`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`
`212480Orig1s000
`
`MULTI-DISCIPLINE REVIEW
`Summary Review
`Office Director
`Cross Discipline Team Leader Review
`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
`204671/Supplement 14
`NDA 212480
`Gilead Sciences, Incorporated.
`February 28, 2019
`August 28, 2019
`Sovaldi
`sofosbuvir (SOF)
`Oral tablets: 200 mg
`Oral pellets: 150 mg and 200 mg
`Pediatric Patients 3 to < 12 years of age: For treatment
`of genotype 2 or genotype 3 HCV infection
`Weight based dosing (see Table 3 in Labeling)
`
`Approval
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4483174
`
`1
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`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`Table of Contents
`1
`Executive Summary.................................................................................................................5
`Summary of Regulatory Action....................................................................................................5
`II Benefit-Risk Assessment.........................................................................................................6
`Conclusions Regarding Benefit and Risk.....................................................................................8
`Patient Experience Data...........................................................................................................9
`1.
`2. Background............................................................................................................................11
`2.1.
`Product Information.......................................................................................................13
`2.2.
`Summary of Regulatory Activity Related to Submission..............................................13
`2.3.
`Summary of Study Protocol...........................................................................................13
`2.4.
`Protocol Amendments ...................................................................................................17
`Product Quality......................................................................................................................18
`3.
`4. Nonclinical Pharmacology/Toxicology.................................................................................18
`5. Clinical Pharmacology...........................................................................................................18
`6. Clinical Microbiology............................................................................................................18
`7. Clinical/Statistical-Efficacy...................................................................................................18
`7.1.
`Cohort 2: 6 to < 12 years old .........................................................................................18
`7.1.1.
`Disposition of Subjects..........................................................................................18
`7.1.2.
`Demographic and Baseline Characteristics ...........................................................19
`7.1.3.
`Efficacy Results at Week 12 after Discontinuation of Treatment (6 to < 12 years
`old)
`20
`7.2.
`Cohort 3: 3 to < 6 years old ...........................................................................................21
`7.2.1.
`Disposition of Subjects..........................................................................................21
`7.2.2.
`Demographic and Baseline Characteristics ...........................................................22
`7.2.3.
`Efficacy Results at Week 12 after Discontinuation of Treatment (3 to < 6 years
`old)
`23
`Safety .....................................................................................................................................25
`8.1.
`Cohort 2: 6 to < 12 years old .........................................................................................26
`8.2.
`Cohort 3: 3 to < 6 years old ...........................................................................................29
`8.3.
`Special Populations........................................................................................................32
`8.4.
`Drug Interactions ...........................................................................................................32
`8.5.
`Use in Pregnancy and Lactation ....................................................................................32
`9. Advisory Committee Meeting ...............................................................................................32
`10.
`Pediatrics............................................................................................................................33
`
`8.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4483174
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`Other Relevant Regulatory Issues .....................................................................................33
`11.
`Submission Quality and Integrity ..................................................................................33
`11.1
`Compliance with Good Clinical Practices.....................................................................33
`11.2
`Financial Disclosures.....................................................................................................33
`11.3
`Labeling .............................................................................................................................34
`12.
`Postmarketing Recommendations .....................................................................................39
`13.
`Recommended Comments to the Applicant ......................................................................40
`14.
`References......................................................................................................................................41
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
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`Reference ID: 4483174
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`Table of Tables
`Patient Experience Data Relevant to this Application (check all that apply)..................................9
`Table 1: Dosage of Sofosbuvir by Weight ....................................................................................15
`Table 2: Recommended Dosing for Ribavirin in Combination Therapy with HARVONI for
`Pediatric Patients 3 Years and Older .....................................................................................16
`Table 3. Demographics and Baseline Characteristics....................................................................19
`Table 4. Baseline HCV Characteristics (6 to < 12 years Old).......................................................20
`Table 5. Number and Percentage of Subjects with HCV RNA <LLOQ by On Treatment Visit
`and by Genotype....................................................................................................................21
`Table 6. Demographics and Baseline Characteristics....................................................................22
`Table 7. Baseline HCV Characteristics (3 to < 6 years Old).........................................................23
`Table 8. Number and Percentage of Subjects with HCV RNA <LLOQ by On Treatment Visit
`and by Genotype....................................................................................................................24
`Table 9. Overall Summary of Adverse Events ..............................................................................26
`(6 to < 12 Years Old) (Safety Analysis Set)..................................................................................26
`Table 10. Overall Summary of Common Adverse Events in at Least 10% of Subjects by
`Treatment Group (6 to < 12 Years Old) ................................................................................27
`Table 11. Treatment Related Adverse Events in > 1 Subject by Treatment Group (6 to < 12
`Years Old)..............................................................................................................................28
`Table 12. Overall Summary of Adverse Events (3 to < 6 Years Old) (Safety Analysis Set)........30
`Table 13. Treatment Related Adverse Events in at Least 2 Subjects by Treatment Group (3 to < 6
`Years Old)..............................................................................................................................31
`Table 14. Treatment Related Adverse Events in > 1 Subject by Treatment Group (3 to < 6 Years
`Old)........................................................................................................................................31
`Dose received by weight as per protocol versus what is recommended in the label.....................34
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4483174
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`1 Executive Summary
`Summary of Regulatory Action
`The new drug application (NDA) for SOVALDI (sofosbuvir; SOF) 150 mg and 200 mg oral
`pellets and the supplemental NDA for SOF 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. SOF will be approved for the treatment of chronic
`hepatitis C virus (HCV), genotypes 2 or 3 infection in pediatric patients 3 years of age and older
`without cirrhosis or with compensated cirrhosis in combination with ribavirin.
