sBLA Number: 125127 / 319

Related IND Numbers: --(b)(4)---

Reviewer Name, Division, and Mail Code:

Clinical Reviewer: Melisse Baylor, MD. CBER/OVRR/DVRPA/DVRPA, HFM-475
Supervisory Reviewer: Douglas Pratt, MD, MPH, Branch Chief, CBER/OVRR/DVRPA, HFM-475

Submission Received by FDA: September 18, 2008

Review Completed: October 19, 2009

PRODUCT

Proper Name: Influenza virus vaccine
Proposed Trade Name: Fluarix
Product Formulation:

The 2008-2009 vaccine contains HA from three influenza strains (total HA = 45 µg)
A/Solomon Islands/3/2006 (H1N1): 15 µg
A/Wisconsin/67/2005 (H3N2): 15 µg
B/Malaysia/2506/2004: 15 µg

Fluarix contains the following excipients: sodium chloride, ----------------(b)(4)-------------------------------------------------------------(b)(4)-------------------------------------------------------------------------, α-tocopheryl hydrogen succinate, polysorbate 80, octoxynol 9, and water for injection.

No adjuvant is included in this vaccine. No preservative is contained in the vaccine. The tip cap and the rubber plunger of the needleless prefilled syringes contain latex.

Applicant: GlaxoSmithKline Biologicals
Pharmacologic Class or Category: Vaccine
Proposed Indication: Active immunization for the prevention of disease caused by influenza subtypes A and type B contained in the vaccine. Fluarix is approved for use in persons 3 years of age and older.
Proposed Population: Persons 3 years of age and older
Dosage Form and Route of Administration: Fluarix is supplied in a single-dose 0.5 mL prefilled syringe to be administered by intramuscular injection

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2. Table of Contents

    

   Section Title Page Number
   1 Title and General Information - 1
   2 Table of Contents - 2
   3 Executive Summary - 3
   4 Significant Findings from Other Review Disciplines - 9
   5 Clinical and Regulatory Background - 9
   6 Clinical Data Sources - 11
   7 Human Pharmacology - 12
   8 Clinical Studies - 13
   8.1 Study Fluarix-US-005 - 13
   8.2 Study Fluarix-US-056 - 36
   8.3 Study Fluarix-US-062 - 45
   9 Overview of Effectiveness Across Trials - 55
   10 Overview of Safety Across Trials - 58
   11 Dose Regimen and Administration - 59
   13 Conclusions – Overall - 59
   14 Recommendations - 59
   15 Labeling - 59

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3. Executive Summary

   3.1 Recommendation on Regulatory Action

   In the opinion of the clinical reviewer, the data submitted by the Applicant in this pediatric efficacy supplement support the approval of the trivalent inactivated influenza vaccine Fluarix for active immunization of persons 3 years of age and older against influenza disease caused by influenza virus subtypes A and B contained in the vaccine. The recommendation for the approval of Fluarix in pediatric patients is based on immunogenicity and safety data from three clinical trials in pediatric subjects.

   3.2 Recommendation on Postmarketing Actions

   No new postmarketing studies or actions were requested.

   3.3 Summary of Clinical Findings

   The conclusions about the immunogenicity and safety of Fluarix in children 3 years of age and older were primarily based on the results of Study Fluarix-US-005. Study Fluarix-US-005 was a Phase III, randomized, observer-blind study to evaluate the immunogenicity and safety of Fluarix compared with Fluzone® (Sanofi Pasteur) in healthy children 6 months and older. Subjects were stratified by age (6 months to < 3 years, 3 to < 5 years, and 5 to < 18 years), and randomized to receive either Fluarix or Fluzone. Subjects in the two younger age subgroups (6 months to < 3 years, 3 to < 5 years) were randomized in a 1:1 ratio to Fluarix or Fluzone. Subjects in the 5 to < 18 year cohort were randomized in a 3:1 ratio to Fluarix or Fluzone. The primary immunogenicity objective was to demonstrate the immunological non-inferiority of Fluarix compared to Fluzone in children 6 months to < 5 years of age based on serum antibody titers in a Hemaggluination Inhibiion (HI) assay evaluated as:: 1) geometric mean titers (GMTs), and 2) seroconversion rate and percentage of subjects with HI titers ≥ 1:40 post-vaccination. The secondary immunogenicity objectives were to demonstrate non-inferiority of Fluarix compared to Fluzone based on HI antibody titers in subgroups of children 6 months to < 36 months of age, and in children 3 years to < 5 years of age.

