r ... ""'·~
`( ~ DEPARTMENT OF HEALTH AND HUMAN SERVICES
`,~}~
`
`IND 77732
`
`Dow Pharmaceutical Sciences (DPS)
`Attention: Charity Abelardo, RAC
`Acting Senior Director, Regulatory Affairs
`1330 Redwood Way
`Petaluma, CA 94954-7121
`
`Dear Ms. Abelardo:
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`MEETING MINUTES
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for IDP-108 (efinaconazole) Solution, 10%.
`
`We also refer to the meeting scheduled on April 17, 2012 between representatives of your firm
`and the FDA. The purpose of the meeting was to gain agreement that the information contained
`in the technical data sections are adequate for a 505(b)(l) NDA filing and to gain feedback for
`questions related to content/format of the NDA. Yourpremeeting briefing package (submitted
`February 22, 2012) provides background and questions for discussion.
`
`We acknowledge email with Barbara Gould on April 15, 2012, notifying us that after receipt and
`review of the premeeting communication consisting of Agency responses to your questions, you
`have determined that the responses to your questions are sufficient and additional discussion is
`not necessary.
`
`This letter and the enclosed final responses represent the official record.
`
`If you have any questions, call Barbara Gould, Chief, Project Staff Management, at (301) 796-
`4224.
`
`Sincerely,
`
`{See appended electronic signature page)
`
`Susan J. Walker, M.D., F.A.A.D.
`Director
`Division of Dermatology and Dental Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
`
`Enclosure - Final Responses
`
`Reference ID: 3130189
`
`ACRUX DDS PTY LTD. et al.
`
`EXHIBIT 1504
`
`IPR Petition for
`
`U.S. Patent No. 7,214,506
`
`Page 1 of 25
`
`

`

`FINAL RESPONSES
`
`IND 077732
`
`Product: (efinaconazole) Solution, 10%
`
`Regulatory Path: 505(b)(l)
`
`Sponsor: Dow Pharmaceutical Sciences
`
`Proposed Indication: Topical treatment of
`18 years or older
`
`-~-- !bl<
`
`41onychomycosis in patients
`
`Type of Meeting: Type B
`
`Meeting Date: April 18, 2012
`
`Introductory Comment:
`
`This material includes the Agency's final responses to the questions submitted for your
`meeting scheduled for April 18, 2012, at 10:00 am in White Oak Building 22 between
`Dow Pharmaceutical Sciences and the Division of Dermatology and Dental Products.
`This material was shared to promote a collaborative and successful discussion at the
`meeting. After receipt of the preliminary responses, you had two options:
`
`• If these answers and comments were clear to you and you determined that further
`discussions were not required, you had the option of canceling the meeting.
`
`• If you determined that discussion was needed for only some of the original
`questions, you had the option of reducing the agenda and/or changing the format
`of the meeting (e.g., from face-to-face to telecon).
`
`You conveyed to Barbara Gould via email on April 15, 2012 that the responses to your
`questions were sufficient and additional discussion was not necessary. However, you
`requested clarification with regard to the responses provided under Question 2 and the
`additional information requested by FDA for inclusion in the NDA submission. As such,
`the below responses represent our final responses to your questions.
`
`Purpose of the Meeting:
`To gain agreement that the information contained in the technical data sections are
`adequate for a 505(b)(l) NDA filing and to gain feedback for questions related to
`content/format of the NDA.
`·
`
`Regulatory Correspondence.History
`
`We have had the following meetings with you:
`
`CDER/OC/DSI Pre-NOA Request
`
`Page 3 of25
`
`Reference ID: 3130189
`
`Page 2 of 25
`
`

