CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`204427Orig1s000
`
`MEDICAL REVIEW(S)
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`FlatWing Ex. 1040, p. 1
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`

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`CLINICAL REVIEW
`
`Application Type NDA
`Application Number 204,427
`Priority or Standard Standard
`
`Submit Date July 29, 2013
`Received Date July 29, 2013
`PDUFA Goal Date July 29, 2014
`Division / Office DDDP
`
`Reviewer Name Milena Lolic, M.D., M.S.
`Review Completion Date March 11, 2014
`
`Established Name Tavaborole solution 5%
`Trade Name Kerydin
`Therapeutic Class Oxaborole antifungal
`Applicant Anacor Pharmaceuticals Inc.
`
`Formulation Solution
`Dosing Regimen Daily for 48 weeks
`Indication Onychomycosis
`Intended Population Adults
`
`Template Version: March 6, 2009
`
`Reference ID: 3477657
`
`FlatWing Ex. 1040, p. 2
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`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`Table of Contents
`
`2
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 7
`1.1 Recommendation on Regulatory Action ............................................................. 7
`1.2 Risk Benefit Assessment.................................................................................... 7
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies ... 8
`1.4 Recommendations for Postmarket Requirements and Commitments ................ 8
`INTRODUCTION AND REGULATORY BACKGROUND ........................................ 9
`2.1 Product Information ............................................................................................ 9
`2.2 Currently Available Treatments for Proposed Indication................................... 10
`2.3 Availability of Proposed Active Ingredient in the United States ........................ 12
`2.4
`Important Safety Issues with Consideration to Related Drugs.......................... 12
`2.5 Summary of Presubmission Regulatory Activity Related to Submission .......... 12
`2.6 Other Relevant Background Information .......................................................... 13
`3 ETHICS AND GOOD CLINICAL PRACTICES....................................................... 13
`3.1 Submission Quality and Integrity ...................................................................... 13
`3.2 Compliance with Good Clinical Practices ......................................................... 13
`3.3 Financial Disclosures........................................................................................ 27
`4 SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES ......................................................................................................... 28
`4.1 Chemistry Manufacturing and Controls ............................................................ 28
`4.2 Clinical Microbiology......................................................................................... 29
`4.3 Preclinical Pharmacology/Toxicology ............................................................... 33
`4.4 Clinical Pharmacology...................................................................................... 34
`4.4.2 Pharmacodynamics.................................................................................... 35
`4.4.3 Pharmacokinetics....................................................................................... 35
`5 SOURCES OF CLINICAL DATA............................................................................ 38
`5.1 Tables of Studies/Clinical Trials ....................................................................... 38
`5.2 Review Strategy ............................................................................................... 39
`5.3 Discussion of Individual Studies/Clinical Trials................................................. 40
`6 REVIEW OF EFFICACY......................................................................................... 48
`Efficacy Summary...................................................................................................... 48
`6.1
`Indication .......................................................................................................... 49
`6.1.1 Methods ..................................................................................................... 49
`6.1.2 Demographics............................................................................................ 50
`6.1.3 Subject Disposition .................................................................................... 51
`6.1.4 Analysis of Primary Endpoint ..................................................................... 52
`6.1.5 Analysis of Secondary Endpoints(s)........................................................... 53
`6.1.6 Other Endpoints ......................................................................................... 55
`
`Reference ID: 3477657
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`2
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`FlatWing Ex. 1040, p. 3
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`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`6.1.7 Subpopulations .......................................................................................... 55
`6.1.8 Analysis of Clinical Information Relevant to Dosing Recommendations .... 56
`6.1.9 Discussion of Persistence of Efficacy and/or Tolerance Effects................. 56
`6.1.10 Additional Efficacy Issues/Analyses........................................................... 57
`7 REVIEW OF SAFETY............................................................................................. 59
`Safety Summary ........................................................................................................ 59
`7.1 Methods............................................................................................................ 60
`7.1.1 Studies/Clinical Trials Used to Evaluate Safety ......................................... 60
`7.1.2 Categorization of Adverse Events.............................................................. 63
`7.1.3 Pooling of Data Across Studies/Clinical Trials to Estimate and Compare
`Incidence.................................................................................................... 63
`7.2 Adequacy of Safety Assessments .................................................................... 63
`7.2.1 Overall Exposure at Appropriate Doses/Durations and Demographics of
`Target Populations..................................................................................... 63
`7.2.2 Explorations for Dose Response................................................................ 65
`Study AN2690-ONYC-200/200A............................................................................ 68
`7.2.3 Special Animal and/or In Vitro Testing ....................................................... 70
`7.2.4 Routine Clinical Testing ............................................................................. 70
`7.2.5 Metabolic, Clearance, and Interaction Workup .......................................... 71
`7.2.6 Evaluation for Potential Adverse Events for Similar Drugs in Drug Class .. 71
`7.3 Major Safety Results ........................................................................................ 71
`7.3.1 Deaths........................................................................................................ 71
`7.3.2 Nonfatal Serious Adverse Events .............................................................. 72
`7.3.3 Dropouts and/or Discontinuations .............................................................. 75
`7.3.4 Significant Adverse Events ........................................................................ 77
`7.3.5 Submission Specific Primary Safety Concerns .......................................... 78
`7.4 Supportive Safety Results ................................................................................ 80
`7.4.1 Common Adverse Events .......................................................................... 80
`7.4.2
`Laboratory Findings ................................................................................... 82
`7.4.3 Vital Signs.................................................................................................. 83