   Non-inferiority criteria were not met for any of the three vaccine strains when compared by GMTs or when compared by seroconversion rate for the age group 6 months to 5 years. Analysis by pre-defined and stratified age groups showed lower serum HI antibody titers in the 6 month to 35 month age group. The non-inferiority comparisons for subjects 36 through 59 months of age are shown in the tables below.

   Table 1: Study Fluarix-US-005 – Non-Inferiority Comparison of Post-Vaccination Geometric Mean Titers of HI Antibodies for 36-59 Month Age Group and Treatment Arm (ATP immunogenicity Cohort)

   	GMTs		Ratio GMTs Fluzone/Fluarix (UL 95% CI*)
   	Fluzone	Fluarix
   A/New Caledonia	163.7	134.7	0.97 (1.53)
   A/Wisconsin	489.0	453.6	1.08 (1.34)
   B/Malaysia	63.0	55.1	1.14 (1.52)

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61
   * Non-inferiority demonstrated if the upper limit of the 95% confidence interval (CI) for GMT Fluzone/GMT Fluarix < 1.5

   Table 2: Study Fluarix-US-005 – Non-Inferiority Comparison of Seroconversion Rates for 36-59 Month Age Group and Treatment Arm (ATP immunogenicity Cohort)

   	GMTs		Seroconversion Rates Fluzone minus Fluarix (UL 95% CI*)
   	Fluzone	Fluarix
   A/New Caledonia	72.3%	72.7%	-0.45% (7.89%)
   A/Wisconsin	70.5%	70.9%	-0.45% (8.05%)
   B/Malaysia	55.5%	53.2%	2.27% (11.52%)

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61
   * Non-inferiority demonstrated if the upper limit of the 95% CI for the difference in seroconversion rate Fluzone- Fluarix < 10%

   According to the study protocol, non-inferiority would be demonstrated if the upper bound of the 95% confidence interval for the ratio of GMTs was ≤ 1.5 and if the upper bound of the 95% confidence interval for the comparison of seroconversion rates was ≤ 10. The results for the 35 month to 59 month age group met these pre-defined study criteria for three of the six study endpoints, and narrowly missed the other three endpoints. Although the criteria used to define the non-inferiority margin were those typically used by CBER, the clinical correlation of these statistical criteria are unknown, and it is unlikely that the small differences in results would be clinically significant, as the pre-defined margins were narrowly exceeded.

   In addition, immunogenicity in subjects 36 months to 59 months of age was also supported by the secondary endpoint analyses in which seroconversion rates and percentage of subjects with post-vaccination titers ≥ 1:40 were evaluated. These results are shown in the table below.

   Table 3: Study Fluarix-US-005 – Seroconversion (SC) Rate and Percentage of Subjects with HI Titer Post-Vaccination of ≥ 1:40 (ATP Cohort for Immunogenicity)

   Seroconversion Rate	Value	LL 95% CI#
   A/New Caledonia	62%	58%
   A/Wisconsin	64%	59.5%
   B/Malaysia	38%	34%
   % of Subjects with HI titer ≥ 1:40	Value	LL 95% CI
   A/New Caledonia	71%	66%
   A/Wisconsin	77%	73%
   B/Malaysia	40%	35.5%

   *SC=seroconversion, #LL 95% CI=lower limit of 95% confidence interval
   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61

   Criteria specified in CBER Guidance [FDA Guidance for Industry ““Clinical Data Needed to Support the Licensure of Seasonal Inactivated Influenza Vaccines] for HI titers in adults used as surrogate endpoints reasonably likely to predict clinical benefit under accelerated approval regulations, are as follows: the post-vaccination seroconversion rate is 40% or greater for each vaccine strain, and the percentage of subjects with post-vaccination HI titers ≥ 1:40 is 70% or greater for each vaccine strain. Applying these criteria to 36 to 59 month old children in this study, both influenza A strains met criteria, but not the influenza B strain.

   Immunogenicity in children three years of age and older was also supported by the results from Study FLU-056. In this study, a thimerosal-free formulation was compared to a thimerosal-reduced formulation of Fluarix in children from 6 months to 71 months.

   Reviewer comment: The currently licensed formulation of Fluarix is thimerosal free.

   Study subjects were stratified by age into two subgroups: 6 months to 35 months and 36 months to 71 months. Immunogenicity results for the older age group and for both formulations are shown in the table below.

