`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`
`APPLICATION NUMBER:
`
`205834Orig1s000
`
`
`Harvoni
`
`ledipasvir and sofosbuvir
`
`Gilead Sciences, Inc.
`
`October 10, 2014
`
`for the treatment of chronic hepatitis C (CHC)
`genotype 1 infection in adults
`
`Trade Name:
`
`
`Generic Name:
`
`Sponsor:
`
`Approval Date:
`
`Indication:
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`205834Orig1s000
`
`CONTENTS
`
`Reviews / Information Included in this NDA Review.
`
`
`
`Approval Letter
`Other Action Letters
`Labeling
`REMS
`Summary Review
`Officer/Employee List
`Office Director Memo
`Cross Discipline Team Leader Review
`Medical Review(s)
`Chemistry Review(s)
`Environmental Assessment
`Pharmacology Review(s)
`Statistical Review(s)
`Microbiology/Virology Review(s)
`Clinical Pharmacology/Biopharmaceutics Review(s)
`Other Reviews
`Risk Assessment and Risk Mitigation Review(s)
`Proprietary Name Review(s)
`Administrative/Correspondence Document(s)
`
`
`X
`
`X
`
`X
`X
`X
`X
`X
`X
`
`X
`X
`
`X
`X
`
`X
`X
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`
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`
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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`205834Orig1s000
`APPROVAL LETTER
`
`
`
`
`
`
`
`
`
`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`
`NDA 205834
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Gilead Sciences, Inc.
`Attention: Michele Anderson
`Associate Director, Regulatory Affairs
`333 Lakeside Drive
`Foster City, CA 94404
`
`
`Dear Ms. Anderson:
`
`Please refer to your New Drug Application (NDA) dated February 7, 2014, received
`February 10, 2014, submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for Harvoni™ (ledipasvir and sofosbuvir) tablets, 90 mg/400mg.
`
`We acknowledge receipt of your amendments dated:
`
`February 27, 2014 (2)
`February 28, 2014
`March 4, 2014
`March 11, 2014
`March 13, 2014
`March 25, 2014
`March 28, 2014
`April 25, 2014
`May 1, 2014
`May 2, 2014
`May 5, 2014
`May 20, 2014
`
`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
`this application.
`
`This new drug application provides for the use of Harvoni™ (ledipasvir and sofosbuvir) tablets
`for the treatment of chronic hepatitis C, genotype 1 infection.
`
`We have completed our review of this application, as amended. It is approved, effective on the
`date of this letter, for use as recommended in the enclosed agreed-upon labeling text.
`
`
`May 21, 2014
`May 27, 2014
`June 5, 2014
`June 18, 2014
`June 19, 2014
`June 26, 2014
`June 30, 2014
`July 1, 2014
`July 3, 2014
`July 7, 2014
`July 8, 2014
`July 14, 2014
`
`July 16, 2014
`July 29, 2014
`August 4, 2014
`August 7, 2014
`August 11, 2014
`August 14, 2014
`July 19, 2014
`September 3, 2014
`September 17, 2014 (2)
`September 18, 2014
`September 24, 2014
`
`Reference ID: 3643151
`
`
`
`NDA 205834
`Page 2
`
`
`CONTENT OF LABELING
`
`As soon as possible, but no later than 14 days from the date of this letter, submit the content of
`labeling [21 CFR 314.50(l)] in structured product labeling (SPL) format using the FDA
`automated drug registration and listing system (eLIST), as described at
`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
`patient package insert). Information on submitting SPL files using eLIST may be found in the
`guidance for industry SPL Standard for Content of Labeling Technical Qs and As, available at
`http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
`CM072392.pdf.
`
`The SPL will be accessible via publicly available labeling repositories.
`
`CARTON AND IMMEDIATE CONTAINER LABELS
`
`Submit final printed immediate container label that are identical to the enclosed immediate
`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
`Regulatory Submissions in Electronic Format – Human Pharmaceutical Product Applications
`and Related Submissions Using the eCTD Specifications (June 2008). Alternatively, you may
`submit 12 paper copies, with 6 of the copies individually mounted on heavy-weight paper or
`similar material. For administrative purposes, designate this submission “Final Printed
`Container Labels for approved NDA 205834.” Approval of this submission by FDA is not
`required before the labeling is used.
`
`Marketing the product(s) with FPL that is not identical to the approved labeling text may render
`the product misbranded and an unapproved new drug.
