common nonserious event reported for NMS. Publications specific to NMS identify common AEs of hiccups and sore throat and a general similarity to AE profiles of other oral NRTs.

9. Label Comprehension Study #181093

9.1. Background and Executive Summary

9.1.1. General Background on Label Comprehension Studies Label comprehension studies (LCS) are conducted for most new nonprescription NDA products. If consumers cannot understand—or are not even aware of—what the label says relative to safe and effective use, chances are they will not correctly self-medicate.

FDA asks applicants to conduct LCS to address questions such as: • Is the wording understandable to the average consumer? • Does it convey the key concepts for the safe use of the product? • Does it convey the key concepts, such as dosing regimen, that are necessary for effective use of the product?

In designing an LCS, an applicant needs to identify the most important communication objectives to be assessed as primary endpoints. These are the most important concepts, from the viewpoint of safety and efficacy, that need to be understood by consumers. Generally, if a labeled statement appears on other OTC products in the same therapeutic category, the statement does not need to be tested or retested in a new LCS, although even previously used language may need to be tested or retested if it appears in a different context. Target thresholds are established a priori and are based on the clinical implications if consumers fail to adequately understand the labeled items. Therefore, applicants are to provide the clinical justifications for the thresholds. For instance, for a hypothetical nonprescription product, a target threshold for comprehension of “do not use if you have liver disease” could be established at 90%, because there would be serious medical consequences for the consumer with liver disease if the consumer were to use the product.

Adequate comprehension is assessed by comparing the established threshold with the lower bound of the two-sided exact 95% confidence interval (CI) for the comprehension rate. For example, if the lower bound of the confidence interval is 92% and the target threshold is 90%, adequate comprehension would be demonstrated. The lower bound is utilized because it accounts for the uncertainty in the estimate of the comprehension rate. FDA typically asks applicants to have a minimum of 22 to 28% limited literacy (LL) representation in their consumer studies. Participants in consumer studies are typically administered the Rapid Estimate of Adult Literacy in Medicine (REALM) test, which is a validated literary assessment tool. For the purposes of nonprescription regulatory consumer studies, LL is defined as scoring <60 on the REALM, which represents a health literacy level of eighth grade or below.

Secondary communication objectives are intended to address areas less critical to safe and appropriate use, yet clinically relevant. Secondary communication objectives typically are not assessed against target thresholds.

Pivotal LCSs usually enroll as demographically diverse a population as possible. Generally, the studies include from 300 to 600 participants from a variety of testing sites across the United States. Often sponsors conduct preliminary qualitative iterative and pilot testing of the proposed DFL to optimally enhance it prior to the pivotal test.

In an LCS, participants in individual one-on-one interviews are given the Drug Facts Label to read at their own pace. They are then asked questions about the label, and they can refer to it as much as they want. It is not a test of memory, but rather an “open book” test to assess whether consumers are aware of and can understand key elements presented in the DFL. Study questionnaires need to be constructed targeting the communications objectives in an unbiased way. Label comprehension studies typically employ many scenario questions, describing hypothetical consumers and their medical situations to test the ability of the consumer to apply the information from the label.

Ultimately, LCSs assess comprehension, and not behavior. Therefore, LCSs are usually necessary as the foundation of successful OTC development programs. If a proposed label does not facilitate sufficient comprehension by consumers, it is far less likely that consumers would

then be able to use the product in a safe and efficacious manner. Therefore, ideally LCS provides a foundational opportunity to optimize the DFL. 9.1.2. Executive Summary The pivotal Label Comprehension Study (LCS) for nicotine mouth spray was a single-visit, multisite study designed to evaluate comprehension of the key communication objectives on the proposed OTC Drug Facts Label. The study was completed with 504 participants including 130 (25.8%) limited literacy participants. Of the four primary comprehension objectives, three met the prespecified target threshold for correct responses. The primary objective of “Rinse immediately with water if you spray in eyes as irritation will occur” did not meet the prespecified lower bound (LB) target threshold of 80%. Comprehension scores for this endpoint were low regardless of literacy, as many participants in all subgroups stated that they did not see this instruction on the DFL.

There are three steps under “Directions” in the OTC DFL (see Figure 15). Steps 1, 2, and 3 provide directions for use for weeks 1 to 6, weeks 7 to 9, and weeks 10 to 12, respectively. The study’s primary objectives assessing comprehension of Step 1’s maximum number of sprays per dose and sprays per day were well understood by the overall study population and particularly by normal literacy participants. The primary objective of “Do not inhale while spraying” was similarly well understood.

One of the eight secondary comprehension endpoints, “Step 3: Continue reducing the number of sprays per day so that you are not using more than 4 sprays per day during week 12”, did not show evidence of adequate understanding (67.1% point estimate [PE]). In general, the percentage of study participants understanding the labeled 12-week therapeutic regimen substantially decreased from Step 1 to Step 3. Additionally, the percentage of participants who understood all three steps was very low, at only 48% of the total study population (52.4% of normal literacy participants and 35.4% of limited literacy participants).

Comprehension of the secondary objective of total 12 weeks duration of therapy was not adequately assessed by the relevant study question. The secondary objective of “Step 2– start reducing the number of sprays per day” was also not adequately assessed, as it did not define the relevant timeframe of 7 weeks.

