CENTER FOR DRUG EVALUATION AND
`
`
`
` RESEARCH
`
`
`
`
` APPLICATION NUMBER:
`
`
`212477Orig1s000
`
`
`
`
` SUMMARY AND CLINICAL
`
`REVIEW
`
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`
`
` Clinical Review, Cross-Discipline Team Leader Review and Division
`
`Director Summary Memo
`
`
`Date
`
`From
`
`Subject
`
`NDA# and Supplement#
`Applicant
`Date of Submission
`PDUFA Goal Date
`Proprietary Name
`Established or Proper Name
`
`Dosage Form(s)
`
`Applicant Proposed
`Indication(s)/Population(s)
`
` Applicant Proposed Dosing
`Regimen(s)
`Recommendation on Regulatory
`Action
`
`August 27, 2019
`Samer El-Kamary, MD, MPH, Medical Officer
`Kimberly Struble, PharmD, Cross-Discipline Team
`Leader
`Debra Birnkrant, MD, Division Director
`Combined Clinical Review, Cross-Discipline Team
`Leader Review and Division Director Summary Memo
`205834/Supplement 29
`212477
`Gilead Sciences, Incorporated.
`February 28, 2019
`August 28, 2019
`Harvoni
`Ledipasvir/Sofosbuvir (LDV/SOF)
`Oral tablets:
`45 mg ledipasvir and 200 mg sofosbuvir
`
`Oral pellets:
`45 mg ledipasvir and 200 mg sofosbuvir
`
`33.75 mg ledipasvir and 150 mg sofosbuvir
`
`Pediatric Patients 3 to < 12 years of age: For treatment
`
`of genotype 1, 4, 5 and 6 HCV infection
`Weight based dosing (see Table 2)
`
`Approval
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`1
`
`Reference ID: 4482913
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`Table of Contents
`Table of Contents.............................................................................................................................2
`
`I. Executive Summary.................................................................................................................5
`
`Summary of Regulatory Action....................................................................................................5
`
`II. Benefit-Risk Assessment .........................................................................................................6
`
`Conclusions Regarding Benefit and Risk .....................................................................................9
`
`Patient Experience Data.........................................................................................................10
`
`1
`2. Background............................................................................................................................12
`
`2.1.
`Product Information.......................................................................................................14
`
`2.2.
`Summary of Regulatory Activity Related to Submission..............................................14
`
`2.3.
`Summary of Study Protocol...........................................................................................14
`
`2.4.
`Protocol Amendments ...................................................................................................18
`
`3. Product Quality......................................................................................................................19
`
`4. Nonclinical Pharmacology/Toxicology .................................................................................19
`
`5. Clinical Pharmacology...........................................................................................................19
`
`6. Clinical Microbiology............................................................................................................19
`
`7. Clinical/Statistical-Efficacy...................................................................................................19
`
`7.1.
`6 to < 12 years old cohort ..............................................................................................20
`
`7.1.1.
`Disposition of Subjects ..........................................................................................20
`
`7.1.2.
`Demographic and Baseline Characteristics ...........................................................20
`
`7.1.3.
`Efficacy Results at Week 12 after Discontinuation of Treatment (6 to < 12 years
`
`old)
`23
`
`7.2.
`3 to < 6 years old cohort ................................................................................................24
`
`7.2.1.
`Disposition of Subjects ..........................................................................................24
`
`7.2.2.
`Demographic and Baseline Characteristics ...........................................................25
`
`7.2.3.
`Efficacy Results at Week 12 after Discontinuation of Treatment (3 to < 6 years
`
`old)
`27
`
`8. Safety .....................................................................................................................................29
`
`8.1.
`6 to < 12 years old cohort ..............................................................................................29
`
`8.2.
`3 to < 6 years old cohort ................................................................................................33
`
`8.3.
`Special Populations........................................................................................................36
`
`8.4.
`Drug Interactions ...........................................................................................................36
`
`8.5.