   Table 4: Study FLU-056 - Seroconversion Rate and Percentage of Subjects 36 to 71 Months of Age with HI Titers ≥ 1:40 Post-Vaccination (with Lower Limit of 95% Confidence Interval)

   	Seroconversion Rate		% of Subjects with HI ≥ 1:40
   	Thim Free N=23	Thim Red N=27	Thim Free N=23	Thim Red N=27
   H1N1	74% (52%)	85% (66%)	78% (56%)	85% (66%)
   H3N2	78% (56%)	89% (71%)	96% (78%)	96% (81%)
   B	87% (66%)	89% (71%)	87% (66%)	89% (71%)

   Source: sBLA 125127, SN 319, CSR for FLU-056, Table 16, page 63 and Table 18, page 69

   Although not pre-specified success criteria, CBER HI antibody criteria described in the FDA Guidance were met in 36 to 71 month olds for seroconversion for both formulations and all three strains (i.e., 95% LL > 40%). The criteria for percentage of subjects with a post-vaccination HI titer of 1:40 or greater (i.e., 95% LL > 70%) were met for the H3N2 strain in the thimerosal-free arm and for the H3N2 and B strains in the thimerosal-reduced arm. The small sample size may have resulted in wider confidence intervals, so it is important to note that the point estimates met the CBER criteria for all six endpoints and for both the US-licensed thimerosal-free formulation and the thimerosal-reduced formulation.

   The serum HI antibody response after vaccination with Fluarix was evaluated in older children (6 to 13 years of age) in Study Fluarix-062. In this open-label study, subjects were stratified by age into two cohorts: 6 to 9 years and 10 to 13 years. Immunogenicity results for both age groups are shown below.

   Table 5: Study Fluarix-062 – Immunogenicity Results (ATP Cohort for Immunogenicity)

   Influenza Strain	Seroconversion Rate		Seroconversion Factor
   	%	LL 95% CI*	Value	LL 95% CI*
   Subjects 6-9 Years of Age
   A/H1N1	98%	92.6%	41	32.6
   A/H3N2	84%	75%	15	11.9
   B	97%	91.0	26	21.4
   Subjects 10-13 Years of Age
   A/H1N1	85%	76.6%	50.2	36.2
   A/H3N2	78%	69.2%	10.3	8.2
   B	85%	76.6%	12.6	10.4

   *LL 95% CI = lower limit of the 95% confidence interval
   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Table 17, 18, and 20, pages 49-52

   As shown above, the CBER criteria were met for all three influenza strains and for both age groups.

   The totality of these data supports the effectiveness of Fluarix in children 3 years of age and older. Post-vaccination serum HI antibody titers were similar in children from 36 months to 59 months after vaccination with Fluarix or with Fluzone. The antibody response in children from 35 months to 71 months was substantial in Study FLU-052. The results for Study Fluarix-062 met the CBER criteria in subjects 6 years to 13 years of age.

   Safety of Fluarix in children 36 and older was supported by results from all three studies. However, the usefulness of the results from Studies FLU-056 and Fluarix-062 are limited due to the lack of a comparator and the open-label, single arm design of Fluarix-062. The percentages of subjects with local solicited adverse reactions in Study Fluarix-US-005 are shown in the table below.

   Table 6: Study Fluarix-US-005 – Percentage of Subjects with Individual Local Solicited Adverse Reactions by Age and Treatment Arm

   	36-59 Months		5-<18 Years
   	Fluarix N=350	Fluzone N=341	Fluarix N=1348	Fluzone N=451
   Pain
   Any	39%	41%	59%	57%
   Grade 3	1.7%	1.5%	1.0%	0.9%
   Redness
   Any	24%	21%	19%	17%
   Grade 3	0.3%	0	1.1%	0.7%
   Swelling
   Any	15%	15%	15%	14%
   Grade 3	0	0	1.6%	0.7%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 44-46, pages 85-87

   In Study Fluarix-US-005, local solicited adverse reactions, particularly pain, were commonly observed in children. The percentage of subjects with local solicited adverse reactions was similar between the two vaccine arms. Pain was reported in more than one-third of subjects. In older children, 5 years to 17 years, pain (59% of subjects) was more common than in younger children. Redness and swelling at the injection site were reported in more than 10% of children.

   General solicited events for children in the 35 month to 59 month age group in Study Fluarix-US-005 are shown in the table below.