`

`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`lND077732
`Meeting Minutes
`TypeB
`
`• 8/17/2009 - End of Phase 2 Meeting
`
`We have sent the following correspondences:
`11/24/2009 -Advice
`•
`• 4/14/2010 - Advice/Information Request
`• 4/ 14/2010 - Advice/Information Request
`• 4/ 14/20 IO - Advice/Information Request
`• 8/30/2010 - Advice
`• 2/ 14/2011 - Advice/Information Request
`• 2/25/2011 - Advice
`• 3/ 16/2011 - Advice
`• 4/ 18/2011 - Advice
`
`Regulatory
`Question (1):
`Does the Agency agree that efinaconazole solution meets the regulatory standards for
`priority review?
`
`Response:
`No, the Agency does not agree that efinaconazole solution for the treatment of
`onychomycosis qualifies for priority review. You have not provided an adequate
`rationale that your proposed product provides for a significant improvement over existing
`therapies for a non-life threatening disease.
`
`In order to qualify for priority review, you will need to provide an adequate rationale that
`your proposed product has the potential to provide significant advances in the treatment
`of onychomycosis. There are several currently approved therapies for onychomycosis.
`The preliminary efficacy analysis for your proposed product claims to show a primary
`efficacy response rate of about 16%, which is similar to at least one currently approved
`therapy. Approximately 84% of subjects would fail to respond to your proposed
`treatment.
`Chemistry, Manyfacturing and ~ontrols <CMC}
`
`No CMC questions were submitted in the briefing package for this meeting. After
`reviewing the limited CMC information provided in the briefing package, we have the
`following comments:
`
`1. The proposed drug substance specification should include tests on chiral purity
`and residual solvents with appropriate acceptance criteria.
`
`2. Address the issues of
`(bJ<' lcarried over
`----------------'="'==-,------
`from excipients for drug product in the proposed NOA.
`
`Reference ID: 3130189
`
`4
`
`Page 3 of 25
`
`

`

`IND077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`3. To support the proposed container/closure system for the drug product, provide
`test results of USP<661> for each formulation-contacting packaging component.
`Additionally, due to the high level
`(b)(.JJ in the proposed
`c...;..;...;..;.;. ___ (b' )(~l
`formulation. Qrovide the results of the extractables study
`<b><41 and your investigation on leachables in the- re-g~i-str_a_t~io-n- sta- b1=·1i"""·ty- -
`
`studies.
`
`Pharmacology/Toxicology
`
`Question (1) :
`Does the Agency agree that the completed nonclinical program, as detailed in Section 8,
`is sufficient to characterize efinaconaozle toxicity for the NDA and that no other studies
`are required?
`
`Response:
`Yes.
`
`Question [2]:
`Does the Agency agree that the toxicity evaluation of the impurities have been fully
`addressed and no further studies will be required?
`
`Response:
`Yes.
`
`Question (3) (microbiology question [lJ):
`Does the Agency agree with the proposed format and location for the specified studies
`and respective CTD sections described above?
`
`Response:
`Yes, the Agency agrees with the proposed format and location of clinical microbiology
`summaries and study reports.
`
`Clinical
`
`Question (1):
`Does the Agency agree to waive phototoxicity and photoallergy studies?
`
`Response:
`Yes, a waiver is likely to be appropriate at the time ofNDA review. rI..h.e suqmitted
`spectra for IDP-108A solutions, 5% and 10% w/w, and the IDP-108L
`(bH
`1 % and 10%, and their excipients do not demonstrate any absorbance m the wavelength
`range of290 to 700nm.
`
`4J solutions,
`
`Question (2):
`Based on the completion of the clinical program as detailed in Section 9, does the agency
`agree that the clinical program is adequate to support approval of efmaconazole solution
`
`ReferencelD:3130189
`
`5
`
`Page 4 of 25
`
`

`

`IND 077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`with an indication for the topical treatment o~
`- - - -
`patients 18 years or older?
`
`.
`.
`h
`(br(4!
`onyc omycos1s m
`
`Response:
`The clinical program presented in Section 9 appears to be adequate to meet NDA filing
`requirements; however, the adequacy of data and NDA approval will be the subject of the
`Agency NDA review.
`
`Question (3):
`Does the Agency agree that the total patient exposure is adequate to support approval of
`the NDA?
`
`Response:
`It does appear that sufficient exposure to efinaconazole solution has been established to
`satisfy the ICH E l A guidelines. The adequacy of the safety data will be reviewed during
`the NDA review process, and supplementary safety information may be requested should
`additional safety issues be identified.
`
`Question (4):
`
`based upon the conditions described?
`
`Does the Agency agree that ---------------------
`
`(b)(4l
`
`Response:
`---------------
`A
`Biostatistics
`
`(b) (4'
`
`Question (1):
`The complete list of efinaconazole clinical studies (IND and non-IND) is presented in
`Table 17. T he datasets for the following clinical trials will be included in the NDA in
`CDISC format:
`• DPS1-IDP-108-P3-0 l (Phase 3 safety and efficacy)
`• DPSI-IDP- 108-P3-02 (Phase 3 safety and efficacy)
`• DPS1-IDP- 108-P2-0 1 (Phase 2 safety and efficacy)
`• DPSI-IDP-108-Pl -03 (Phase 1 PK)
`The datasets for all other IND studies (DPSI-IDP- 108-PI-Ol and DPSI-IDP-108-Pl -02)
`will be included in the NDA as SAS transport files. Datasets for the remaining two
`clinical studies not conducted under IND 077732 will not be included.
`
`Does the Agency agree with the provision of the files in this format?
`
`Response:
`1. The electronic datasets for clinical studies in should be submitted in SAS transport
`form (.xpt).
`
`Reference ID: 3130189
`
`6
`
`Page 5 of 25
`
`