`7.4.4 Electrocardiograms (ECGs) ....................................................................... 83
`7.4.5 Special Safety Studies/Clinical Trials......................................................... 84
`7.4.6
`Immunogenicity.......................................................................................... 87
`7.5 Other Safety Explorations................................................................................. 87
`7.5.1 Dose Dependency for Adverse Events ...................................................... 87
`7.5.2 Time Dependency for Adverse Events....................................................... 88
`7.5.3 Drug-Demographic Interactions ................................................................. 89
`7.5.4 Drug-Disease Interactions.......................................................................... 91
`7.5.5 Drug-Drug Interactions............................................................................... 91
`7.6 Additional Safety Evaluations ........................................................................... 92
`7.6.1 Human Carcinogenicity.............................................................................. 92
`7.6.2 Human Reproduction and Pregnancy Data................................................ 92
`7.6.3 Pediatrics and Assessment of Effects on Growth ...................................... 93
`
`Reference ID: 3477657
`
`3
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`FlatWing Ex. 1040, p. 4
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`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`7.6.4 Overdose, Drug Abuse Potential, Withdrawal and Rebound...................... 95
`7.7 Additional Submissions / Safety Issues............................................................ 95
`8 POSTMARKET EXPERIENCE............................................................................... 95
`
`9 APPENDICES ........................................................................................................ 96
`9.1
`Literature Review/References .......................................................................... 96
`9.2
`Labeling Recommendations ............................................................................. 96
`9.3 Advisory Committee Meeting............................................................................ 96
`9.4. Clinical Investigator Financial Disclosure ......................................................... 96
`
`Reference ID: 3477657
`
`4
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`FlatWing Ex. 1040, p. 5
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`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`Table of Tables
`
`Table 1 List of Investigators for Trial 301.................................................................... 14
`Table 2 List of Investigators for Trial 302.................................................................... 20
`Table 3 Minimum Inhibitory Concentration for AN2690, and Comparator Drugs Against
`19 Test Strains of Fungi................................................................................. 30
`Table 4 MIC and MFC (in μg/mL) of AN2690 in Clinical Isolates................................ 30
`Table 5 Summary of Mycology Results for Phase 3 Trials.......................................... 31
`Table 6 Tavaborole Susceptibility against Screening Isolates .................................... 32
`Table 7 Tavaborole Susceptibility from Last Isolates.................................................. 32
`Table 8 Pharmacokinetic Parameters for Tavaborole Solution 5%............................. 36
`Table 9 Tavaborole Clinical Studies ........................................................................... 38
`Table 10 Phase 3 Trial Schedule.................................................................................. 43
`Table 11 IGA Scale from Phase 3 Trials....................................................................... 45
`Table 12 Local Tolerability Scale from Phase 3 Trials................................................... 47
`Table 13 Analysis Sets ................................................................................................. 49
`Table 14 Baseline Demographics-ITT .......................................................................... 50
`Table 15 Baseline Disease Characteristics-ITT............................................................ 50
`Table 16 Disposition of Subjects-ITT ............................................................................ 51
`Table 17 Primary Endpoint Analysis ............................................................................. 52
`Table 18 Complete Cure Rates under Missing Data Sensitivity Analyses .................... 53
`Table 19 Secondary Endpoints Analysis....................................................................... 53
`Table 20 Trials Used for Safety Assessment................................................................ 61
`Table 21 Demographics-Safety Population................................................................... 63
`Table 22 Summary of AEs-Trial 201............................................................................. 66
`Table 23 Summary of AEs-Trial 203............................................................................. 68
`Table 24 Summary of AEs-Trial 200/200A.................................................................... 69
`Table 25 SAE in Tavaborole Solution 5% Arm-Phase 3 ............................................... 72
`Table 26 SAE in Vehicle Arm-Phase 3 ......................................................................... 73
`Table 27 SAEs from Phase 2 Trials.............................................................................. 74
`Table 28 Subject Discontinuations................................................................................ 75
`Table 29 Summary of AEs Leading to Subject Discontinuation from the Trials ............ 76
`Table 30 Treatment Discontinuations............................................................................ 76
`Table 31 Severe Adverse Reactions............................................................................ 77
`Table 32 Application Site Reactions ............................................................................. 78
`Table 33 Number of Subjects with Local Signs and Symptoms.................................... 79
`Table 34 Distribution of Severe Local Signs and Symptoms ........................................ 79
`Table 35 Most Common AEs Occurring in >1% of Subjects......................................... 80
`Table 36 Adverse Events Occurring in >2% of Tavaborole –Treated Subjects and at the
`Greater Frequency that Vehicle ..................................................................... 81
`Table 37 Laboratory Findings Occurring in >2 Tavaborole –Treated Subjects and at the
`Greater Frequency that Vehicle ..................................................................... 83
`Table 38 Summary of Mean Cumulative Data (Irritation Phase)................................... 85
`
`Reference ID: 3477657
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`5
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`FlatWing Ex. 1040, p. 6
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`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`Table of Figures
`
`Figure 1 Approved Drugs for Onychomycosis Treatment............................................ 11
`Figure 2 Trial Flow ....................................................................................................... 41
`Figure 3 Complete Cure Rates over Time.................................................................... 57
`Figure 4 Efficacy by Analysis Center (Trial 301) .......................................................... 58
`Figure 5 Efficacy by Analysis Center (Trial 302) .......................................................... 58
`Figure 6 Number of Subjects Exposed to Tavaborole.................................................. 65
`Figure 7 Subjects Disposition....................................................................................... 75
`
`Reference ID: 3477657
`
`6
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`FlatWing Ex. 1040, p. 7
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`

