CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`203567Orig1s000
`
`OTHER ACTION LETTERS
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA 203567
`
`COMPLETE RESPONSE
`
`
`
`Dow Pharmaceutical Sciences
`Attention: Sean Humphrey, MS
`Manager, Regulatory Affairs
`1330 Redwood Way
`Petaluma, CA 94954
`
`
`Dear Mr. Humphrey:
`
`Please refer to your New Drug Application (NDA) dated July 25, 2012, received July 26, 2012,
`submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act for (efinaconazole)
`Topical Solution, 10%.
`
`We acknowledge receipt of your amendments dated August 6, 10, and 20, September 26,
`October 17, and 22, December 6, 7, 14, 19, and 20, 2012; and January 9 and 17, March 18 and
`29, 2013.
`
`We have completed our review of this application, as amended, and have determined that we
`cannot approve this application in its present form. We have described our reasons for this
`action below and, where possible, our recommendations to address these issues.
`
`PRODUCT QUALITY
`
`The quality of the product can not be assured due to:
`
`1. Inadequate manufacturing process and control information of the filling/capping
`operation.
`
`Per 21 CFR 314.50 (d)(1)(ii)(c), the application shall contain the proposed or actual master
`production record, including a description of the equipment, to be used for the manufacture
`of a commercial lot of the drug product or a comparably detailed description of the
`production process for a representative batch of the drug product. The description is expected
`to be included in Section 3.2.P.3 of the application.
`
` process in the Section P.3 as
`The application did not describe the filling/capping
`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.
`
`
`
`
`
`
`Reference ID: 3307534
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 203567
`Page 2
`
`
`2. Inadequate specification for the drug product.
`
` fill stored at 25ºC confirms a significant
`Stability study results on weight loss for the
`loss of formulation ingredient(s) in multiple units (referred to as true leakers in this letter)
`which eventually showed residues on the outside of the bottles. 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. Multiple
`technologies with different leak-detection principles such as pressure or voltage
`differentiation are available for evaluation.
`
`
`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. Additionally, the presence of a significant number
`of true leakers has been confirmed through the weight loss study. These observations
`indicate that the proposed container closure system does not provide adequate protection for
`the drug product.
`
`• True leakers and latent leakers have been detected for multiple batches in the weight loss
`study.
`
`• The greater failure incidence in package integrity test for later time points indicates that
` is not the only cause responsible for the failure.
`
`
`• The non-specific
`method employed for leakage detection can not discern the cause
`of exterior residue (i.e. filling line dripping/vibration or true leakage), and can not detect
`non-residue-producing leaks.
`
`4. Inadequate stability data to assure the expiration dating period.
`
`The stability data presented in Section 3.2.P.8 (stability) of the application were generated
`from batches manufactured using a manufacturing process which is not representative of
`commercial production process.
`
`INFORMATION NEEDED TO RESOLVE DEFICIENCIES
`
`1. Regarding manufacturing process and control 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.
`
` •
`
`
`
`Reference ID: 3307534
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 203567
`Page 3
`
`
`
`• 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.
`
`2. 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.
`
`
`
`
`3. Regarding integrity of the container closure system:
`
`
`• 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.
`
`4. Regarding stability data:
`
`
`•
`
`In addition to the data described in the Item 1 above, provide in-use stability data for the
`drug product packaged in the to-be-marketed container/closure system.
`
`
`ADDITIONAL COMMENTS
`
`The following comments are provided to enhance the Agency’s understanding of the quality of
`clinical batches. They are not approvability issues. However, the requested information should
`be included in your resubmission.
`
`
`• Appendix II of Report 129 states that all bottles from batch DP1444 were weighed, with
`the acceptance criteria to be specified in the batch record. Provide the following
`information:
`o
`the acceptance criteria;
`o weight results (summarized in table format); and
`o full accountability of all bottles; and the fate of bottles that failed the check.
`
`• Report 129 states that leaking bottles from batch DP1453 were stored for further
`evaluation. Provide the following information:
`o results of
` evaluation (e.g., assay, weigh loss, etc.);
`
`
`
`
`
`Reference ID: 3307534
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 203567
`
`Page 4
`
`0 full accountability of all bottles sent to
`studies; and
`0 experimental details.
`
`PREA RE UIREMENTS
`
`cum»
`
`, including those bottles sent to clinical
`
`The Agency does not concur with your proposal
`
`(hm)
`
`You will need to update your Pediatric Study Plan (PSP) which describes your study proposals,
`or your PSP can provide additional information regarding the incidence and prevalence of
`onychomycosis in pediatric populations and comment on the feasibility of conducting adequate
`clinical trials in such populations
`mar
`
`The PSP must contain an outline of the pediatric study or studies that you plan to conduct
`(including, to the extent practicable study objectives and design, age groups, relevant endpoints,
`and statistical approach). For additional guidance on submission of the PSP, including a PSP
`Template, please refer to:
`hflpJ/wwwfda.gov/D111gs/DevelopmentApprovalProcess/DevelopmentResources/ucm049867.ht
`m . In addition, you may contact the Pediatric and Maternal Health Staff at 301-796-2200 or
`email pdit@fda.hhs.gov.
`
`LABELING
`
`We reserve comment on the proposed labeling until the application is otherwise adequate. If you
`revise labeling, your response must include updated content of labeling [21 CFR 314.50(l)(1)(i)]
`in structured product labeling (SPL) format as described at
`hm; ://www.fda . gov/ForIndusfl/DataStandards/StructuredProductLabelingzdefault.htm.
`
`SAFETY UPDATE
`
`When you respond to the above deficiencies, include a safety update as described at
`21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and
`clinical studies/trials of the drug under consideration regardless of indication, dosage form, or
`dose level.
`
`1. Describe in detail any significant changes or findings in the safety profile.
`
`2. When assembling the sections describing discontinuations due to adverse events, serious
`adverse events, and common adverse events, incorporate new safety data as follows:
`
`0 Present new safety data from the studies/clinical trials for the proposed indication
`using the same format as the original NDA submission.
`0 Present tabulations of the new safety data combined with the original NDA data.
`
`Reference ID: 3307534
`
`