`

`IND 077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`2. You should submit both SDTM datasets (raw data directly from the CRF in
`standardized format) and analysis datasets for the Phase 2 and 3 studies. Each
`analysis dataset should include the treatment assignments, baseline assessments, and
`key demographic variables. The analysis datasets should include all variables needed
`for conducting all primary, secondary, and sensitivity analyses included in the study
`report. For endpoints that include imputations, both observed and imputed variables
`should be included and clearly identified.
`
`3. For Study DPSI-IDP-108-Pl-03 (Phase 1 PK) we recommend that you provide the
`raw and calculated PK parameters in a SAS transport file as well.
`
`4. Include dataset documentation ( define.xml and define.pd±) for SDTM and analysis
`datasets. Definition files for raw datasets modeled according to CDISC/SDTM IG and
`standards should be submitted as .xml file types ( define.xml). Refer to CDISC's
`Defme.XML page for assistance/guidance related to creating define.xml files for
`CDISC/SDTM data. Also, for ease of viewing by the reviewer and printing, submit
`corresponding defme.pdf files in addition to the defme.xml. The analysis dataset
`documentation (define.pdf file) should include sufficient detail, such as definitions or
`descriptions of each variable in the data set, algorithms for derived variables
`(including source variables used), and descriptions for the codes used in factor
`variables.
`
`5. Statistical programs for any non-standard analyses should be submitted.
`
`6. If any subjects were enrolled in more than one study, include a unique subject ID that
`permits subjects to be tracked across multiple studies.
`
`In addition to the electronic data sets, the NDA submission should include the following
`items for the Phase 2 and 3 studies:
`
`a. Study protocols including the statistical analysis plan, all protocol amendments
`(with dates), and an annotated copy of the Case Report Form (which maps
`variables in the datasets to the CRF).
`
`b. The generated treatment assignment lists and the actual treatment allocations
`(along with date of enrollment) from the trials.
`
`Question [2]:
`Datasets will be provided for the clinical studies conducted under IND 077732 and
`included in the eCTD NDA. Does the Agency agree that submission of data listings will
`not be necessary?
`
`Response:
`Yes, provided that the information is included in the electronic datasets.
`
`Reference 10: 3130189
`
`7
`
`Page 6 of 25
`
`

`

`IND 077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`Question [3]:
`Statistical analysis of the safety data for the 52 week Phase 3 trials DPSI-IDP-108-P3-0l
`and DPSI-IDP-108-P3-02 conducted with the to-be-marketed formulation will be pooled
`and presented in the Integrated Summary of Safety (ISS).
`
`Does the Agency agree with the statistical analysis plan for pooling of safety data as
`described above for the Phase 3 clinical studies?
`
`Response:
`Your approach appears reasonable. If you intend to pool safety data from earlier phase
`studies, provide justification and methods in which these pooled safety data is
`appropriate. In addition to the information required in the Integrated Summary of Safety
`to aid our review, please provide the following:
`
`• Shift tables for all laboratory values for both outside the normal range and outside
`the range that is considered clinically significant. Please provide the normal
`range of values for all parameters, the threshold for concern for a clinically
`significant change and your justification for why this threshold is appropriate.
`
`Question [4]:
`--·-~=-·''"'''""'""'"'" .. ,,~tJltistical analysis of the efficacy data for the 52 week Phase 3 trials DPSI-IDP-108-P3-
`. · 01 'and DPSI-IDP-108-P3-02 conducted with the to-be-marketed formulation will be
`pooled and presented in the Integrated Summary of Efficacy (ISE).
`
`Does the Agency agree with the statistical analysis plan for pooling of efficacy data?
`
`Response:
`Your approach appears reasonable.
`
`In addition to the information required in the Integrated Summary of Effectiveness to aid
`our review, please provide the following:
`• Provide a detailed analysis for race (i.e., beyond white vs. non-white)
`• Provide a detailed analysis for age subgroups.
`• Provide a rationale for why the data presented represents a demonstration of
`substantial evidence of effectiveness for the proposed indication.
`Refer to the Guidance for Industry: Integrated Summary of Effectiveness
`(http://www.fda.gov/downioads/Drugs/GuidanceComplianceRegulatoryinformation/Guid
`ances/UCM079803.pdf) for additional information on what to include in the ISE.
`
`The Study Data Specifications require the submission to include all datasets in the SAS
`Transport format (v5). Any questions regarding the Study Data Specifications can be
`submitted to esub@fda.hhs.gov.
`
`Reference ID: 3130189
`
`8
`
`Page 7 of 25
`
`

