CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`214187Orig1s000
`
`SUMMARY REVIEW
`
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`

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`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`Clinical Review, Cross-Discipline Team Leader Review and Division
`Director Summary Review
`
`Date
`May 28, 2021
`
`
`Samer El-Kamary, MD, MPH
`Yodit Belew, MD, Cross-Discipline Team Leader
`From
`Poonam Mishra, MD, MPH, Deputy Division Director (Safety)
`
`
`Subject
`
`CombinedClinical Review, Cross-Discipline Team Leader
`Review and Division Director Summary Review
`
`NDA# and Supplement#
`208341/Supplement 17; 214187 (Original)
`
`
`Applicant
`
`Gilead Sciences, Incorporated.
`
`Date of Submission
`
`December 15, 2020
`
`
`
`
`
`PDUFAGoalDate June 14, 2021
`
`Proprietary Name
`
`Epclusa®
`
`Established or Proper Name
`
`Sofosbuvit/Velpatasvir (SOF/VEL)
`
`Oraltablets:
`=
`400 mg of sofosbuvir and 100 mgofvelpatasvir
`=
`200 mg sofosbuvir and 50 mg ofvelpatasvir
`Oral pellets:
`=
`200 mg sofosbuvir and 50 mg ofvelpatasvir
`=
`150 mg sofosbuvir and 37.5 mg of velpatasvir
`
`
`Dosage Form(s)
`
`Applicant Proposed
`Indication(s)/Population(s)
`
`Pediatric Patients 3 to < 6 years of age: For treatment of
`genotype 1, 2, 3, 4, 5 or 6 chronic HCV infection
`
`Applicant Proposed Dosing
`Regimen(s)
`
`Weight based dosing (see Table 2)
`
`Recommendation on Regulatory|Approval
`Action
`
`CDERCrossDiscipline Team Leader Review Template
`Version date: October 10, 2017
`
`1
`
`Reference ID: 4803217
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`Table of Contents
`Table of Contents.............................................................................................................................2
`Table of Tables ................................................................................................................................4
`1. Benefit-Risk Assessment.........................................................................................................5
`Patient Experience Data...................................................................................................................9
`2. Background............................................................................................................................10
`2.1.
`Product Information.......................................................................................................11
`2.2.
`Summary of Regulatory Activity Related to Submission..............................................11
`2.3.
`Summary of Study Protocol...........................................................................................12
`2.4.
`Protocol Amendments ...................................................................................................13
`2.4.1
`Amendment 1.........................................................................................................13
`2.4.2
`Amendment 2.........................................................................................................14
`2.4.3
`Amendment 3.........................................................................................................14
`2.4.4
`Amendment 4.........................................................................................................15
`Product Quality......................................................................................................................15
`3.
`3. Nonclinical Pharmacology/Toxicology .................................................................................15
`4. Clinical Pharmacology...........................................................................................................15
`5. Clinical Microbiology............................................................................................................15
`6. Clinical/Statistical-Efficacy...................................................................................................16
`6.1
`Disposition of Subjects..................................................................................................16
`6.2
`Demographic and Baseline Characteristics ...................................................................16
`6.3
`Efficacy Results at Week 12 after Discontinuation of Treatment (3 to < 6 years old)19
`Safety .....................................................................................................................................21
`7.1.
`Adverse Events ..............................................................................................................21
`7.2.
`Special Populations........................................................................................................25
`7.3.
`Drug Interactions ...........................................................................................................25
`7.4.
`Use in Pregnancy and Lactation ....................................................................................26
`8. Advisory Committee Meeting ...............................................................................................26
`9.
