CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`210455Orig1s000
`
`ADMINISTRATIVE and CORRESPONDENCE
`DOCUMENTS
`
`
`
`
`
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`
`
`IND 113456
`
`
`MEETING PRELIMINARY COMMENTS
`
`
`Janssen Research & Development, LLC.
`Attention: Karen Gerry, BSc
`Associate Director, Global Regulatory Affairs
`1125 Trenton-Harbourton Road
`Titusville, NJ 08560
`
`Dear Ms. Gerry:
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for darunavir/cobicistat/emtricitabine/tenofovir
`alafenamide (D/C/F/TAF) fixed dose combination tablet.
`
`We also refer to your December 20, 2016, correspondence requesting a pre-NDA meeting to
`discuss and seek concurrence from the Agency regarding the proposed content and format of the
`NDA submission in support of the registration of the D/C/F/TAF FDC tablet for the treatment of
`HIV-1 infection.
`
`Our preliminary responses to your meeting questions are enclosed.
`
`You should provide, to the Regulatory Project Manager, a hardcopy or electronic version of
`any materials (i.e., slides or handouts) to be presented and/or discussed at the meeting.
`
`In accordance with 21 CFR 10.65(e) and FDA policy, you may not electronically record the
`discussion at this meeting. The official record of this meeting will be the FDA-generated
`minutes.
`
`If you have any questions, call me at (301) 796-0807.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Myung-Joo Patricia Hong, M.S.
`Senior Regulatory Project Manager
`Division of Antiviral Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`Reference ID: 4054687
`
`
`
`

`

`IND 113456
`Page 2
`
`
`ENCLOSURE:
` Preliminary Meeting Comments
`
`
`
`Reference ID: 4054687
`
`

`

`
`
`
`
`
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`PRELIMINARY MEETING COMMENTS
`
`
`Type B
`pre-NDA
`
`Meeting Type:
`Meeting Category:
`
`Meeting Date and Time:
`Meeting Location:
`
`Application Number:
`IND 113456
`Product Name:
`darunavir/cobicistat/emtricitabine/tenofovir alafenamide
`(D/C/F/TAF) fixed dose combination tablet
`
`Indication:
`Treatment of HIV-1 infection
`Sponsor/Applicant Name: Janssen Research & Development, LLC.
`
`Introduction:
`
`This material consists of our preliminary responses to your questions and any additional
`comments in preparation for the discussion at the meeting scheduled for February 14, 2017,
`1 PM, between Janssen Research & Development, LLC. and the Division of Antiviral
`Products. We are sharing this material to promote a collaborative and successful
`discussion at the meeting. The meeting minutes will reflect agreements, important issues,
`and any action items discussed during the meeting and may not be identical to these
`preliminary comments following substantive discussion at the meeting. If you determine
`that discussion is needed for only some of the original questions, you have the option of
`reducing the agenda. Contact the Regulatory Project Manager (RPM) if there are any
`major changes to your development plan, the purpose of the meeting, or the questions
`based on our preliminary responses, as we may not be prepared to discuss or reach
`agreement on such changes at the meeting.
`
`1.0
`
`Due to an unmet medical need for a protease inhibitor (PI)-based single-tablet regimen, Janssen
`(Sponsor) and Gilead Sciences, Inc. (Gilead) have co-formulated the nucleotide reverse
`transcriptase inhibitor (NtRTI) tenofovir (TFV)-prodrug tenofovir alafenamide (TAF, 10 mg)
`with the PI darunavir (DRV, D; 800 mg), the pharmacokinetic (PK) enhancer cobicistat (COBI,
`C; 150 mg), and the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine (FTC, F; 200
`mg) to form the first PI-based fixed-dose combination (FDC) single-tablet option for oral once
`daily use (D/C/F/TAF). The D/C/F/TAF tablet offers the additional advantage of including an
`N(t)RTI backbone that has an improved renal and bone safety profile compared with a tenofovir
`disoproxil fumarate (TDF)-containing backbone. The development program of the D/C/F/TAF
`FDC product is based on six clinical studies conducted with the FDC tablet in adults:
`
`February 14, 2017, 1 - 2 PM
`Teleconference
`
`BACKGROUND
`
`
`
`
`Reference ID: 4054687
`
`

