CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203567Orig1s000
`
`MEDICAL REVIEW(S)
`
`
`
`
`
`
`
`
`
`

`

`CLINICAL REVIEW RESUBMISSION
`
`505(b)(1)
`Application Type
`203-567
`Application Number(s)
`Priority or Standard Standard
`
`Submit Date(s) 20-DEC-2013
`Received Date(s)
`20-DEC-2013
`PDUFA Goal Date 20-JUN-2014
`Division / Office DDDP/ODE III
`
`Reviewer Name(s) Gary Chiang MD, MPH
`Review Completion Date 8-MAY-2014
`
`efinaconazole
`Established Name
`Jublia™
`(Proposed) Trade Name
`antifungal
`Therapeutic Class
`Applicant Dow Pharmaceutical Sciences
`
`Formulation(s) Topical solution 10%
`Dosing Regimen Once daily
`Indication(s) Onychomycosis
`Intended Population(s) Adults 18 years and older
`
`Template Version: March 6, 2009
`
`Reference ID: 3503721
`
`

`

`Clinical Review
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`Table of Contents
`
`1 RECOMMENDATIONS/RISK BENEFIT ASSESSMENT......................................... 4
`1.1 Recommendation on Regulatory Action .................................................................. 4
`1.2 Risk Benefit Assessment........................................................................................ 4
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies.............. 5
`1.4 Recommendations for Postmarket Requirements and Commitments........................... 5
`SIGNIFICANT EFFICACY/SAFETY ISSUES RELATED TO OTHER REVIEW
`DISCIPLINES........................................................................................................... 5
`4.1 Chemistry Manufacturing and Controls ................................................................... 5
`SOURCES OF CLINICAL DATA ............................................................................. 8
`
`5
`
`4
`
`6 REVIEW OF EFFICACY.......................................................................................... 8
`Efficacy Summary.......................................................................................................... 8
`Proposed Indication............................................................................................... 8
`6.1
`7 REVIEW OF SAFETY.............................................................................................. 9
`Safety Summary............................................................................................................. 9
`Pediatrics and Assessment of Effects on Growth................................................ 9
`7.6.3
`9 APPENDICES......................................................................................................... 10
`Labeling Recommendations ................................................................................. 11
`9.2
`9.3 Advisory Committee Meeting .............................................................................. 25
`
`Reference ID: 3503721
`
`2
`
`

`

`Clinical Review
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`Table of Tables
`
`Table 1: Summary of Primary and Secondary Efficacy Endpoints at Week 52 ............... 8
`Table 2: Adverse Reactions Reported by at Least 1% of Subjects Treated for up to 48
`Weeks............................................................................................................. 14
`Table 3: Efficacy Endpoints.......................................................................................... 19
`
`Reference ID: 3503721
`
`3
`
`