`Use in Pregnancy and Lactation ....................................................................................36
`
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`2
`
`Reference ID: 4482913
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`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`9. Advisory Committee Meeting ...............................................................................................36
`
`10. Pediatrics................................................................................................................................37
`
`11. Other Relevant Regulatory Issues .........................................................................................37
`
`11.1
`Submission Quality and Integrity ..................................................................................37
`
`11.2 Compliance with Good Clinical Practices.....................................................................37
`
`11.3
`Financial Disclosures.....................................................................................................37
`
`12. Labeling .................................................................................................................................38
`
`13. Postmarketing Recommendations .........................................................................................43
`
`14. Recommended Comments to the Applicant ..........................................................................43
`
`References......................................................................................................................................44
`
`Appendix 1.....................................................................................................................................45
`
`Appendix 2.....................................................................................................................................46
`
`
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`Version date: October 10, 2017
`
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`Reference ID: 4482913
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`

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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`Table of Tables
`Patient Experience Data Relevant to this Application (check all that apply)................................10
`
`Table 1: Dosage of LDV/SOF by Weight in Study Protocol GS-US-337-1116 ...........................16
`
`Table 2: Recommended Dosing for Ribavirin in Combination Therapy with HARVONI for
`
`Pediatric Patients 3 Years and Older .....................................................................................17
`
`Table 4. Baseline HCV Characteristics (6 to < 12 years Old).......................................................22
`
`Table 5. Number and Percentage of Subjects with HCV RNA <LLOQ by On Treatment Visit
`
`and by Genotype ....................................................................................................................24
`
`Table 6. Demographics and Baseline Characteristics....................................................................26
`
`Table 7. Baseline HCV Characteristics (3 to < 6 years Old).........................................................27
`
`Table 8. Number and Percentage of Subjects with HCV RNA <LLOQ by On Treatment Visit
`
`and by Genotype ....................................................................................................................28
`
`
`Table 9. Overall Summary of Adverse Events (6 to < 12 Years Old) (Safety Analysis Set).......30
`
`Table 10. Overall Summary of Common Adverse Events in at Least 10% of Subjects by
`
`Treatment Group (6 to < 12 Years Old) ................................................................................31
`
`Table 11. Treatment Related Adverse Events in > 1 Subject by Treatment Group (6 to < 12
`
`Years Old)..............................................................................................................................32
`
`Table 12. Overall Summary of Adverse Events (3 to < 6 Years Old) (Safety Analysis Set)........34
`
`Table 13. Treatment Related Adverse Events in at Least 1% of Subjects by Treatment Group (3
`
`to < 6 Years Old) ...................................................................................................................35
`
`Table 14. Treatment Related Adverse Events in > 1 Subject by Treatment Group (3 to < 6 Years
`
`Old) ........................................................................................................................................35
`
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`4
`
`Reference ID: 4482913
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
` Executive Summary
`I.
`
` Summary of Regulatory Action
`
`The new drug application (NDA) for HARVONI® (ledipasvir/sofosbuvir; LDV/SOF) 33.75
`mg/150 mg and 45 mg/200 mg oral pellets and the supplemental NDA for LDV/SOF 45/200 mg
`tablets are submitted by Gilead Sciences. The NDA was reviewed by the multi-disciplinary
`review team and each discipline recommended approval for the NDA. I, the signatory authority
`for this application, concur with the recommendations from the review team. LDV/SOF will be
`approved for children three years of age and older with:
` Genotype 1, 4, 5, or 6 infection without cirrhosis or with compensated cirrhosis
` Genotype 1 infection with decompensated cirrhosis, in combination with ribavirin
` Genotype 1 or 4 infection who are liver transplant recipients
`without cirrhosis or with compensated cirrhosis, in combination with
`ribavirin.
`The Applicant submitted a multicenter, open-label, non-comparative trial in which 124 children
`(90 children 6 to < 12 years old, and 34 children 3 to < 6 years old), were enrolled and followed
`for 12 weeks after discontinuation 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 the sofosbuvir were
`evaluated. The LDV/SOF dose was based on the child’s weight, with tablets for those who could
`swallow them and pellets for the younger age groups. The LDV exposure, SOF exposure and the
`
`exposure for its major metabolite, GS-331007, were similar to those seen in the adolescent (12 to
`< 18 year old) age group and in adults. This trial was not powered for true statistical analysis of
`safety or efficacy. However, the results were compared to the efficacy results of Phase 3 trials of
`LDV/SOF in adults and adolescents.