`
`The Applicant submitted a multicenter, open-label, non-comparative trial in which 54 children
`(41 children 6 to < 12 years old, and 13 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 sofosbuvir dose was based on the child’s weight, with tablets for those who could
`swallow them and pellets for the younger age groups. The 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 SOF in
`adults and adolescents.
`The efficacy outcome, as measured by sustained virologic response 12 weeks after treatment
`discontinuation (SVR12) was a 100% genotype 2 and 3 in all subjects except one, who
`discontinued treatment due to unplatability of the drug. All children who achieved SVR12 also
`normalized their ALT. None of them had virologic failure (breakthrough, rebound or
`nonresponse) or relapse. The drug 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
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`Reference ID: 4483174
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`II Benefit-Risk Assessment
`
`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
`Benefit-Risk Dimensions
`
`Analysis of
`Condition
`
` 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.
`
`Current
`Treatment
`Options
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4483174
`
`Chronic HCV infection (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 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.
`
`The availability of another therapy, particularly
`one that is all-oral, with a much higher efficacy and
`safety is highly desirable.
`
`6
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`Dimension
`
`Evidence and Uncertainties
`
`Conclusions and Reasons
`
` To support an efficacy claim for the use of SOF (Sovaldi) for the treatment of
`children with chronic hepatitis C (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-334-1112), which is a Phase 3, open-label, non-
`comparator trial.
` In this study, 54 subjects aged 3 years to less than 12 years of age with chronic HCV
`infection genotype 2 (n=18) were treated with SOF + RBV once daily for 12
`weeks; and those with genotype 3 (n=36) were treated with SOF + RBV once
`daily for 24 weeks.
` The study demonstrated that 100% of patients who received the treatment
`achieved a sustained virolocal response at week 12 (SVR12) which is an
`indication of complete viral clearence and cure. Also, all subjects who completed
`the treatment also achieved ALT normalization.
`
`Benefit
`
`Risk and Risk
`Management
`
`SOF had a few mild side-effects, the most common of which were vomiting,
`headache, fatigue, cough, nasopharyngitis, decreased appetite, 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.
`
`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.
`
`CDER Cross Discipline Team Leader Review Template
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`Reference ID: 4483174
`
`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 took
`the treatment, 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.
`SVR12 rates were comparable between age
`cohorts and similar to adolescents and adults.
`The frequency of side-effects observed in this
`study were all mild and similar to those noted in
`adolescents and adults.
`
`Based on the available safety profile for SOF, no
`Risk Evaluation and Mitigation Strategy (REMS) is
`recommended at this time.
`
`7
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`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 the 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 for SOF/RBV in children 3 years to less than 12 years of age with CHC genotype 2
`and 3 is favorable as demonstrated by the high SVR12 rates. SVR12 rate was a 100% genotype
`2 and 3 in all subjects except one, who discontinued treatment due to unplatability of the drug
`Also, all subjects who completed the treatment also achieved ALT normalization. SOF/RBV was
`safe and well tolerated with 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 these children with HCV genotype 2 and 3 infection a safe and effective all-oral
`treatment option.
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
`
`Reference ID: 4483174
`
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`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-334-1112. See Appendix 1 for a
`summary of the data collected in this study.
`
` Clinical outcome assessment (COA) data, such as
` Patient reported outcome (PRO)
`
` Observer reported outcome (ObsRO)
`
`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
`include:
`discussed, if
`applicable
`-
`Clinical study report
`CSR for Study GS-
`US-334-1112
`Synopsis, Section 12.1
`Clinical study report
`CSR for Study GS-
`US-334-1112
`Synopsis, Section 12.1
`-
`-
`-
`
`□ 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-334-1112.
`
`Module 2.5, Section
`2.5; GS-US-334-1112
`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)
`
`-
`
`-
`
`-
`-
`
`-
`
`-
`
`-
`
`-
`
`CDER Cross Discipline Team Leader Review Template
`Version date: October 10, 2017
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`Reference ID: 4483174
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`□ Patient experience data was not submitted as part of this application. -
`
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`Reference ID: 4483174
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`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
`
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`Reference ID: 4483174
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`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.
`
`Sofosbuvir was first approved for commercial marketing in the United States (US) on 06
`December 2013 and in the European Union (EU) on 16 January 2014, for use in combination
`with ribavirin (RBV) for the treatment of chronic HCV with genotype 2 and 3 infection in adults.
`The marketing application for SOF was updated on 07 April 2017 in the US and on 14
`September 2017 in the EU to expand the indication for the treatment of patients 12 years of age
`and older, or weighing at least 35 kg (in the US only), with genotype 2 or 3 HCV infection.
