CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`208341Orig1s000
`
`RISK ASSESSMENT and RISK MITIGATION
`REVIEW(S)
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`Department of Health and Human Services
`Public Health Service
`Food and Drug Administration Center for
`Drug Evaluation and Research Office of
`Surveillance and Epidemiology
`Office of Medication Error Prevention and Risk Management
`Risk Evaluation and Mitigation Strategy (REMS) Review
`
`
`Date:
`
`Reviewer:
`
`April 18, 2016
`
`Erin Hachey, PharmD, Division of Risk Management (DRISK)
`
`Acting Team Leader:
`
`Jamie Wilkins Parker, PharmD, DRISK
`
`Acting Division Director: Kellie Taylor, PharmD, MPH, DRISK
`
`
`
`Evaluation to determine if a REMS is necessary
`
`Subject:
`
`Sofosbuvir/Velpatasvir 400 mg / 100 mg fixed-dose
`Drug Name(s):
`combination (FDC)
`
`Nucleotide analog inhibitor of Hepatitis C virus (HCV)
`Therapeutic Class:
`nonstructural protein 5B (NS5B) polymerase and nonstructural
`
`protein 5A (NS5A) inhibitor
`
`
`One tablet orally once daily
`Dosage and Route:
`Treatment of hepatitis C virus (HCV) infection in adult patients
`Proposed Indication:
`with HCV genotypes (GT) 1, 2, 3, 4, 5, or 6
`
`Application Type/Number: NDA 208341
`Sponsor:
`Gilead Sciences, Inc.
`OSE RCM #:
`2015-2434
`
`*** This document contains proprietary and confidential information that should not be released
`to the public. ***
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`Reference ID: 3918827
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`INTRODUCTION
`1
`This review by the Division of Risk Management (DRISK) evaluates whether a risk evaluation
`and mitigation strategy (REMS) for the new molecular entity (NME) fixed-dose combination
`(FDC) of sofosbuvir/velpatasvir (SOF/VEL) is necessary to ensure the benefits of this product
`outweigh its risks. A new drug application (NDA 208341) for SOF/VEL was received on
`October 28, 2015, from Gilead Sciences, Inc. (Gilead). The proposed indication for SOF/VEL is
`the treatment of adult patients with chronic Hepatitis C virus (HCV) genotypes (GT) 1, 2, 3, 4, 5,
`or 6. Velpatasvir is the NME component of the application and will be available only in the FDC
`product currently under review. Sofosbuvir is approved for use as a single entity (Sovaldi, NDA
`204671) and in combination with ledipasvir in an FDC tablet (Harvoni, NDA 205834) for the
`treatment of chronic HCV in adults, and does not have a REMS. The Sponsor did not include a
`proposed REMS or risk management plan for SOF/VEL in this submission.
`1.1 Background
`1.1.1 Disease Background
`HCV infection is a serious and potentially life-threatening disease. It affects 3-5 million people
`in the U.S. Infection with the single-stranded RNA virus hepatitis C can result in both acute and
`chronic hepatitis. Approximately 20 to 30 percent of newly infected persons develop signs and
`symptoms of an acute illness, which can include fever, fatigue, loss of appetite, and other non-
`specific symptoms. Although the acute disease is usually self-limited, the immune response is
`mostly insufficient to eradicate the virus such that acute infection leads to chronic infection in
`60% to 80% of cases. Chronic HCV infection is associated with ongoing liver inflammation and
`often follows a progressive course over years to decades, increasing the risk of liver fibrosis,
`cirrhosis, and hepatocellular carcinoma.
`
`HCV lacks a proofreading mechanism during replication that leads to frequent viral mutations
`and viral heterogeneity. At least seven distinct HCV genotypes and more than 60 subtypes have
`been identified, with varying geographic distribution. Genotype 1 (GT 1) is the most common
`genotype in the United States (72%), with GT 2 (11%), GT 3 (9%), and GT 4 (6%) being less
`common, and GT 5 and 6 occur uncommonly (≤ 1%) in the U.S. The viral diversity and
`heterogeneity have prevented the development of a vaccine and also affect the completeness of
`response to antiviral therapy.