`
`MARKET PACKAGE
`
`Please submit one market package of the drug product when it is available to the following
`address:
`
`
`Linda C. Onaga, MPH
`Food and Drug Administration
`Center for Drug Evaluation and Research
`White Oak Building 22, Room: 6321
`10903 New Hampshire Avenue
`Silver Spring, Maryland
`Use zip code 20903 if shipping via United States Postal Service (USPS).
`Use zip code 20993 if sending via any carrier other than USPS (e.g., UPS, DHL, FedEx).
`
`
`
`
`Reference ID: 3643151
`
`
`
`NDA 205834
`Page 3
`
`
`ADVISORY COMMITTEE
`
`Your application for Harvoni™ (ledipasvir and sofosbuvir) tablets was not referred to an FDA
`advisory committee because the application did not raise significant safety or efficacy issues that
`were unexpected and because outside expertise was not necessary as there were no significant
`issues identified that would benefit from an advisory committee discussion.
`
`REQUIRED PEDIATRIC ASSESSMENTS
`
`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
`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 are waiving the pediatric study requirement from birth to less than 3 years because necessary
`studies are impossible or highly impracticable. This is because spontaneous clearance is possible
`and very few patients in this age group require treatment.
`
`We are deferring submission of your pediatric studies for ages 3 to 17 years for this application
`because this product is ready for approval for use in adults and the pediatric studies have not
`been completed.
`
`Your deferred pediatric studies required by section 505B(a) of the FDCA are required
`postmarketing studies. The status of these postmarketing studies must be reported annually
`according to 21 CFR 314.81 and section 505B(a)(3)(B) of the FDCA. These required studies are
`listed below.
`
`
`2780-1
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment response
`(using sustained virologic response) of ledipasvir/sofosbuvir in pediatric subjects
`3 to 17 years of age with chronic hepatitis C.
`
`
`
`
`
`2780-2
`
`Final Protocol Submission: 07/14/2014
`Trial Completion:
`
`06/30/2018
`Final Report Submission:
`02/28/2019
`
`Collect and analyze long-term safety data for subjects enrolled in the pediatric
`ledipasvir/sofosbuvir safety, pharmacokinetic and efficacy study. Data collected
`should include at least 3 years of follow-up in order to characterize the long-term
`safety of ledipasvir/sofosbuvir including growth assessment, sexual maturation
`and characterization of ledipasvir/sofosbuvir resistance associated substitutions in
`viral isolates from subjects failing therapy.
`
`Final Protocol Submission: 05/15/2014
`Trial Completion:
`
`02/28/2023
`Final Report Submission:
`08/31/2023
`
`Reference ID: 3643151
`
`
`
`NDA 205834
`Page 4
`
`
`
`Submit the protocol(s) to your IND 115268, with a cross-reference letter to this NDA.
`
`Reports of these required pediatric postmarketing studies must be submitted as a new drug
`application (NDA) or as a supplement to your approved NDA with the proposed labeling
`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
`PEDIATRIC ASSESSMENTS" in large font, bolded type at the beginning of the cover letter of
`the submission.
`
`POSTMARKETING REQUIREMENTS UNDER 505(o)
`
`Section 505(o)(3) of the FDCA authorizes FDA to require holders of approved drug and
`biological product applications to conduct postmarketing studies and clinical trials for certain
`purposes, if FDA makes certain findings required by the statute.
`
`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
`risks of carcinogenicity and treatment-emergent viral substitutions with Harvoni™ (ledipasvir
`and sofosbuvir) treatment durations up to 24 weeks. Initially, the proposed duration of dosing for
`Harvoni™ (ledipasvir and sofosbuvir) for hepatitis C genotype 1 treatment ranged 8 to 12 weeks.
`During the review of the Harvoni™ (ledipasvir and sofosbuvir) application, FDA determined
`that longer durations of therapy resulted in higher efficacy for certain populations. These
`durations dictate the need for carcinogenicity studies in accordance with 21 CFR 314.50 (d)(2)
`and the ICH M3 (R2) and S1A guidances. In addition, we are aware of viral variants with
`treatment-emergent substitutions in subjects who relapsed during Harvoni™ (ledipasvir and
`sofosbuvir) clinical trials. The impact on the serious risk of resistance and persistence of some of
`these substitutions is not completely understood.
