`
`
`
`Trade Name:
`
`
`
`Generic or Proper
`Name:
`
`Sponsor:
`
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Approval Package for:
`
`APPLICATION NUMBER:
`
` 208341Orig1s000
`
`
`Epclusa Tablet, 400 mg/100 mg
`
`sofosbuvir and velpatasvir
`
`Gilead Sciences, Inc.
`
`June 28, 2016
`
`For the treatment of adult patients with chronic hepatitis C
`virus (HCV) genotypes 1, 2, 3, 4, 5, or 6 infection:
` Without cirrhosis or with compensated cirrhosis; and
` With decompensated cirrhosis for use in combination
`with ribavirin.
`
`Approval Date:
`
`
`Indication:
`
`
`

`

`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`208341Orig1s000
`
`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 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
`X
`X
`
`

`

`
`
`
`
`
`
`
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`
`APPLICATION NUMBER:
`208341Orig1s000
`
`
`APPROVAL LETTER
`
`

`

`
`
`
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`
`
`
`
`
`NDA 208341
`
`
`
`
`
`Food and Drug Administration
`Silver Spring MD 20993
`
`NDA APPROVAL
`
`
`Gilead Sciences, Inc.
`Attention: Prachi Shah, MBS, RAC
`Manger, Regulatory Affairs
`333 Lakeside Drive
`Foster City, CA 94404
`
`
`Dear Ms. Shah:
`
`Please refer to your New Drug Application (NDA) dated and received October 28, 2015, and
`your amendments submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act
`(FDCA) for EPCLUSA® (sofosbuvir and velpatasvir) tablet, 400 mg/100 mg.
`
`This new drug application provides for the use of EPCLUSA® (sofosbuvir and velpatasvir) tablet
`for the treatment of adult patients with chronic hepatitis C virus (HCV) genotypes 1, 2, 3, 4, 5, or
`6 infection:
`• without cirrhosis or with compensated cirrhosis; and
`• with decompensated cirrhosis for use in combination with ribavirin.
`
`We also acknowledge receipt of the information related to the EPCLUSA® (sofosbuvir and
`velpatasvir) tablet, 400 mg/100 mg, for the Gilead Access Program that was reviewed as a part
`of this application.
`
`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.
`
`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, text for
`the patient package insert, Medication Guide). 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
`/UCM072392.pdf.
`
`
`Reference ID: 3951919
`
`

`

`NDA 208341
`Page 2
`
`
`The SPL will be accessible via publicly available labeling repositories.
`
`
`IMMEDIATE CONTAINER LABELS
`
`Submit final printed immediate container labels that are identical to the enclosed immediate
`container labels submitted on May 18, 2016 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 208341.” 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: 6360
`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).
`
`
`
`ADVISORY COMMITTEE
`
`Your application for EPCLUSA was not referred to an FDA advisory committee because the
`application did not raise significant safety or efficacy issues that were unexpected and outside
`expertise was not necessary as there were not significant issues that would benefit from an
`advisory committee discussion.
`
`REQUIRED PEDATRIC 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.
`
`
`Reference ID: 3951919
`
`

`

`NDA 208341
`Page 3
`
`
`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 HCV clearance is
`possible and very few patients in this age group require treatment.
`
`We are deferring submission of your pediatric studies for ages 3 years to less than 18 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)(C) of the FDCA. These required studies are
`listed below.
`
`
`3092-1
`
`
`
`3092-2
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment response
`(using sustained virologic response) of sofosbuvir and velpatasvir in pediatric
`subjects 12 through less than 18 years of age with chronic hepatitis C virus
`infection.
`
`
`
`
`
`06/2016
`03/2019
`09/2019
`
`Final Protocol Submission:
`Study Completion:
`
`Final Report Submission:
`
`Conduct a study to evaluate the pharmacokinetics, safety and treatment response
`(using sustained virologic response) of sofosbuvir and velpatasvir in pediatric
`subjects 3 through less than 12 years of age with chronic hepatitis C virus
`infection.
`
`
`
`
`
`
`
`06/2016
`10/2020
`04/2021
`
`Final Protocol Submission:
`Study Completion:
`
`Final Report Submission:
`
`Submit the protocols to your IND 118605, with a cross-reference letter to this NDA.
`
`Reports of these required pediatric postmarketing studies must be submitted as an 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.
`
`
`Reference ID: 3951919
`
`