`

`IND 113456
`Page 2
`
`
`
`• Two pivotal Phase 3 studies (TMC114IFD3013 and TMC114FD2HTX3001), which are
`still ongoing;
`
`
`o Study TMC114FD2HTX3001 in HIV-infected, ART-naïve adult subjects
`o Study TMC114IFD3013 in HIV-infected, virologically-suppressed adult subjects
`
`• One completed Phase 2 study conducted by Gilead; and
`• Three completed Phase 1 studies, of which two were conducted by the Sponsor and one
`by Gilead.
`
`
`This program is complemented, as appropriate, by studies from the development programs of the
`individual compounds, i.e., studies conducted in adolescents, studies to assess the QT effects,
`studies in special populations such as subjects with renal impairment, hepatic impairment and
`subjects co-infected with hepatitis B, and drug-drug interaction studies.
`
`Gilead has transferred further development of the FDC tablet to Janssen and, subject to
`regulatory approval, the manufacturing, registration, distribution and commercialization of the
`product worldwide.
`
`The primary purpose of the meeting is to discuss and seek concurrence from the Agency
`regarding the proposed content and format of the NDA submission in support of the registration
`of the D/C/F/TAF FDC tablet for the treatment of HIV-1 infection.
`
`The proposed NDA submission is targeted for September 2017.
`
`2.0
`
`Your questions are in bold italics and DAVP comments are in standard font.
`
`2.1.
`
`Q1: As there are no new non-clinical studies included in this NDA, the Sponsor will only
`provide a non-clinical overview in Module 2.4. Does the Division agree with this approach?
`
`FDA Response: Yes, we agree with your proposal.
`
`2.2.
`
`Q2: The Sponsor plans to align the drug-drug interaction information and recommendations for
`the D/C/F/TAF FDC with the approved Prescribing Information for the respective separate agents.
`Additional drug-drug interactions based on an up-to-date status of new drug approvals and/or
`Prescribing Information updates for relevant concomitant drugs will be included, as applicable.
`Since D/C/F/TAF is a complete treatment regimen for HIV-infection, drug-drug interaction data
`with other HIV antiretrovirals (ARVs) will however not be included in the D/C/F/TAF FDC
`Prescribing Information. Does the Division agree with this approach?
`
`
`DISCUSSION
`
`Pharmacology/Toxicology
`
`Clinical Pharmacology
`
`Reference ID: 4054687
`
`2
`
`

`

`Clinical
`
`IND 113456
`Page 3
`
`
`FDA Response: In general the proposed approach for addressing drug-drug interactions is
`acceptable. The need for additional drug-drug interaction studies will be a review issue.
`
`2.3
`
`Q3: The Sponsor proposes to discuss and submit the analysis of the individual Phase 2/3
`studies, and will not perform an integrated analysis of these studies. Does the Division agree
`with this proposal?
`
`FDA Response: Yes, we agree with your proposal.
`
`Q4: The Sponsor proposes to submit narratives and case report forms (CRFs) as outlined in
`the Sponsor Position. Does the Division agree with this strategy for inclusion of narratives
`and CRFs?
`
`FDA Response: No, we do not agree. Narratives and CRFs should be submitted for all deaths,
`SAEs, and AEs leading to discontinuation of study drug, regardless of causality. With respect to
`adverse events (AEs) of special interest, given that the Phase 3 trials are comparing TAF to TDF,
`please submit narratives for all events of bone fractures, proximal renal tubulopathy and uveitis,
`regardless of severity or causality. Your analysis plan should include the list of terms used to
`identify these cases. In addition, an analysis of subclinical proximal renal tubulopathy cases,
`based on objective laboratory abnormalities, should be included in your reports, as has been done
`for recent submissions of clinical trial data involving TAF- and TDF-containing drug products.
`For the other listed events, which reflect safety concerns associated with darunavir, i.e., skin
`reactions/rash, hepatotoxicity, lipid abnormalities and coronary artery events, we concur with
`your strategy to submit narratives only for Grade 3 or 4 events that are at least possibly related to
`study drug; however, given that all subjects will be exposed to darunavir or a PI, we suggest that
`these cases not be limited to the D/C/F/TAF FDC arms.
`
`Q5: The Sponsor proposes to submit the safety data of the 2 ongoing Phase 3 studies as
`follows:
`
`• A primary safety analysis up to the individual subjects’ Week 48 (or earlier in case of
`discontinuations) visits as cut-off date;
`
`• Safety data ‘as available in the database’ after the individual Week 48 visit up to a
`maximum of 90 days prior to the US NDA submission date, focusing on deaths, SAEs and
`discontinuations.
`
`Does the Division agree with the proposed safety reporting periods at the time of NDA
`submission?
`
`FDA Response: Yes, we agree with your proposal.
`
`
`Reference ID: 4054687
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`

