CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`203567Orig1s000
`
`SUMMARY REVIEW
`
`
`
`
`

`

`DiVision Deputy Director Review
`
`Summary Review for Regulatory Action
`
`electronic stamp)
`tanka Kukich, IVID
`From
`
`Subject
`Deputy Director Summary Review
`NBA
`203567
`
`Applicant Name
`
`Date of Submission
`
`PDUFA Goal Date
`
`Proprietary Name /
`Established
`S .
`
`Name
`
`Dow Pharmaceutical Sciences/Valeant Pharmaceuticals
`North America LLC
`
`December 20, 2013
`
`June 20, 2014
`
`JUBLIA/Efinaconazole
`
`
`
`Dosa _e Forms / Stren_ h
`Proposed Indication(s)
`
`To a ical solution, 10%
`Treatment of onychomycosis of the toenails due to
`Trichophyton rubrmn or Trichophyton
`mentagrophvtes
`Action/Recommended Action for Approval
`NME:
`
`Material Reviewed/Consulted
`
`0ND Action Packa - e, includin:
`
`Names of disci n line reviewers
`
`OND=0fice ofNew Drugs
`DDMAC=Division of Drug Marketing, Advertising and Communication
`0513: 05:: of Surveillance and Epidemiology
`DMEPA=Division of Medication Error Prevention and Analysis
`DSI=Division of Scientific Investigations
`DDRE= Division of Drug Risk Evaluation
`DRISK=Division ofRisk Management
`CD'IIPCross—Discipline Team Leader
`
`Page 1 of 7
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`Reference ID: 3516809
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`

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`Division Deputy Director Review
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`Signatory Authority Review Template
`
`1. Introduction
`
`This is a resubmission in response to the Agency’s original action of May13, 2013 and
`provides for the use of JUBLIA (efinaconazole) topical solution, 10% for the treatment of
`onychomycosis of the toenails due to Trichophyton mentagrophytes or Trichophyton rubrum.
`
`Efinaconazole is a new molecular entity, an azole antifungal agent, for the topical treatment of
`onychomycosis (tinea unguium) of the toenails. It is applied to toenails, the nail folds, nail bed,
`hyponychium, and undersurface of the nail plate once daily for 48 weeks using a flow-through
`brush applicator.
`
`IND for IDP-108 (efinaconazole) was submitted by Dow Pharmaceutical Sciences on June 14,
`2007 and NDA on July 26, 2012. Initially, this application received a Complete Response
`action on May 13, 2013 because of the lack of sufficient chemistry, manufacturing, and
`controls (CMC) information. The CMC deficiencies included, but were not limited to, brush-
`cap assembly, integrity of the container /closure system, inadequate specification for the drug
`product, and inadequate stability data to assure the expiration period.
`
`The applicant has replaced the original container with a similar container closure system that
`does not leak under accelerated or long-term conditions when stored in either horizontal or
`vertical position. The formulation, manufacturing process, specifications and analytical
`methods for the drug substance, excipients, and the final product are the same as described in
`the original NDA. The container closure and the location of the finished product
`manufacturing have been changed. Additionally, a more rigorous in-process control for the
`packaging operation has been added.
`
`JUBLIA has been approved in Canada, however, has not been marketed at the time of
`resubmission of the NDA.
`
`This review will discuss issues under sections 3, 10, 11, 12, and 13 that are related to
`information provided in resubmission of this NDA. For the complete review of other sections
`please refer to the Summary Review for Regulator Action, April 24, 2013.
`
`2. Background
`
`Onychomycosis is a chronic fungal infection of nail plate due to dermatophytes,
`nondermatophytes and yeasts. Common dermatophytes causing onychomycosis (tinea
`unguium) are Trichophyton mentagrophytes, Trichophyton rubrum, and Epidermophyton
`floccosum. The prevalence rate of onychomycosis is 2% to 14%. It is more prevalent in adults
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`Page 2 of 7
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`Reference ID: 3516809
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`Division Deputy Director Review
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`and is less common in children (prevalence rate 0.2% to 2.6%). Often patients with a chronic
`tinea pedis and tinea manuum also have infection of the nails. The infection usually starts at
`the distal edge of the nail, presented as an opaque White, then yellow to brown patch at the side
`and distal tip of the nail. Some of the poor prognostic factors include, but are not limited to,
`area of nail involvement >50%, presence of dermatophytoma, matrix involvement, and
`immunosuppression. The criteria for diagnosis of onychomycosis include clinical evaluation,
`potassium hydroxide (KOH) microscopic evaluation, and flmgal culture.