`

`Clinical Review
`
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`| recommend that NDA 204,427 Kerydin (tavaborole solution, 5%) be approved for the
`treatment of onychomycosis of the toenail caused by Trichophyton rubrum or
`Trichoghfion mentagrophytes.
`
`Two phase 3 trials (AN2690-O-NYC301 and AN2690-O-NYC-302) demonstrated the
`efficacy and safety of tavaborole solution, 5% for adult patients with t_oenai|
`onychomycosis caused by Trichoghfion rubrum or Trichoghfion mentagroghfles.
`
`This reviewer’s recommended indication differs from the
`
`“m"
`
`that the applicant proposes. The
`recommended indication is based on the population which was studied and for whom
`the safety and effectiveness has been demonstrated:
`
`1. Safety and efficacy of Kerydin was studied in subjects with onychomycosis of
`toenails
`“m"
`
`2. The submission characterized the mycology and susceptibility of strains of
`Trichophyton rubrum and Trichophyton mentagrophytes obtained from clinical
`isolates of subjects treated with Kerydin.
`“m
`
`1.2 Risk Benefit Assessment
`
`The risk to benefit assessment for this application is based on the clinical trial results.
`
`The primary efficacy endpoint, defined as the proportion of subjects with complete cure
`of toenail onychomycosis at Week 52, was achieved by 7% of subjects treated with
`Kerydin in trial 301 and by 9% in trial 302. Complete cure for vehicle-treated subjects
`was 1% and 2% for respective trials (p5 0.001 ). The analysis of secondary endpoints
`(mycological cure and treatment success) supported the primary endpoint. While
`modest, the observed treatment effect is comparable to the only other approved topical
`product in USA for the treatment of toenail onychomycosis (Penlac® (ciclopirox) topical
`solution 8%).
`
`Reference ID: 3477657
`
`FIatWing EX- 1040, p. 8
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`FlatWing Ex. 1040, p. 8
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`