`
`The standard measure of efficacy for antiviral therapy is the absence of detectable HCV RNA,
`termed sustained virologic response (SVR), documented 12 weeks after the end of treatment
`(SVR12)1, and considered a virologic cure. The type and duration of antiviral therapy selected is
`dependent on the viral genotype, the patient’s baseline disease and host factors, the patient’s
`prior treatment experience and response, among other factors.
`
`
`
`1 Viswanathan P and Connelly S. Division of Antiviral Products, Clinical Review of SOF/VEL, NDA 208341, dated March
`29, 2016.
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`Reference ID: 3918827
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`HCV has been treated with combinations of indirect acting antivirals and direct acting antivirals
`(DAA). The indirect acting agents typically used include interferon alpha and ribavirin (RBV),
`which have broad antiviral activity, but are associated with many toxicities and modest efficacy
`against HCV. DAA are designed to target specific non-structural HCV proteins involved in
`RNA replication. Some agents inhibit the non-structural protein (NS) 3/4A serine protease,
`which cleaves the HCV polyprotein into several polypeptides with distinct functions. Other
`DAAs target the NS5A protein necessary for viral assembly and replication, or inhibit the NS5B
`RNA-dependent RNA polymerase responsible for replication of HCV RNA. Various DAAs of
`the same class may have similar targets; however, their degrees of activity across the HCV GTs
`may differ.2
`
`Great progress has been made in improving SVR12 rates among patients with all stages of
`hepatic dysfunction. However, at this time, no DAA regimens are approved for patients with
`decompensated cirrhosis and GT 2, 4, 5, or 6 HCV infection. Therefore, a need exists for well-
`tolerated and cost-effective DAA combinations that provide the highest rates of viral eradication
`in all patients (including those with advanced liver disease), the broadest spectrum of action on
`viral genotypes showing minimal or no clinical resistance, and the shortest treatment duration.3
`1.1.2 Product Background
`
`Sofosbuvir/velpatasvir (SOF/VEL) is a fixed dose combination (FDC) tablet containing two
`direct acting antiviral (DAA) agents which interfere with the replication of HCV. Velpatasvir is
`a novel HCV NS5A inhibitor that has demonstrated potent antiviral activity against GT 1, 2, 3,
`4, 5, and 6 HCV infection. Sofosbuvir is an HCV nucleotide analog NS5B polymerase inhibitor
`that has been approved for use in combination with other agents for the treatment of chronic
`HCV infection in adults, in the United States, the European Union, and more than 20 other
`countries worldwide.
`
`The Sponsor’s proposed indication is treatment of patients with chronic HCV infection;
`intended subpopulations include treatment-naïve (TN) and treatment-experienced (TE) patients,
`and patients with compensated and decompensated cirrhosis. The Sponsor’s recommended
`dosage and treatment duration for non-cirrhotic patients and patients with compensated cirrhosis
`(Child-Pugh Class A) is one (400 mg/ 100 mg) tablet by mouth once daily for 12 weeks. The
`recommended treatment regimen for patients with decompensated cirrhosis (Child-Pugh Class
`B or C) is one tablet by mouth once daily, in combination with ribavirin (RBV), for 12 weeks.
`When administered with SOF/VEL, the recommended dosage of RBV is based on weight: 1000
`mg per day for patients < 75 kg, and 1200 mg per day for patients weighing at least 75 kg,
`divided and administered twice daily with food. The Sponsor has not proposed a different dose
`or duration of SOF/VEL based on HCV GT or prior treatment experience. At this time, dosing
`recommendations are still under review. A dosage recommendation cannot be made for patients
`with severe renal impairment or end stage renal disease. The combination regimen of SOF/VEL
`and RBV is contraindicated in patients for whom RBV is contraindicated.
`
`2 Viswanathan P and Connelly S. Division of Antiviral Products, Clinical Review of SOF/VEL, NDA 208341, dated March
`29, 2016.
`3 Aghemo, A., & De Francesco, R. (2013). New horizons in hepatitis C antiviral therapy with direct‐acting antivirals.
`Hepatology, 58(1), 428‐438.
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`1.2 REGULATORY HISTORY
`The following is a summary of the regulatory history for NDA 208341 relevant to this review:
`
`September 30, 2013: The Sponsor was granted Fast Track designation for SOF/VEL for the
`treatment of chronic HCV GT 1, 2, 3, 4, 5, and 6.