`IND 113456
`Page 4
`
`
`Q6: The Sponsor proposes to use the NDA filing date as the data cut-off date for an NDA
`safety update. Does the Division agree with the proposed NDA safety update cut-off date and
`content?
`
`FDA Response: Yes, we agree with your proposal.
`
`2.4
`
`Q7: For the planned NDA, the Sponsor proposes to:
`
`Submit Clinical Data Interchange Standards Consortium (CDISC)-compliant Study Data
`Tabulation Model (SDTM)/Analysis Data Model (ADaM) data set packages for the Phase 3
`studies TMC114IFD3013 and TMC114FD2HTX3001 and Phase 1 studies
`TMC114FD2HTX1001 and TMC114FD2HTX1002. The CDISC package will contain the
`following:
`
`
`Data Sets/Other
`
`o Four SDTMs (one for each of the 2 Phase 3 studies and 2 Phase 1 studies)
`o Four ADaMs (one for each of the 2 Phase 3 studies and 2 Phase 1 studies)
` Generate Statistical Analysis Plan (SAS) transport files containing patient, endpoint,
`genotypic and phenotypic data as outlined in Draft Guidance, Attachment to Guidance on
`Antiviral Product Development –Conducting and Submitting Virology Studies to the
`Agency - Guidance for Submitting HIV-1 Resistance Data (February 2014) for the 2
`Phase 3 studies TMC114IFD3013 and TMC114FD2HTX3001 that collect resistance data.
`Virology data sets will also be provided in CDISC format. A preliminary resistance data
`structure will be shared before assembling formal clinical trial resistance data sets.
`
`• Not include SAS Programs.
`
`Does the Division agree with the above proposals?
`
`FDA Response: Please include SAS programs in the NDA submission. The programs should
`include those to generate ADaM datasets from the raw datasets as well as those to generate the
`main efficacy and safety results in the clinical reports. In addition to the datasets in CDISC
`format, we also request specifications for the efficacy outcomes dataset, i.e., ADEFFOUT.XPT.
`Please see the attached appendix (Attachment 2) for the details.
`
`2.5 Regulatory
`
`Q8: The Sponsor proposes to provide Financial Disclosure information for the 2 Phase 3
`studies TMC114IFD3013 and TMC114FD2HTX3001 in the D/C/F/TAF NDA. Does the
`Division agree with this approach?
`
`FDA Response: Yes, we agree with your proposal.
`
`
`
` •
`
`Reference ID: 4054687
`
`4
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`