`

`Clinical Review
`
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`In two pivotal phase 3 clinical trials, the most common adverse reactions were
`application site reactions (rate occurrence 7%) and ingrown toenail (3%), and the vast
`majority of which were mild to moderate in intensity and resolved spontaneously.
`Severe reactions were rare and did not differ between the groups (0.6% and 0.5% for
`active and vehicle). The incidence of serious adverse events (SAE) was similar between
`subjects treated with Kerydin and vehicle (2.5% versus 2.4%, respectively). None of the
`SAEs appear to be related to the treatment. The safety review of supportive trials from
`phase 2 was comparable to pivotal trials.
`
`In conclusion, benefits outweigh the risks for the recommended indication. If approved,
`Kerydin could offer an additional therapeutic option for toenail onychomycosis. Topical
`tavaborole may be a reasonable option for patients with onychomycosis who are unable
`to tolerate oral antifungal agents or do not wish to undergo more comprehensive topical
`treatment required for Penlac® use. The adverse events associated with the drug
`product can be adequately informed by labeling. The label also provides adequate
`information for instructions for use.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`There are no recommendations for a specific postmarketing risk management plan
`beyond labeling. Routine risk minimization measures such as professional labeling,
`prescription status, and spontaneous adverse event reporting, comprise an adequate
`risk management plan for this application.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`Kerydin was studied in the adult population only.
`
`and Assessment of Effects on Growth).
`
`(I!) (4)
`
`(7.6.3 Pediatrics
`
`“m"
`The request
`was presented to Pediatric Review Committee (PeRCAgi
`February 5, 2014. The Committee agreed with the Division
`recommended a partial waiver for subjects less than 6 years of
`
`age.
`
`It is my recommendation that partial waiver be granted for pediatric subjects less than
`12 years of age. The decision is based on section 505B (a)(4)(B)(iii) of the Pediatric
`Research Equity Act where the Agency may grant the partial waiver if the drug or
`biological product (1) does not represent a meaningful therapeutic benefit over existing
`therapies for pediatric patients in that age group and (2) is not likely to be used by a
`substantial number of pediatric patients in that age group). The cut off age of 12 years is
`
`Reference ID: 3477657
`
`FlatWing EX- 1040, P- 9
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`FlatWing Ex. 1040, p. 9
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`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`based on literature review. For full discussion on the selected age recommended for
`partial waiver see Section 7.6.3.
`
`Given that adult studies are complete and ready for approval, I recommend that a
`deferral to conduct studies in pediatric subjects 12-18 years is warranted. Due to similar
`clinical presentation of toenail onychomycosis in adults and adolescents, drug
`effectiveness can be extrapolated from adults; however a safety study is needed to
`address potential differences in systemic bioavailability and local tolerability. Thus, my
`recommendation is that the following PMR be attached to this NDA approval:
`
`1. Pharmacokinetic/safety/tolerability trial in pediatric subjects with toenail
`onychomycosis ages 12 years to 17 years 11 months.
`2 Introduction and Regulatory Background
`
`Onychomycosis is a chronic fungal infection of toenails and/or fingernails. It is estimated
`that 15-20% of persons in United States between 40 and 60 years old have
`onychomycosis1. Older age, tinea pedis, and immunodeficiency are some of the risk
`factors for acquiring onychomycosis.
`
`The most common site of infection is the toenail. The most common type of toenail
`onychomycosis is distal subungual onychomycosis and the most common
`dermatophytes causing distal subungual onychomycosis are Trichophyton rubrum, and
`Trichophyton mentagrophytes. Fingernail onychomycosis is more likely to be caused by
`yeasts, most commonly Candida albicans2.
`
`The clinical manifestations of onychomycosis include separation of the nail plate from
`the nail bed (onycholysis), subungual hyperkeratosis, and changes in the nail plate that
`make it thicker, brittle, and discolored. Symptoms include toenail discomfort when
`walking including pain and social embarrassment.
`
`Treatment may be indicated from both medical and psychosocial perspectives. Without
`treatment, the disease can cause progressive damage to the nail unit, and can spread
`to infect other nails, the skin, or potentially predispose to secondary bacterial infections
`(in immunocompromised populations).
`
`2.1 Product Information
`
` boronic acid complex (5-fluoro-1, 3-dihydro-1-hydroxy-2,1-
`Tavaborole is a
`benzoxaborole) with molecular weight of 151.93 Da. Its structural formula is:
`
`Reference ID: 3477657
`
`9
`
`(b) (4)
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`FlatWing Ex. 1040, p. 10
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`