   Table 7: Study Fluarix-US-005 – Percentage of Subjects from 36 Months to 59 Months of Age with Individual General Solicited Adverse Reactions and Treatment Arm

   	36-59 Months
   	Fluarix N=341	Fluzone N=356
   Drowsiness
   Any	14%	20.5%
   Grade 3	0.6%	0.9%
   Fever
   Any	8.0%	8.8%
   Grade 3	1.4%	2.1%
   Irritability
   Any	22%	24%
   Grade 3	0.9%	0.3%
   Loss of Appetite
   Any	15%	17%
   Grade 3	1.1%	0.9%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 49-50, pages 90-92

   Fever was reported in 8% of children in the younger age group. In children from 36 months to 59 months, drowsiness, irritability, and decreased appetite were observed in more than 10% of subjects. The frequency of general solicited adverse reactions was similar in the two vaccine arms.

   General solicited events for children from 5 years to 17 years of age in Study Fluarix-US-005 are shown in the table below.

   Table 8: Study Fluarix-US-005 – Percentage of Subjects 5- <18 Years of Age with Individual General Solicited Adverse Reactions by Age and Treatment Arm

   	Fluarix N=1348	Fluzone N=451
   Arthralgia	6.3%	6.7%
   Fatigue	21%	19.5%
   Fever	5.0%	3.5%
   Headache	16%	17%
   Muscle Ache	30%	29.5%
   Shivering	3.3%	3.8%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 48, pages 89

   In subjects from 5 to 17 years of age, myalgia, fatigue, and headache were all reported in more than 10% of subjects. Again, the percentage of subjects with each individual general solicited adverse reaction was similar in the two vaccine arms.

   Unsolicited adverse reactions were consistent with those illnesses commonly reported during childhood. Serious adverse events were uncommon in all three studies; of the 2466 subjects who were vaccinated with Fluarix in these three trials, serious AEs were reported in 17 or 0.7% of subjects. No serious AE was judged by the investigator as vaccine-related. There were no deaths in any of the studies.

   In summary, there was no safety signal noted on review of the pediatric studies of Fluarix. The most commonly observed adverse events in the clinical studies were adverse reactions, particularly pain, at the injection site. In addition, drowsiness, irritability and decreased appetite were frequently reported in children from 36 to 59 months of age while myalgia, fatigue, and headache were reported in those from 5 to 17 years of age. Other adverse events reported were consistent with commonly observed childhood illnesses.

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4. Significant Findings from Other Review Disciplines

   This supplemental BLA contained clinical data only.

   In his Statistical Review, Dr Ahnn concluded that the expanded age indication should not be granted, because the indication is based on a post-hoc subgroup analysis of 36 to 59 month age group. However, in the opinion of this reviewer, the use of the safety and immunogenicity from a subgroup based on age is valid since the study was stratified by age and examination of immunogenicity by age was a study objective.

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5. Clinical and Regulatory Background

    

   5.1 Disease or Health-Related Condition(s) Studied and Available Interventions

   Influenza infection in the United States is characterized by seasonal epidemics, usually occurring during the winter months. During the years 1990-1999, influenza infection was responsible for an average of 36,000 deaths per year in the United States. The rates of infection are highest among children; serious illness and death are reported more frequently among children with chronic underlying medical conditions that place them at increased risk of complications. Influenza vaccination is the primary method for preventing influenza illness and its severe complications. In certain circumstances, antiviral medication can be an important adjunct to the vaccine for prevention and control of influenza.

   The Advisory Committee on Immunization Practices (ACIP) publishes recommendations for groups of persons who should be targeted for routine administration of influenza vaccine; these include but are not limited to children aged 6 months to 18 years, persons greater than or equal to 65 years of age, persons with chronic medical conditions, and health care workers.

   Fluarix was licensed on August 31, 2005 for the prevention of influenza subtypes A and B contained in the vaccine under the accelerated approval regulations for use in adults; the indication was based on the immune response elicited by Fluarix in clinical studies. Traditional approval of Fluarix was granted on October 1, 2009, based on the efficacy of Fluarix in the prevention of culture-confirmed influenza illness caused by community acquired influenza strains similar to those contained in the vaccine. Vaccine efficacy was demonstrated in a randomized, placebo-controlled, clinical efficacy study for prevention of culture-confirmed influenza in 7652 adults 18 to 64 years of age. In this study, the influenza attack rate for Fluarix recipients was1% compared to 2.3% in placebo recipients for an overall vaccine efficacy of 66.9% (lower limit of 95% confidence interval: 51.9%).