This product’s DFL—unchanged from the LCS (Figure 15)—incorporates an outer flap that contains Uses and Warnings; the Directions for Use are only visible to the consumer if s/he opens the flap and looks at the back of the flap. Many communications objectives in this study were less well understood by those participants who did not open the flap until the study interviewer prompted them to do so. Although there were study artifacts encompassed in the LCS (many participants stated that they had been reluctant to possibly damage the study carton); nonetheless, these findings could be considered in any potential enhancements.

9.1.3. Regulatory History of LCS #18109 In March 2017, FDA and the Applicant discussed the low continuous abstinence rates from the naturalistic study NICTDP3038. FDA noted that there had been no revisions to the Applicant’s proposed DFL resulting from this study and encouraged the Applicant to develop and test an alternative DFL that was fully informed by the study’s findings. FDA emphasized that naturalistic studies could potentially yield rich qualitative insights as to labeling enhancements on the DFL that might potentially improve consumer adherence.

The Applicant did revise the DFL subsequent to the naturalistic study for the LCS, but it is not clear whether this was based on any insights from the naturalistic study. As Figure 15 and Figure 17 illustrate, the LCS-tested DFL differed from the naturalistic study DFL in the organization of content and formatting of the Directions for Use, particularly with regard to the labeled Steps. The LCS-tested DFL for the first time also incorporated a carton flap that needed to be opened by the user, with the outer panel displaying Use and Warning, and the inner left side panel displaying the critical Directions for Use.

In May 2018, FDA provided written comments on the Applicant’s proposed LCS protocol. FDA directed the Applicant to provide justification as to why the proposed secondary objective of “start reducing the number of sprays per day” did not contain the associated timeframe (7 to 9 weeks) for this step. FDA’s thinking was that the subjects in the naturalistic study might not have fully understood the DFL’s timetables for reducing sprays, which in turn could have impacted efficacy. FDA also recommended to the Applicant in the written comments to incorporate a secondary objective as to comprehension of the total duration of the full course of therapy.

9.2. Study Design and Conduct

Objectives The objective of the pivotal LCS was to evaluate comprehension of the DFL content specific to the nicotine mouth spray.

Study Design The LCS was conducted in September 2018 with a total of 504 unique participants. The study population included males and females, ages 18+, in ten geographically dispersed sites in the United States. All participants were either currently smokers or attempting to quit smoking. There were a total of 130 limited literacy participants, comprising 25.8% of the study population.

The four primary objectives were composed of the communication objectives on the DFL with high potential for a safety risk: • Directions: – Do not inhale when spraying. – Rinse immediately with water if you spray in eyes as irritation will occur.

– Step 1 – Maximum number of sprays per hour – 4 sprays per hour – Step 2 – Maximum number of sprays per day – 64 sprays per day

The prespecified target lower bound (LB) threshold for all primary objectives was 80%.

The eight secondary communication objectives for this study were comprised of novel messages that communicated important information but had a lesser potential for safety risk. As is typical for secondary objectives, no LB thresholds were set. Below are the objectives that the Applicant stated were to be assessed: 1. Step 1 – Use 1 to 2 sprays when you would normally smoke a cigarette or have a craving to smoke. 2. Step 1 – Use the second spray if your cravings are not reduced within a few minutes. 3. For best results, do not swallow for 2 to 3 seconds after spraying. 4. Step 2 – Start reducing the number of sprays per day. 5. Step 2 – By the end of week 9 you should be using HALF the average number of sprays per day that you used in Step 1. 6. Step 3 – Continue reducing the number of sprays per day so that you are not using more than 4 sprays per day during week 12. 7. To increase your chance of success it is important to use the nicotine mouth spray according to the following 12-week schedule. 8. When using this product, hiccups or minor mouth and throat irritation may occur. Stop use and ask a doctor if these problems persist or worsen over the course of treatment.

The Applicant did not provide the requested justification in the NDA as to why the secondary objective #4 of “Step 2 – Start reducing the number of sprays per day” – did not seek to assess understanding that this Step was to begin at week 7. The scenario question posed in the LCS was: “Lamar has been using this product for 6 weeks. He is getting ready to start Step 2. According to the label, what should Lamar do now?” This scenario could be viewed as implicitly cuing the correct answer on the week 7 timing in the wording of the question. Although the point estimate (PE) for comprehension of this was stated by the Applicant to be 94.4%, the timing of when to start reducing sprays was not adequately assessed. Therefore, this review does not further analyze objective #4. It instead relies on another secondary objective, #5, “Step 2 – By the end of week 9 you should be using half the average number of sprays per day that you used in Step 1,” to represent comprehension of the general concept of reducing dosing at some point so that by the end of week 9 half of the doses are used.

Similarly, regarding FDA’s request to assess participant comprehension of total therapy duration (objective #7), the Applicant incorporated objective #7 with the corresponding question into the study. However, it was a true/false question in which the question wording contained the correct answer: “True or false: To help you succeed in quitting, it is important to use the nicotine mouth spray according to the 12-week schedule.” Although the PE for comprehension of this was stated to be 96%, the overall duration of therapy was not adequately assessed due to both the question wording and the fact that the true/false question had a 50-50 chance of being answered correctly by anyone without knowledge of the product.

The remaining six secondary objectives have been further analyzed as well as categorized by this reviewer into two separate but related groups – one focusing on key dosing steps (objectives #1, #5, and #6 above) – and the other focusing on general product use (objectives #2, #3, and #8 above).