`
`Efinaconazole is an azole antifimgal agent that inhibits fimgal lanosterol 14-01 demethylase
`involved in ergosterol biosynthesis. Loss of ergosterol in the flmgi cell wall may be
`responsible for the fimgistatic and flmgicidal activity. Efmaconazole has been shown to be
`active against Trichophyton mentagrophvtes and Trichophyton rubrum, both, invitro and in the
`clinical setting.
`
`Regulatory issues regarding the development program for this product were discussed with the
`applicant at the End-of—Phase 2 meeting on August 4, 2009 and Pre-NDA meeting on April 11,
`2012. The Type A meeting was held on July 17, 2013 to discuss the Complete Response
`Letter. In addition, there were a number of interactions with the applicant during the
`development of efmaconazole lmder the IND and during the review process of the submitted
`NDA. These interactions included teleconferences, correspondences, and advice letters.
`
`3. CMCIDevice
`
`Each gram of JUBLIA contains 100 mg of efmaconazole in a clear, colorless to pale yellow
`solution. It is manufactured by
`(”N0
`
`. The drug substance is insoluble in water. The alcohol content is
`approximately (m4) w/w in the product.
`
`In the Complete Response letter, the following product quality issues were identified: a)
`inadequate manufacturing process and control information of the filling/capping;
`M“)
`operation, b) inadequate specification for the drug product, c) inadequate integrity of the
`container closure system, and d) inadequate stability data to assure the expiration dating
`period.
`
`In this submission, the applicant proposed a new container closure system of similar design
`that includes 10 mL HDPE bottle with a flow-through brush applicator. The container closure,
`packaging operations, and the manufacturing facility are new. Manufacturing process
`included all necessary controls to assure drug product quality, 24 months stability data on three
`representative batches in the new container were submitted, and information on Kaken’s
`cGMP manufacturing facility was also included.
`
`Drug product specification and analytical methods for the drug substance, excipients, and the
`formulation were not changed from the original submission.
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`Division Deputy Director Review
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`Based on Chemistry Manufacturing and Controls assessment, 1) the DMF has been reviewed
`and found adequate to support manufacturing process for efinaconazole, 2) the drug product
`specification and analytical methods were found acceptable for assuring the identity, strength,
`purity, and quality of drug product, 3) the new container closure system and control of filling
`operation were adequately addressed previous concerns, 4) results of 24-month stability
`studies supported 36-month expiration period, 5) the cGMP compliance of facilities (including
`the new drug product manufacturer proposed in the resubmission) has been deemed acceptable
`by the Office of Compliance.
`
`The new product packing configuration appears sufficiently similar regarding application
`technique and amount of product delivered to the one used in clinical trials. Therefore, the new
`container closure presentation does not change safety and efficacy conclusion reached in the
`clinical trials where previous packaging was used.
`
`Efinaconazole formulation is flammable due to high alcohol content.
`
`4. Nonclinical Pharmacology/Toxicology
`
`Refer to the previous Summary Review for Regulatory Action of April 24, 2013
`
`5. Clinical Pharmacology/Biopharmaceutics
`
`Refer to the previous Summary Review for Regulatory Action of April 24, 2013
`
`6. Clinical Microbiology
`
`Refer to the previous Summary Review for Regulatory Action of April 24, 2013
`
`7. Clinical/Statistical-Efficacy
`
`No additional clinical trials were conducted since Complete Response Action was issued for
`this application.
`
`Refer to the previous Summary Review for Regulatory Action of April 24, 2013
`
`8. Safety
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`Division Deputy Director Review
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`There is no new safety information submitted in this application. Efinaconazole was approved
`in Canada on October 2, 2013, however, has not been launched there at the time of the NDA
`resubmission.
`
`Refer to the previous Summary Review for Regulatory Action of April 24, 2013
`
`9. Advisory Committee Meeting
`
`Refer to the previous Summary Review for Regulatory Action of April 24, 2013
`
`
`10.