`

`Clinical Review
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`1 Recommendations/Risk Benefit Assessment
`
`1.1 Recommendation on Regulatory Action
`
`Dow Pharmaceutical Sciences has re-submitted a New Drug Application for JUBLIA™ (efinaconazole
`solution, 10%) with a proposed indication of once daily topical treatment of onychomycosis of the toenail (tinea
`unguium) in patients 18 years and older. The applicant successfully demonstrated safety and efficacy in two
`adequate and well controlled clinical trials for the treatment of onychomycosis in patients 18 years and older,
`when used once daily for 48 weeks.
`
`The original NDA was submitted on July 26, 2012 and this submission received a complete response due to
`Chemistry Manufacturing and Control (CMC) deficiencies on May 13, 2013, principally related to leakage of
`the container closure system
` The nonclinical, clinical pharmacology and clinical programs
`submitted with the original application were found generally acceptable though labeling negotiations were not
`initiated once it became clear that the bottle leakage would preclude approval of the application.
`
`On December 20, 2013 the applicant re-submitted their NDA to with a new container closure system to address
`the CMC deficiencies. The applicant has redesigned the container closure system and provided data that no
`leakage has occurred. No new nonclinical information was provided, and no new clinical pharmacology or
`clinical trials were conducted for this resubmission.
`
`The critical CMC review issues that concluded with a Complete Response from the first review cycle have been
`resolved. The new container closure system has been found to be acceptable for marketing and the applicant
`has provided appropriate information to provide sufficient data to assure the identity, strength, purity, and
`quality of the drug product. The new bottle with a brush applicator dispenses drug product with similar quantity
`and distribution as the container/closure system used in the Phase 3 clinical trials so that additional clinical
`trials are not required.
`
`This reviewer is in agreement with the CMC recommendation for approval, and the clinical recommendation is
`for approval of this application.
`
`1.2 Risk Benefit Assessment
`
`The risk to benefit assessment for this application is primarily based on the clinical trial results, which were
`extensively reviewed in the initial cycle and documented in the clinical review dated April 13, 2013. In the two
`pivotal Phase 3 clinical trials, the most common adverse events associated with the drug product were
`application site reactions (application site dermatitis and application site vesicles). There were no deaths or
`serious adverse events attributed to the drug product. In the two combined pivotal Phase 3 clinical trials, a
`greater percentage of subjects in the JUBLIA™ group relative to the Vehicle group achieved “Complete Cure”
`(clinical cure as well as mycological cure) at Week 52 (16.6% versus 4.3%, respectively), demonstrating that
`the drug product was effective in treating toenail onychomycosis.
`
`Reference ID: 3503721
`
`4
`
`(b) (4)
`
`

`

`Clinical Review
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`The proposed product labeling includes warnings and precautions regarding local sensitivity and irritation
`reactions. This drug product has minor local side effects and insignificant systemic effects. The adverse events
`associated with the drug product can be adequately informed by labeling. The label also provides adequate
`information for instructions for use.
`
`In conclusion, there are few risks associated with the use of this topical product for the treatment of toenail
`onychomycosis. The effectiveness of this topical onychomycosis product ranges from 9.7% to 14.5%
`(“Complete Cure”). The benefits include relatively low systemic effects making this topical treatment ideal for
`patients that cannot take oral antifungals for the treatment of toenail onychomycosis.
`
`1.3 Recommendations for Postmarket Risk Evaluation and Mitigation Strategies
`
`No post-market risk evaluation or mitigation strategies are recommended. Labeling is adequate to convey
`benefits and risks to patients and prescribers.
`
`1.4 Recommendations for Postmarket Requirements and Commitments
`
`The initial review by the Pediatric Review Committee (PeRC) has recommended that the prevalence of
`onychomycosis in children is sufficient to warrant studies in ages 6 years and above. On the re-submission of
`this application, a Pediatric Plan was submitted with a request for a full waiver for subjects under the age of 12
`years old. The Pediatric Plan submitted by the applicant did not include a pharmacokinetic evaluation. The
`review of this proposed study is in Section 7.6.3.
`
`Reviewer’s comment: The Division has reviewed a wide range of literature and concluded that studying
`onychomycosis in subjects 12 years and above is appropriate for onychomycosis as adequate numbers of
`culture positive subjects under age 12 are few in number and studies would be impractical. The review team
`discussed this issue with the PeRC and recommends a PMR with at least 40 pediatric subjects 12 years and
`older with a pharmacokinetic population of 16 subjects. . Efficacy can be extrapolated from the adult data.
`
`4 Significant Efficacy/Safety Issues Related to Other Review Disciplines
`
`The action recommended by the CMC reviewer is for approval. The applicant has demonstrated sufficient data
`to assure the identity, strength, purity, and quality of the drug product. The previous container closure issues
`related to leakage of the bottle have been resolved with a new bottle/brush assembly
`
`. There is no other safety or efficacy issue from other disciplines.
`
`4.1 Chemistry Manufacturing and Controls
`
`The original NDA 203567 was not approved during the first review cycle. The CMC deficiencies identified
`during the first review cycle were communicated to the sponsor in the CR action letter.
`
`The deficiencies and remedies are captured in the CMC review.
`
`Reference ID: 3503721
`
`5Error! No document variable supplied.
`
`(b) (4)
`
`

