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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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` NDA 205834
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`Food and Drug Administration
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` Silver Spring MD 20993
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` NDA APPROVAL
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`Gilead Sciences, Inc.
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`Attention: Michele Anderson
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`Associate Director, Regulatory Affairs
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`333 Lakeside Drive
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`Foster City, CA 94404
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`Dear Ms. Anderson:
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`Please refer to your New Drug Application (NDA) dated February 7, 2014, received
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`February 10, 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
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`(FDCA) for Harvoni™ (ledipasvir and sofosbuvir) tablets, 90 mg/400mg.
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`We acknowledge receipt of your amendments dated:
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`February 27, 2014 (2)
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`February 28, 2014
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`March 4, 2014
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`March 11, 2014
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`March 13, 2014
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`March 25, 2014
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`March 28, 2014
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`April 25, 2014
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`May 1, 2014
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`May 2, 2014
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`May 5, 2014
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`May 20, 2014
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`We also acknowledge receipt of the information related to the Harvoni™ (ledipasvir and
`sofosbuvir) tablets, 90 mg/400 mg, for the Gilead Access Program that was reviewed as a part of
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`this application.
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`This new drug application provides for the use of Harvoni™ (ledipasvir and sofosbuvir) tablets
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`for the treatment of chronic hepatitis C, genotype 1 infection.
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`We have completed our review of this application, as amended. It is approved, effective on the
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`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
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` May 21, 2014
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` May 27, 2014
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` June 5, 2014
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` June 18, 2014
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` June 19, 2014
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` June 26, 2014
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` June 30, 2014
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` July 1, 2014
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` July 3, 2014
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` July 7, 2014
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` July 8, 2014
` July 14, 2014
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`July 16, 2014
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`July 29, 2014
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`August 4, 2014
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`August 7, 2014
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`August 11, 2014
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`August 14, 2014
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`July 19, 2014
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`September 3, 2014
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`September 17, 2014 (2)
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`September 18, 2014
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`September 24, 2014
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`Reference ID: 3643151
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` NDA 205834
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` Page 2
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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
`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). Information on submitting SPL files using eLIST may be found in the
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`guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at
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`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
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`The SPL will be accessible via publicly available labeling repositories.
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`CARTON AND IMMEDIATE CONTAINER LABELS
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`Submit final printed immediate container label that are identical to the enclosed immediate
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`container label as soon as they are available, but no more than 30 days after they are printed.
`Please submit these labels electronically according to the guidance for industry Providing
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`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008). Alternatively, you may
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`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
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`similar material. For administrative purposes, designate this submission “Final Printed
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`Container Labels for approved NDA 205834.” Approval of this submission by FDA is not
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`required before the labeling is used.
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`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
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`the product misbranded and an unapproved new drug.
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`MARKET PACKAGE
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`Please submit one market package of the drug product when it is available to the following
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`address:
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`Linda C. Onaga, MPH
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`Food and Drug Administration
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`Center for Drug Evaluation and Research
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`White Oak Building 22, Room: 6321
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`10903 New Hampshire Avenue
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`Silver Spring, Maryland
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`Use zip code 20903 if shipping via United States Postal Service (USPS).
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`Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
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`Reference ID: 3643151
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` NDA 205834
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` Page 3
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` ADVISORY COMMITTEE
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`Your application for Harvoni™ (ledipasvir and sofosbuvir) tablets was not referred to an FDA
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`advisory committee because the application did not raise significant safety or efficacy issues that
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`were unexpected and because outside expertise was not necessary as there were no significant
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`issues identified that would benefit from an advisory committee discussion.
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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
` 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 studies required by section 505B(a) of the FDCA are required
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` postmarketing studies. The status of these postmarketing studies must be reported annually
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` according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These required studies are
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` listed below.
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` 2780-1
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`Conduct a study to evaluate the pharmacokinetics, safety and treatment response
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` (using sustained virologic response) of ledipasvir/sofosbuvir in pediatric subjects
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` 3 to 17 years of age with chronic hepatitis C.