`Pediatrics................................................................................................................................26
`10. Other Relevant Regulatory Issues .........................................................................................26
`10.1
`Submission Quality and Integrity ..................................................................................26
`10.2
`Compliance with Good Clinical Practices.....................................................................27
`10.3
`Financial Disclosures.....................................................................................................27
`11. Labeling .................................................................................................................................27
`
`7.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`2
`
`Reference ID: 4803217
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`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`12. Postmarketing Recommendations .........................................................................................32
`13. Recommended Comments to the Applicant ..........................................................................32
`14. References..............................................................................................................................33
`Appendix 1.....................................................................................................................................34
`Appendix 2.....................................................................................................................................36
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`3
`
`Reference ID: 4803217
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`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`Table of Tables
`Patient Experience Data Relevant to this Application (check all that apply)................................10
`Table 1. Demographics and Baseline Characteristics....................................................................19
`Table 2. Baseline HCV Characteristics (3 to < 6 years Old).........................................................21
`Table 3. Number and Percentage of Subjects with HCV RNA <LLOQ by Treatment Visit........23
`Table 4. Overall Summary of Adverse Events (3 to < 6 Years Old) (Safety Analysis Set)..........25
`Table 5. Treatment Related Adverse Events in at Least 5% of Subjects by Treatment Group (3 to
`< 6 Years Old) .......................................................................................................................25
`Table 6. Treatment Related Adverse Events in > 1 Subject by Treatment Group (3 to < 6 Years
`Old)........................................................................................................................................26
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`4
`
`Reference ID: 4803217
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`1. Benefit-Risk Assessment
`
`Benefit-Risk Integrated Assessment
`The pharmacokinetic (PK), safety, and efficacy data submitted in this supplemental New Drug Application (sNDA) under NDA 208341 and the initial
`marketing application under NDA 214187 for 200 mg/50 mg and 150mg/37.5 mg oral pellets formulation support approval of sofosbuvir/velpatasvir
`(Epclusa®, SOF/VEL) for the treatment of chronic hepatitis C virus infection in children 3 to < 6 years of age and provides for an age-appropriate pediatric
`formulation. Throughout the review of this sNDA and NDA, no deficiencies that would preclude approval were identified. Epclusa was studied in a
`multicenter, open-label, non-comparative trial (Study GS-US-342-1143) in which 216 children (102 children 12 to < 18 years; 73 children 6 to < 12 years old,
`and 41 children 3 to < 6 years old), were enrolled and followed for 24 weeks , after completion of study treatment. The trial design comprised two phases: a
`PK lead-in phase and a treatment phase in which the safety and efficacy of SOF/VEL were evaluated. The SOF/VEL dose selection was weight-based, and
`formulation was selection based on the participant’s ability to swallow tablets; those who could not swallow tablets were administered the pellets
`formulation. The study consisted of the three cohorts: Cohort 1 (12 to < 18 years); Cohort 2 (6 to < 12 years) and Cohort 3 (3 to < 6 years). SOF/VEL is
`approved for children 6 to < 18 years (Cohorts 1 and 2). Only data for Cohort 3 are presented in this review.
`The key objective of this pediatric study was to identify a dose(s) for use in pediatric patients based on targeting an exposure in children that is similar to the
`approved adult doses. The observed exposures from VEL, SOF, and SOF major metabolite, GS-331007, in Cohort 3 were similar to those seen in the older
`children (6 to < 18 year old), and in adults. Therefore, the efficacy of SOF/VEL is extrapolated from the adult to pediatric population 3 years and older. Other
`objectives for the study include to describe the safety of SOF/VEL in pediatric subjects; and collect virologic outcome (efficacy).
`The efficacy outcome for the overall group, as measured by sustained virologic response 12 weeks after treatment completion (SVR12), was 82.9% (34/41);
`with an SVR12 of 87.5% (28/32) for genotype 1; 50% (3/6) for genotype 2; 100% (2/2) for genotype 3; and 100% (1/1) for genotype 4. Alanine
`aminotransferase (ALT) normalization was also observed. A total of 7 subjects (17.1%) did not achieve SVR12 due to drug discontinuation, without evidence
`of virologic failure. Of these 7 children, 5 discontinued the drug on Day 1 due to adverse reactions –vomiting or spitting up of drug (likely due to unplatability
`of the drug); one discontinued the treatment on Day 7 due to non-compliance; and one discontinued study drug on Day 20 due to other adverse reactions.