   There are currently two trivalent, inactivated, split-virion vaccines licensed in the U.S. for prevention of seasonal influenza in children. Fluzone is approved for use in children 6 months of age and older, and Fluvirin is approved for use in children four years of age and older. There is also a live, attenuated intranasal vaccine approved for use in children 2 years of age and older. This supplemental BLA provides immunogenicity and safety data to support the use of Fluarix in children 3 to 17 years of age.

   5.2 Important Information from Pharmacologically Related Products, Including Marketed Products

   Influenza vaccines have been available since the 1940s. Six trivalent inactivated influenza virus vaccines (Fluarix, Fluzone, Fluarix, Fluvirin, FluLaval and Afluria) are currently licensed in the United States for use in adults. Of these, Fluzone is approved for use in children from 6 months to 17 years of age, and Fluvirin is approved for use in children 4 years to 17 years of age. A live attenuated trivalent vaccine, FluMist, is also licensed in the U.S. for the prevention of influenza illness in healthy subjects 2-49 years of age.

   Worldwide surveillance of influenza provides an estimate of the strains of influenza that might be in circulation in the United States. Each year, changes to the antigen content of the vaccine are made based on these surveillance mechanisms so that the vaccine might offer optimal protection from the influenza strains in circulation.

   5.3 Previous Human Experience with the Product Including Foreign Experience

   GSK Biologicals has been marketing Fluarix globally since 1992. Fluarix was licensed in the U.S. on August 31, 2005 for the prevention of influenza in persons 18 years of age and older under the accelerated approval regulations; the indication was based on the immune response elicited by Fluarix in clinical studies. Traditional approval of Fluarix was granted on October 1, 2009. This approval was based on the efficacy of Fluarix in the prevention of culture-confirmed influenza illness caused by community acquired influenza strains similar to those contained in the vaccine. Fluarix is now registered for use in 104 countries. More than (b)(4) million doses of Fluarix have been distributed.

   5.4 Regulatory Background Information (FDA-Sponsor Meetings, Advisory Committee Meetings, Commitments)

   CBER and GSK discussed the contents of this BLA in a telephone conference on June 10, 2008. The background material for this telecon was submitted to IND -(b)(4)- (Submission 121), which included the Clinical Study Report for study Fluarix-056 and preliminary results for Study Fluarix-US-005.

   The data in this supplement were not discussed at an advisory committee meeting.

   The protocol for Fluarix-US-005 was submitted to IND -(b)(4)- on July 10, 2006. The final study report for Fluarix-US-005 was submitted in this supplemental BLA. Studies FLU-056 and Fluarix-062 were not conducted under U.S. IND; these study protocols were not submitted to CBER for review. The study reports for FLU-056 and Fluarix-062 were included in this supplemental BLA.

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6. Clinical Data Sources (both IND and non-IND), Review Strategy and Data Integrity

    

   6.1 Material Reviewed

   This supplemental BLA was submitted electronically. The clinical sections, labeling, and financial information were also reviewed. This included the Clinical Study Reports, the pertinent Case Report Tabulations, and Case Report Forms.

   6.1.1 BLA/NDA Volume Numbers Which Serve as a Basis for the Clinical Review

   The supplement contained 12 Items. The following Items were reviewed by this reviewer: Item 1 Table of Contents, Item 2 Labeling, Item 3 Summary, Item 8 Clinical, Item 11 Case Report Tabulations, Item 12 Case Report Forms, and Item 19 Financial Information.

   6.2 Table of Clinical Studies

   Data from three clinical studies were provided in this BLA. These studies are summarized in the following table.

   Table 9: Clinical Studies Included in sBLA

   Study	Type	Control	# Subjects*	Age (yrs)	Country
   Fluarix-US-005	Randomized, double blind, immunogenicity and safety	Fluzone	3325	6 months to <18 years	United States
   FLU-056	Randomized, double-blind, immunogenicity and safety	Thimerosal-free formulation	157	6 months to <6 years	Germany
   Fluarix-062	Open-label, single arm, immunogenicity and safety	---	224	6 – 13 years	Germany

   * Total Vaccinated Cohort
   Source: BLA 125127/ SN 319, Item 3, Table 1, pages 35-36

   6.3 Good Clinical Practices (GCP) and Data Integrity

   Fluarix-US-005 was conducted at multiple sites in the United States. The applicant reported that these studies were conducted in accordance with Good Clinical Practice. The study protocol and informed consent were approved by an investigational review board. Three clinical sites (Metairie, Louisiana; Madera, California; and Austin, Texas) were inspected by FDA office of Compliance and Biologics Quality. Although there were a few minor irregularities in study conduct observed at inspection, the Bioresearch Monitoring Branch reviewer concluded that there were no problems that impacted the data submitted in the BLA.