Viewing of the Drug Facts Label by Study Participants During each individual interview, study participants were given the currently proposed nicotine mouth spray package, which contained an empty dispenser and the Drug Facts Label (DFL) on the outside of the package. The DFL begins on the outer facing flap, which displays Use and Warnings only. The outer flap then lifts up to reveal an inner panel on the back of the flap, which displays the actual dosing Directions for Use. (There is also a third panel that consists of the Quick Start Guide). The DFL is illustrated below in Figure 14; a yellow highlighted corner of the outer panel, with arrows, states: “Lift Here for Complete Drug Facts Label”:

Figure 14. LCS DFL

Source: Applicant NDA Submission

For those participants who didn’t open the flap initially, the interviewer informed them that there were other panels to look at. The interviewer then posed additional questions about why they did not open the flap, as well as what could be changed on the outer label to make it more clear to open the flap. Participants were then given the opportunity to review the inner DFL panels. Once the participant had finished reading, the label comprehension interview began.

9.3. Study Results

Table 39 depicts the demographics of the study participant for the total population and by literacy.

Table 39. Demographics of Study Population

Source: Applicant NDA Submission Abbreviations: GED, general equivalency degree; REALM, Rapid Estimate of Adult Literacy in Medicine

9.3.1. Visibility of Directions for Use At the onset of the study, 75.4% of participants opened the flap while 24.6% (n=124) did not open the flap until prompted (see Table 40). Most of the participants who did not open the flap maintained later during the questioning that it was clear to them that the flap opened (some voiced the concern that they might have damaged the study carton by opening the flap), while n=24 stated that they did not see the prompt to open the flap. An additional n=8 stated that they read everything else on the outer label, and n=2 stated that they did not think it was important to read the inner label as “all OTC medicines say the same thing.” In total, it appears that at a minimum, 34/504, or 6.7%, did not know or care to open the flap to read the entire DFL.

Table 40. Opened vs. Did not Open Drug Fact Label Flap Opening Flap Actions N (%) Opened flap unprompted 348 (69.0%) Asked for permission to open the flap 32 (6.3%) Total that opened the flap 380 (75.4%) Did not open flap until prompted 124 (24.6%) Source: Applicant NDA Submission

It is difficult to extrapolate these results to what would happen in real life, as artifacts of the study could have biased more participants to read the inner back flap than would actually be the case, or, conversely, biased fewer participants to read the inner back flap than would actually be the case. Nonetheless, qualitative insights can be provided. Because the dosing and step-down instructions are on the inner back flap, it is important for consumers to take the time to look at this flap when using the product.

Below are the demographics of the relevant subgroups who opened/did not open the flap until prompted.

Table 41. Demographics of Study Population by Opening of Flap

Source: Applicant Data Submission abc Denotes statistically significant difference using a T-Test calculation Abbreviations: GED, general equivalency degree; REALM, Rapid Estimate of Adult Literacy in Medicine

A comparison of this table with Table 39 shows that compared with the overall study population, those who did not lift the DFL flap until directed to were older, African-American, less educated, and of more limited literacy. 9.3.2. Primary Endpoint Analysis The primary objective of Step 1- Maximum number of sprays per day – 64 sprays per day was understood by 89.5% (86.47% LB) of the total study population. This direction appears on the inner back flap of the DFL. Table 43 shows that comprehension of this objective was much lower (77.4% PE) among those who needed to be prompted to open the flap, as contrasted with those who opened the flap unprompted (93.1% PE). Table 44 shows that there was a substantial difference in comprehension of this objective between normal literacy and limited participants (93.3% v 79.5% PE). Table 45 shows that the comprehension differences were underscored in a comparison between normal literacy participants who proactively opened the flap (96.2% PE) versus limited literacy participants who needed to be prompted to open the flap (66.7% PE).

Similar trends existed for comprehension of Step 1, maximum number of sprays per hour – 4 per hour. This was understood by 91.9% (89.13% LB) of the total study population. Table 43 shows that the comprehension of this objective was lower among those who needed to be prompted to open the flap (86.3% PE) versus those who opened the flap unprompted (94% PE). Table 44 shows that there was a substantial difference in comprehension of this objective between normal literacy (94.9% PE) and limited literacy (83.1% PE) participants. And Table 45 shows that the comprehension differences were highlighted in a comparison between normal literacy participants who proactively opened the flap (95.8% PE) versus limited literacy participants who needed to be prompted to open the flap (71.8% PE).

The primary objective “Do not inhale when spraying” scored well overall (88.9% LB). Comprehension of this objective was higher among those who opened the flap unprompted (93.7% PE) versus who needed to be prompted to open the flap (84.7% PE). There were substantial differences in comprehension between normal literacy participants (93.3% PE) versus limited literacy participants (86.9% PE). Table 45 shows the comprehension differences between normal literacy participants who opened the flap unprompted (95.4% PE) versus limited literacy participants who needed to be prompted to open the flap (82.1% PE).

The primary objective “Rinse immediately with water if you spray in eyes as irritation will occur” was the only primary objective that scored lower than the target threshold, at a LB of 73.89%. For this objective only, those who opened the flap unprompted had similar lower comprehension to those who needed to be prompted to open the flap; normal literacy participants had the same lower comprehension as limited literacy participants. Overall, many participants stated that they did not notice this instruction.