`

`•
`
`•
`
`NDA 208341
`Page 4
`
`
`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:
`• assess a signal of a serious risk of increased toxicity, including rhabdomyolysis, as a
`result of a potential pharmacokinetic-based interaction between atorvastatin and the
`components of EPCLUSA (sofosbuvir and velpatasvir);
`identify unexpected serious risks in HCV/HIV-1 coinfected patients receiving EPCLUSA
`(sofosbuvir and velpatasvir) concurrently with HIV antiretroviral therapy,
`• assess a known serious risk of toxicity due to elevated exposure to tenofovir levels in
`HCV/HIV-1 coinfected patients receiving EPCLUSA (sofosbuvir and velpatasvir) with
`a tenofovir-containing regimen;
`• assess a known serious risk of virologic failure and persistence of treatment-emergent
`drug resistant viral populations in hepatitis C virus genotype 3 patients with cirrhosis that
`may limit future re-treatment options;
`identify serious adverse events including progression of liver disease, liver-related
`mortality, or liver failure requiring liver transplantation in patients with decompensated
`Child-Pugh Turcotte (CPT) C cirrhosis treated with EPCLUSA (sofosbuvir and
`velpatasvir).
`
`
`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.
`
`Finally, we have determined that only a clinical trial (rather than a nonclinical or observational
`study) will be sufficient to:
`
`
`•
`
`•
`
`• assess a signal of a serious risk of increased toxicity, including rhabdomyolysis, as a
`result of a potential pharmacokinetic-based interaction between atorvastatin and the
`components of EPCLUSA (sofosbuvir and velpatasvir);
`identify unexpected serious risks in HCV/HIV-1 coinfected patients receiving EPCLUSA
`(sofosbuvir and velpatasvir) concurrently with HIV antiretroviral therapy,
`• assess a known serious risk of toxicity due to elevated exposure to tenofovir levels in
`HCV/HIV-1 coinfected patients receiving EPCLUSA (sofosbuvir and velpatasvir) with
`a tenofovir-containing regimen;
`• assess a known serious risk of virologic failure and persistence of treatment-emergent
`drug resistant viral populations in hepatitis C virus genotype 3 patients with cirrhosis that
`may limit future re-treatment options;
`identify serious adverse events including progression of liver disease, liver-related
`mortality, or liver failure requiring liver transplantation in patients with decompensated
`Child-Pugh Turcotte (CPT) C cirrhosis treated with EPCLUSA (sofosbuvir and
`velpatasvir).
`
`
`Therefore, based on appropriate scientific data, FDA has determined that you are required to
`conduct the following:
`
`
`Reference ID: 3951919
`
`

`

`NDA 208341
`Page 5
`
`
`
`3092-3
`
`
`
`
`3092-4
`
`
`The timetable you submitted on June 7, 2016, states that you will conduct this trial according to
`the following schedule:
`
`
`Conduct a drug interaction trial to evaluate the interaction between sofosbuvir and
`velpatasvir and atorvastatin.
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`08/2016
`12/2016
`05/2017
`
`Submit the final clinical report and datasets for the ongoing trial GS-US-342-1202
`(ASTRAL-5), titled “A Phase 3, Open-label Study to Investigate the Efficacy and
`Safety of Sofosbuvir/GS-5816 Fixed Dose Combination for 12 weeks in Subjects
`with Chronic Hepatitis C Virus (HCV) and Human immunodeficiency Virus
`(HIV)-1 Coinfection,” to provide safety data in HIV-1/HCV co-infected subjects
`receiving sofosbuvir and velpatasvir concurrently with HIV antiretroviral therapy.
`
`
`The timetable you submitted on May 13, 2016, states that you will conduct this trial according to
`the following schedule:
`
`
`
`
`
`08/2016
`12/2016
`
`
`Trial Completion:
`Final Report Submission:
`
`Conduct a trial in hepatitis C virus genotype 3 infected subjects with cirrhosis
`treated with sofosbuvir and velpatasvir to determine if the addition of ribavirin
`improves the efficacy (i.e., sustained virologic response rate) and reduces the rate
`of virologic failure.
`
`3092-5
`
`3092-6
`
`
`The timetable you submitted on May 13, 2016, states that you will conduct this trial according to
`the following schedule:
`
`
`
`
`
`06/2017
`06/2018
`
`
`Trial Completion:
`Final Report Submission:
`
`Collect, analyze, and submit data from the HCV infected subjects with
`decompensated Child-Pugh Turcotte (CPT) C cirrhosis treated with
`sofosbuvir/velpatasvir regimen to obtain safety data in a broader decompensated
`cirrhosis population (genotype 1-6 HCV infection).
`
`
`The timetable you submitted on May 13, 2016, states that you will conduct this trial according to
`the following schedule:
`
`
`Final Protocol Submission:
`Trial Completion:
`
`Final Report Submission:
`
`
`
`
`
`08/2016
`05/2018
`05/2019
`
`Reference ID: 3951919
`
`