   Fluarix-056 and Fluarix-062 were conducted in Germany according to Good Clinical Practice guidelines as defined by the Declaration of Helsinki and by the European Union (CPMP/ICH/135/95).

   6.4 Financial Disclosures

   According to the Applicant, it is GSK policy to not compensate investigators in a way in which the compensation is affected by study outcome. Therefore, there are no disclosures for compensation that might have affected the outcome of the studies in this supplement [as required in 21 CFR 54.2 (a), (b), and (f)]. There were also no significant payments ($25,000 or more) to any clinical investigator, and no investigator had a $50,000 or more equity interest in the study vaccine [as required in 21 CFR 54.4 (a)(3)(iii-iv), 54.2(b-c)].

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7. Human Pharmacology

   No human pharmacology data were submitted in this application.

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8. Clinical Studies

   The proposed indication for Fluarix is the active immunization for the prevention of disease caused by influenza subtypes A and type B contained in the vaccine. Fluarix is approved for use in persons 3 years of age and older.

   8.1. Fluarix-US-005

   A Phase III, single-blind, randomized study to evaluate the immunogenicity and safety of Fluarix (GSK Biologicals) compared with Fluzone (sanofi pasteur) administered intramuscularly in children (6 months of age and older)

   8.1.1 Objective/Rationale

   The primary objectives were:

   • to demonstrate the immunological non-inferiority of Fluarix compared to Fluzone in children 6 months to < 5 years of age and
   • to detect rare adverse events, defined as serious adverse events with an occurrence rate of ≥ 1/300, in children (6 months to < 18 years) vaccinated with Fluarix.

   The secondary immunogenicity objectives were:

   • to compare the immunogenicity of Fluarix and Fluzone at 28 and 49 days using geometric mean titers (GMTs), and
   • to compare the seroconversion rate and percentage of subjects with HI titers ≥ 1:40 post-vaccination in subgroups of children 6 months to < 36 months of age to those in children 3 to < 5 years of age.

   The secondary safety objective was to compare local and general solicited adverse reactions, unsolicited adverse events, and serious adverse events in subjects vaccinated with Fluarix and Fluzone in both the overall study population and in age-stratified groups.

   8.1.2 Design Overview

   Subjects were stratified by age (6 months to < 3 years, 3 to < 5 years, and 5 to < 18 years) and randomized to receive either Fluarix or Fluzone. Subjects in the two younger age subgroups (6 months to < 3 years, 3 to < 5 years) were randomized in a 1:1 ratio to Fluarix or Fluzone. Subjects in the 5 to < 18 year cohort were randomized in a 3:1 ratio to Fluarix or Fluzone.

   A 0.5 mL dose was administered to children at least 36 months of age and a 0.25 ml dose was administered to children ages 6-35 months of age. Children ages 6 months to 9 years who had not previously received a seasonal influenza vaccine received two doses, at day 0 and at day 28 (range from day 28 to day 35).. Children who had previously received a seasonal influenza vaccine received one dose, and children ages 9-18 years of age received one dose, regardless of history of previous seasonal influenza vaccine. All doses were administered intramuscularly in the deltoid muscle, preferably of the non-dominant arm.

   Subjects who were receiving two doses of study vaccine were seen in the study clinic at baseline and on Days 28 and 49. Subjects receiving a single dose were seen in clinic at baseline and on Day 28 only. All subjects were contacted by telephone six months after the first study vaccination. Subjects were followed for approximately 180 days in total.

   Demographic data, medical history including influenza vaccination history, directed physical examination, urine pregnancy test for female subjects of childbearing potential, and baseline body temperature were performed before vaccination. Subjects were monitored for 15 minutes immediately following vaccination.