`
`May 15, 2015: The Sponsor was granted Breakthrough Therapy designation for SOF/VEL for
`the treatment of chronic HCV GT 3, 4, 5, and 6 infection in treatment naïve patients.
`
`May 26, 2015: A Pre-NDA meeting was held between the Agency and the Sponsor via
`teleconference. One agreement resulting from this meeting was the involvement of an
`Independent Adjudication Committee (IAC) to screen for potential cases of drug-induced liver
`injury (DILI) in the pivotal Phase 2 and 3 trials for SOF/VEL.
`
`October 28, 2015: An original NDA submission was received by the Agency from Gilead for
`SOF/VEL (NDA 208341) for the treatment of adult patients with chronic (HCV) genotypes 1,
`2, 3, 4, 5, or 6. The Sponsor did not submit a proposed REMS.
`
`February 11, 2016: The Mid-Cycle communication was held between the Agency and the
`Sponsor via teleconference. The Agency informed the Sponsor that, based on the currently
`available data, the review team had not identified any major safety concerns for SOF/VEL.
`
`There is no Advisory Committee planned for this application.
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`MATERIALS REVIEWED
`2
`The following is a list of materials that informed our review:
`• Gilead. Proposed Prescribing Information for SOF/VEL, dated October 28, 2015.
`• Gilead. Clinical Overview for SOF/VEL, dated October 28, 2015.
`• Gilead. Summary of Clinical Efficacy for SOF/VEL, dated October 28, 2015.
`• Gilead. Summary of Clinical Safety for SOF/VEL, dated October 28, 2015.
`• Gilead. Proposed Prescribing Information for SOF/VEL, dated October 28, 2015.
`o Updated March 31, 2016.
`• Viswanathan P and Connelly S. Division of Antiviral Products, Clinical Review of
`SOF/VEL, NDA 208341, dated March 29, 2016.
`• Pratt, B. DRISK, REMS Review for Ledipasvir/Sofosbuvir, dated July 18, 2014.
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`RESULTS OF REVIEW
`3
`3.1 Overview of Clinical Program
`
`The safety and efficacy of SOF/VEL for the treatment of patients with chronic HCV were
`evaluated in a Phase 2 dose-ranging study, and four randomized pivotal Phase 3 trials which
`evaluated a total of 1302 subjects in the SOF/VEL treatment arms. SVR12 was the primary
`efficacy endpoint in all SOF/VEL Phase 2 and 3 studies. The pivotal trial populations varied
`based on the subjects’ HCV GT and cirrhosis status, and pre-specified historical control rates
`were used to determine comparative statistical significance. All major HCV genotypes and
`many different HCV subtypes were treated with SOF/VEL.
`
`Trial 342-0109 was a Phase 2 dose-ranging study that evaluated 323 patients to determine the
`efficacy and safety of 2 doses of VEL (25 mg and 100 mg) combined with 400 mg SOF, with
`or without RBV, administered for 12 weeks in treatment-experienced (TE) subjects with or
`without cirrhosis and GT 1 or 3 HCV infection. This trial provided the only data in the
`SOF/VEL clinical program for the use of RBV in GT 3 cirrhotics. The overall SVR12 rates
`were 89% and 96% in the SOF/VEL and SOF/VEL + RBV groups, respectively, with a
`treatment difference of -8% [95% CI -28%, 10%]. The Clinical reviewers concluded that the
`difference in SVR12 rates between the two groups was not statistically significant because the
`sample size was small and the 95% CI included 0. The Clinical reviewers also noted that,
`among GT3 subjects, SVR rates were higher for the 100 mg VEL dose than the 25 mg dose;
`however, the role of RBV was less clear.
`
`ASTRAL-1 (Trial 342-1138) is an ongoing Phase 3, double-blind, placebo-controlled trial
`assessing the antiviral efficacy, safety, and tolerability of SOF/VEL in treatment-naïve (TN)
`and TE subjects with compensated liver disease and HCV GT 1, 2, 4, 5, or 6. A total of 740
`subjects were randomized in a 5:1 ratio to receive SOF/VEL for 12 weeks (n=624) or placebo
`for 12 weeks (n=116). However, due to the small size of the affected population, all subjects
`with GT5 HCV infection were enrolled into the SOF/VEL 12-week group. The trial met its
`primary efficacy endpoint with an overall SVR12 rate of 99% in the SOF/VEL group and 0%
`in the placebo group. Four subjects in the SOF/VEL group did not achieve SVR12 due to
`missing data; the Clinical reviewer noted that, though they were coded as failures, they were
`not true virologic failures.