`

`Clinical Review
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`A. Deficiency 1.
`operation. The
`Inadequate manufacturing process and control information of the filling/capping
`application did not describe the filling/capping
` process in the Section P.3 as well as in the Master
`Batch Record with sufficient details and specifics to ensure the process is robust and can produce batches with
`acceptable leakage rate.
`
`
`
`In order to address deficiency 1, the sponsor was asked to provide the following information:
` Update Section P.3 and Master Batch Record with a description for the optimized commercial process,
`including details of the filling/capping
` operation with all in-process controls and operation
`ranges of process parameters.
`Produce three production batches using the optimized processes, and submit a minimum of 12 months
`of long-term and 6 months of accelerated stability data, including failure rate due to leakage, for both
`upright as well as horizontal orientations.
`Two of the batches should be at least pilot scale batches. The process must be the one to be validated
`for routine production, and the batches must be manufactured using the to be-marketed
`container/closure system.
` Assay results should be generated for leaking units whenever feasible.
`
`
`
`B. Deficiency 2.
`Inadequate specification for the drug product. For a product with a volatile organic formulation and a known
`history of leakage, the use of a sensitive and specific method for leak detection is critical to ensure the quality of
`the product.
`
`In order to address deficiency 2, the sponsor was asked to provide the following information:
` Update the specification for the drug product to include a specific and sensitive leakage test method
`and its acceptance criterion.
` The leakage test method must be validated and should not rely on
`detect leaks. Validation data for the method must be provided.
`
` to
`
`C. Deficiency 3.
`Inadequate integrity of the container closure system. Batch release and stability data submitted in the
`application show unacceptable number of failure incidences for package integrity. These observations indicate
`that the proposed container closure system does not provide adequate protection for the drug product.
`
`In order to address deficiency 3, the sponsor was asked to provide the following information:
` Establish a control strategy to ensure the integrity of container closure system without leakage.
` Provide complete description of the to-be-marketed container/closure system and any modifications to
`the system since the initial submission of the NDA.
` Provide representative samples (three units) of the to-be-marketed product.
`
`The container closure system is fitted with a
`container/closure system:
`
` cap. The figure below shows components of the
`
`Reference ID: 3503721
`
`6Error! No document variable supplied.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`Clinical Review
`
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`Blush
`
`Inside plug with a Blush assembly
`
` Cap
`
`i
`
`Insideplug
`
`Bottle
`
`The inside plug/brush
`
`brush from
`
`MW, and inside plug 311d cap 0f
`
`(m4)
`. The bottle is made of HDPE,
`“m". All materials are manufactured by
`mm
`
`D. Deficiency 4.
`Inadequate stability data to assure the expiration datingperiod. The stability data presented in the application
`were generatedfrom batches manufactured using a manufacturing process which is not representative of
`commercialproduction process.
`
`In order to address deficiency 4, the sponsor was asked to provide the following information:
`o
`In addition to the data described in the deficiency 1 above, provide in-use stability data for the drug
`product packaged in the to-be-marketed container/closure system.
`
`The CMC review concludes that the information provided in this resubmission to address the deficiencies is
`acceptable.
`
`Reviewer ’s comments:
`
`Ihe applicant has provided suflicient data to assure the identity, purity, and quality ofthe drugproduct. The
`previous issue ofcontainer closure system has been resolved with the new assembly. The applicant has
`provided suflicient stability data, and the leaking bottle issues appear to have been successfully resolved with
`the container closure redesign.
`
`Reference ID: 3503721
`
`7Error! No document variable supplied.
`
`