`

`IND 113456
`Page 5
`
`
`Additional Comments:
`
`Chemistry, Manufacturing and Controls
`
` •
`
` Please indicate how much stability data will be provided at the time of NDA submission. We
`note that different formulations have been used during the development process. If you are
`going to rely, in whole or in part, on stability data for slightly different developmental
`batches please indicate how these tablets differ from the marketed tablets. Please also
`discuss any plans to bridge between different tablets (e.g., Phase 3 to commercial, supportive
`stability to primary stability).
`
`
`Clinical Pharmacology
`
` •
`
` You proposed the use of D/C/F/TAF in adolescents based on prior pediatric studies including
`E/C/F/TAF Study GS-US-292-0106. D/C/F/TAF results in lower TAF exposure compared to
`F/TAF 200/25 mg, which has similar TAF exposure as E/C/F/TAF. Study GS-US-292-0106
`alone, therefore, will not be sufficient to establish similar TAF exposures from D/C/F/TAF in
`adolescents compared to adults. In your NDA submission, you should provide data and/or a
`detailed justification to support the prediction of similar TAF exposures from D/C/F/TAF in
`adolescents compared to adults.
`
`PREA REQUIREMENTS
`
`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
`active ingredients (which includes new salts and new fixed combinations), new indications, new
`dosage forms, new dosing regimens, or new routes of administration are required to contain an
`assessment of the safety and effectiveness of the product for the claimed indication(s) in
`pediatric patients unless this requirement is waived, deferred, or inapplicable.
`
`We acknowledge your Agreed iPSP dated June 30, 2015. Your Agreed iPSP, along with any
`requests for waivers or deferrals, should be included in your New Drug Application.
`
`PRESCRIBING INFORMATION
`
`In your application, you must submit proposed prescribing information (PI) that conforms to the
`content and format regulations found at 21 CFR 201.56(a) and (d) and 201.57 including the
`Pregnancy and Lactation Labeling Rule (PLLR) (for applications submitted on or after June 30,
`2015). As you develop your proposed PI, we encourage you to review the labeling review
`resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation
`Labeling Final Rule websites, which include:
`
`Reference ID: 4054687
`
`5
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`

`

`IND 113456
`Page 6
`
`
`
`
`• The Final Rule (Physician Labeling Rule) on the content and format of the PI for human
`drug and biological products.
`• The Final Rule (Pregnancy and Lactation Labeling Rule) on the content and format of
`information related to pregnancy, lactation, and females and males of reproductive
`potential.
`• Regulations and related guidance documents.
`• A sample tool illustrating the format for Highlights and Contents, and
`• The Selected Requirements for Prescribing Information (SRPI) − a checklist of
`important format items from labeling regulations and guidances.
`• FDA’s established pharmacologic class (EPC) text phrases for inclusion in the
`Highlights Indications and Usage heading.
`
`
`The application should include a review and summary of the available published literature
`regarding drug use in pregnant and lactating women, a review and summary of reports from your
`pharmacovigilance database, and an interim or final report of an ongoing or closed pregnancy
`registry (if applicable), which should be located in Module 1. Refer to the draft guidance for
`industry – Pregnancy, Lactation, and Reproductive Potential: Labeling for Human Prescription
`Drug and Biological Products – Content and Format
`(http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
`UCM425398.pdf).
`
`Prior to submission of your proposed PI, use the SRPI checklist to ensure conformance with the
`format items in regulations and guidances.
`
`ABUSE POTENTIAL ASSESSMENT
`
`Drugs that affect the central nervous system, are chemically or pharmacologically similar to
`other drugs with known abuse potential, or produce psychoactive effects such as mood or
`cognitive changes (e.g., euphoria, hallucinations) need to be evaluated for their abuse potential
`and a proposal for scheduling will be required at the time of the NDA submission
`[21 CFR 314.50(d)(5)(vii)]. For information on the abuse potential evaluation and information
`required at the time of your NDA submission, see the draft guidance for industry, Guidance for
`Industry Assessment of Abuse Potential of Drugs, available at:
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM198650.pdf
`
`MANUFACTURING FACILITIES
`
`To facilitate our inspectional process, we request 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.
`
`
`Reference ID: 4054687
`
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`

`IND 113456
`
`Page 7
`
`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 infonnation is provided
`in the attachment titled, “Product name, NDA/BLA 012345, Establishment Information for Form
`356h.”
`
`Federal
`
`Site Address
`
`Establishment
`
`Indicator
`
`(FBI) or
`Registration
`Number
`
`Manufacturing Step(s)
`or Type of Testing
`Establishment
`
`a’erson Title)
`
`Site Address
`
`Onsite Contact
`
`
`
`Officeof Scientific Investi ations OS Re uests
`
`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 those inspections (Item I and II). This information is requested for all major trials
`used to support safety and efficacy in the application (i.e., phase 2/3 pivotal trials). Please note
`that if the requested items are provided elsewhere in submission in the format described, the
`Applicant can describe location or provide a link to the requested information.
`The dataset that is requested in Item [H below is for use in a clinical site selection model that is
`being piloted in CDER. Electronic submission of the site level dataset is voluntary and is
`intended to 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 081 requested items should be placed within an
`eCTD submission (Attachment 1, Technical Instructions: Submitting Bioresearch Monitoring
`(BIMO) Clinical Data in eCTD Format).
`
`Reference ID: 4054687
`
`