`

`Clinical Review
`
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`The composition of tavaborole topical solution, 5% is presented below:
`
`Components
`
`Tavaborole
`
`Alcohol
`
`Propylene Glycol
`Edctatc Calcium Disodilun
`
`Source: Applicant's Table 1 from 3.2.P1
`
`Quality Standard
`
`In-house
`
`Function
`
`Active
`
`Concentration
`
`(°/n w/W)
`
`5.00
`
`USP
`
`USP
`USP
`
`
`
`There are no novel excipients used in the drug product.
`
`I
`
`2.2 Currently Available Treatments for Proposed Indication
`
`The treatment duration of onychomycosis is often long as the disease is difficult to
`eradicate and has a tendency to recur". Current therapeutic approaches include
`mechanical or chemical nail avulsion, topical therapy, oral therapy, or a combination of
`these treatment modalities“. Treatment choice depends on the clinical pattern of
`onychomycosis, the thickness of the involved nails, and the number of affected nails as
`well as patient motivation and preference.
`
`Reference ID: 3477657
`
`FIatWing EX- 1040, P- 11
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`

`

`Clinical Review
`
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`Figure 1 Approved Drugs for Onychomycosis Treatment
`
` Systemic
`200mg bid x 1wklmonth
`
`Griseofulvin
`
`Itraconazole
`(Lamisil)
`(Sporanox)
`
`Continuous
`Toenais with or without
`
`Toenail or fligemails
`fingernails
`
`fngemais involvement
`250mgld x 6 weeks
`500—1000mglday until
`
`
`
`infection cleared
`200mgld x12mks
`
`
`toenails
`
`250mgld x 12 weeks Pulse (2 pulses)
`
`
`anemails only
`
`
`
`Terbinafine
`
`Ciclopirox
`(Penlac)
`
`Toenail or fingernails
`once daily x 48 weeks
`
`Systemic therapy includes oral agents (e.g., Lamisil®, Sporanox®) which have efficacy
`rates of 14%-38 %. There is only one topical agent -Penlac®, approved in USA in 1999
`for onychomycosis. However, Penlac® has lower efficacy than oral agents (about 8%)
`and it's labeling requires regular debridement of the nail by a health professional as
`adjunctive therapy.
`
`The major efficacy issue with development of topical treatments for onychomycosis to
`date is achievement of sufficient drug concentrations at the nail bed due to poor nail
`permeability.
`
`Reference ID: 3477657
`
`FIatWing EX- 1040, P- 12
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`11
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`FlatWing Ex. 1040, p. 12
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`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`2.3 Availability of Proposed Active Ingredient in the United States
`
`Tavaborole is a new molecular entity thus not available in the United States and has not
`been marketed in any other country.
`
`2.4 Important Safety Issues with Consideration to Related Drugs
`
`There are no related drugs to tavaborole as it belongs to a new therapeutic class of
`oxaborols. There are safety issues related to all other approved drugs for
`onychomycosis treatment.
`
`Major concerns with griseofulvin are hypersensitivity and numerous drug-drug
`interactions. Itriconazole and terbinafine may induce hepatotoxicity and require that liver
`function tests be monitored during the treatment. Additionally, itraconazole has a boxed
`warning for multiple drug interactions and CHF.
`
`The only topical agent, ciclopirox may cause irritation of the periungual area, observed
`in 5% of patients.
`
`2.5 Summary of Presubmission Regulatory Activity Related to Submission
`
`Relevant pre-submission regulatory activity for tavaborole (AN2690) was notable for the
`following:
`
` Pre-IND Meeting October 3, 2005
` Guidance Meeting June 11, 2007
`o The population studied will be reflected in labeling.
` Guidance Meeting August 13, 2008
` End-of-Phase 2 Meeting October 8, 2009. Division comments included:
`o Evaluation of the primary endpoints at Week 52 after 48 weeks of
`treatment appears acceptable