`

`Clinical Review
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`The only outstanding issue as of the date of this review is the final report from the Office of Compliance
`regarding the recommendation for the manufacturing establishments and final, agreed upon labeling.
`
`5 Sources of Clinical Data
`
`No new clinical trial results or other information are presented in this resubmission. Only CMC information is
`presented in this submission.
`
`6 Review of Efficacy
`
`Efficacy Summary
`The efficacy summary provided here is derived from the original review. No new clinical trial data was
`submitted in this review cycle.
`
`The efficacy evaluation included one Phase 2 study and two Phase 3 clinical trials. A summary of the protocols
`are described in Section 5. The formulation of the Phase 2 study (DPSI-IDP-108-P2-01) is not the to-be-
`marketed formulation; whereas, the Phase 3 clinical trials used the final to-be-marketed formulation of the drug
`product.
`
`Reviewer’s Comment: The summary of the primary efficacy endpoint provided in Table 1 will be used in the
`labeling of the product. Note that “Complete or almost complete cure” was specified in the second version of
`the SAP as defined by ≤5% affected toenail and mycological cure (negative KOH and culture).
`
`Table 1: Summary of Primary and Secondary Efficacy Endpoints at Week 52
`Study P3-01
`Study P3-02
`Vehicle
`Vehicle
`N=214
`N=201
`7 (3.3%)
`11 (5.5%)
`
`p-value
`
`<0.001
`
`IDP-108
`N=580
`88 (15.2%)
`
`p-value
`
`<0.001
`
`<0.001
`<0.001
`<0.001
`
`IDP-108
`N=656
`117 (17.8%)
`
`Complete Cure
`Complete or almost
`17 (7%)
`173 (26%)
`complete cure *
`Mycologic Cure
`36 (17%)
`362 (55%)
`1.6 (0.4)
`5.0 (0.2)
`Unaffected new growth (mm)
`Source: Agency Biostatistical Review (Dr. Kathy Fritsch)
`* Endpoint specified in SAP version 2
`
`<0.001
`<0.001
`<0.001
`
`136 (23%)
`310 (53%)
`3.8 (0.2)
`
`15 (7%)
`34 (17%)
`0.9 (0.4)
`
`6.1 Proposed Indication
`
`JUBLIA™ (efinaconazole cream, 10%) is indicated for the topical treatment of onychomycosis in the toenails
`(tinea unguium) of adults 18 years and older.
`
`Reference ID: 3503721
`
`8Error! No document variable supplied.
`
`

`

`Clinical Review
`
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`7 Review of Safety
`
`Satem Summagg
`
`The complete safety evaluation of the clinical program for JUBLIATM (efmaconazole) Topical Solution, 10%
`was reviewed in the first cycle. No new data is presented in this re-submission.
`
`7.6.3
`
`Pediatrics and Assessment of Effects on Growth
`
`This application triggers PREA as directed to a new active ingredient.
`
`The initial PeRC meeting was held on January 23, 2012 to discuss efinaconazole solution, 10%. The
`applicant’s request
`(him was recommended to be denied on the evaluation
`that
`M“)
`
`In the re-submission, the applicant requests a full waiver for pediatrics age 0 to 11 years old. The applicant
`referenced published literature which shows that there is low prevalence of onychomycosis in patients 12 years
`and younger that would make a study in these subjects impractical due to an inability to enroll adequate number
`of subjects in a reasonable period of time. The applicant also requested a partial waiver for pediatric subjects 12
`to 18 years of age, with reasoning that adult data is ready for approval and that a pediatric study will be
`completed with the proposed time line.
`
`The proposed timeline:
`
`Final Protocol Submission: September 2014 (based on 3 months afier approval)
`
`Final Subject Completion: March 2018
`
`Final Study Report: September 2018
`
`On 30-APR—2014, a second PeRC meeting was held to discuss efinaconazole topical solution for the treatment
`of onychomycosis. The PeRC again disagreed with the Division’s recommendation
`m“)
`The PeRC agreed that the incidence of onychomycosis in pediatric
`subjects is low relative to the incidence in adults; however, the sponsor’s data suggest that there are a small but
`consistent number of Visits each year for this diagnosis in children less than 12 years of age. The Division
`provided data that onychomycosis in North America for children lmder the age of 12 is significantly less than
`that of Greenland or Japan, where some of these studies showing higher incidences are done. The Division also
`pointed out that identifying culture positive onychomycosis subjects under age 12 would be impractical, despite
`literature date for “visits” for onychomycosis. Recommended endpoints for this indication require culture and
`KOH positive subjects. PeRC also recommended that studies be done in pediatrics down to 2 years of age and
`would ask the sponsor to attempt to enroll to that age, but if the sponsor is unable to enroll patients, despite
`good faith attempts, a waiver could be issue later.
`
`The PeRC agreed with the Division that a deferral for pediatric subjects aged 2 to less than 17 years is
`appropriate as adult data is ready for the products approval.
`
`9Error! No document variable supplied.
`
`Reference ID: 3503721
`
`