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`2780-2
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` Final Protocol Submission: 07/14/2014
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` 06/30/2018
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` Trial Completion:
` Final Report Submission:
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` 02/28/2019
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`Collect and analyze long-term safety data for subjects enrolled in the pediatric
`ledipasvir/sofosbuvir safety, pharmacokinetic and efficacy study. Data collected
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`should include at least 3 years of follow-up in order to characterize the long-term
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`safety of ledipasvir/sofosbuvir including growth assessment, sexual maturation
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`and characterization of ledipasvir/sofosbuvir resistance associated substitutions in
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`viral isolates from subjects failing therapy.
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`Final Protocol Submission: 05/15/2014
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`02/28/2023
`Trial Completion:
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`Final Report Submission:
`08/31/2023
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`Reference ID: 3643151
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` NDA 205834
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` Page 4
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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 these 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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`changes you believe are warranted based on the data derived from these studies. When
`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 REQUIREMENTS UNDER 505(o)
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`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
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`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
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`We have determined that an analysis of spontaneous postmarketing adverse events reported
`under subsection 505(k)(1) of the FDCA will not be sufficient to identify the unexpected serious
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`risks of carcinogenicity and treatment-emergent viral substitutions with Harvoni™ (ledipasvir
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`and sofosbuvir) treatment durations up to 24 weeks. Initially, the proposed duration of dosing for
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`Harvoni™ (ledipasvir and sofosbuvir) for hepatitis C genotype 1 treatment ranged 8 to 12 weeks.
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`During the review of the Harvoni™ (ledipasvir and sofosbuvir) application, FDA determined
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`that longer durations of therapy resulted in higher efficacy for certain populations. These
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`durations dictate the need for carcinogenicity studies in accordance with 21 CFR 314.50 (d)(2)
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`and the ICH M3 (R2) and S1A guidances. In addition, we are aware of viral variants with
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`treatment-emergent substitutions in subjects who relapsed during Harvoni™ (ledipasvir and
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`sofosbuvir) clinical trials. The impact on the serious risk of resistance and persistence of some of
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`these substitutions is not completely understood.
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`Furthermore, the new pharmacovigilance system that FDA is required to establish under section
`505(k)(3) of the FDCA will not be sufficient to assess these serious risks.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
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`conduct the following:
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`Final Report Submission:
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`12/31/2015
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`Reference ID: 3643151
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`2780-3
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`Submit the ledipasvir 2 year rat carcinogenicity study
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`The timetable you submitted on August 19, 2014, states that you will conduct this study
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`according to the following schedule:
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` NDA 205834
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` Page 5
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` 2780-4
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` Submit the ledipasvir 26-week carcinogenicity study in rasH2 mice
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`The timetable you submitted on August 19, 2014, states that you will conduct this study
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`according to the following schedule:
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`01/31/2015
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`Final Report Submission:
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`Submit an analysis of longitudinal data on persistence of NS5A resistance
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`substitutions from subjects who did not achieve SVR12 in Phase 2 studies of
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`LDV with other DAAs.
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`The timetable you submitted on August 19, 2014, states that you will conduct this study
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`according to the following schedule:
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`2780-5
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`2780-6
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`Final Protocol Submission: 06/21/2012
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`03/31/2015
`Final Report Submission:
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`Conduct a study to assess the impact of NS5B substitutions A112T, E127G, and
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`S473T on the phenotypic susceptibility of sofosbuvir in the GT1a HCV replicon
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`system.