`
`In this supplemental NDA, sofosbuvir was evaluated in a single open-label, uncontrolled,
`pharmacokinetic (PK), safety, and efficacy trial in 104 children 3 to less than 18 years old in
`eight countries (US, UK, Australia, New Zealand, Belgium, Germany, Italy and the Russian
`Federation). regimens. 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 SOF and RBV regimens,
`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 fulfills the single outstanding post-
`marketing requirement (PMR) under the Pediatric Research Equity Act (PREA):
` PMR 2110-1 under PREA to provide PK, safety and treatment response data for 3 to <18
`year HCV-infected children. Here they provide data for 3 to < 12 year olds.
`The efficacy supplement also supports a new 200 mg tablet and is a response to the pediatric
`written request.
`
`This supplement provides the data for evaluating the proposed indication for SOF in the
`treatment of chronic HCV infection in pediatric patients 3 to < 18 years old with genotype 2 or 3
`HCV infection. Only data for pediatric subjects 3 to < 12 years old are presented in this clinical
`review. The proposed treatment regimens are SOF+RBV for 12 weeks in patients with genotype
`2 HCV infection, and SOF+RBV for 24 weeks in patients with genotype 3 HCV infection.
`
`The proposed recommendation for the use of SOF in pediatric patients aged 3 to < 12 years old is
`supported by PK, efficacy, and safety data from the Phase 2 Study GS-US-334-1112. Data for
`adolescent subjects 12 to < 18 years old were previously presented in the GS-US-334-1112
`Interim Clinical Study Report (CSR), and final data through post-treatment Week 24 are
`presented in the GS-US-334-1112 Final CSR. For a full clinical review of the data for
`adolescent subjects 12 to < 18 years old, please refer to Dr. Melisse Baylor’s review in the
`original NDA 204671.
`
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`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
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`Product Information
`
`2.1.
`Tablets
`SOVALDI is the brand name for sofosbuvir, a nucleotide analog inhibitor of HCV NS5B
`polymerase. Each Sovaldi tablet contains 200 mg or 400 mg of sofosbuvir. The tablets include
`the following inactive ingredients.
`
`Pellets
`SOVALDI pellets, 150 mg or 200 mg, are for oral administration, supplied as white to off-white
`pellets in unit-dose packets. Each unit-dose packet contains 150 mg or 200 mg of sofosbuvir.
`The pellets include the following inactive ingredients.
`2.2.
`Summary of Regulatory Activity Related to Submission
`In the US, Study GS-US-334-1112 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 in the treatment of HCV infection was submitted to the
`FDA as a Proposed Pediatric Study Request to Investigational New Drug (IND) 106739
`on 12 December 2012 (Serial No. 0243) and to New Drug Application (NDA) 204671 on
`05 April 2013 (Seq No. 0000).
` An updated version of the pediatric plan was submitted to NDA 204671 on 09 August
`2013 (Seq No. 0015).
` A Written Request (WR) for studies of 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 included changing the age
`groups being studied to pediatric subjects 3 to < 12 years of age (Seq No. 0195).
`
`As per this review, the applicant submitted the sNDA 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-334-1112, entitled, A Phase 2, Open-Label, Multicenter, Multi-cohort, Single-Arm
`Study to Investigate the Safety and Efficacy of Sofosbuvir + Ribavirin in Adolescents and
`Children with Genotype 2 or 3 Chronic HCV Infection; is a two-phase, pharmacokinetic, safety,
`and efficacy study of sofosbuvir and ribavirin for the treatment of pediatric subjects with
`genotype 2 or 3 chronic HCV infection. The trial was designed to enroll 100 pediatric subjects
`from 3 to <18 years of age sequentially by descending age cohort (50 adolescents subjects 12 to
`< 18 years of age; and 50 children 3 to < 12 years of age). Subjects of 3 age groups were enrolled
`
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`Reference ID: 4483174
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`

`

`Clinical Review, Cross-Discipline Team Leader Review and Division Director Summary Memo
`
`in a sequential fashion: 12 to < 18 years old, followed by 6 to < 12 years old, and 3 to < 6 years
`old.
`
`The first cohort enrolling adolescent subjects, 12 to <18 years of age, and collecting safety and
`efficacy through week 12 after the completion of treatment was completed in June 2016 and was
`submitted as an interim Clinical Study Report to support the safety and efficacy of sofosbuvir in
`adolescents. The data was reviewed and the drug approved for this adolescent age group in 2017.
`This report only presents the clinical review of the data for the next two cohorts: 6 to < 12
`years of age, and 3 to < 6 years of age.
`
`Subjects received the following regimen based on HCV genotype:
` Subjects with genotype 2 HCV infection: SOF+RBV for 12 weeks
` Subjects with genotype 3 HCV infection: SOF+RBV for 24 weeks
`
`The trial was conducted in two phases. The first phase was a pharmacokinetic (PK) lead-in
`phase, and the second was a treatment phase. The primary objective of the pharmacokinetic lead-
`in phase was to evaluate the steady state PK and confirm the dose of SOF in HCV-in