   Subjects and their parents/guardians were given a diary cards to record temperature, any local and/or general adverse events occurring on the day of vaccination (day 0) and during the next 3 subsequent days (days 1-3), and perceived adverse events for 3 days, with instructions to call the investigator immediately for any adverse events perceived as serious. Solicited local adverse reactions monitored in the diary card were pain, redness, and swelling. Solicited general adverse reactions monitored varied by age. In subjects 6 months to < 5 years of age, solicited general adverse reactions were fever, irritability/fussiness, drowsiness, and loss of appetite. In subjects from 5 to < 18 years of age, the solicited general adverse events were fatigue/tiredness, fever, headache, generalized muscle aches, shivering, and joint pain. Parents / guardians were to record the diameter of any redness or swelling at the injection site; reactions from > 0 to ≤ 20 mm were considered Grade 1, reactions > 20 to ≤ 50 mm were considered Grade 2, and reactions > 50 mm were considered Grade 3. The exact temperature was also to be recorded; Grade 1 fever was ≥ 38.0 to ≤ 38.5º C, Grade 2 was > 38.6 to < 39.0º C, and Grade 3 was > 39.0º C. The intensity of other solicited adverse events was categorized as Grade 1 if easily tolerated, Grade 2 if interfered with daily activities, and Grade 3 if prevented normal, everyday activities.

   Reviewer comment: The intensity of local solicited adverse reactions may vary by subject age. For example a 5.0 cm reaction (Grade 2) on a six month old covers a larger percentage of the arm than a 5.0 cm reaction (Grade 2) on a 16 year old.

   Information was collected for unsolicited adverse events occurring during the 28 days after the first vaccination and during the 21 days after the second vaccination. Information on serious adverse events was collected for the entire study period (approximately 180 days).

   Blood was collected for HI antibody response at the baseline visit and at day 28 for primed subjects and at day 49 for un-primed individuals (21 days after the second vaccine).

   8.1.3 Population

   Subjects from 6 months to < 18 years of age were enrolled in the study. Written informed consent was obtained from each subject’s parent or guardian; assent was obtained from subjects older than 10 years of age.

   Children were excluded from study participation for a history of allergy to any component of the study vaccines including egg and chicken protein, for a history of hypersensitivity to any vaccine, for a history of Guillain-Barré within 6 weeks of receiving an influenza vaccine, for receipt of the influenza vaccine for the current season (2006-07), and for acute disease at the time of enrollment (moderate or severe illness with or without fever).

   Females of child bearing potential were required to have a negative urine pregnancy test prior to vaccination. Pregnant and lactating females were excluded from study participation.

   Subjects were not excluded for administration of influenza vaccine in a previous season or for recent receipt of routine, registered childhood vaccinations.

   8.1.4 Products mandated by the protocol

   Fluarix was provided as pre-filled syringes with an injectable volume of 0.25 or 0.5 mL. The influenza antigens used were those recommended for the Northern Hemisphere 2006-2007 influenza season. Each 0.5 mL contained 15 µg of the following antigens (45 µg total):

   A/New Caledonia/20/99 (H1N1),
   A/Wisconsin/67/2005 (H3N2), and
   B/Malaysia/2506/2004.

   The Fluarix formulation used contained trace amounts of thimerosal (≤ 1 µg of mercury per 0.5 mL dose, maximum of 0.0025 mg/dose).

   Fluzone was provided in 5 mL vials of vaccine, individual doses of either 0.25 mL or 0.5 mL were withdrawn from the vial using a needle and syringe. The Fluzone vials contained thimerosal as a preservative; each 0.5 mL dose of Fluzone contained 25 µg of mercury. As described above for Fluarix, the influenza antigens recommended for the Northern Hemisphere 2006-07 influenza season were used for Fluzone.

   8.1.5 Endpoints

   The primary immunogenicity endpoints were:

   1) the geometric mean titers (GMTs) of serum hemagglutinin (HI) antibodies with 95% CI pre- and post-vaccination (at day 28 or day 49) for each vaccine strain, and

   2) the seroconversion rate, defined as the proportion of subjects with either a pre-vaccination HI titer of <1:10 with a post-vaccination titer ≥ 1:40 or a pre-vaccination HI titer ≥ 1:10 with a minimum of a four fold increase in post-vaccination titer.

   Serologic tests were performed at the GSK central laboratory in Dresden, Germany. For each vaccine strain within each group, the GMT of HI antibodies at day 0 and post-vaccination (day 21 or day 51), were calculated by taking the anti-log of the mean of the log titer transformations (titers below the cut-off 1:10 were given the arbitrary value of half the cut off for calculation purpose).

   The secondary endpoints for immunogenicity were the following:

   • For each vaccine strain, proportion of vaccinees with a serum HI titer ≥ 1:40 and 95% confidence intervals, and
   • For each vaccine strain, proportion of vaccinees with four-fold increase in HI titer, if baseline titer is < 1:40.