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`The timetable you submitted on August 19, 2014, states that you will conduct this study
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`according to the following schedule:
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`Final Report Submission:
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`03/31/2015
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`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
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`study) will be sufficient to assess signals for unexpected serious risks in and provide dosing
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`recommendations for patients with advanced liver disease and/or in patients receiving
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`concomitant immunosuppressive agents post-liver transplantation. Compared with subjects
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`enrolled in the phase 3 Harvoni™ (ledipasvir and sofosbuvir) registrational trials, the
`decompensated liver disease/post-liver transplantation population is overall a sicker population
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`with known associated comorbidities and thus there is a potential risk for serious toxicities in this
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`population. In addition, only a clinical trial will be sufficient to assess the potential risk of
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`elevated exposure to sofosbuvir in the setting of Harvoni™ (ledipasvir and sofosbuvir) and
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`cyclosporine coadministration. Finally, only a clinical trial will be sufficient to assess a known
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`serious risk of elevated exposure to tenofovir levels in chronic hepatitis C and HIV-1 co-infected
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`patients receiving concomitant Harvoni™ (ledipasvir and sofosbuvir) and Atripla (efavirenz,
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`emtricitabine, tenofovir disoproxil fumarate, or its components) and to provide dosing
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`recommendations for this population.
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`Therefore, based on appropriate scientific data, FDA has determined that you are required to
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`conduct the following:
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`2780-7
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`Submit the final report and datasets for the ongoing trial GS-US-337-0123,
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`entitled “A Phase 2, Multicenter, Open-Label Study to Investigate the Safety and
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`Reference ID: 3643151
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`

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` NDA 205834
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` Page 6
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`2780-8
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` Efficacy of Sofosbuvir/Ledipasvir Fixed-Dose Combination + Ribavirin
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` Administered in Subjects Infected with Chronic HCV who have Advanced Liver
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` Disease or are Post-Liver Transplant”, in order to provide safety data and dosing
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` recommendations for subjects with decompensated cirrhosis and/or in subjects
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` receiving concomitant immunosuppressive agents post-liver transplant (e.g.
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` cyclosporine).
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`The timetable you submitted on August 19, 2014, states that you will conduct this trial according
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`to the following schedule:
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`Final Protocol Submission: 08/07/2013
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`03/31/2015
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`Trial Completion:
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`Final Report Submission:
`09/30/2015
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`Submit the final report and datasets for the ongoing trial GS-US-337-0115,
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`entitled “A Phase 3, Multicenter, Open-Label Study to Investigate the Safety and
`Efficacy of Sofosbuvir/Ledipasvir Fixed-Dose Combination for 12 Weeks in
`Subjects with Chronic Genotype 1 or 4 Hepatitis C Virus (HCV) and Human
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`Immunodeficiency Virus (HIV)-1 Co Infections” in order to obtain additional
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`safety data in subjects receiving concomitant ledipasvir/sofosbuvir and Atripla (or
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`its components) and to provide dosing recommendations for co-infected subjects.
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`The timetable you submitted on August 19, 2014, states that you will conduct this trial according
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`to the following schedule:
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`Final Protocol Submission: 12/02/2013
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`03/15/2016
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`Trial Completion:
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`Final Report Submission:
`09/16/2016
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`Submit the protocol(s) to your IND 115268, with a cross-reference letter to this NDA. Submit all
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`final report(s) to your NDA. Prominently identify the submission with the following wording in
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`bold capital letters at the top of the first page of the submission, as appropriate: “Required
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`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
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`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
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`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
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`study or clinical trial required under this section. This section also requires you to periodically
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`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
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`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
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`report annually on the status of any postmarketing commitments or required studies or clinical
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`trials.
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`FDA will consider the submission of your annual report under section 506B and 21
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`CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
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`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
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`Reference ID: 3643151
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`

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` NDA 205834
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` Page 7
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` 314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
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` include a report on the status of any study or clinical trial otherwise undertaken to investigate a
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` safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
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` on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
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` result in enforcement action.
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`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
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`We remind you of your postmarketing commitments:
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` 2780-9
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` Submit an interim report from the ongoing trial GS-US-248-0122, entitled, “A
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` Long Term Follow-up Registry for Subjects Who Achieve a Sustained Virologic
` Response to Treatment in Gilead-Sponsored Trials in Subjects with Chronic
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` Hepatitis C Infection”, with the three year follow-up data from: GS-US-337-0102
` (ION-1), GS-US-337-0109 (ION-2), GS-US-337-0108 (ION-3).