Table 42. Primary Endpoints for Total Population

Source: Applicant NDA Submission *Lower and upper two-sided exact 95%confidence interval (CI). Abbreviations: CI, confidence interval

Table 43. Primary Endpoints by Opening of Flap

Source: Applicant NDA Submission c Denotes statistically significant difference using a T-Test calculation Abbreviation: DFL, Drug Fact Label

Table 44. Primary Endpoints by Literacy

Source: Applicant NDA Submission bDenotes statistically significant difference (p<=0.05) using a t-test calculation

Table 45. Primary Endpoints by Opening of Flap and Literacy Opened DFL Asked Permission to Did Not Open DFL Unprompted Open DFL Until Prompted N=348 N=32 N=124 Normal Low Normal Low Normal Low Literacy Literacy Literacy Literacy Literacy Literacy N=263 N=85 N=263 N=85 N=263 N=85 Primary Endpoint n % n % n % n % n % n % Directions Step 1: Maximum 252 95.8 75 88.2 24 92.3 5 83.3 79 92.9 28 71.8 number of sprays per hour – 4 sprays per hour Directions Step 1: Maximum 253 96.2 71 83.5 26 100.0 5 83.3 70 82.4 26 66.7 number of sprays per day – 64 sprays per day Directions Do not inhale when 251 95.4 75 88.2 25 96.2 6 100.0 73 85.9 32 82.1 spraying Directions Rinse immediately when water if you spray in 206 78.3 63 74.1 24 92.3 5 83.3 63 74.1 31 79.5 eyes as irritation will occur Source: FDA Statistics Abbreviation: DFL, Drug Fact Label

9.3.3. Secondary Endpoint Analysis Key Dosing Steps Table 46 displays the overall secondary endpoint results related to Steps 2 and 3. For Step 2, overall 82.3% (PE) of all study participants understood that by the end of week 9, dosing should be reduced to half of the dosing in Step 1. However, for Step 3, only 67.1% (PE) of total participants understood that no more than 4 doses per day should be used by week 12.

Table 46. Secondary Endpoints: Key Dosing Steps

Source: Applicant NDA Submission

Table 47 shows that comprehension of “Step 1 – Use 1 to 2 sprays when you would normally smoke a cigarette or have a craving to smoke”, was understood by 91.1% of those who opened the DFL unprompted, and by 79.8% of those who did not open the flap until prompted to do so. By contrast, both of these subgroups had the same low comprehension of the reduced dosing in Step 3.

Table 47. Secondary Endpoints: Key Dosing Steps by Opening Flap

Source: Applicant NDA Submission

Table 48 shows that both normal literacy (NL) and limited literacy (LL) participants had equally low comprehension of the reduced dosing in Step 3.

Table 48. Secondary Endpoints: Key Dosing Steps by Literacy

Source: Applicant NDA Submission

Table 49 further illustrates the low comprehension for Step 3, even for normal literacy participants who opened the flap unprompted. Here we can see that although 91.3% (PE) of this subgroup understood Step 1, only 68.1% comprehended Step 3.

Table 49. Secondary Endpoints: Key Dosing Steps by Opening Flap and Literacy Opened DFL Asked Permission to Did Not Open DFL Until Unprompted Open DFL Prompted N=348 N=32 N=124 Normal Limited Normal Limited Normal Limited Literacy Literacy Literacy Literacy Literacy Literacy Secondary N=263 N=85 N=26 N=6 N=85 N=39 Endpoint n % n % n % n % n % n % Directions Step 1: Use—1-2 sprays when you would normally smoke a cigarette or have a craving to 240 91.3 77 90.6 25 96.2 3 50.0 71 83.5 28 71.8 smoke (use the second spray if your cravings are not reduced within a few minutes)

Opened DFL Asked Permission to Did Not Open DFL Until Unprompted Open DFL Prompted N=348 N=32 N=124 Normal Limited Normal Limited Normal Limited Literacy Literacy Literacy Literacy Literacy Literacy Secondary N=263 N=85 N=26 N=6 N=85 N=39 Endpoint n % n % n % n % n % n % Directions Step 2: By the end of week 9 you should be using HALF the 232 88.2 65 76.5 24 92.3 5 83.3 66 77.7 23 59.0 average number of sprays per day that you used in Step 1. Directions Step 3: Continue reducing the number of sprays per day so 179 68.1 55 64.7 17 65.4 5 83.3 61 71.7 21 53.9 that you are not using more than 4 sprays per day during week 12. Source: FDA Statistics Abbreviation: DFL, Drug Fact Label

General Use Table 50 illustrates that the secondary objectives “For best results do not swallow for 2-3 seconds after spraying” and “Use the second spray if your cravings are not reduced within a few minutes” were well understood by the overall study population. (93.7% and 93.1%, PE, respectively). By contrast, “When using this product, hiccups or minor mouth and throat irritation may occur. Stop use and ask a doctor if these problems persist or worsen over the course of treatment” was less well comprehended at 81.2% (PE) of the study population.

Table 50. Secondary Endpoints: General Use

Source: Applicant NDA Submission

Table 51 reveals that comprehension of the “hiccups/minor mouth/throat irritation” was not impacted by whether participants opened the DFL flap unprompted. This is not surprising, since, unlike other labeled statements assessed as communication objectives in the LCS, this statement appears on the DFL’s outer flap (81% versus 79%, PE).