`SOF/VEL was generally found to be safe and reasonably well tolerated with no Grade 3 or higher adverse events, no serious adverse events and no deaths.
`The most commonly observed adverse events were similar to those seen in adults and were mild in severity, though there was a greater proportion of
`children 3 to < 6 years old who expereinced vomiting (15%) and spitting up (10%), compared to the older age groups.
`In conclusion, the benefit of SOF/VEL for the treatment of chronic hepatitis C virus infection outweighs the risks, as demonstrated in this study; and approval
`of SOF/VEL (sofosbuvir/velpatasvir, Epclusa®) for the treatment of chronic hepatitis C virus infection in children 3 to < 6 years of age is recommended by the
`review team. I, the signatory authority for this application, concur with the recommendations made by the multi-disciplinary review team.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4803217
`
`5
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`Benefit-Risk Dimensions
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
` Chronic HCV (CHC) infection remains a significant global health cause of chronic
`liver disease, cirrhosis, hepatocellular carcinoma and death.
` Hepatitis C virus (HCV) is easily transmissible through percutaneous and
`parenteral exposure, and the majority of pediatric HCV infections in the US are
`the result of vertical transmission.
` Children with CHC tend to have a mild clinical course but in some cases can
`result in serious liver inflammation and even liver failure. The long-term
`complications of liver fibrosis and cirrhosis can occur over many years, and
`when HCV infection starts in early childhood, the likelihood of developing
`these complications by early adulthood is very high.
` There is no vaccine and no post-exposure immunoprophylaxis available for HCV.
` Pegylated interferon alfa with ribavirin (PEG-IFN/RBV) is approved for children >
` years. However it is poorly tolerated with unfavorable safety profile, and is
`curative in only about half of children. Furthermore, PEG-IFN is an injectable
`medication.
` Sovaldi® (SOF) is approved in patients 3 years of age and older with HCV
`genotype 2 or 3 without cirrhosis or with compensated cirrhosis for use in
`combination with ribavirin.
` Harvoni® (a fixed dose combination (FDC) of ledipasvir [LDV] and SOF) is
`approved in pediatric patients 3 years and older with chronic HCV infection
`with:
`o Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated
`cirrhosis
`o Genotype 1 infection with decompensated cirrhosis for use with
`ribavirin
`o Genotype 1 or 4 infection who are liver transplant recipients without
`cirrhosis or with compensated cirrhosis, for use with ribavirin.
` Mavyret (a FDC of glecaprevir and pibrentasvir) is approved for pediatric patients
`
`CHC remains a major cause of morbidity and
`mortality worldwide. While it has a mild
`prognosis in most children, it can become serious
`in some cases. Furthermore, when acquired early
`in childhood, it can lead to the development of
`serious or fatal complications by early adulthood.
`This can result in a debilitating disease with
`significant limitations in a person’s professional
`and personal activities, disability, reduced healthy
`life expectancy, and potential years of life lost.
`
`Four treatments are available for adolescents;
`fewer for children less than 12 years of age. Some
`of the available therapies require coadministation
`with RBV under certain circumstances.
` Pegylated interferon/ribavirin is only
`approximately 50% effective, is injectable
`(pegylated interferon), and is associated with
`many serious adverse reactions.
` Sovaldi® and Harvoni® need to be combined
`with ribavirin (RBV) under certain
`circumstances; RBV is associated with
`toxicities.
` Mavyret is available for children 12 years and
`older and is currently under review for children
`3 – 12 years of age with PDUFA goal date of
`June 10, 2021.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4803217
`
`6
`
`(b
`)
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`12 years of age and older or weighing at least 45 kg with HCV genotype 1, 2, 3,
`4, 5 or 6 infection or genotype 1 infection who previously were treated with an
`HCV NS5A inhibitor or an NS3/4A protease inhibitor but not both.