`

`IND077732
`Meeting Minutes
`TypeB
`
`Questions for Clarification:
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`Clarifying Question [1]:
`The response to Biostatistics Question [ 1] (lines 157 to 169) found on lines 171 to 210
`was very much appreciated. Additionally, we would like to confirm our understanding
`related to the following question.
`
`The two clinical studies not conducted under IND 077732 (KP-103-02 and KP-103-02
`extracted from Table 17 below) were conducted by our development partner Kaken
`Pharmaceutical Co., LTD. The demonstration of safety and efficacy does not depend on
`the results of these studies. The full clinical study reports are being submitted in the NOA
`only as ancillary information obtained during the clinical development program. Both
`non-IND studies will be summarized in the Integrated Summary of Safety. On lines 166
`to 167 we indicated that the datasets for these studies would not be included in the NOA.
`
`Does the Agency agree that these datasets do not need to be included in the NDA?
`
`Extract from Pre-NOA Meeting Briefing :Oocument fTable 17 i,age 491
`Type of
`Location of Objective(s) of
`Study Design and
`No.of
`Test Products;
`Study/
`the Study
`Study
`Type of
`Dosage Regimen; Subjects
`(Study
`Report/Type
`Route of
`Control/Treatment
`Identifier)
`ofReoort
`Duration
`Administration
`Phase 1
`Investigation
`of
`efinaconazole
`concentration
`in nails (Non-
`IND Study)
`KP-103-03
`
`Section
`5.3.4.2/Full
`
`To investigate
`efinaconazole
`concentrations in
`the effected vs
`normal toenails as
`well as the first vs
`second toenail
`with different nail
`thickness
`
`Healthy
`Subjects or
`Diagnosis
`of Patients
`
`Diseased
`
`Open label study with 5%and 10%
`repeated application of efinaconazole
`efinaconazole to all
`applied topically
`toenails./28 days
`once daily
`
`40
`
`Phase 1 Skin
`irritation and
`photosensitiz
`ation(Non-
`IND Study)
`KP-103-02
`
`Evaluation of Skin
`irritation and
`Section
`5.3.5.1/Full photosensitization
`of efinaconazole
`
`Positive control and
`negative controlled
`Placebo, 0.2%
`Patch test and photo
`sodium lauryl
`patch test using Latin
`sulfate, deionized
`square method skin
`water, 1 %, 5% and
`irritation and
`photosensitization of
`10% Solution
`single application in
`applied topically
`step 1. Skin irritation once daily
`of repeated application
`for 7. days./7 days .
`
`56
`
`Healthy
`adult males
`
`Reference 10: 3130189
`
`9
`
`Page 8 of 25
`
`