Table 51. Secondary Endpoints: General Use by Opening Flap

Source: Applicant NDA Submission

Table 52 reveals that there were no major literacy differences in comprehension of the secondary objectives “For best results do not swallow for 2 to 3 seconds after spraying” and for “Use the second spray if your cravings are not reduced within a few minutes”. Although limited literacy participants had less comprehension of “When using this product, hiccups or minor mouth and throat irritation may occur” than normal literacy participants, comprehension of this objective still was not particularly high among normal literacy participants (83.2% NL versus 75.4% LL, PE).

Table 52. Secondary Endpoints: General Use by Literacy

Source: Applicant NDA Submission

9.3.4. Additional Analyses

Combined Comprehension of Dosing Steps 1 to 3 FDA analyzed how many participants comprehended all three dosing steps—Steps 1, 2, and 3. Below, Table 53 depicts combined primary and secondary objectives most related to Step 1 dosing only, where a correct comprehension was defined by correctly comprehending all three objectives. As illustrated, a total of 76.4% (PE) study participants overall comprehended the three most relevant aspects of Step 1 (NL 81.3% versus LL 62.3%).

Table 53. Combined Comprehension of Dosing Step 1 Total Population Normal Literacy Limited Literacy Combined Endpoint Related to Step 1 N=504 N=374 N=130 Dosing n % n % n % Directions Step 1: Maximum number of sprays per hour – 4 sprays per hour Directions Step 1: Maximum number of sprays per day 385 76.4 304 81.3 81 62.3 – 64 sprays per day Directions Step 1: Use 1-2 sprays when you would normally smoke a cigarette or have a craving to smoke Source: FDA Statistics

Next, we looked at how many participants understood all three dosing steps, the combined Step 1 depicted in Table 53, plus Steps 2 and 3. This combined comprehension included five objectives in total, and a correct comprehension is defined by correctly comprehending all five objectives. As Table 54 shows, only 48% (PE) of the overall study population understood the directions for all three dosing steps, with a significant minority of limited literacy participants (35.4%) understanding these directions.

Table 54. Combined Comprehension of Dosing Steps 1, 2, and 3 Total Population Normal Literacy Limited Literacy Combined Endpoints Related to Steps 1, N=504 N=374 N=130 2, and 3 Dosing n % n % n % Step 1 Directions Step 1: Maximum number of sprays per hour – 4 sprays per hour Directions Step 1: Maximum number of sprays per day – 64 sprays per day Directions Step 1: Use 1-2 sprays when you would normally smoke a cigarette or have a craving to smoke 242 48.0 196 52.4 46 35.4 Step 2 Directions Step 2: By the end of week 9 you should be using HALF the average number of sprays per day that you used in Step 1. Step 3 Directions Step 3: Continue reducing the number of sprays per day so that you are not using more than 4 sprays per day during week 12. Source: FDA Stats

9.3.5. Conclusions For most objectives, participants scored reasonably well on comprehension. However, this analysis highlights that understanding the multiple steps in the dosing directions, as currently depicted on labeling, may be problematic for consumers. Although those with limited literacy scored particularly low, it is atypical for normal literacy consumers in LCS to score as low as they did in this study on comprehension of Step 3. It is unclear whether any such lack of understanding directly leads to a lack of efficacy, or whether someone can still quit successfully without adequately understanding all of the steps.

The flap was not used in the naturalistic study, so the extra step of needing to open the flap to look at the directions on the back was not an additional factor in the low efficacy in that trial. However, it would appear that the flap still might contribute to lower comprehension of key messages.

The relatively lower comprehension (among all literacy subgroups) of “rinse immediately with water if you spray into the eyes as irritation will occur” may underscore a need to move this statement from “Directions” to “When Using this Product,” or to highlight it in its current section some other way.

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10. Human Factors Validation Study

The Applicant conducted a human factors (HF) validation study to evaluate 39 subjects’ ability to correctly perform the critical tasks for self-administration of the proposed nicotine mouth spray as described in the labeling (e.g., unlock, prime, align, administer simulated sprays, and lock), and to evaluate subjects’ ability to comprehend a key message related to priming (when to prime). The study was conducted with labels, labeling, and packaging configuration that was representative of the intend-to-market product, however, the mouth spray device provided to the subjects in the HF study was empty. While we generally agree with the overall methodology of the HF study, there are some limitations in the data collected because the tested device was empty.9

Specifically, the empty spray device limits the robustness of the data collected for the subtasks “No inhalation when spraying” and “No swallowing for 2 to 3 seconds after spraying” under the “Administer simulated spray(s)” task. Because an empty device does not provide representative feeling of the solution in the mouth, results observed for these subtasks may not be fully representative of whether users would inhale or swallow when they feel the solution is sprayed into the mouth. Moreover, swallowing and inhaling are difficult actions to observe in a HF simulation; thus, use of a placebo-filled device may be unlikely to eliminate the limitations of this study. For the “No inhalation when spraying” subtask, the study moderator observed whether subjects heaved the chest, which no subjects did. We note that GSK indicates in the submission that inhalation of the spray is mitigated by the small droplet size.10 Thus, despite the HF data limitations, we find the residual risk associated with this subtask acceptable.

For the “No swallowing” subtask, the study moderator observed whether subjects’ throats showed signs of swallowing, which was observed in one subject. Swallowing too quickly may result in inadequate time for the drug to be absorbed oromucosally and may potentially lead to inadequate dosing. However, users may redose the proposed product up to the maximum of 4 sprays per hour and 64 sprays per day based on their cravings during the first 6 weeks. Additionally, while the HF study data are limited, the LCS provided in the submission demonstrated that the labeling instructions related to not swallowing were well understood by the study population (94.1% success in normal literacy and 92.3% success in limited literacy groups). Thus, we have no further recommendations for the labeling associated with this subtask.