`

`IND 113456
`Page 8
`
`
`I.
`
`
`
`
`
`
`
`
`
`Request for general study related information and comprehensive clinical
`investigator information (if items are provided elsewhere in submission, describe
`location or provide link to requested information).
`
`1. Please include the following information in a tabular format in the original NDA for each
`of the completed pivotal 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. Location of Principal Investigator: Address (e.g., Street, City, State, and Country) and
`contact information (i.e., phone, fax, email). If the Applicant is aware of changes to a
`clinical investigator’s site address or contact information since the time of the clinical
`investigator’s participation in the study, we request that this updated information also
`be provided.
`
`2. Please include the following information in a tabular format, by site, in the original NDA
`for each of the completed pivotal clinical trials:
`
`a. Number of subjects screened at each site
`b. Number of subjects randomized at each 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 pivotal clinical trials:
`
`a. Location at which sponsor trial documentation is maintained (e.g., , monitoring plans
`and reports, training records, data management plans, drug accountability records,
`IND safety reports, or other sponsor records as described ICH E6, Section 8). This is
`the actual physical site(s) where documents are maintained and would be available for
`inspection
`b. Name, address and contact information of all Contract Research Organization (CROs)
`used in the conduct of the clinical trials and brief statement of trial related functions
`transferred to them. If this information has been submitted in eCTD format
`previously (e.g., as an addendum to a Form FDA 1571, you may identify the
`location(s) and/or provide link(s) to information previously provided.
`c. The location at which trial documentation and records generated by the CROs with
`respect to their roles and responsibilities in conduct of respective studies is
`maintained. As above, this is the actual physical site where documents would be
`available for inspection.
`
`4. For each pivotal trial, provide a sample annotated Case Report Form (or identify the
`location and/or provide a link if provided elsewhere in the submission).
`
`
`Reference ID: 4054687
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`

`IND 113456
`Page 9
`
`
`
`
`II.
`
`
`
`
`5. For each pivotal trial provide original protocol and all amendments ((or identify the
`location and/or provide a link if provided elsewhere in the submission).
`
`Request for Subject Level Data Listings by Site
`
`1. For each pivotal trial: Site-specific individual subject data listings (hereafter referred to as
`“line listings”). For each site, provide line listings for:
`
`
`a. Listing for each subject consented/enrolled; for subjects who were not
`randomized to treatment and/or treated with study therapy, include reason not
`randomized and/or treated
`b. Subject listing for treatment assignment (randomization)
`c. Listing of subjects that discontinued from study treatment and subjects that
`discontinued from the study completely (i.e., withdrew consent) with date and
`reason discontinued
`d. Listing of per protocol subjects/ non-per protocol subjects and reason not per
`protocol
`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,
`including a 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, of testing (e.g., laboratory, ECG) 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 ID: 4054687
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`