`o The proposed primary endpoint, complete cure of the target great toenail
`is acceptable
` SPA received August 4, 2010 and the Agreement Letter sent on September 13,
`2010
` Guidance Meeting November 14, 2012
`o The Division will consider a partial waiver from pediatric studies that is
`supported by evidence
` Pre-NDA Meeting May 13, 2013
`
`Reference ID: 3477657
`
`12
`
`FlatWing Ex. 1040, p. 13
`
`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`Comment: The content of this NDA is consistent with the prior agreements with the
`Division.
`
`2.6 Other Relevant Background Information
`
`Tavaborole solution 5% was developed by Anacor Pharmaceuticals. The code name
`was designated as AN2690. Schering Plough was also involved with part of the clinical
`development and the code name for that phase was SCH 900340.
`
`Throughout the clinical review, the terms tavaborole, tavaborole solution 5 %, and
`AN2690 reflect the same product and are used interchangeably.
`
`3 Ethics and Good Clinical Practices
`
`3.1 Submission Quality and Integrity
`
`The overall quality of the clinical information contained in this submission was
`acceptable.
`
`3.2 Compliance with Good Clinical Practices
`
`The applicant affirmed that the studies were conducted in accordance with the ethical
`principles originating from the Declaration of Helsinki and the International Conference
`on Harmonization (ICH) harmonized tripartite guidelines for Good Clinical Practice and
`the compliance with local and FDA regulatory requirements. The protocol and Informed
`Consent Forms were reviewed by the Investigations Review Board (IRB) associated
`with the trial sites or by consulting central IRB. Written informed consents were obtained
`from subjects at the first (baseline) visit.
`
`The Division of Scientific Investigators (DSI) was consulted to review the conduct of
`both clinical trials, and included the inspections of site 301-122 in Baltimore, MD and
`site 302-325 in Evansville, IN. Both sites were selected by the Division based on high
`number of patients enrolled and the high number of treatment responders.
`
`DSI inspections of the trial sites have been completed but the review is pending.
`
`Reference ID: 3477657
`
`13
`
`FlatWing Ex. 1040, p. 14
`
`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`Table 1
`
`List of Investigators for Trial 301
`
`Reference ID: 3477657
`
`14
`
`FlatWing Ex. 1040, p. 15
`
`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
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`Reference ID: 3477657
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`15
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`FlatWing Ex. 1040, p. 16
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`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
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`Reference ID: 3477657
`
`16
`
`FlatWing Ex. 1040, p. 17
`
`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
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`Reference ID: 3477657
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`17
`
`FlatWing Ex. 1040, p. 18
`
`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
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`Reference ID: 3477657
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`18
`
`FlatWing Ex. 1040, p. 19
`
`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`Source: Applicant’s Table 30 from 5.2
`
`Reference ID: 3477657
`
`19
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`FlatWing Ex. 1040, p. 20
`
`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
`
`Table 2
`
`List of Investigators for Trial 302
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`Reference ID: 3477657
`
`20
`
`FlatWing Ex. 1040, p. 21
`
`

`

`Clinical Review
`Milena Lolic, MD, MS
`NDA 204,427
`Kerydin (tavaborole) Topical Solution, 5%
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