`
` To support an efficacy claim for the use of SOF/VEL for the treatment of children
`with CHC infection 3 to < 6 years old, the applicant submitted efficacy and
`safety results from a single study (Study/Trial GS-US-342-1143), which is a
`Phase 3, open-label, non-comparator trial to evaluate a 12-week regimen of
`SOF/VEL.
` In this study, 41 subjects aged 3 years to less than 6 years of age with chronic
`HCV infection genotype 1 (n=32), genotype 2 (n=6), genotype 3 (n=2) and
`genotype 4 (n=2) were treated with SOF/VEL once daily for 12 weeks in
`treatment-naive subjects. Among the proportion (~25%) of participants
`evaluated, no cirrhosis was detected.
` The study demonstrated the effectiveness of SOF/VEL among those who
`received treatment. While the overall sustained virolocal response at week 12
`(SVR12) was 82.9% (34/41), the SVR12 was 100% among the 34 subjects who
`completed treatment. A total of 87.5% of patients with genotype 1, 50% with
`genotype 2, 100% with genotype 3 and 100% with genotype 4 who received
`the treatment achieved SVR12 which is an indication of complete viral
`clearance and cure. Additionally, among subjects who achieved SVR12,
`normalization of ALT was observed.
` Seven subjects 17.1% (7/34) did not achieve SVR12 due to early drug
`discontinuation, and had no evidence of virologic failure.
`Few adverse events were observed with Epclusa (SOF/VEL); the most common
`adverse reactions were vomiting, product use issues (spitting up of drug), fatigue
`and irritability. All events were mild or moderate in severity (Grade 1 or 2). No
`drug-related serious adverse events no deaths were reported.
`
`Of the 7 children who discontinued the drug, 5 discontinued it on Day 1 due to
`
` Benefit
`
` Risk and Risk
`Management
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4803217
`
`SOF/VEL was efficacious in clearing HCV in
`children 3 to < 6 years old. This viral clearance led
`to a ALT normalization in all the children who
`achieved SVR12.
`
`Long-term studies in children and adults have
`demonstrated that clearance of HCV
`(spontaneosly or by treatment) eliminates
`hepatic inflammation and prevents or reduces
`long-term complications such as fibrosis,
`cirrhosis, liver failure and hepatocellular cancer
`(HCC) complications. Therefore, long-term viral
`suppression in children 3 to < 6 years old can
`reasonably be presumed to prevent or lead to
`fewer complications later in their life.
`
`The frequency and severity of the adverse events
`observed in this study were similar to those
`noted in adolescents and adults.
`
`Based on the totality of safety data for SOF/VEL,
`no Risk Evaluation and Mitigation Strategy
`
`7
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`Dimension
`
`Evidence and Uncertainties
`
`adverse reactions of vomiting or spitting up of drug (likely due to poor platability);
`one discontinued the treatment on Day 7 due to non-compliance; and one
`discontinued the drug on Day 20 due to oher adverse reactions.
`
`SOF/VAL had no notable effects on development or growth (baseline to
`posttreatment Week 12) in Tanner stage, bone age, height, weight and body mass
`index (BMI) percentiles, and vital signs.
`
`Conclusions and Reasons
`
`(REMS) is recommended at this time.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4803217
`
`8
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`Patient Experience Data
`Patient Experience Data for Epclusa in children 3 to < 6 years old with chronic HCV infection
`were collected within the clinical trials. The table below summarizes Patient Experience Data
`Relevant to this Application, as described in Study GS-US-342-1143. See Appendix 1 for a
`summary of the data collected in this study.
`Patient Experience Data Relevant to this Application (check all that apply)
` The patient experience data that was submitted as part of the application
`include:
`
`Section where
`discussed, if
`applicable
`-
`Clinical study report
`(CSR) for Study GS-
`US-342-1143, Section
`12.1
`CSR for Study GS-
`US-342-1143, Section
`12.1
`-
`-
`-
`
` Clinical outcome assessment (COA) data, such as
` Patient reported outcome (PRO)
`
` Observer reported outcome (ObsRO)
`
`□ Clinician reported outcome (ClinRO)
`□ Performance outcome (PerfO)
`□ Qualitative studies (e.g., individual patient/caregiver interviews,
`focus group interviews, expert interviews, Delphi Panel, etc.)