`
`The efficacy outcome, as measured by sustained virologic response 12 weeks after treatment
`discontinuation (SVR12) was 98.3% (119/121) for genotype 1 and 100% (3/3) for genotype 4,
`
`and they also normalized their alanine aminotransferase (ALT). Only two subjects did not
`achieve SVR12 and did not normalize their ALT (one had a virologic failure [relapse] and
`
`another one had discontinued treatment due to unplatability of the drug). LDV/SOF was safe and
`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 nature. The overall Benefit-Risk is favorable as described in the Benefit-Risk Assessment
`below.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`5
`
`Reference ID: 4482913
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`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`
`
` II. Benefit-Risk Assessment
`
`Benefit-Risk Dimensions
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`
`
` 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 active CHC inflammation 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 > 3
`
`year. However it has a poor tolerability and safety profile, and are curative in
`
`only a small fraction. Furthermore, PEG-IFN is an injectable medication.
` Although the proportion of children 3 to <12 years or older who will be
`
`
`recommended for treatment are relatively few, safer all-oral treatment options
`are needed.
`
` 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 can lead to the development of serious
`
`
`or fatal complications by early adulthood. This can
`
`result in a debilitating disease at the prime
`productive years of an individual, with significant
`
`limitations in a person’s professional and personal
`
`activities, disability, reduced healthy life
`expectancy, and potential years of life lost.
`
`
`
` There is only one other treatment option for
` children younger than 12 years of age infected
`
`
`with CHC, pegylated interferon/ribavirin which is
`
`only effective in about half the cases, is injectable
`(pegylated interferon), and has many serious side-
`
`effects.
`
`Analysis of
`Condition
`
`Current
`Treatment
`Options
`
`
`
`The availability of another therapy, particularly
`one that is all-oral, with a much higher efficacy and
`
`safety is highly desirable.
`
`6
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4482913
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Benefit
`
`  To support an efficacy claim for the use of LDV/SOF (Harvoni) for the treatment of
`
`
` children with CHC infection in children 3 to < 12 years old, the applicant
` submitted the 24 Week efficacy and safety results from a single study (Study
`
`
` Trial GS-US-337-1116), which is a Phase 3, open-label, non-comparator trial.
` In this study, 126 subjects aged 3 years to less than 12 years of age with chronic
`
`
` HCV infection genotype 1 (n=120), and genotype 4 (n=3) were treated with
`LDV/SOF once daily for 12 weeks (treatment Naive with/without cirrhosis; or
`treatment experienced without cirrhosis); one subject with genotype 1 was
`
`treated with LDV/SOF once daily for 24 weeks (treatment experienced with
`cirrhosis); and two subjects with genotype 3 (n=2) were treated with LDV/SOF +
`ribavirin (RBV) for 24 weeks.
` Given that Harvoni is not approved for treatment of genotype 3, the efficacy of
`
`
`genotype 3 was not taken into consideration, and only the safety data related to
`these two subjects was assessed. These were also the only two subjects in this
`
`cohort to receive RBV, thereby providing information on safety and tolerability
`of RBV with LDV/SOF for 24 weeks .
` The study demonstrated a high efficacy among those who received treatment. A
`total of 98.3% of patients with genotype 1, and 100% with genotype 4 who
`received the treatment achieved a sustained virolocal response at week 12
`
`(SVR12) which is an indication of complete viral clearance and cure. Also, all
`subjects who achieved SVR12 achieved ALT normalization.