We also identified use failures (UF) and use difficulties (UD) with the critical tasks associated with priming (18 UF, 1 UD), unlocking (6 UF, 17 UD), and locking (6 UF) tasks. Failures associated with the priming task may potentially result in users not getting a full first dose; however, the proposed directions for use are “1-2 sprays when you would normally smoke … or have a craving to smoke…”, a maximum dose of “4 sprays per hour”, and may be redosed up to the maximum 64 sprays per day based on users’ cravings during the first 6 weeks. Thus, any failure to prime would self-correct throughout the treatment duration and the device would be

9 FDA advised the Applicant to perform the HF study with a placebo-filled device (i.e., a liquid that is representative in consistency and viscosity to the proposed nicotine solution). Applicant was not able to replicate the consistency and viscosity of the proposed nicotine solution; thus, the HF study was conducted with an empty device. 10 Source: \\cdsesub1\evsprod\nda208425\0004\m1\us\11415-labeling-history-01.pdf

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fully primed during the first hour of use. Additionally, we expect failures related to locking and unlocking the device would also self-correct with repeated use. Familiarity with the unlocking/locking mechanism as a learning effect was observed in the study; after familiarization with the product, the subjects demonstrated less difficulty with the locking mechanism.

Based on the HF study results and subjective feedback from study subjects, residual risks can be mitigated through further optimization of the proposed product’s labels and labeling. The labels and labeling modifications are expected to further clarify the proposed instructions and are not expected to introduce any new use-related risks; therefore, additional HF validation data are not necessary.

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11. Appendix

11.1. Summary of Presubmission Activities

McNeil Consumer Healthcare, the original IND holder (IND 77479), met with the Agency on June 18, 2007, to discuss the proposed clinical development program for NMS as an OTC product. At that time, two open label, single-dose pharmacokinetic studies were completed.

The main advice given by the Agency was as follows: • Multi-dose PK study (A6431117) should use Nicorette 4 mg per hour as per gum labeling, also lozenge should be incorporated as comparator due to better bioavailability. The Applicant agreed to add a 4 consecutive spray arm to the single dose study and a 4 mg lozenge arm to both proposed PK studies. • One standard efficacy trial and another “naturalistic,” placebo-controlled actual use trial was to be conducted, for a total of two efficacy studies. In the actual use study, a broader population including patients with health problems would be enrolled. The Applicant would also conduct efficacy studies using spray to open mouth rather than sublingual and agreed to address droplet size and potential for accidental pulmonary exposure. • The Agency recommended a pilot dose administration study at that time, to demonstrate that consumers could properly administer the mouth spray based on the proposed labeling alone, without the aid of coaching and/or directions from the study personnel. • Despite the Agency recommending a dose counter mechanism in the nicotine canister to help subjects keep track of use and monitor compliance, the Applicant stated that they would not market the product with a dose counter and would not employ one during their studies. • Instead, the Applicant would capture use and compliance data by using diaries and weighing the amount of product used at each visit. There was disagreement as to identifying the appropriate mechanism in assessing compliance and adverse events over 24 weeks. • The Agency recommended a study of taste preference and acceptability with the study drug, capsaicin and the vehicle alone, before proceeding with the clinical trial, to prevent confounding from a higher dropout rate in the placebo arm due to bad taste from the capsaicin in placebo. The Applicant stated that they believe that the amount of capsaicin used in the placebo would not cause it to be unpalatable and suggested a qualitative study to compare the acceptability of capsaicin versus nicotine. The Applicant would look at local irritation in both treatment arms, and if any signal arose they would then utilize a placebo that does not contain capsaicin. • The Applicant would provide information for the label comprehension study after efficacy studies are completed. • Visual oral inspections were to be done according to the Applicant’s proposed time points. The assessment had to be performed by a licensed dentist, or an examiner well- trained in oral pathology.

The Applicant submitted the initial IND package November 8, 2007 with revised protocols for two pharmacokinetic studies and the standard pivotal efficacy trial (A6431111) to evaluate the

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efficacy and safety of NMS in smokers. The naturalistic, actual use study protocol was under development at that time.

(b) (4)

At an End-of-Phase 2 meeting September 22, 2009, the Applicant informed the Agency that the placebo-controlled efficacy/safety trial, Protocol A6431111 was initiated in Europe without Agency review of the final protocol. The Applicant then proposed a design for a second naturalistic study that was not placebo-controlled.

The Applicant was reminded that the ongoing study (A6431111) involved patients receiving instruction and encouragement from study staff, which, if successful, would be sufficient for assessment of efficacy when it is used adequately and according to the labeling instructions. However, this study alone would not be sufficient to demonstrate the efficacy of this product when used in the over-the-counter setting, where instructions and encouragement are not provided. Regarding the proposed naturalistic study (without placebo control), the Agency reminded the Applicant that other products for OTC marketing have been successfully evaluated in controlled naturalistic studies as part of the development program.

The Applicant also informed the Agency at this End-of-Phase 2 meeting that a pilot and a full Label Comprehension Study (LCS) was completed. The Agency reminded the Applicant that at the first pre-IND (PIND) meeting, they were advised to base the proposed label on data generated from efficacy trials. If the efficacy trials yield information which necessitates label revision, the results of the completed LCS may not be valid. If the first efficacy trial (A6431111) was successful in demonstrating efficacy, and no information emerged to necessitate revision of the proposed label, then it would be reasonable to proceed with the second naturalistic efficacy trial using the current version of the label. The Applicant was advised that the proposed label may need further revision following the phase 3 program.