`
`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.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`2780-3
`
`Submit the ledipasvir 2 year rat carcinogenicity study
`
`
`The timetable you submitted on August 19, 2014, states that you will conduct this study
`according to the following schedule:
`
`
`Final Report Submission:
`
`
`12/31/2015
`
`Reference ID: 3643151
`
`
`
`NDA 205834
`Page 5
`
`
`
`2780-4
`
`Submit the ledipasvir 26-week carcinogenicity study in rasH2 mice
`
`
`The timetable you submitted on August 19, 2014, states that you will conduct this study
`according to the following schedule:
`
`
`01/31/2015
`
`Final Report Submission:
`
`Submit an analysis of longitudinal data on persistence of NS5A resistance
`substitutions from subjects who did not achieve SVR12 in Phase 2 studies of
`LDV with other DAAs.
`
`
`The timetable you submitted on August 19, 2014, states that you will conduct this study
`according to the following schedule:
`
`
`2780-5
`
`2780-6
`
`Final Protocol Submission: 06/21/2012
`Final Report Submission:
`03/31/2015
`
`Conduct a study to assess the impact of NS5B substitutions A112T, E127G, and
`S473T on the phenotypic susceptibility of sofosbuvir in the GT1a HCV replicon
`system.
`
`
`The timetable you submitted on August 19, 2014, states that you will conduct this study
`according to the following schedule:
`
`
`Final Report Submission:
`
`03/31/2015
`
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to assess signals for unexpected serious risks in and provide dosing
`recommendations for patients with advanced liver disease and/or in patients receiving
`concomitant immunosuppressive agents post-liver transplantation. Compared with subjects
`enrolled in the phase 3 Harvoni™ (ledipasvir and sofosbuvir) registrational trials, the
`decompensated liver disease/post-liver transplantation population is overall a sicker population
`with known associated comorbidities and thus there is a potential risk for serious toxicities in this
`population. In addition, only a clinical trial will be sufficient to assess the potential risk of
`elevated exposure to sofosbuvir in the setting of Harvoni™ (ledipasvir and sofosbuvir) and
`cyclosporine coadministration. Finally, only a clinical trial will be sufficient to assess a known
`serious risk of elevated exposure to tenofovir levels in chronic hepatitis C and HIV-1 co-infected
`patients receiving concomitant Harvoni™ (ledipasvir and sofosbuvir) and Atripla (efavirenz,
`emtricitabine, tenofovir disoproxil fumarate, or its components) and to provide dosing
`recommendations for this population.
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`2780-7
`
`Submit the final report and datasets for the ongoing trial GS-US-337-0123,
`entitled “A Phase 2, Multicenter, Open-Label Study to Investigate the Safety and
`
`Reference ID: 3643151
`
`
`
`NDA 205834
`Page 6
`
`
`
`
`
`2780-8
`
`Efficacy of Sofosbuvir/Ledipasvir Fixed-Dose Combination + Ribavirin
`Administered in Subjects Infected with Chronic HCV who have Advanced Liver
`Disease or are Post-Liver Transplant”, in order to provide safety data and dosing
`recommendations for subjects with decompensated cirrhosis and/or in subjects
`receiving concomitant immunosuppressive agents post-liver transplant (e.g.
`cyclosporine).
`
`
`The timetable you submitted on August 19, 2014, states that you will conduct this trial according
`to the following schedule:
`
`
`Final Protocol Submission: 08/07/2013
`Trial Completion:
`
`03/31/2015
`Final Report Submission:
`09/30/2015
`
`Submit the final report and datasets for the ongoing trial GS-US-337-0115,
`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
`Immunodeficiency Virus (HIV)-1 Co Infections” in order to obtain additional
`safety data in subjects receiving concomitant ledipasvir/sofosbuvir and Atripla (or
`its components) and to provide dosing recommendations for co-infected subjects.
`
`
`The timetable you submitted on August 19, 2014, states that you will conduct this trial according
`to the following schedule:
`
`
`Final Protocol Submission: 12/02/2013
`Trial Completion:
`
`03/15/2016
`Final Report Submission:
`09/16/2016
`
`
`
`Submit the protocol(s) to your IND 115268, with a cross-reference letter to this NDA. Submit all
`final report(s) to your NDA. Prominently identify the submission with the following wording in
`bold capital letters at the top of the first page of the submission, as appropriate: “Required
`Postmarketing Protocol Under 505(o)”, “Required Postmarketing Final Report Under
`505(o)”, “Required Postmarketing Correspondence Under 505(o)”.
`
`Section 505(o)(3)(E)(ii) of the FDCA requires you to report periodically on the status of any
`study or clinical trial required under this section. This section also requires you to periodically
`report to FDA on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Section 506B of the FDCA, as well as 21 CFR 314.81(b)(2)(vii) requires you to
`report annually on the status of any postmarketing commitments or required studies or clinical
`trials.