`
`
` In HCV-infected adults, LDV/SOF is approved to treat patients with genotype 5 or
`
`
`
`6; however, no genotype 5 or 6 pediatric subjects were enrolled in the current
`trial. HCV genotype does not affect LDV/SOF exposure and previous trials in
`adults have demonstrated that an equivalent LDV/SOF exposure is efficacious in
`adults with chronic HCV genotype 5 and 6. Therefore, the submitted PK data are
`adequate to support the efficacy of LDV/SOF for treatment of HCV genotypes 5
`
`or 6 in patients 3 years of age and older. A similar rationale is used to support
`
`
`dosing recommendations for pediatric patients with HCV genotype 1 infection
`
`who have decompensated cirrhosis (Child-Pugh B or C) and for pediatric patients
`
`LDV/SOF was highly efficacious in clearing HCV in
`
`children 3 to < 12 years old. This viral clearance led
`to a ALT normalization in all the children who
`achieved SVR12, which is reflective of reduced
`hepatic inflammation.
`
`
`Given long-term studies in children adults,
`clearance of HCV (spontaneosly or by treatment)
`
`
`stops resultant liver inflammation and prevents or
`reduces long-term complications such as fibrosis,
`
`cirrhosis, liver failure and hepatocellular
`complications. It is reasonable to assume that
`long-term viral suppression in children 3 to < 12
`years old would also prevent or lead to fewer
`complications later in their life.
`
`
`The SVR12 results were similar between the age
`
`cohorts and also similar with the adult and
`adolescent population.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4482913
`
`7
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`with HCV genotype 1 or 4 infection who are liver transplant recipients without
`cirrhosis or with compensated cirrhosis
`
` Risk and Risk
`
`
`Management
`
`LDV/SOF had a few mild side-effects, the most common of which were vomiting,
`
`
`headache, fatigue, nausea, pyrexia, abdominal pain, cough,vomiting and diarrhea. All
`
`
`of them were categorized as mild (Grade 1 or 2 Adverse Events). There were no
`
`drug-related Serious Adverse Events, and no deaths. Only one child discontinued the
`
`drug due to inability to take the drug due to the sensation of an abnormal taste.
`
` The frequency of side-effects observed in this
`
`
`
` study were all mild and similar to those noted in
`adolescents and adults. The safety results were
`
`similar between the age cohorts and also similar
`
`with the adolescent population.
`
`
`There were no notable effects of treatment on development or growth
`(baseline to posttreatment Week 24) in Tanner stage, bone age, height, weight
`and Body Mass Index (BMI) percentiles, and vital signs.
`
`Based on the available safety profile for LDV/SOF,
`no Risk Evaluation and Mitigation Strategy (REMS)
`is recommended at this time.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4482913
`
`8
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`
`
` Conclusions Regarding Benefit and Risk
`
` CHC remains a major cause of morbidity and mortality worldwide. While CHC has a mild prognosis in most children, CHC can
`
`become serious in some cases. Currently, pegylated interferon/ribavirin is only treatment option for children less than 12 years of age
`who are infected with CHC. Pegylated interferon/ribavirin is only effective in about half the cases, is injectable (pegylated interferon),
`and has many serious side-effects. The overall benefit-risk assessment of LDV/SOF is favorable as demonstrated by the high SVR12
`rates (98.3% (119/121) for genotype 1 and 100% (3/3) for genotype 4). LDV/SOF was safe and 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 nature. The availability of LDV/SOF for children less than 12 years of age is a major public health
`
`benefit and offers children three years of age and older with HCV genotype 1, 4, 5 and 6 infection a safe and effective all-oral
`treatment option.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4482913
`
`9
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`1 Patient Experience Data
`Patient Experience Data for Harvoni in children 3 to < 12 years old with HCV infection were collected within the clinical trials. The
`table below presents where Patient Experience Data Relevant to this Application is described in Study GS-US-337-1116. 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
`
` Section where
`discussed, if
`include:
`applicable
`-
`Clinical study report
`CSR for Study GS­
`US-337-1116
`Synopsis, Section 12.1
`Clinical study report
`CSR for Study GS­
`US-337-1116
`Synopsis, Section 12.1
`-
`-
`-
`
`-
`
`-
`
`-
`-
`
`Module 2.5, Section
`2.5; GS-US-337-1116
`
`10
`
` 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
`
`
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4482913
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`GS-US-337-1116.
`
`
`
`CSR Synopsis,
`Sections 8.1.4, 8.2.4,
`8.3.4.