`

`Clinical Review
`
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`Reviewer ’s comments: The Division has reviewed the literature submitted by the applicant, as well as,
`researched literature independently, and it is our conclusion that the lack ofprevalence with culture positive
`onychomycosis in children under the age of 12 will limit any successfill clinical study to inform safety ofthis
`product. The Division concludes that such trials are impractical. The applicant has submitted a Pediatric Plan
`down to the age of 12 years old.
`
`Pro osed Pediatric Plan:
`
`
`
`Reviewer ’s comment: The safety ofthis trial in pediatric subjects is acceptable. At this time, the Division will
`accept the pediatric trial as proposed in subjects 12 years and older. The Division appreciates PeRC ’s input
`into the matter; however, in order to be consistent with other applications with the same indications, the
`Division will not require pediatric studies down to 2 years ofage.
`
`The Agency will require a
`pharmacokinetic sub study within this pediatric trial based on recommendations ofthe clinicalpharmacology
`review team.
`
`9 Appendices
`
`Reference ID: 3503721
`
`10Error! No document variable supplied.
`
`

`

`Clinical Review
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`9.2 Labeling Recommendations
`
`The trade name, JUBLIA™, has been found acceptable by the Office of Prescription Drug Promotion (OPDP).
`
`Labeling negotiations are ongoing. The finalized label will be attached to the approval letter.
`
`Currently Proposed Label:
`
`4
`
`Reference ID: 3503721
`
`13 Page(s) of Draft Labeling have been Withheld in Full as b4 (CCI/TS) immeidately following this page
`
`

`

`Clinical Review
`Gary Chiang MD, MPH
`505 (b)(1) NDA 203567
`efinaconazole solution, 10%
`
`9.3 Advisory Committee Meeting
`
`An Advisory Committee Meeting was not conducted because this drug product has clinically
`insignificant systemic absorption and causes few adverse events. The Agency’s experience with
`topical azole antifungals is ample that advice from an Advisory Committee is not required with
`this drug product.
`
`Reference ID: 3503721
`
`25Error! No document variable supplied.
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`GARY T CHIANG
`05/08/2014
`
`DAVID L KETTL
`05/16/2014
`
`Reference ID: 3503721
`
`

`

`MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN
` SERVICES
` FOOD AND DRUG ADMINISTRATION
` OFFICE OF DRUG EVALUATION III
`
`DATE: May 13, 2013
`
`FROM: Victoria Kusiak, M.D.
`
`SUBJECT: Office Deputy Director Memo
`
`TO: NDA 203567, efinaconazole Topical Solution, 10%
` Dow Pharmaceutical Sciences
`
`Summary
`
`Efinaconazole is a new molecular entity that belongs to the triazole antifungal drug class.
`The proposed indication for this product is once daily topical treatment of onychomycosis
`of the toenail. This daily treatment should continue for 48 weeks. Efinaconazole is
`packaged in a 10 mL bottle with a brush applicator. It is not currently marketed in any
`country.
`
`Onychomycosis is the condition of fungal infection of the nail and can be caused by
`yeasts and non-dermatophyte molds. It is characterized by hyperkeratosis of the nail bed,
`yellow to brownish discoloration of the nail plate, onycholysis and paronychial
`inflammation. The mechanism of action of efinaconazole is similar to that of other azole
`antifungal compounds and is secondary to lanosterol 14α-demethylase inhibition
`resulting in blockage of ergosterol depletion and accumulation of 14-α methyl sterols,
`leading to mycosal cell death.
`
`The clinical program for efinaconazole consists of four Phase 1 trials which include a
`maximal use pharmacokinetic (PK) trial in subjects with severe onychomycosis and a PK
`trial in healthy subjects, one Phase 2 safety and efficacy trial and two Phase 3 safety and
`efficacy trials in subjects with mild to moderate onychomycosis. While clinical review
`identified no significant safety or efficacy issues that would have precluded approval,
`significant packaging integrity issues were identified early in the review cycle such that
`the product quality cannot be assured with the chemistry manufacturing and controls
`(CMC) procedures described within the application.
`
`These CMC issues include (but are not limited to) problems with the brush-cap assembly,
`potential leachables from the container/closure system, incomplete details of the
`process/control information provided in the NDA, inadequate proposed product package
`integrity test(s), inadequate stability data, and produced batches with a leakage rate of
` These issues were communicated to the applicant in the 74 day letter, in a Discipline
`Review Letter (DRL) issued on March 8, 2013, and during a teleconference with the
`applicant for the purposes of clarification on March 20, 2013.
`
`
`
`Reference ID: 3307650
`
`1
`
`(b)
`(4)
`
`