`
`Pediatrics
`
`Safety and efficacy of JUBLIA in pediatric subjects under age 18 have not been studied.
`
`The applicant has requested a partial waiver to study pediatric age group <12 years of age,
`under the Pediatric Research Equity Act, codified in 21 CFR 314.55. This request for partial
`waiver was granted because of low prevalence of onychomycosis in subjects 12 years of age
`and younger based on literature review. Studies in this patient population would be impossible
`or highly impractical because of inability to enroll adequate number of subject in this age
`group within reasonable time period.
`
`The applicant has requested deferral of pediatric studies in pediatric subjects ≥ 12 to 17 years
`of age. The applicant proposed to submit; a) final protocol- September 30, 2014, b) complete
`trial-March 31, 2018, and c) submit the final study report-September 30, 2018. This proposed
`pediatric plan was found to be acceptable and PREA PMR will be issued.
`
`11.
`
`Other Relevant Regulatory Issues
`
`There are no other unresolved relevant regulatory issues.
`
`12.
`
`Labeling
`
`There are no unresolved labeling issues at this time. Labeling discussions were focused on
`indication and the presentation of efficacy results. The primary efficacy endpoint was
`Complete Cure at Week 52, 4 weeks after completion of treatment. Complete Cure was
`defined as 0% clinical involvement of the target toenail (clear toenail) and negative fungal
`culture and negative KOH.
`
`Efficacy results for both pivotal trials are provided in the table below.
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`Division Deputy Director Review
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`Efficacy Results for P3-01 and P3-02 Trials
`Study P3-01
`Efinaconazole
`N=656
`117 (17.8%)
`173 (26.4%)
`
`Vehicle
`N=214
`7 (3.3%)
`15 (7.0%)
`
`Study P3-02
`Efinaconazole
`Vehicle
`N=580
`N=201
`88 (15.2%)
`11 (5.5%0
`136 (23.4%)
`15 (7.5%)
`
`Complete Curea
`Complete or Almost
`complete Cureb
`34 (16.9%)
`310 (53.4%)
`36 (16.8%)
`363 (55.2%)
`Mycologic Curec
`a. Complete Cure defined as 0% clinical involvement of the target toenail (clear nail), negative KOH, and
`negative fungal culture
`b. Complete or Almost complete Cure defined as area ≤5 of involvement of the target toenail negative
`KOH, and negative fungal culture
`c. Mycologic Cure negative KOH, and negative fungal culture
`
`Information that efinaconazole solution is flammable is included in How Supplied/Storage and
`Handling Section of the labeling, Patient Counseling Information, and Patient Information.
`
`Carton and immediate container labels were found to be acceptable.
`
`The proposed proprietary name, JUBLIA was found to be acceptable by OSE/DMEPA
`recommendation.
`
`13.
`
`Decision/Action/Risk Benefit Assessment
`
`NDA 203567 for JUBLIA (efinaconazole) topical solution 10% is recommended to be
`approved for the treatment of onychomycosis of the toenails due to Trichophyton
`mentagrophytes or Trichophyton rubrum. I am in agreement with the recommendation of the
`review team that this application should be approved.
`
`There is sufficient evidence of safety and efficacy based on adequate and well controlled trials
`demonstrating that JUBLIA, efinaconazole, 10% topical solution was superior to vehicle in
`total clearing of fungal infection of the target nail when applied once daily to the toenails for
`48 weeks using a flow-through brush applicator. Assessment of Complete Cure included
`clinical evaluation (0% involvement of the target toenail), negative fungal culture, and
`negative KOH.
`
`The most frequently reported adverse events were application site reaction and ingrown
`toenails.
`
`There are no risk management activities recommended beyond the routine monitoring and
`reporting of adverse events.
`
`Under Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), a multicenter, randomized,
`double-blind study evaluating the safety and pharmacokinetics of JUBLIA topical solution
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`Division Deputy Director Review
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`versus vehicle in pediatric subjects ages 12 to less than 17 years with onychomycosis of the
`toenails will be conducted post-approval because NDA for JUBLIA is ready for approval.
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`Page 7 of 7
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`Reference ID: 3516809
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`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`STANKA KUKICH
`06/02/2014
`
`Reference ID: 3516809
`
`