` □ 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
`
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`11
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`2. Background
`Hepatitis C virus (HCV) is the main cause of chronic liver disease worldwide, and the global
`prevalence of chronic HCV was estimated to average 1% in 2015, for a total of 71 million
`individuals {The Polaris Observatory HCV Collaborators 2017, World Health Organization
`(WHO) 2018b}. Globally, there are an estimated 2.1 to 3.5 million children 15 years of age or
`younger with chronic HCV {Nwaohiri 2018, European Association for the Study of the Liver
`(EASL) 2018a}. The prevalence varies by geographic location, with an estimated prevalence of
`
`0.4% in Europe and the United States (US), for a total of forty-six thousand children in the US;
`and up to 6% in resource-limited countries {El-Shabrawi 2013, Khaderi 2014}.
`
`Most children chronically infected with HCV are asymptomatic or have mild nonspecific
`symptoms. In approximately 20%, clinical symptoms are present in the first 4 years of life, with
`hepatomegaly being the most frequent sign (10%); and in some cases severe liver disease is
`encountered {Mohan 2010}. Many, but not all, perinatally infected children will have
`intermittently or persistently abnormal alanine aminotransferase (ALT) or aspartate
`aminotransferase (AST) levels, particularly in the first 2 years of life. Despite the more favorable
`prognosis compared to adults, approximately 4% to 6% of children with chronic HCV infection
`have evidence of advanced fibrosis or cirrhosis, and some children will eventually require liver
`transplantation for end-stage liver disease {Hu 2010}.
`
`The primary goal of treating HCV in children is to prevent HCV-related complications from
`occurring during childhood or later in adulthood. Although progression to cirrhosis typically
`
`takes place over a period of 10-30 years, four to five percent of HCV-infected children develop
`advanced liver fibrosis or cirrhosis during childhood, some of whom develop advanced liver
`disease requiring liver transplantation {Mack 2012}. In addition, chronic HCV is associated with
`extrahepatic disorders in children including glomerulonephritis and central nervous system HCV
`
`infection, which has been associated with developmental delay, learning disorders and cognitive
`deficits {Mack 2012}.
`
`Currently available treatment for children younger than 12 years of age with chronic HCV
`infection is limited to pegylated interferon (IFN) and ribavirin combination therapy.
`Approximately 75% of patients who received IFN and RBV will experience at least one adverse
`event, 10-20% of patients will prematurely discontinue IFN and RBV, and 20-30% will require
`dose modification of one of the two drugs. IFN-related toxicities include bone marrow
`depression, flu-like symptoms, neuropsychiatric disorders, and autoimmune syndromes. The
`
`main toxicity associated with ribavirin is hemolytic anemia {Manns 2006}. Weight loss and
`reduced height growth have been observed in children receiving IFN and RBV {Jonas 2012,
`Wirth 2012}.
`
`Although direct acting antivirals (DAA) have been FDA-approved for treatment of chronic HCV
`infection in adults since 2011, and in adolescents older than 12 years of age since 2017, none
`have been approved for use in pediatric patients younger than 12 years. Treatment of chronic
`HCV with DAAs has resulted in a shorter duration of treatment than with IFN and RBV
`regiments, higher percentages of subjects with SVR compared to IFN and RBV, and has allowed
`12
`
`CDER Cross Discipline Team Leader Review Template
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`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`for IFN-free treatment. As such, the current international guidelines recommend that in subjects
`younger than 12 years, treatment should be deferred until direct antiviral agents are available
`{American Association for the Study of Liver Diseases (AASLD) 2017, European Association
`for the Study of the Liver (EASL) 2018b, Indolfi 2018, World Health Organization (WHO)
`2018a}. Therefore, it is important to have DAAs available for treatment of chronic HCV
`infection in younger children.