`

`
`In summary, the Office of New Drug Quality Assessment (ONDQA) has determined that
`the information as provided in the NDA is not adequate to assure the identity, strength,
`purity and quality of the drug product, and as such the application cannot be approved.
`
`This memo documents my concurrence with the recommendation of the Division of
`Dermatology and Dental Products (DDDP) for a complete response (CR) action for
`efinaconazole, 10% solution for the treatment of onychomycosis of the toenail in adults.
`Before this application may be approved, the following must be satisfactorily completed:
`
`Regarding manufacturing process and control information:
`• Update Section P.3 and the Master Batch Record with a description for the
`optimized commercial process, including details of the
`filling/capping
` operation with all in-process controls and operation
`ranges of process parameters.
`• Produce three production batches using the optimized processes and submit a
`minimum of 12 months of long term and 6 months of accelerated stability data,
`including failure rate due to leakage, for both upright and horizontal positions.
`• Two of the batches should be at least pilot scale batches. The process used must
`be the one to be validated for routine production, and the batches must be
`manufactured using the to-be-marketed container/closure system.
`• Assay results should be generated for leaking units whenever feasible.
`Regarding the specification for the drug product:
`• Update the specification for the drug product to include a specific and sensitive
`leakage test method and its acceptance criterion.
`• The leakage test method must be validated and should not rely on
` to detect leaks. Validation data for the method must be
`
`
`
`provided.
`Regarding the integrity of the container closure system:
`• Establish a control strategy to ensure the integrity of a container/closure
`system without leakage.
`• Provide a complete description of the to-be-marketed container/closure system
`and any modifications to the system since the initial submission of the NDA.
`• Provide representative samples (three units) of the to-be-marketed product.
`Regarding stability data:
`•
`In addition to the data described in the section headed manufacturing and
`control information, provide in-use stability data for the drug product packaged
`in the to-be-marketed container/closure system.
`
`
`Regulatory History
`
` A
`
` pre-IND meeting was held with the applicant on December 18, 2006. IND 077732 was
`opened on May 8, 2007 with a proposed 21 day cumulative irritation study to evaluate
`efinaconazole in healthy subjects. An end of phase 2 meeting was held August 4, 2009.
`No SPA review was requested.
`
`
`
`
`Reference ID: 3307650
`
`2
`
`(b) (4)
`
`(b) (4)
`
`