(b) (4)

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(b) (4)

• The Applicant powered the study to adequately address both efficacy and safety in an OTC environment, and asked if sample size (1,500 randomized to active or placebo in a 2:1 ratio) was appropriate. The Agency noted that the estimated sample size was based on the need to establish an adequate safety database and was larger than needed for the purposes of establishing efficacy, assuming that the product has an efficacy comparable to other nicotine replacement products. Therefore, it has the potential to identify a statistically significant difference between groups even if the quit rates are low and similar.

(b) (4)

The Applicant submitted a new protocol on November 2, 2011 as an SPA: NICTDP3038, titled “A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study using a

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Naturalistic Clinical Model to measure the Efficacy and Safety of a Novel Nicotine Replacement Therapy in Smokers Motivated to Quit." (b) (4)

The sample size for this new study was 1,200:600 per treatment arm (active versus placebo), which was established to address the high (40%) subject dropout rate expected for this trial. The Applicant estimated that a total of 360 subjects would complete 12 weeks of active product treatment.

The Agency agreed that sufficient numbers of subjects should be recruited such that >300 subjects complete 12 weeks use of active drug and recommended that at least half of these subjects should smoke >20 cigarettes per day. The Agency also reminded the Applicant that the estimated sample size is based on the need to establish an adequate safety database and is larger than needed for the purpose of establishing efficacy.

(b) (4)

The Applicant sent an amended protocol April 27, 2015 and informed the Agency of change in corporate Applicant June 29, 2015 from McNeil Consumer Healthcare Division of McNeil-PPC, Inc. to Johnson & Johnson Consumer Inc., McNeil Consumer Health Division. A completed study report for study CO-140121222102-SCCT (formerly NICTDP3038) was submitted September 28, 2016.

The Agency received a Letter of Authorization on February 24, 2017 for GlaxoSmithKline Consumer Healthcare (GSKCH) to cross-reference IND 77479 for GSKCH’s meeting request PIND 133467 for the same product.

GSKCH met with the Agency March 21, 2017 to discuss revised labeling, the pivotal label comprehension study and human factors studies required for OTC approval of nicotine mouth spray. The Agency expressed concerns regarding the large discrepancy of quit rates between the two pivotal phase 3 studies (A6431111 and NICTDP3038) and provided extensive advice on risk analysis and human factors studies.

The Applicant requested another meeting with the Agency on March 2, 2018 to further discuss pivotal label comprehension and summative human factors studies. The Agency provided written responses with extensive advice on human factors and label comprehension studies in lieu of a meeting on May 24, 2018. In the written responses, the Agency also expressed concerns that the

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evidence provided by the Applicant at that time was not sufficient for an NDA submission. The Agency reminded the Applicant of the need to address the Agency’s concerns regarding the low quit rates in study NICTDP3038, which was conducted in a real-world, naturalistic setting, and additional clinical data would be needed to demonstrate that the revised labeling supports safe and effective use of the product in the OTC setting.

The Applicant submitted an initial pediatric study plan (iPSP) on May 1, 2018 to request a Pediatric Research Equity Act waiver, which was granted October 8, 2018. Final NDA submission was December 20, 2018. No pre-NDA meeting to discuss format and content was requested or held.

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11.2. Drug Facts Label and Directions for Use

Figure 15. DFL Tested in the LCS

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Figure 16. DFL Submitted in the NDA

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Figure 17. DFL Used in Naturalistic Study

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Figure 18. Directions for Use in Clinical Trial

Source: Draft Labeling Text

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Figure 19. Example of Nicotine Gum DFL

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12. Glossary

ADAE Adverse Event Analysis AE adverse event AUC area under the concentration-time curve CAR continuous abstinence rate CIL Consumer Information Leaflet CO carbon monoxide CRF case report form DFL Drug Facts Label DPV Division of Pharmacovigilance EMA European Medicines Agency FAERS FDA Adverse Events Reporting System FAS Full Analysis Set FDA Food and Drug Administration FMQ FDA Medical Dictionary for Regulatory Activities Query GERD gastroesophageal reflux disease GSD global safety database GSK GlaxoSmitKline GSKCH GlaxoSmithKline Consumer Healthcare HF human factors HTN hypertension IND investigational new drug IRB Institutional Review Board LB lower bound LCS label comprehension studies LL limited literacy NDA New Drug Application NL normal literacy NMS nicotine mouth spray NRT nicotine replacement therapy OR odds ratios OSE Office of Surveillance and Epidemiology OTC over-the-counter PD pharmacodynamic PK pharmacokinetic PT preferred term REALM Rapid Estimate of Adult Literacy in Medicine RX prescription SAE serious adverse event SPA Special Protocol Assessment UD use difficulties UF use failures UMC Uppsala Monitoring Centre VMI visual mouth inspection WHO World Health Organization

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13. References

Alexander, S, 2015, Girl, 12, poisons classmates with nicotine spray which her SCHOOL prescribed, Daily Star, London, UK: Express Newspapers. Accessed July 29, 2019, https://www.dailystar.co.uk/news/latest-news/433415/Quitting-smoking-nicotine-spray-school- pupils-overdose.