`
`Ledipasvir/sofosbuvir (LDV/SOF, Harvoni®) was first approved for commercial marketing in the
`United States (US) on 10 October 2014, and is indicated for the treatment of genotype 1, 4, 5, or
`6 HCV infection. The marketing application for LDV/SOF was updated on 07 April 2017 in the
`US to expand the indication for the treatment of patients 12 years of age and older, or weighing
`at least 35 kg, with genotype 1, 4, 5, or 6 HCV infection. A country-specific protocol amendment
`was created to allow for the enrollment of pediatric subjects with genotype 3 in Europe to receive
`LDV/SOF+RBV x 24 weeks. Because LDV/SOF is not approved for genotype 3 adults in the
`United States, no genotype 3 pediatric subjects were enrolled in the US, and they were not
`included in this clinical review.
`
`In this supplemental NDA, LDV/SOF was evaluated in a single open-label, uncontrolled,
`pharmacokinetic (PK), safety, and efficacy trial in 124 children 3 to less than 18 years old in four
`countries (US, UK, Australia and New Zealand). The goal of pediatric development in HCV was
`to determine whether the PK and safety in children was similar to that of adults, given that the
`HCV disease process is similar to adults. An open-label, uncontrolled design was considered
`acceptable because of the high SVR12 rates reported in adolescent and adult subjects treated
`with LDV/SOF, and the ethical concerns associated with the poor response rate and toxicity
`associated with use of IFN-containing regimens.
`
`Electronic materials submitted included the final Clinical Study Report (CSR) and the
`accompanying datasets as required. This pediatric supplement (NDA 205834) fulfills the
`following outstanding post-marketing requirements (PMR) under the Pediatric Research Equity
`Act (PREA):
` PMR 2780-1 under PREA to provide data for 3 to <18 year old HCV-infected children.
` PMR 2983-1 and 2985-1 to evaluate the PK, safety and HCV treatment response of
`LDV/SOF in children 3 to <18 years of age.
`The efficacy supplement also supports a new oral pellet formulation for children (NDA 212477)
`mg tablet and is a response to the pediatric written request.
`
`This supplement provides the final data from Study GS-US-337-1116 through post-treatment
`Week 24 from in a Final Clinical Study Report (CSR) for evaluating the proposed indication for
`LDV/SOF in the treatment of genotype 1 and 4 chronic HCV infection for all children 3 to < 18
`
`
`year old. Although the protocol allowed for the enrollment of genotypes 5 and 6, none could be
`enrolled. Only data for pediatric subjects 3 to < 12 years old are presented in this clinical
`review. Data for the adolescent age group 12 to < 18 years old were presented in the GS-US­
`
`337-1116 Interim CSR submitted in 2016, and the LDV/SOF was approved for that age group in
`
`2017. For a full clinical review of the data for adolescent subjects 12 to < 18 years old, please
`refer to Dr. Virginia Sheikh’s review in the original NDA 205834.
`
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`13
`
`Reference ID: 4482913
`
`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`Product Information
`
`2.1.
`Tablets
`HARVONI tablets are fixed-dose combination tablets containing ledipasvir and sofosbuvir for
`oral administration. Ledipasvir is an HCV NS5A inhibitor and sofosbuvir is a nucleotide analog
`inhibitor of HCV NS5B polymerase. Each 90 mg/400 mg tablet contains 90 mg ledipasvir and
`400 mg sofosbuvir. Each 45 mg/200 mg tablet contains 45 mg ledipasvir and 200 mg sofosbuvir.
`
`Pellets
`HARVONI oral pellets are for oral administration, supplied as small, orange pellets in unit-dose
`packets. Each unit-dose of HARVONI oral pellets contains either 45 mg ledipasvir and 200 mg
`sofosbuvir or 33.75 mg ledipasvir and 150 mg sofosbuvir
`
` Summary of Regulatory Activity Related to Submission
`2.2.
`
`
`In the US, Study GS-US-336-1117 was conducted in accordance with postmarketing
`requirements under the Pediatric Research Equity Act (PREA) (21 U.S.C. 355c).
` The agreed pediatric plan for LDV/SOF in the treatment of HCV infection was submitted
`
`to the FDA to Investigational New Drug (IND) 115268 on 02 January 2014(Serial No.
`0119) and to New Drug Application (NDA) 205834 on 08 February 2014(Seq No. 0000).
`
` A Written Request (WR) for studies of LDV/SOF 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 10 February 2017 (Amendment 2), which includ