`IND 113456
`Page 10
`
`
`
`
`
`
`III. Request for Site Level Dataset:
`
`OSI is piloting a risk based model for site selection. Voluntary electronic submission of site
`level datasets is intended to facilitate the timely selection of appropriate clinical sites for FDA
`inspection as part of the application and/or supplement review process. If you wish to
`voluntarily provide a dataset, please refer to the draft Guidance for Industry Providing
`Submissions in Electronic Format – Summary Level Clinical Site Data for CDER’s Inspection
`Planning” (available at the following link
`http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire
`ments/UCM332468.pdf ) for the structure and format of this data set.
`
`
`
`
`
`
`
`
`Reference ID: 4054687
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`IND 113456
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`
`
`Appendix:
`
`
`A.
`
`
`Attachment 1
`Technical Instructions:
`Submitting Bioresearch Monitoring (BIMO) Clinical Data in eCTD Format
`
`Data submitted for OSI review belongs in Module 5 of the eCTD. For items I and II in
`the chart below, the files should be linked into the Study Tagging File (STF) for each
`study. Leaf titles for this data should be named “BIMO [list study ID, followed by brief
`description of file being submitted].” In addition, a BIMO STF should be constructed
`and placed in Module 5.3.5.4, Other Study reports and related information. The study ID
`for this STF should be “bimo.” Files for items I, II and III below should be linked into
`this BIMO STF, using file tags indicated below. The item III site-level dataset filename
`should be “clinsite.xpt.”
`
`
`
`DSI Pre-
`NDA
`Request
`Item1
`I
`I
`
`STF File Tag
`
`Used For
`
`Allowable
`File Formats
`
`data-listing-dataset
`annotated-crf
`
`data-listing-dataset
`
`Data listings, by study
`Sample annotated case report
`form, by study
`Data listings, by study
`(Line listings, by site)
`Site-level datasets, across
`studies
`data-listing-data-definition Define file
`
`data-listing-dataset
`
`.pdf
`.pdf
`
`.pdf
`
`.xpt
`
`.pdf
`
`In addition, within the directory structure, the item III site-level dataset should be placed
`in the M5 folder as follows:
`
`
`
`It is recommended, but not required, that a Reviewer’s Guide in PDF format be included.
`If this Guide is included, it should be included in the BIMO STF. The leaf title should be
`“BIMO Reviewer Guide.” The guide should contain a description of the BIMO elements
`being submitted with hyperlinks to those elements in Module 5.
`
`II
`
`III
`
`III
`
`
`B.
`
`
`
`
`C.
`
`
`
`
`1 Please see the OSI Pre-NDA/BLA Request document for a full description of requested data files
`
`Reference ID: 4054687
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`IND 113456
`Page 12
`
`
`References:
`
`eCTD Backbone Specification for Study Tagging Files v. 2.6.1
`(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequire
`ments/ElectronicSubmissions/UCM163560.pdf)
`
`FDA eCTD web page
`(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Elect
`ronicSubmissions/ucm153574.htm)
`
`For general help with eCTD submissions: ESUB@fda.hhs.gov
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
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`Reference ID: 4054687
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`IND 113456
`Page 13
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`Attachment 2
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`Specifications for Efficacy Outcomes Dataset
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`The dataset should have only one record per subject and should include information as outlined
`in detail in the table below for the following:
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`• Demographic variables
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`• Baseline characteristics (e.g., baseline genotypic and phenotypic data, stratification
`factors)
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`• Exposure variables (e.g., first and last dosing date)
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`• Population flags (e.g., intent to treat, per-protocol)
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`• Efficacy outcomes (e.g., primary, secondary)
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`• Covariates and subgroup variables
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`• Subject disposition variables
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`The table below includes recommendations for variable name, variable label, and codes and
`provides comments.2
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`Table 1. Efficacy Outcomes and Related Covariates (ADEFFOUT)3
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`Reference ID: 4054687
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`21 Pages have been Withheld in Full as b4 (CCI/TS) immediately following this page
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`Contains Nonbinding Recommendations
`Draft — Not for Implementation
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`GLOSSARY OF ABBREVIATIONS AND ACRONYMS
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`Analysis Data Model
`ADaM
`adverse event
`AE
`antiretroviral therapy
`ART
`baseline carried forward
`BLCF
`baseline observation carried forward
`BOCF
`CD4+
`cluster of differentiation 4 positive