`□ Patient-focused drug development or other stakeholder meeting
`summary reports
`□ Observational survey studies designed to capture patient experience
`data
`□ Natural history studies
`□ Patient preference studies (e.g., submitted studies or scientific
`publications)
` Other: (Please specify) Swallowability of oral tablets and
`palatability of oral pellet formulation were assessed in Study
`GS-US-342-1143.
`
`Module 2.5 (Clinical
`Overview), Section
`2.5;
`GS-US-342-1143
`CSR, Sections 8.1.4,
`8.2.4.
`□ Patient experience data that were not submitted in the application, but were considered in this
`review:
`□ Input informed from participation in meetings with patient
`stakeholders
`□ Patient-focused drug development or other stakeholder meeting
`summary reports
`□ Observational survey studies designed to capture patient
`experience data
`□ Other: (Please specify)
`□ Patient experience data was not submitted as part of this application. -
`
`-
`
`-
`
`-
`-
`
`-
`
`-
`
`-
`
`-
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`9
`
`Reference ID: 4803217
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`2. Background
`Hepatitis C virus infection is a global health challenge with an estimated global prevalence of
`1%, for a total of 71 million individuals worldwide chronically infected with HCV {The Polaris
`Observatory HCV Collaborators 2017, World Health Organization (WHO) 2018b}. Hepatitis C
`virus has significant genetic (RNA sequence) variability; 8 major genotypes have been
`identified: genotypes 1 and 3 are the most prevalent globally (46% and 30%, respectively) while
`genotypes 2, 4, and 6 represent approximately 23% of cases, genotypes 5 and 7 comprise < 1%,
`and genotype 8 has only been identified in 4 patients {Borgia 2018, Messina 2015}. There is also
`considerable geographic variability in genotype distribution {Messina 2015}. Although less
`information is available about HCV in children, the global prevalence in 2018 of HCV infection
`in children from birth to 18 years has been estimated to be 0.13%, or 3.26 million children; over
`half (1.83 million) were aged 12 to 18 years {Schmelzer 2020}. Prevalence also varies by
`geographic location, with prevalence rates estimated to be 0.04% in Western Europe and 0.06%
`in the United States (US) compared with rates of 0.40% in Eastern Europe and up to 1.74% in
`Mongolia. Approximately 50% of the children with HCV infection were estimated to be living in
`Pakistan, China, India, and Nigeria.
`
`The natural history of chronic HCV infection in children differs from that in adults since HCV
`infection in children is relatively benign. Most children chronically infected with HCV are
`asymptomatic or have mild nonspecific symptoms. However, cirrhosis has been reported in
`approximately 1% to 2% of adolescents and children with chronic HCV infection, and advanced
`liver disease and decompensated cirrhosis have been reported in children as young as 3 years of
`age and as early as 1 year after infection {Indolfi 2019}. Disease progression also may occur
`many years after the initial infection. At the time of a retrospective review of 1049 patients
`infected with HCV as children, cirrhosis developed in 32% of patients at a median of 33 years
`following diagnosis; 5% developed hepatocellular carcinoma (HCC), 4% had a liver transplant,
`and overall mortality was 3% {Modin 2019}.
`
`The goal of HCV treatment in both pediatric and adult populations is virus eradication, thereby
`preventing progressive hepatic inflammation, hepatic fibrosis, cirrhosis, and liver failure that
`result in the need for liver transplantation. The development and approval of safe and effective
`direct-acting antivirals (DAAs) have transformed the treatment and course of chronic HCV
`infection. Several DAA therapies containing sofosbuvir (SOF; Sovaldi®), an HCV
`nonstructural protein (NS) 5B-directed inhibitor, have been approved for the treatment of adults
`with chronic HCV infection {EPCLUSA® 2017, HARVONI® 2017, SOVALDI® 2017,
`Vosevi® 2017}. Sovaldi® (SOF) and Harvoni® (a fixed-dose combination [FDC] of ledipasvir
`[LDV] and SOF; LDV/SOF) also have been approved in the US and European Union (EU) for
`the treatment of patients 3 years of age and older or
` (in the US only).