`

`NDA 208341
`Page 6
`
`
`
`3092-7
`
`
`Submit the protocols to your IND 118605, with a cross-reference letter to this NDA. Submit all
`final reports 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
`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:
`
`
`Collect, analyze, and submit data on subjects with cirrhosis including
`decompensated cirrhosis who achieve sustained virologic response following
`treatment with a sofosbuvir/velpatasvir-based regimen to evaluate durability of
`virologic response and to characterize clinical outcomes such as progression or
`regression of liver disease, liver-related mortality, occurrence of hepatocellular
`carcinoma, or liver failure requiring liver transplantation. Data collected should
`include 5 years of follow-up.
`
`
`The timetable you submitted on May 13, 2016, states that you will conduct this trial according to
`the following schedule:
`
`
`
`Study Completion:
`Final Report Submission:
`
`
`
`
`01/2022
`01/2023
`
`
`
`Reference ID: 3951919
`
`

`

`NDA 208341
`Page 7
`
`
`
`3092-8
`
`Conduct site-directed mutant phenotypic analyses of sofosbuvir against an HCV
`genotype 3 replicon with the following substitutions: NS5B_L314F,
`NS5B_L314I, and NS5B_L314P.
`
`
`The timetable you submitted on May 13, 2016, states that you will conduct this trial according to
`the following schedule:
`
`
`
`
`02/2017
`
`Final Report Submission:
`
`Submit clinical protocols to your IND 118605 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,
`Medication Guide, and patient PI (as applicable) to:
`
`
`OPDP Regulatory Project Manager
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Prescription Drug Promotion
`5901-B Ammendale Road
`Beltsville, MD 20705-1266
`
`
`Alternatively, you may submit a request for advisory comments electronically in eCTD format.
`For more information about submitting promotional materials in eCTD format, see the draft
`Guidance for Industry (available
`at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
`s/UCM443702.pdf ).
`
`
`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.
`
`Reference ID: 3951919
`
`

`

`NDA 208341
`Page 8
`
`
`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,
`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.
`
`
`Reference ID: 3951919
`
`

`

`NDA 208341
`Page 9
`
`
`FDA BENEFIT-RISK FRAMEWORK APPLICANT INTERVIEW
`
`FDA has also contracted with Eastern Research Group, Inc. (ERG) to conduct an assessment of
`FDA’s initial phase implementation of the Benefit-Risk Framework (BRF) in human drug
`review. A key element of this evaluation includes interviews with applicants following FDA
`approval of New Molecular Entity (NME) New Drug Applications (NDAs) and original Biologic
`License Applications (BLAs). The purpose of the interview is to assess the extent to which the
`BRF provides applicants with a clear understanding of the reasoning behind FDA’s regulatory
`decisions for NME NDAs and original BLAs.
`
`ERG will contact you to schedule a BRF 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 reports. 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 this evaluation.
`
`If you have any questions, call Linda C. Onaga, MPH, Regulatory Project Manager, at (301)
`796-0759 or the Division mainline at (301) 796-1500.
`
`
`
`Sincerely,
`
`{See appended electronic signature page}
`
`John Farley, MD, MPH
`Deputy Director
`Office of Antimicrobial Products
`Center for Drug Evaluation and Research
`
`
`
`Enclosure(s):
`Content of Labeling
`Container Labeling
`
`Reference ID: 3951919
`
`

`

`---------------------------------------------------------------------------------------------------------
`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
`06/28/2016
`
`Reference ID: 3951919
`
`