`
`ASTRAL-2 (Trial 342-1139) is an ongoing Phase 3, open-label, active-control trial assessing
`TN and TE subjects with compensated liver disease and HCV GT2. A total of 266 subjects
`were randomized to receive SOF/VEL for 12 weeks (n=134) or SOF + RBV (n=136) for 12
`weeks. The percentage of subjects achieving SVR12 was 99.3% in the SOF/VEL group,
`compared with 93.9% in the SOF + RBV group, a treatment difference of 5.4% with 95% CI
`(0.2%, 10.3%).
`
`ASTRAL-3 (Trial 342-1140) is an ongoing Phase 3, open-label, active-control trial assessing
`TN and TE subjects with compensated liver disease and HCV GT3. A total of 552 subjects
`were randomized to receive SOF/VEL for 12 weeks (n=277) or SOF + RBV for 24 weeks
`(n=275). The percentage of subjects achieving SVR12 was 95% in the SOF/VEL group,
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`compared with 80% in the SOF + RBV group, a treatment difference of 15% and 95% CI
`(10%, 20%).
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`ASTRAL-4 (Trial 342-1137) is a Phase 3, open-label trial assessing TN and TE subjects with
`Child-Pugh Class B cirrhosis at screening (with no prior history of a liver transplant) with
`HCV GT 1-6. The Clinical reviewer noted that approximately 10% of the subjects who were
`Child-Pugh Class B at screening, were subsequently reclassified as Class A or C at baseline,
`which demonstrates the dynamic changes in Child-Pugh parameters over time. A total of 267
`subjects were randomized to receive SOF/VEL for 12 weeks (n=90), SOF/VEL + RBV for 12
`weeks (n=88), or SOF/VEL for 24 weeks (n=90).
`
`The percentage of subjects achieving SVR12 was 83.3%, 94.3%, and 85.6% in the SOF/VEL
`for 12 weeks, SOF/VEL + RBV for 12 weeks, and SOF/VEL for 24 weeks groups, respectively.
`The percentage of subjects experiencing relapse was 12.2%, 2.4%, and 8% in the SOF/VEL for
`12 weeks, SOF/VEL + RBV for 12 weeks, and SOF/VEL for 24 weeks groups, respectively.
`Across the four pivotal trials, SOF/VEL demonstrated SVR12 rates ranging from 83-100%
`depending on the regimen, HCV GT, and cirrhosis stage. In addition, SOF/VEL is the first
`direct acting antiviral regimen with potent activity across HCV GT 1-6. According to the
`Clinical reviewers, SOF/VEL is a highly effective, RBV-free, single tablet, once-daily
`treatment option for TN and TE patients with compensated liver disease, regardless of HCV
`GT. Further, treatment with SOF/VEL + RBV confers the highest SVR12 rates observed to date
`across HCV GT 1-6 in subjects with decompensated cirrhosis.4
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`SAFETY CONCERNS
`3.2
`The safety of SOF/VEL for the treatment of adult patients with chronic HCV was evaluated
`based primarily on the four aforementioned Phase 3 trials. The data from Trials ASTRAL-1,
`ASTRAL-2, and ASTRAL-3 were pooled to form the integrated summary of safety (ISS)
`population, while data from ASTRAL-4 were analyzed separately. Additional data was
`obtained from the following three Phase 2 trials:
`• Trial 342-0102: A randomized, open-label, multi-center dose-ranging Phase 2 trial to
`evaluate safety and efficacy (using SVR12 as the primary endpoint) of SOF/VEL with
`or without RBV in 377 subjects with HCV GT 1-6 for 8 or 12 weeks
`• Trial 342-0109: Similar in design to Trial 342-0102, this trial evaluated 323 subjects
`with GT 1 or 3, for 8 weeks
`• Trial 337-0122: Similar in design to Trial 342-0109, this single-center trial evaluated
`103 subjects with GT 3
`
`
`For the purpose of this review, serious adverse events (SAEs) associated with SOF/VEL are
`defined by the regulatory definition of a serious outcome, such as death, a life-threatening
`reaction, or hospitalization (among other outcomes). Severe adverse events (AEs) associated
`with SOF/VEL are defined as Grade 3 or 4 using the GSI Grading Scale for Severity of Adverse
`Events and Laboratory Abnormalities. The Sponsor utilized an independent adjudication
`
`4 Viswanathan P and Connelly S. Division of Antiviral Products, Clinical Review of SOF/VEL, NDA 208341, dated March
`29, 2016.