`

`The NDA was filed July 26, 2012. Packaging integrity issues were identified by the
`ONDQA team prior to the filing meeting, which was held on September 11, 2012.
`
`The 74 Day Letter identified the following potential review issues:
`0
`Inadequate information in the application to assure the strength, purity and
`quality of the drug product due to inadequate information to qualify the
`proposed brush/cap assembly.
`
`0
`
`Inadequate information provided to demonstrate absence of significant
`contaminants in the formulation due to leachables from the proposed
`container/closure system.
`
`Information requests were sent to the applicant during the review cycle requesting
`additional information referable to drug process controls. A DRL was sent to the
`applicant on March 8, 2013 detailing the deficiencies found by ONDQA in the
`application. A teleconference was held with the applicant on March 20, 2013 to provide
`further clarification concerning the above noted deficiencies.
`
`The conclusion of the ONDQA review, as noted above and as documented in an
`addendum to the initial review dated April 11, 2013, affirms that the CMC information
`submitted in the initial application as well as in subsequent submissions to the NDA is
`not adequate for approval.
`
`ChemisflI Manufacturing and Controls {CMC}
`
`The specifics of the CMC issues are detailed in the ONDQA Division Director’s review
`and are summarized here.
`
`The proposed container/closure system for efinaconazole includes a white lOmL HDPE
`bottle (for a mu) fill) with a directly attached brush applicator and a
`m“) cap.
`The brush extends directly from the top of the bottle tip and is used without detaching.
`The user turns the bottle over and brushes the product onto the nail and surrounding skin.
`
`The container closure system is a novel package intended to minimize the exposure of the
`packaged product to any potential external contamination from the infected nail, as the
`brush is not pushed back into the topical solution after wiping on the infected nail.
`
`ONDQA reviewers noted that a high percentage of drug product bottles (greater than
`50%) from the first large scale clinical batches (Batches 1444 and 1453F1) had evidence
`of leakage. The applicant investigated various factors that might be contributing to this
`leakage,
`(um)
`and made modifications
`"'""' for subsequent batches. However, the
`application itself does not describe the adjusted filling/capping
`(m4) process with
`sufficient detail and specifies to ensure that the process is robust and can produce batches
`with acceptable leakage rates. The Pharmaceutical Development section of the
`application includes discussion of the applicant’s proposed enhancements; however, none
`of the recommendations on the process improvements are officially implemented in the
`
`Reference ID: 3307650
`
`

`

`manufacturing process and in the Master Batch Record. The ONDQA recommendation
`regarding the manufacturing process and control information is as follows:
`
`
`• The application should be updated with the optimized process
`• Three production batches should be produced using the optimized
`processes with 12 months of long-term and 6 month of accelerated
`stability data, including failure rates due to leakage (upright and
`horizontal).
`• Two of the batches should be at least pilot scale batches. The process must
`be the one validated for routine production, and use the to-be-marketed
`container/closure system.
` Assay results should be generated for leaking units whenever feasible.
`
`•
`
`
`With regard to drug product specifications, these should include a specific and sensitive
`leakage test method and its acceptance criteria, and the leakage test method must be
`validated and not rely on
` alone to detect leaks.
`
`According to ONDQA reviewers, a significant percentage of stability samples showed
`non-conforming package integrity. Leakage was evident
` for stability
`testing and is believed to have occurred in bottles subsequent to filling. Leakage was
`more likely for samples stored for ≥ one month. ONDQA has concluded that the residues
`found on the exterior surfaces were not exclusively due to
` dripping and
`vibrations of the manufacturing line belt, and that true leakage occurred subsequent to
`release. The following points are notable:
`• True leakers and latent leakers have been detected for multiple batches in a
`weight loss study consisting of 10 units for each orientation (horizontal and
`vertical) per batch, totaling 60 units (3 batches, 2 orientations per batch).
`• Each bottle was visually inspected prior to release and bottles with external
`residue were rejected. Therefore all bottles in the weight study were initially
`considered “non-leaking”.
`• There was greater failure incidence in the package integrity test for later time
`points, as opposed to earlier time points, indicating that the
` is not the
`only cause responsible for the container/closure failure.
`• The non-specific
`method employed for leakage detection cannot discern the
`cause of exterior residue (i.e. filling line dripping/vibration or true leakage) and
`cannot detect non-residue producing leaks.
`
`
`Additionally, the stability data provided are not considered to be representative of the
`stability characteristics of commercial batches which will be produced using an improved
`process, as additional improvements will need to be made in the filling/capping
`
`process as described above. The application should provide in-use stability data for the
`drug product packaged in the to-be-marketed container/closure system.
`
`As currently documented in the application, this