`Epclusa® (a FDC of SOF and VEL) has been approved in the US and is under review in the
`EU for patients 6 to < 18 years of age or weighing ≥ 17 kg.
`
`The availability of oral DAA therapies for pediatric patients with chronic HCV infection
`represents a major therapeutic advance, by eliminating the need for weekly pegylated interferon
`(Peg-IFN) injections and incidence of systemic side effects associated with its use. However,
`SOF is given in combination with ribavirin (RBV) as is LDV/SOF for certain patients; RBV is
`associated with significant toxicities, including hematologic, constitutional, and teratogenic side
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
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`10
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`Reference ID: 4803217
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`(b) (4)
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`effects which may make treatment regimens that include RBV less desirable for treating
`pediatric patients. In addition, treatment duration with either SOF or LDV/SOF is dependent on
`HCV genotype and cirrhosis status, which also may represent a limiting factor for some pediatric
`patients. Therefore, treatment options such as SOF/VEL that do not include RBV, have fixed
`durations regardless of HCV genotype, and are effective across all HCV genotypes would be
`beneficial in the pediatric setting by decreasing the frequency of monitoring and blood tests, and
`increasing patient adherence. Moreover, the availability of a pangenotypic regimen is anticipated
`to be especially beneficial in areas where HCV genotyping may not be readily available or
`routinely performed.
`
`Product Information
`2.1.
`EPCLUSA tablets and pellets contain sofosbuvir and velpatasvir for oral administration.
`Sofosbuvir is a nucleotide analogue of HCV NS5B polymerase and velpatasvir is an HCV NS5A
`inhibitor.
`Tablets
`There are two fixed-dose combination tablet strengths available:
`400 mg/100 mg Tablets: Each tablet contains 400 mg of sofosbuvir and 100 mg of
`
`velpatasvir
`200 mg/50 mg Tablets: Each 200/50 mg tablet contains 200 mg sofosbuvir and 50 mg
`velpatasvir.
`
`
`
`Pellets
`A new pellet formulation in two strengths was submitted with this application:
`200 mg/50 mg Oral Pellets: Each packet contains 200 mg of sofosbuvir and 50 mg of
`
`velpatasvir.
`150 mg/37.5 mg Oral Pellets: Each packet contains 150 mg of sofosbuvir and 37.5 mg of
`velpatasvir.
`
`
`
`Summary of Regulatory Activity Related to Submission
`2.2.
`Study GS-US-342-1143 was conducted in accordance with postmarketing requirements under
`the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c).
` The agreed pediatric plan for SOF/VEL for the treatment of HCV infection was
`submitted to the FDA under the New Drug Application (NDA) 208341 on October 28,
`2015 (Serial No. 0001).
` A Written Request (WR) for studies of SOF/VEL in pediatric patients with HCV
`infection aged 3 to < 18 years was received by Gilead on 02 September 2016.
` The terms of the WR were further negotiated and Gilead agreed to the terms of the
`pediatric WR dated 30 January 2017 (Amendment 2).
`In the EU, a paediatric investigation plan (PIP) for SOF/VEL was agreed on May 8, 2015
`(European Medicines Evaluation Agency [EMEA]-001646-PIP01-14). Minor modifications to
`the original PIP have been agreed since this time, with the most recent EMEA Decision received
`on 18 May 2018 (EMEA-001646-PIP01-14-M02). The design of GS-US-342-1143 reflected the
`PIP decision agreed with the Pediatric Development Committee (PDCO) as part of the
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`11
`
`Reference ID: 4803217
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`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`assessment of the PIP.