`

`IND077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`Response:
`Your proposal is acceptable provided the waiver for phototesting is granted during the
`NDA review. The Agency may have additional information requests related to these
`study reports if safety issues become apparent during the NDA review process.
`
`Extract from Pre-NDA Meeting Briefing Document fTable 17, :,age 491
`Type of
`No.of
`Location of Objective(s) of
`Study Design and
`Test Products;
`Study
`Type of
`Dosage Regimen; Subjects
`Study/
`the Study
`(Study
`Report/Type
`Route of
`Control/Treatment
`Identifier)
`ofRenort
`Administration
`Duration
`Phase 1
`Investigation
`of
`efinaconazole
`concentration
`in nails (Non-
`IND Study)
`KP-103-03
`
`Section
`5.3.4.2/Full
`
`To investigate
`efinaconazole
`concentrations in
`the effected vs
`normal toenails as
`well as the first vs
`second toenail
`with different nail
`thickness
`
`Healthy
`Subjects or
`Diagnosis
`of Patients
`
`Diseased
`
`Open label study with 5%and 10%
`repeated application of efinaconazole
`applied topically
`efinaconazole to all
`once daily
`toenails./28 days
`
`40
`
`Phase 1 Skin
`irritation and
`photosensitiz
`ation(Non-
`IND Study)
`KP-103-02
`
`Evaluation of Skin
`irritation and
`Section
`5.3.5.1/Full photosensitization
`of efinaconazole
`
`Positive control and
`negative controlled
`Placebo, 0.2%
`Patch test and photo
`sodium lauryl
`patch test using Latin
`sulfate, deionized
`square method skin
`water, l %, 5% and
`irritation and
`10% Solution
`photosensitization of
`applied topically
`single application in
`step l. Skin irritation once daily
`of repeated application
`for 7 days./7 days
`
`56
`
`Healthy
`adult males
`
`Clarifying Question (2):
`On lines 232 to 237 the Agency requested the following:
`
`Shift tables for all laboratory values for both outside the normal range and
`outside the range that is considered clinically significant. Please provide the
`normal range of values for all parameters, the threshold for concern for a
`clinically significant change and your justification for why this threshold is
`appropriate.
`
`As requested, the submission will include shift tables to present all laboratory values
`outside the normal range and the normal range for all parameters. As specified in the
`study protocols, the determination of the clinical significance of an outside of normal
`range laboratory value was the decision of the site investigators and did not involve a pre(cid:173)
`specified threshold value. Thus, the tables that present the out of range laboratory values
`do not identify those reported as clinically significant.
`
`Reference 10: 3130189
`
`10
`
`Page 9 of 25
`
`

`

`IND 077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`The tables described above will be augmented with a set that will include only those
`laboratory value shifts from a baseline value of "not clinically significant" to a post
`baseline value of "clinically significant" and visa versa.
`
`Does the combined set of shift tables satisfy the informational request for all laboratory
`values which are both outside the normal range and outside the range as well as
`considered clinically significant?
`
`Response:
`Your proposal is acceptable.
`
`Clarifying Question [3]:
`Re: Question [2] on lines 212 to 215 reads:
`
`Datasets will be provided for the clinical studies conducted under IND 077732
`and included in the eCTD NDA. Does the Agency agree that submission of data
`listings will not be necessary?
`
`The Agency's response on line 218 was:
`
`Yes, provided that the information is included in the electronic datasets.
`
`It is our understanding that for the overall evaluation of the NDA the line listings that
`include all sites combined are not necessary if the information is included in the
`electronic datasets, but site specific individual subject data ("line") listings are requested
`by the Office of Scientific Investigations (OSI) for the Phase 3 studies. In addition, we
`are requested to participate in the OSI pilot program for submission of site-level datasets
`intended to facilitate timely selection of clinical sites for FDA inspection and, by
`extension, Agency evaluation of the NDA.
`
`The additional information requested by OSI (Item 1, 2 and 3) were not anticipated to be
`provided at the time of NDA submission and represent a significant volume of
`information not generally required as part of the original NDA in the form requested.
`DPS would like to propose that the information requested by OSI be provided as an
`Amendment to the NDA within 2 weeks following NDA filing (Day 60).
`
`Does the Agency agree that the additional body of information requested to facilitate
`FDA site inspections can be provided as an Amendment to the NDA?
`
`Response:
`Your New Drug Application should be complete at the time of submission. -
`
`Clarifying Question [4]:
`We would like to take this opportunity to confirm that DPS has submitted a response to
`the letter from the Division dated February 27, 2012, which provided advice and a
`
`Reference ID: 3130189
`
`11
`
`Page 10 of 25
`
`