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` The timetable you submitted on September 24, 2014, states that you will conduct this trial
` according to the following schedule:
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` Final Protocol Submission: 06/21/2012
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` 07/31/2017
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` Trial Completion:
` Final Report Submission:
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` 07/31/2018
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` Submit clinical protocols to your IND 115268 for this product. Submit nonclinical and
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` chemistry, manufacturing, and controls protocols and all postmarketing final reports to this
` NDA. In addition, under 21 CFR 314.81(b)(2)(vii) and 314.81(b)(2)(viii) you should include a
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` status summary of each commitment in your annual report to this NDA. The status summary
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` should include expected summary completion and final report submission dates, any changes in
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` plans since the last annual report, and, for clinical studies/trials, number of patients entered into
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` each study/trial. All submissions, including supplements, relating to these postmarketing
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`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
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` “Postmarketing Commitment Final Report,” or “Postmarketing Commitment
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` 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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`
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`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
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`proposed materials in draft or mock-up form with annotated references, and the package insert
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`to:
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`Reference ID: 3643151
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`

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` NDA 205834
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` Page 8
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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
`
`
` 5901-B Ammendale Road
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` Beltsville, MD 20705-1266
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`
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`
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`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
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`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
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`2253. Form 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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`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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`MEDWATCH-TO-MANUFACTURER PROGRAM
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`The MedWatch-to-Manufacturer Program provides manufacturers with copies of serious adverse
`event reports that are received directly by the FDA. New molecular entities and important new
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`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
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`
`
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`copies of reports for this product. To participate in the program, please see the enrollment
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`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
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`POST APPROVAL FEEDBACK MEETING
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`New molecular entities and new biologics qualify for a post approval feedback meeting. Such
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`meetings are used to discuss the quality of the application and to evaluate the communication
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`process during drug development and marketing application review. The purpose is to learn
`from successful aspects of the review process and to identify areas that could benefit from
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`
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`improvement. If you would like to have such a meeting with us, call the Regulatory Project
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`
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`Manager for this application.
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`PDUFA V APPLICANT INTERVIEW
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`FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
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`and final assessment of the Program for Enhanced Review Transparency and Communication for
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`NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment
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`Letter states that these assessments will include interviews with applicants following FDA action
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`on applications reviewed in the Program. For this purpose, first-cycle actions include approvals,
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`Reference ID: 3643151
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`

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` NDA 205834
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` Page 9
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` complete responses, and withdrawals after filing. The purpose of the interview is to better
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` understand applicant experiences with the Program and its ability to improve transparency and
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` communication during FDA review.
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`ERG will contact you to schedule a PDUFA V applicant interview and provide specifics about
`the interview process. Your responses during the interview will be confidential with respect to
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`
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` the FDA review team. ERG has signed a non-disclosure agreement and will not disclose any
` identifying information to anyone outside their project team. They will report only anonymized
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` results and findings in the interim and final assessments. Members of the FDA review team will
` be interviewed by ERG separately. While your participation in the interview is voluntary, your
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`
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` feedback will be helpful to these assessments.
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`
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`If you have any questions, call Linda C. Onaga, Regulatory Project Manager, at (301) 796-0759
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`or Division mainline at (301) 796-1500
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`
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`Sincerely,
`
` {See appended electronic signature page}
`
` Edward Cox, MD, M.P.H.
`
` Director
` Office of Antimicrobial Products
`
` Center for Drug Evaluation and Research
`
`
`
`
`
`Enclosure(s):
`
`Content of Labeling
`
`
`Carton and Container Labeling
`
`
`
`Reference ID: 3643151
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`JOHN J FARLEY on behalf of EDWARD M COX
`10/10/2014
`Acting on behalf of Edward Cox
`
`Reference ID: 3643151
`
`