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`committee (IAC) to review potential cases of drug-induced liver injury (DILI) because of the
`difficulty in identifying it in patients with HCV. In addition, a thorough hepatic safety review
`was conducted by the Agency’s Clinical reviewers, and the conclusions reached by the
`Agency’s reviewers were compared to those of the IAC.
`
`
`3.2.1 Deaths
`A total of 6 deaths occurred in the ISS population through the time of NDA submission, 3 of
`which occurred more than three months after completing treatment. Three of the events
`occurred in SOF/VEL subjects, and 3 in SOF+RBV subjects. Five of these deaths were
`determined by both the Sponsor and the Clinical reviewer to be unrelated or not likely to be
`related to SOF/VEL treatment. The remaining death was in a subject that had been taking
`SOF+RBV in ASTRAL-3. The subject was found dead in her bed on Day 141 of treatment, and
`the death was attributed to “natural causes.” The Clinical reviewer noted that an autopsy was
`not performed and the Sponsor could not provide any additional information to help adjudicate
`the event. Therefore, the reviewer concluded that the cause of death was unclear, as was the
`contribution of SOF or RBV, or her comorbid conditions.
`
` A
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` total of 10 deaths were reported in ASTRAL-4, 2 of which were treatment-emergent: sepsis
`following duodenal ulcer perforation (SOF/VEL+RBV 12-week), and myocardial infarction in
`a subject with ongoing tobacco use (SOF/VEL 24-week). None of the ten deaths were
`considered treatment-related by the investigator, and the Clinical reviewer concurred.
`
`
`3.2.2 Serious Adverse Events (SAEs)
`
`Serious adverse events (SAEs) were infrequent in the ISS population, occurring in 2% of
`subjects in both the SOF/VEL and SOF+RBV 12-week treatment groups, and 5% of subjects in
`the SOF+RBV 24-week treatment group. There were no SAEs reported in the placebo group.
`In ASTRAL-4, 16-19% of SOF/VEL-treated subjects experienced an SAE, with the most
`frequently-reported in the system organ classes (SOCs) of Infections and Infestations and
`Gastrointestinal disorders. However, SAEs in these SOCs were reported in ≤ 8% in any
`SOF/VEL-containing treatment group and no SAEs were considered by the investigator to be
`related to SOF/VEL. SAEs considered by the investigator to be related to study treatment
`occurred in 2 subjects (0.7%): dyspnea related to RBV and hepatorenal syndrome/
`hypertension/ peritonitis/ sepsis, which was assessed by the IAC as unlikely related to
`SOF/VEL treatment.
`
`No major safety issues concerning SOF/VEL were identified by the Clinical reviewers.
`Sofosbuvir has been associated with serious bradycardia when co-administered with
`amiodarone and another DAA. Therefore, amiodarone treatment was prohibited in the four
`pivotal trials and no cases of serious bradycardia were observed. RBV is associated with
`common adverse reactions and some serious risks, but these safety issues are well known and
`are not exacerbated by concomitant administration with SOF/VEL.5 Section 5 of the SOF/VEL
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`5 Viswanathan P and Connelly S. Division of Antiviral Products, Draft Clinical Review of SOF/VEL, NDA 208341.
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`Prescribing Information will include a Warning and Precaution regarding risks associated with
`serious symptomatic bradycardia related to co-administration of sofosbuvir with amiodarone
`and another DAA, as well as a warning regarding risks associated with RBV therapy.
`
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`3.2.3 Severe Adverse Events
`Grade 3 and 4 adverse events (AEs) occurred infrequently in the ISS population. Subjects in the
`SOF + RBV 24-week arm of ASTRAL-3 had the highest rate of serious AEs, presumably due
`to the longer duration of RBV. No pattern of similar events was observed and most events
`occurred in a single subject. Events occurring in more than 2 subjects in the SOF/VEL group
`included headache (n=5), anxiety (n=3), and acute myocardial infarction determined not to be
`related to the study drug (n=2).