Bailey, SR, EE Crew, EC Riske, S Ammerman, TN Robinson, and JD Killen, 2012, Efficacy and tolerability of pharmacotherapies to aid smoking cessation in adolescents, Paediatr Drugs, 14(2):91-108.

Bolliger, CT, X van Biljon, and A Axelsson, 2007, A nicotine mouth spray for smoking cessation: a pilot study of preference, safety and efficacy, Respiration, 74(2):196-201.

Caldwell, BO, SJ Adamson, and J Crane, 2014, Combination rapid-acting nicotine mouth spray and nicotine patch therapy in smoking cessation, Nicotine Tob Res, 16(10):1356-1364.

Dollerup, J, J Vestbo, T Murray-Thomas, A Kaplan, RJ Martin, E Pizzichini, MMM Pizzichini, A Burden, J Martin, and DB Price, 2017, Cardiovascular risks in smokers treated with nicotine replacement therapy: a historical cohort study, Clin Epidemiol, 9:231-243.

Draft guidance for industry Smoking Cessation and Related Indications: Developing Nicotine Replacement Therapy Drug Products (February 2019)

Food and Drug Administration, 2019, FDA Adverse Event Reporting System, accessed July 29, 2019, https://open.fda.gov/data/faers/.

Hansson, A, P Hajek, R Perfekt, and H Kraiczi, 2012, Effects of nicotine mouth spray on urges to smoke, a randomised clinical trial, BMJ Open, 2(5).

Hartmann-Boyce, J, SC Chepkin, W Ye, C Bullen, and T Lancaster, 2018, Nicotine replacement therapy versus control for smoking cessation, Cochrane Database Syst Rev, 5:CD000146.

Guidance for industry Assessment of Abuse Potential of Drugs (January 2017)

Kraiczi, H, A Hansson, and R Perfekt, 2011, Single-dose pharmacokinetics of nicotine when given with a novel mouth spray for nicotine replacement therapy, Nicotine Tob Res, 13(12):1176-1182.

McRobbie, H, S Thornley, C Bullen, RB Lin, H Senior, M Laugesen, R Whittaker, and P Hajek, 2010, A randomized trial of the effects of two novel nicotine replacement therapies on tobacco withdrawal symptoms and user satisfaction, Addiction, 105(7):1290-1298.

Mills, EJ, P Wu, I Lockhart, K Wilson, and JO Ebbert, 2010, Adverse events associated with nicotine replacement therapy (NRT) for smoking cessation. A systematic review and meta- analysis of one hundred and twenty studies involving 177,390 individuals, Tob Induc Dis, 8:8.

115

Motooka, Y, T Matsui, RM Slaton, R Umetsu, A Fukuda, M Naganuma, S Hasegawa, S Sasaoka, H Hatahira, K Iguchi, and M Nakamura, 2018, Adverse events of smoking cessation treatments (nicotine replacement therapy and non-nicotine prescription medication) and electronic cigarettes in the Food and Drug Administration Adverse Event Reporting System, 2004-2016, SAGE Open Med, 6:2050312118777953.

Nides, M, T Danielsson, F Saunders, R Perfekt, R Kapikian, J Solla, SJ Leischow, and A Myers, 2018, Efficacy and safety of a nicotine mouth spray for smoking cessation; a randomized, multicenter, controlled study in a naturalistic setting, Nicotine Tob Res, DOI: 10.1093/ntr/nty246.

Guidance for industry General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products (November 2017)

Patel, C, S Nguyen, L Cascio, M Mundkur, and DPV Case Definitions Workgroup, 2019, Case Definition: Drug Abuse, Misuse, Dependence, Tolerance, And Withdrawal.

Simons, FE, LR Ardusso, MB Bilo, V Dimov, M Ebisawa, YM El-Gamal, DK Ledford, RF Lockey, J Ring, M Sanchez-Borges, GE Senna, A Sheikh, BY Thong, M Worm, and O World Allergy, 2012, 2012 Update: World Allergy Organization Guidelines for the assessment and management of anaphylaxis, Curr Opin Allergy Clin Immunol, 12(4):389-399.

Simons, FE, LR Ardusso, MB Bilo, YM El-Gamal, DK Ledford, J Ring, M Sanchez-Borges, GE Senna, A Sheikh, BY Thong, and O World Allergy, 2011, World allergy organization guidelines for the assessment and management of anaphylaxis, World Allergy Organ J, 4(2):13-37.

Simons, FE, LR Ardusso, V Dimov, M Ebisawa, YM El-Gamal, RF Lockey, M Sanchez-Borges, GE Senna, A Sheikh, BY Thong, M Worm, and O World Allergy, 2013, World Allergy Organization Anaphylaxis Guidelines: 2013 update of the evidence base, Int Arch Allergy Immunol, 162(3):193-204.

Tonnesen, P, H Lauri, R Perfekt, K Mann, and A Batra, 2012, Efficacy of a nicotine mouth spray in smoking cessation: a randomised, double-blind trial, Eur Respir J, 40(3):548-554.

U.S. Department of Health and Human Services, 2014, The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon General, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion and Office on Smoking and Health.

Wang, TW, K Asman, AS Gentzke, KA Cullen, E Holder-Hayes, C Reyes-Guzman, A Jamal, L Neff, and BA King, 2018, Tobacco Product Use Among Adults - United States, 2017, MMWR Morb Mortal Wkly Rep, 67(44):1225-1232.

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