`Centers for Disease Control and Prevention
`CDC
`case report file
`CRF
`fusion inhibitor
`FI
`genotypic sensitivity score
`GSS
`integrase strand transfer inhibitor
`INSTI
`integrated summary of effectiveness
`ISE
`International Organization for Standardization
`ISO
`intent to treat
`ITT
`last observation carried forward
`LOCF
`last value carried forward
`LVCF
`MedDRA Medical Dictionary for Regulatory Activities
`mITT
`modified intent to treat
`MIX
`multiple investigational agents
`mL
`milliliter
`NNRTI
`non-nucleoside reverse transcriptase inhibitor
`NRTI
`nucleoside reverse transcriptase inhibitor
`OBT
`optimized background treatment
`PI
`protease inhibitor
`PSS
`phenotypic sensitivity score
`SAP
`statistical analysis plan
`SAE
`serious adverse event
`uL
`microliter
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`Reference ID: 4054687
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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/
`----------------------------------------------------
`
`MYUNG JOO P HONG
`02/10/2017
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`Reference ID: 4054687
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`IND 113456
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`Food and Drug Administration
`Silver Spring MD 20993
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`MEETING MINUTES
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`Janssen Research and Development, L.L.C.
`Attention: Karen Gerry, BSc
`Manager, Global Regulatory Affairs
`1125 Trenton-Harbourton Road
`Titusville, NJ 08560
`
`
`Dear Ms. Gerry:
`
`Please refer to your Investigational New Drug Application (IND) submitted under section 505(i)
`of the Federal Food, Drug, and Cosmetic Act for darunavir, cobicistat, emtricitabine, and
`tenofovir alafenamide (D/C/F/TAF) fixed-dose combination tablet.
`
`We also refer to the teleconference between representatives of your firm and the FDA on
`October 22, 2014. The purpose of the meeting was to discuss the design of the proposed Phase 3
`study and the suitability of the study to serve as the pivotal study to support the submission of the
`planned New Drug Application (NDA).
`
` A
`
` copy of the official minutes of the teleconference is enclosed for your information. Please
`notify us of any significant differences in understanding regarding the meeting outcomes.
`
`If you have any questions, call Stacey Min, Pharm.D., Senior Regulatory Project Manager at
`(301) 796-4253 or (301) 796-1500.
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`Debra Birnkrant, M.D.
`Director
`Division of Antiviral Products
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
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`
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`Enclosure:
`Meeting Minutes
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`Reference ID: 3651236
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`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
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`MEMORANDUM OF MEETING MINUTES
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`B
`End of Phase 2
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`Meeting Type:
`Meeting Category:
`
`Meeting Date and Time: October 22, 2014; 2:30 -3:30 pm, EST
`Meeting Location:
`Teleconference
`
`Application Number:
`Product Name:
`
`Linda Lewis, M.D., Medical Team Leader
`Stacey Min, Pharm.D., Senior Regulatory Project Manager
`
`113456
`Darunavir, cobicistat, emtricitabine, and tenofovir alafenamide
`(D/C/F/TAF) fixed-dose combination tablet
`Indication:
`Treatment of HIV-1 Infection
`Sponsor/Applicant Name: Janssen Research and Development, L.L.C.
`
`Meeting Chair:
`Meeting Recorder:
`
`FDA ATTENDEES
`Debra Birnkrant, M.D., Director, Division of Antiviral Products (DAVP)
`Jeffrey Murray, M.D., MPH, Deputy Director, DAVP
`Linda Lewis, M.D., Medical Team Leader, DAVP
`William Tauber, M.D., Medical Officer, DAVP
`Adam Sherwat, M.D., Acting Medical Team Leader, DAVP
`Kimberly Struble, Pharm.D., Medical Team Leader, DAVP
`Takashi Komatsu, Ph.D., RAC, Clinical Virology Reviewer, DAVP
`Lisa Naeger, Ph.D., Clinical Virology Reviewer, DAVP
`Julian O’Rear, Ph.D., Clinical Virology Team Leader, DAVP
`Mario Sampson, Pharm.D., Clinical Pharmacology Reviewer, Division of Clinical Pharmacology
`IV (DCP IV)
`Islam Younis, Ph.D., Clinical Pharmacology Team Leader, DCP IV
`Thomas Hammerstrom, Ph.D., Biometrics Reviewer, Division of Biometrics IV (DB IV)
`Guoixing Soon, Ph.D., Biometrics Team Leader, DB IV
`Karen Winestock, Chief Project Management Staff, DAVP
`Stacey Min, Pharm.D., Senior Regulatory Project Manager, DAVP
`Felicia Duffy, RN, BSN, MSEd, Risk Management Analyst, Division of Risk Management
`(DRISK)
`Naomi Redd, Pharm.D., Acting Team Leader, DRISK
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`SPONSOR ATTENDEES (Janssen)
`Katia Boven, MD, Senior Director, Global Clinical Development
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`Reference ID: 3651236
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`BACKGROUND
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`IND 113456
`Page 2
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`
`Herta Crauwels, PhD, Associate Scientific Director, Clinical Pharmacology
`Goedele De Smedt, MD, Senior Director, Compound Development Team Leader