`

`IND 077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`request for information regarding the Statistical Analysis Plans (SAPs) for the Phase 3
`studies. The response was submitted on March 22, 2012 (S-0055).
`
`The briefing book for the Pre-NDA meeting was submitted prior to our receipt of the
`Division's letter and request for information (S-0053; February 21, 2012). Consequently,
`our meeting briefing materials submitted in preparation for the Pre-NDA meeting did not
`reflect our intentions for inclusion of the analyses based on the Divisions
`recommendation to follow the originally approved SAPs.
`
`Based on the Agency's recommendations, and for purposes of completeness, the two
`Phase 3 clinical study reports and the overall integrated summary of efficacy will include
`the analyses defined and described within the originally approved SAPs (SAP Version 1)
`that follow the original versions of the protocols, as well as the analyses defined and
`described in the revised SAPs that were approved prior to database lock and unblinding
`of the treatment assignments (SAPs Version 2).
`
`The clinical overview and summary in the NDA will focus on the Agency's preferred
`secondary analysis endpoints (i.e., those based on SAP version 1) and will describe all
`other analyses (i.e., those based on SAP version 2) as supportive.
`
`Does the Agency concur with our plan to implement the Division's recommendations?
`
`Response:
`Your proposal appears reasonable.
`
`Administrative Comments
`
`1. Comments shared today are based upon the contents of the briefing document, which
`is considered to be an informational aid to facilitate today's discussion. Review of
`information submitted to the IND or NDA might identify additional comments or
`information requests.
`
`2. For applications submitted after February 2, 1999, the applicant is required either to
`certify to the absence of certain financial interests of clinical investigators or disclose
`those financial interests. For additional information, please refer to 21 CPR 54 and
`21 CPR 314.50(k).
`
`3. We remind you of the Pediatric Research Equity Act of 2007 which requires all
`applications for a new active ingredient, new dosage form, new indication, new route
`of administration, or new dosing regimen to contain an assessment of th~ safety and
`effectiveness of the drug for the claimed indications in all relevant pediatric
`subpopulations unless this requirement is waived or deferred.
`
`4. Pediatric studies conducted under the terms of section 505A of the Federal Food,
`Drug, and Cosmetic Act may result in additional marketing exclusivity for certain
`products. You should refer to the Guidance for Industry: Qualifying for Pediatric
`
`Reference ID: 3130189
`
`12
`
`Page 11 of 25
`
`

`

`IND 077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`Exclusivity for details. If you wish to qualify for pediatric exclusivity you should
`submit a "Proposed Pediatric Study Request". FDA generally does not consider
`studies submitted to an NDA before issuance of a Written Request as responsive to
`the Written Request. Applicants should obtain a Written Request before submitting
`pediatric studies to an NDA.
`
`PRESCRIBING INFORMATION
`
`Proposed prescribing information (PI) submitted with your application must conform to
`the content and format regulations found at 21 CFR 201.56 and 201.57.
`
`Summary of the Final Rule on the Requirements for Prescribing Information for Drug
`and Biological Products, labeling guidances, sample tool illustrating Highlights and Table
`of Contents, an educational module concerning prescription drug labeling, and fictitious
`prototypes of prescribing information are available at:
`http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryinformation/LawsActsandRul
`es/ucm084159.htm. We encourage you to review the information at this website and use
`it as you draft prescribing information for your application.
`
`MANUFACTURING FACILITIES
`
`To facilitate our inspectional process, the Office of Manufacturing and Product Quality in
`CDER's Office of Compliance requests that you clearly identify in a single location,
`either on the Form FDA 356h, or an attachment to the form, all manufacturing facilities
`associated with your application. Include the full corporate name of the facility and
`address where the manufacturing function is performed, with the FEI number, and
`specific manufacturing responsibilities for each facility.
`
`Also provide the name and title of an onsite contact person, including their phone
`number, fax number, and email address. Provide a brief description of the manufacturing
`operation conducted at each facility, including the type of testing and DMF number (if
`applicable). Each facility should be ready for GMP inspection at the time of submission.
`
`Consider using a table similar to the one below as an attachment to Form FDA 356h.
`Indicate under Establishment Information on page 1 of Form FDA 356h that the
`information is provided in the attachment titled, "Product name, NDA/BLA 012345,
`Establishment Information for Form 356h."
`
`Reference 10: 3130189
`
`13
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`IND077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`Federal
`
`Establishment
`
`Drug
`
`Site Name
`
`Site Address
`
`(FEI) or
`
`Indicator
`
`Registration
`
`Number
`
`(CFN)
`
`Number
`
`(if
`applicable)
`
`Master Manufacturing Step(s)
`File
`
`or Type of Testing
`[Establishment
`function]
`
`1.
`
`2.
`
`Corresponding names and titles of onsite contact:
`
`Site Name
`
`Site Address
`
`Onsite Contact
`(Person, Title)
`
`Phone and
`Fax
`number
`
`Email address
`
`1.
`
`2.
`
`The Office of Scientific Investigations (OSI) requests that the following items be
`provided to facilitate development of clinical investigator and sponsor/monitor/CRO
`inspection assignments, and the background packages that are sent with those
`assignments to the FDA field investigators who conduct the inspections (Item I and II).
`The dataset that is requested as per Item III below, is. for use in a clinical site
`selection model that is being piloted in CDER. Electronic submission of site level
`datasets will facilitate the timely selection of appropriate clinical sites for FDA inspection
`as part of the application and/or supplement review process.
`This request also provides instructions for where OSI requested items should be placed
`within an eCTD submission (Attachment 2, Technical Instructions: Submitting
`Bioresearch Monitoring (BIMO) Clinical Data in eCTD Format).
`
`I. Request for general study related information and specific Clinical Investigator information (if
`items are provided elsewhere in submission, describe location or provide link to requested
`information).
`
`Reference ID: 3130189
`
`14
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`Page 13 of 25
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`