`As per this review, the applicant submitted the sNDA and NDA in accordance with FDA
`guidelines. The quality and integrity of the submission were adequate, and the material was
`reviewable as submitted. According to the applicant, the pivotal trial was conducted in
`conformance with Good Clinical Practice standards and applicable local regulatory requirements
`and laws regarding ethical committee review, informed consent, and the protection of human
`subjects participating in biomedical research. These standards are consistent with the
`requirements of the US Code of Federal Regulations (CFR) Title 21, Part 312 (21CFR312).
`2.3.
`Summary of Study Protocol
`Trial GS-US-342-1143, entitled, A Phase 2, Open-Label, Multicenter, Multi-cohort Study to
`Investigate the Safety and Efficacy of Sofosbuvir/Velpatasvir in Adolescents and Children with
`Chronic HCV Infection; is a phase 2, open-label, multicohort, 2-part study that evaluated the PK,
`safety, and antiviral activity of SOF/VEL in pediatric subjects aged 3 to < 18 years with chronic
`HCV infection.
`Approximately 200 subjects were planned for enrollment: approximately 100 adolescent subjects
`12 to < 18 years old and approximately 100 pediatric subjects 3 to < 12 years old. Subjects could
`be either treatment naive or treatment experienced, with at least 20 and up to 40 subjects allowed
`to be treatment experienced. Enrollment in the three, age groups was sequential; first enrolling
`the 12 to < 18 year-old group, followed by the 6 to < 12 and the 3 to < 6 year-old groups.
`This study consisted of a PK lead-in phase (Cohorts 1, 2, and 3) and a treatment phase (Groups 1
`and 2) within each age group:
` Group 1 (including Cohort 1):
`o Adolescent subjects 12 to < 18 years old
` Group 2 (including Cohorts 2 and 3):
`o Pediatric subjects 6 to < 12 years old
`o Pediatric subjects 3 to < 6 years old
`Pharmacokinetic Lead-In Phase
`The PK lead-in phase evaluated and confirmed the age-appropriate SOF/VEL dose by analyzing
`the PK, safety, and antiviral activity of SOF/VEL through 7 days of dosing. At least 17 subjects
`were planned to be enrolled into each age-based cohort to receive the following treatments:
`
` Cohort 1 (12 to < 18 years old): Subjects received SOF/VEL FDC 400/100 mg (total
`daily dose) once a day for 7 days.
` Cohort 2 (6 to < 12 years old): Subjects received SOF/VEL FDC 200/50 mg (total
`daily dose) once a day for 7 days.
` Cohort 3 (3 to < 6 years old, with at least 6 subjects weighing ≥ 17 kg and at least 6
`subjects weighing < 17 kg):
`o Subjects weighing ≥ 17 kg received SOF/VEL FDC 200/50 mg (total daily dose) once a
`day for 7 days. Subjects weighing < 17 kg received SOF/VEL FDC 150/37.5 mg (total
`daily dose) once a day for 7 days.
`Subjects underwent an intensive PK evaluation on Day 7.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`12
`
`Reference ID: 4803217
`
`

`

`NDA 208341 Supplement 17; NDA 214187
`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Review
`
`Treatment Phase
`Subjects who completed the PK lead-in phase were immediately enrolled into the treatment
`phase with no interruption of study drug administration. Additional subjects were enrolled into
`the treatment phase upon confirmation of the appropriateness of the dose from the PK lead-in
`phase.
`
`Approximately 100 subjects, including subjects from Cohort 1 of the PK lead-in phase, were
`planned to be enrolled into Group 1:
` Group 1 (12 to < 18 years old): Subjects received SOF/VEL FDC 400/100 mg (total
`dose) orally, once daily for 12 weeks.
`
`Approximately 100 subjects, including subjects from Cohort 2 (6 to < 12 years old) and Cohort
`3 (3 to < 6 years old) of the PK lead-in phase, were planned to be enrolled into Group 2:
` Group 2 (6 to < 12 years old): Subjects received SOF/VEL FDC 200/50 mg (total
`daily dose) orally, once daily for 12 weeks.
` Group 2 (3 to < 6 years old):
`o Subjects weighing ≥ 17 kg received SOF/VEL FDC 200/50 m