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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`NDA 205834/S-6
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`Food and Drug Administration
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` Silver Spring MD 20993
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`SUPPLEMENT APPROVAL
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`Gilead Sciences, Inc.
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`Attention: Prachi Shah, MBS, RAC
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`Associate Manager, Regulatory Affairs
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`333 Lakeside Drive
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`Foster City, CA 94404
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`Dear Ms. Shah:
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`Please refer to your Supplemental New Drug Application (sNDA) dated and received May 15,
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`2015, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (FDCA) for
`Harvoni® (ledipasvir/sofosbuvir), fixed-dose combination tablet, 90 mg/400 mg.
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`This Prior Approval supplemental new drug application provides for the following change:
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`• To expand the indication to include treatment of genotype 4, chronic hepatitis C virus
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`infection based upon the results from studies GS-US-337-0115 (ION-4) and GS-US-337
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`1119
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`APPROVAL & LABELING
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`We have completed our review of this supplemental application, as amended. It is approved,
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`effective on the date of this letter, for use as recommended in the enclosed, agreed-upon labeling
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`text.
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`CONTENT OF LABELING
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`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
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`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
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`automated drug registration and listing system (eLIST), as described at
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`http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm. Content
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`of labeling must be identical to the enclosed labeling (text for the package insert and text for the
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`patient package insert), with the addition of any labeling changes in pending “Changes Being
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`Effected” (CBE) supplements, as well as annual reportable changes not included in the enclosed
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`labeling.
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`Information on submitting SPL files using eList may be found in the guidance for industry titled
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`“SPL Standard for Content of Labeling Technical Qs and As at
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`Reference ID: 3846226
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` NDA 205834/S-6
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` Page 2
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`http://www.fda.gov/downloads/DrugsGuidanceComplianceRegulatoryInformation/Guidances/U
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` CM072392.pdf
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`The SPL will be accessible from publicly available labeling repositories.
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`Also within 14 days, amend all pending supplemental applications that includes labeling changes
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`for this NDA, including CBE supplements for which FDA has not yet issued an action letter,
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`with the content of labeling [21 CFR 314.50(l)(1)(i)] in MS Word format, that includes the
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`changes approved in this supplemental application, as well as annual reportable changes and
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`annotate each change. To facilitate review of your submission, provide a highlighted or marked-
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`up copy that shows all changes, as well as a clean Microsoft Word version. The marked-up copy
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`should provide appropriate annotations, including supplement number(s) and annual report
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`date(s).
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`REQUIRED PEDIATRIC ASSESSMENTS
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`Under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c), all applications for new
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`active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of
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`administration are required to contain an assessment of the safety and effectiveness of the
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`product for the claimed indication(s) in pediatric patients unless this requirement is waived,
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`deferred, or inapplicable.
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`We are waiving the pediatric study requirement from birth to less than 3 years because necessary
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`studies are impossible or highly impracticable. This is because spontaneous clearance is possible
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`and very few patients in this age group require treatment.
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`We are deferring submission of your pediatric studies for ages 3 to 17 years for this application
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`because this product is ready for approval for use in adults and the pediatric studies have not
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`been completed.
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`Your deferred pediatric study required by section 505B(a) of the FDCA is a required
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`Postmarketing study. The status of the postmarketing study must be reported annually according
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`to 21 CFR 314.81 and section 505B(a)(3)(C) of the FDCA. This required study is listed below.
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` Conduct a study to evaluate the pharmacokinetics, safety and treatment response (using
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` sustained virologic response) of ledipasvir/sofosbuvir in pediatric subjects 3 through 17
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` years of age with chronic hepatitis C.
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`2985-1
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`Final Protocol Submission: 07/2014 (Completed)
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`06/2018
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`Study Completion:
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`Final Report Submission:
`02/2019
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`Submit the protocol(s) to your IND 115268, with a cross-reference letter to this NDA.
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`Reports of required pediatric postmarketing studies must be submitted as a new drug
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`application (NDA) or as a supplement to your approved NDA with the proposed labeling
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`Reference ID: 3846226
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` NDA 205834/S-6
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` Page 3
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` changes that are warranted based on the data derived from the studies. When
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` submitting the reports, please clearly mark your submission "SUBMISSION OF REQUIRED
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` PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
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` the submission.
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`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
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`We remind you of your postmarketing commitment:
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` 2985-2
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` Conduct a study to characterize the cell culture antiviral activity of ledipisvir
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`against representative HCV subtype 4b and 4r isolates, including those with
`amino acid variability (relative to subtypes 4a and 4d) at NS5A positions 28, 30,
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`31 and 93.
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`The timetable you submitted on October 21, 2015, states that you will conduct this study
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`according to the following schedule:
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`Final Protocol Submission: Not Applicable
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`Not Applicable
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`Study Completion:
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`Final Report Submission:
`06/2016
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`Under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a status summary
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`of each commitment in your annual report to this NDA. The status summary should include
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`expected study completion and final report submission date and any changes in plans since
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`the last annual report. All submissions, including supplements, relating to these
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`postmarketing commitments should be prominently labeled “Postmarketing Commitment
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`Protocol,” “Postmarketing Commitment Final Report,” or “Postmarketing
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`Commitment Correspondence.”
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`PROMOTIONAL MATERIALS
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`You may request advisory comments on proposed introductory advertising and promotional
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`labeling. To do so, submit the following, in triplicate, (1) a cover letter requesting advisory
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`comments, (2) the proposed materials in draft or mock-up form with annotated references, and
`(3) the package insert(s) to:
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`OPDP Regulatory Project Manager
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`Office of Prescription Drug Promotion (OPDP)
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`5901-B Ammendale Road
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`Beltsville, MD 20705-1266
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`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
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`For more information about submitting promotional materials in eCTD format, see the draft
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`Reference ID: 3846226
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` NDA 205834/S-6
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` Page 4
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` Guidance for Industry (available at:
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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` You must submit final promotional materials and package insert(s), accompanied by a Form
` FDA 2253, at the time of initial dissemination or publication [21 CFR 314.81(b)(3)(i)]. Form
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` FDA 2253 is available at
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083570.pdf.
`Information and Instructions for completing the form can be found at
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`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
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`more information about submission of promotional materials to the Office of Prescription Drug
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`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
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`All promotional materials that include representations about your drug product must be promptly
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`revised to be consistent with the labeling changes approved in this supplement, including any
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`new safety information [21 CFR 314.70(a)(4)]. The revisions in your promotional materials
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`should include prominent disclosure of the important new safety information that appears in the
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`revised package labeling. Within 7 days of receipt of this letter, submit your statement of intent
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`to comply with 21 CFR 314.70(a)(4) to the address above, by fax to 301-847-8444, or
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`electronically in eCTD format. For more information about submitting promotional materials in
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`eCTD format, see the draft Guidance for Industry (available at:
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM443702.pdf ).
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`REPORTING REQUIREMENTS
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`We remind you that you must comply with reporting requirements for an approved NDA
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`(21 CFR 314.80 and 314.81).
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`If you have any questions, call Mammah Sia Borbor, Regulatory Project Manager, at (301) 796
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`7731.
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`Sincerely,
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`{See appended electronic signature page}
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`Debra Birnkrant, MD
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`Director
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`Division of Antiviral Products
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`Office of Antimicrobial Products
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`Center for Drug Evaluation and Research
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`ENCLOSURE:
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`Content of Labeling
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`Reference ID: 3846226
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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/
`----------------------------------------------------
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`DEBRA B BIRNKRANT
`11/12/2015
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`Reference ID: 3846226
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`(
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