`IND 077732
`Meeting Minutes
`TypeB
`
`Office of Drug Evaluation III
`Division of Dermatology and Dental Products
`
`1. Please include the following information in a tabular format in the original NDA for each of the
`completed Phase 3 clinical trials:
`a. Site number
`b. Principal investigator
`c. Site Location: Address ( e.g. Street, City, State, Country) and contact information (i.e., phone,
`fax, email)
`d. Current Location of Principal Investigator (ifno longer at Site): Address (e.g. Street, City,
`State, Country) and contact information (i.e., phone, fax, email)
`
`2. Please include the following information in a tabular format by site in the original NDA for each
`of the completed Phase 3 clinical trials:
`a. Number of subjects screened for each site by site
`b. Number of subjects randomized for each site by site
`c. Number of subjects treated who prematurely discontinued for each site by site
`
`3. Please include the following information in a tabular format in the NDA for each of the completed
`Phase 3 clinical trials:
`a. Location of Trial Master File [actual physical site(s) where documents are maintained and
`would be available for inspection]
`b. Name, address and contact information of all CROs used in the conduct of the clinical trials
`c. The location (actual physical site where documents are maintained and would be available for
`inspection) for all source data generated by the CROs with respect to their roles and
`responsibilities in conduct of respective studies
`d. The location (actual physical site where documents are maintained and would be available for
`inspection) of sponsor/monitor files ( e.g. monitoring master files, drug accountability files,
`SAE files, etc.)
`
`4. For each pivotal trial provide a sample annotated Case Report Form (if items are provided
`elsewhere in submission, please describe location or provide a link to requested information).
`5. For each pivotal trial provide original protocol and all amendments (if items are provided
`elsewhere in submission, please describe location or provide a link to requested information).
`
`II.
`
`Request for Subject Level Data Listings by Site
`1. For each pivotal trial: Site-specific individual subject data ("line") listings. For each site provide
`line listings for:
`a. Listing for each subject/number screened and reason for subjects who did not meet eligibility
`requirements
`b. Subject listing for treatment assignment (randomization)
`c. Subject listing of drop-outs and subjects that discontinued with date and reason
`d. Evaluable subjects/ non-evaluable subjects and reason not evaluable
`e. By subject listing of eligibility determination (i.e., inclusion and exclusion criteria)
`f. By subject listing, of AEs, SAEs, deaths and dates
`g. By subject listing of protocol violations and/or deviations reported in the NDA, description of
`the deviation/violation
`h. By subject listing of the primary and secondary endpoint efficacy parameters or events. For
`derived or calculated endpoints, provide the raw data listings used to generate the
`derived/calculated endpoint.
`i. By subject listing of concomitant medications (as appropriate to the pivotal clinical trials)
`j. By subject listing, oflaboratory tests performed for safety monitoring
`-
`
`2. We request that one PDF file be created for each pivotal Phase 2 and Phase 3 study using the
`following format:
`
`Reference 10: 3130189
`
`15
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`Page 14 of 25
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`

`fND 077732
`Meeting Minutes
`T ypeB
`
`Office of Drug Evaluation III
`Divis ion of Dermatology and Dental Pro