`

`NDA 203567
`Page 5
`
`
`
`•
`
`Include tables that compare frequencies of adverse events in the original NDA with
`the retabulated frequencies described in the bullet above.
`• For indications other than the proposed indication, provide separate tables for the
`frequencies of adverse events occurring in clinical trials.
`
`
`3. Present a retabulation of the reasons for premature trial discontinuation by incorporating
`the drop-outs from the newly completed trials. Describe any new trends or patterns
`identified.
`
`4. Provide case report forms and narrative summaries for each patient who died during a
`clinical trial or who did not complete a trial because of an adverse event. In addition,
`provide narrative summaries for serious adverse events.
`
`5. Describe any information that suggests a substantial change in the incidence of common,
`but less serious, adverse events between the new data and the original NDA data.
`
`6. Provide updated exposure information for the clinical studies/trials (e.g., number of
`subjects, person time).
`
`7. Provide a summary of worldwide experience on the safety of this drug. Include an
`updated estimate of use for drug marketed in other countries.
`
`
`
`
`
`
`
`
`
`
`
`8. Provide English translations of current approved foreign labeling not previously
`submitted.
`
`
`OTHER
`
`Within one year after the date of this letter, you are required to resubmit or take other actions
`available under 21 CFR 314.110. If you do not take one of these actions, we may consider your
`lack of response a request to withdraw the application under 21 CFR 314.65. You may also
`request an extension of time in which to resubmit the application. A resubmission must fully
`address all the deficiencies listed. A partial response to this letter will not be processed as a
`resubmission and will not start a new review cycle.
`
`Under 21 CFR 314.102(d), you may request a meeting or telephone conference with us to
`discuss what steps you need to take before the application may be approved. If you wish to have
`such a meeting, submit your meeting request as described in the FDA’s “Guidance for Industry -
`Formal Meetings Between the FDA and Sponsors or Applicants,” May 2009 at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM153222.pdf.
`
`The drug product may not be legally marketed until you have been notified in writing that this
`application is approved.
`
`
`
`
`Reference ID: 3307534
`
`

`

`NDA 203567
`Page 6
`
`
`If you have any questions, call Strother D. Dixon, Regulatory Project Manager, at (301) 796-
`1015.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Victoria Kusiak, M.D.
`Deputy Director
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`
`
`
`
`
`Reference ID: 3307534
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`VICTORIA KUSIAK
`05/13/2013
`
`Reference ID: 3307534
`
`