`
`FDA will consider the submission of your annual report under section 506B and 21
`CFR 314.81(b)(2)(vii) to satisfy the periodic reporting requirement under section
`505(o)(3)(E)(ii) provided that you include the elements listed in 505(o) and 21 CFR
`
`Reference ID: 3643151
`
`
`
`NDA 205834
`Page 7
`
`
`314.81(b)(2)(vii). We remind you that to comply with 505(o), your annual report must also
`include a report on the status of any study or clinical trial otherwise undertaken to investigate a
`safety issue. Failure to submit an annual report for studies or clinical trials required under 505(o)
`on the date required will be considered a violation of FDCA section 505(o)(3)(E)(ii) and could
`result in enforcement action.
`
`POSTMARKETING COMMITMENTS SUBJECT TO REPORTING REQUIREMENTS
`UNDER SECTION 506B
`
`We remind you of your postmarketing commitments:
`
`
`2780-9
`
`Submit an interim report from the ongoing trial GS-US-248-0122, entitled, “A
`Long Term Follow-up Registry for Subjects Who Achieve a Sustained Virologic
`Response to Treatment in Gilead-Sponsored Trials in Subjects with Chronic
`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).
`
`
`The timetable you submitted on September 24, 2014, states that you will conduct this trial
`according to the following schedule:
`
`
`Final Protocol Submission: 06/21/2012
`Trial Completion:
`
`07/31/2017
`Final Report Submission:
`07/31/2018
`
`
`Submit clinical protocols to your IND 115268 for this product. Submit nonclinical and
`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
`status summary of each commitment in your annual report to this NDA. The status summary
`should include expected summary completion and final report submission dates, any changes in
`plans since the last annual report, and, for clinical studies/trials, number of patients entered into
`each study/trial. All submissions, including supplements, relating to these postmarketing
`commitments should be prominently labeled “Postmarketing Commitment Protocol,”
`“Postmarketing Commitment Final Report,” or “Postmarketing Commitment
`Correspondence.”
`
`PROMOTIONAL MATERIALS
`
`You may request advisory comments on proposed introductory advertising and promotional
`labeling. To do so, submit, in triplicate, a cover letter requesting advisory comments, the
`proposed materials in draft or mock-up form with annotated references, and the package insert
`to:
`
`Reference ID: 3643151
`
`
`
`NDA 205834
`Page 8
`
`
`
`
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`As required under 21 CFR 314.81(b)(3)(i), you must submit final promotional materials, and the
`package insert, at the time of initial dissemination or publication, accompanied by a Form FDA
`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
`http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM375154.pdf. For
`more information about submission of promotional materials to the Office of Prescription Drug
`Promotion (OPDP), see http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm090142.htm.
`
`REPORTING REQUIREMENTS
`
`We remind you that you must comply with reporting requirements for an approved NDA
`(21 CFR 314.80 and 314.81).
`
`MEDWATCH-TO-MANUFACTURER PROGRAM
`
`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
`biologics qualify for inclusion for three years after approval. Your firm is eligible to receive
`copies of reports for this product. To participate in the program, please see the enrollment
`instructions and program description details at
`http://www.fda.gov/Safety/MedWatch/HowToReport/ucm166910.htm.
`
`POST APPROVAL FEEDBACK MEETING
`
`New molecular entities and new biologics qualify for a post approval feedback meeting. Such
`meetings are used to discuss the quality of the application and to evaluate the communication
`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
`improvement. If you would like to have such a meeting with us, call the Regulatory Project
`Manager for this application.
`
`PDUFA V APPLICANT INTERVIEW
`
`FDA has contracted with Eastern Research Group, Inc. (ERG) to conduct an independent interim
`and final assessment of the Program for Enhanced Review Transparency and Communication for
`NME NDAs and Original BLAs under PDUFA V (‘the Program’). The PDUFA V Commitment
`Letter states that these assessments will include interviews with applicants following FDA action
`on applications reviewed in the Program. For this purpose, first-cycle actions include approvals,
`
`Reference ID: 3643151
`
`
`
`NDA 205834
`Page 9
`
`
`complete responses, and withdrawals after filing. The purpose of the interview is to better
`understand applicant experiences with the Program and its ability to improve transparency and
`communication during FDA review.
`
`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
`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
`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
`feedback will be helpful to these assessments.
`
`If you have any questions, call Linda C. Onaga, Regulatory Project Manager, at (301) 796-0759
`or Division mainline at (301) 796-1500
`
`
`
`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
`
`