`
`In ASTRAL-4, severe AEs considered by the investigator to be related to the study drug
`occurred in 1.5% of all subjects, and ranged from 0-2% across SOF/VEL-containing groups.
`The Clinical reviewers concluded that there was no clear safety signal emerging from the ISS
`and ASTRAL-4 results. The severe AEs in ASTRAL-4 were mainly attributed to infectious
`etiology, RBV use and/or associated with decompensated cirrhosis (hematemesis, hepatic
`encephalopathy, spontaneous bacterial peritonitis).
`
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`3.2.4 Adverse Events of Special Interest (AESI)
`
`3.2.4.1 Safety of SOF/VEL in Subjects with Child-Pugh Class C Cirrhosis
`Safety analyses were performed to determine if any unique safety signals were identified in
`subjects with baseline cirrhosis (ASTRAL-4). Subjects with Child-Pugh Class C cirrhosis (n=11)
`had higher percentages of SAEs in the SOF/VEL+RBV 12-week (50%, n=2) and SOF/VEL 24-
`week (50%, n=3) groups, compared to subjects with baseline Child-Pugh Class A or B
`(approximately 15%) cirrhosis, reflecting more advanced underlying liver disease. These SAEs
`included infectious colitis and cellulitis/skin ulcer in the 12-week group, and incarcerated umbilical
`hernia (fatal), pulmonary hypertension, hepatorenal syndrome/ hypotension/ peritonitis/ sepsis/
`adrenal insufficiency associated with orthotopic liver transplantation in the 24-week group.
`Additional safety data of SOF/VEL-containing therapy in the Child-Pugh Class C population is
`likely to be recommended as a postmarketing requirement (PMR) to further evaluate unique safety
`signals that may impact future labeling. The use of SOF/VEL in this population will be monitored
`further in the postmarketing setting for any potential serious safety signals associated with the
`treatment.
`
`DISCUSSION
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`4
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`DRISK does not recommend a REMS as necessary to ensure the benefits of SOF/VEL outweigh
`the risks. HCV is a serious and life-threatening disease that infects an estimated 3-5 million people
`in the U.S. If left untreated, chronic HCV can lead to life-threatening liver complications, liver
`failure, and possibly, death. The Warnings and Precautions section of the SOF/VEL Prescribing
`Information will include a warning about the risks associated with RBV therapy. These are known
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`risks associated with drug therapies that are currently approved without a REMS. The label will
`also include a warning about the serious risks associated with sofosbuvir when administered with
`amiodarone and another DAA. This risk can be communicated through labeling. Based on the
`currently available data, there is an absence of concerning safety signals unique to the SOF/VEL
`combination. Additional safety data of SOF/VEL-containing therapy in the Child-Pugh Class C
`population may be included in a PMR, which is currently under discussion. The most frequently
`reported severe AEs associated with SOF/VEL are also associated with the approved treatments
`interferon and ribavirin, and none of the currently approved antiviral drugs for HCV infection
`require a REMS to ensure the benefits of treatment outweigh the risks.
`
`The most likely prescribers of SOF/VEL are specialists who are familiar with the management of
`chronic HCV and who understand the risks of treatment using antiviral therapies that have more
`serious safety profiles than this product appears to have. Like the HCV antiviral agents already
`approved, the risks related to SOF/VEL therapy will be communicated through the Prescribing
`Information, and additional measures do not appear to be necessary.
`
`Therefore, based on the currently available data, DRISK and DAVP concurred that a REMS is not
`necessary to ensure the benefits of SOF/VEL outweigh the risks.
`
`CONCLUSION
`
`5
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`At this time, risk mitigation measures beyond professional labeling are not warranted for
`SOF/VEL. Based on the currently available data, DRISK and DAVP concurred that the benefit-
`risk profile for SOF/VEL is acceptable for the treatment of adults with chronic HCV infection, and
`the risks will be communicated to the prescribing community through the labeling. Therefore, a
`REMS is not necessary to ensure the benefits outweigh the risks for SOF/VEL.
`
`Should DAVP have any concerns or questions, or if new safety information becomes available,
`please contact DRISK.
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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/
`----------------------------------------------------
`
`ERIN M HACHEY
`04/18/2016
`
`KELLIE A TAYLOR
`04/19/2016
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`Reference ID: 3918827
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`