   The safety endpoints were the following:

   • Percentage, intensity and relationship to vaccination of solicited local and general signs and symptoms during a 4-day follow-up period (i.e. day of vaccination and 3 subsequent days) after each vaccination for each age strata and overall,
   • Percentage, intensity and relationship to vaccination of unsolicited local and general signs and symptoms during follow-up period(s) after each vaccination as specified for each age strata and overall, and
   • Occurrence of serious adverse events during the entire study. 8.1.6 Statistical considerations

   One co-primary endpoint of the study was to demonstrate the immunological non-inferiority of Fluarix compared to Fluzone in children 6 months to < 5 years of age. The criteria for meeting this objective were:

   • The upper limit of the two-sided confidence interval of the GMT ratio of antibody titers (Fluzone group over Fluarix group) at post-vaccination had to be less than 1.50 for each of the three strains, and
   • The upper limit of the two-sided confidence intervals for the difference in post-vaccination seroconversion rates (Fluzone group minus Fluarix group) had to be less than 10% for each of the three strains.

   The study was designed to enroll an evaluable sample size of 820 subjects. The overall power to meet the co-primary endpoints was 98.5%. This calculation was based on 1) reference values for GMT and seroconversion rate from Study Fluarix Flu-044, a re-registrational study for the EMEA in which 67 children from 6 months to < 5 years of age were vaccinated with Fluarix and 2) overall Type 1 error below 2.5%. In addition, there was a 99% probability of detecting at least one serious adverse event with an occurrence rate of ≥ 1/300 in subjects receiving Fluarix.

   The “According to Protocol” (ATP) cohort was defined as subjects who met all eligibility criteria, complied with all study procedures, and had no elimination criteria during the study. The ATP cohort was used for the primary endpoint analysis, the immunologic non-inferiority of Fluarix as compared to Fluzone.

   The secondary safety analysis consisted of the entire vaccinated cohort. Safety was summarized by descriptive statistical measures, such as percentage reporting serious adverse events, percentage with local adverse events, and so forth.

   The Extended Windows cohort included all subjects who met entry criteria and had immunogenicity endpoints obtained. These subjects were identical to those in the ATP cohort for immunogenicity except the acceptable window for study visits was extended to -7/+7 days.

   Reviewer comment: The Extended Windows cohort was defined post-hoc based on the large percentage of subjects missing the pre-defined study windows; non-compliance with blood sampling schedule was observed in 562 subjects of the 1496 vaccinated (37.6%). Although this is a post-hoc analysis, the use of antibody titers outside of the window should not have resulted in substantial differences in results. In addition, the use of this cohort was discussed and agreed upon with CBER in an e-mail communication dated September 19, 2007.

   8.1.7 Results

   The first subject was enrolled on November 12, 2006 and the last safety follow-up contact was October 19, 2007. The safety database was locked in December 2007.

   8.1.8 Populations enrolled/analyzed/demographics

   Subject distribution

   A total of 3325 subjects were vaccinated in Study Fluarix-US-005: 2115 in the Fluarix group and 1210 in the Fluzone group. The number of subjects who withdrew from the study prematurely and who completed the study is shown in the table below.

   Table 10: Study Fluarix-US-005 – Subject Disposition by Age Cohort

   # of Subjects	6 mos - <3 yrs		3 yrs - <5 yrs		5 to <18 yrs		Total
   	Fluarix	Fluzone	Fluarix	Fluzone	Fluarix	Fluzone	Fluarix	Fluzone
   Vaccinated	375	379	373	369	1367	462	2115	1210
   Completed	326	340	338	334	1340	450	2004	1124
   Withdrawn	49	39	35	35	27	12	111	86
   Reasons for premature study discontinuation
   SAEs#	0	0	0	0	0	0	0	0
   Non-serious AE	1	0	0	0	0	0	1	0
   Protocol violation	4	1	1	0	0	0	5	1
   Consent withdrawn	14	9	10	8	3	1	27	18
   Moved from area	1	2	0	1	0	0	1	3
   Lost to F/U*, completed vaccination	9	11	15	13	19	8	43	32
   Lost to F/U*, incomplete vaccination	17	15	6	12	2	2	25	29
   Other	3	1	3	1	3	1	9	3

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 9, page 50
   #SAEs=serious adverse events, *F/U=follow-up

   All but two of the subjects were included in the total vaccinated cohort. These two subjects in the Fluzone group were allotted study numbers but not vaccinated. A total of 197 subjects were discontinued from the study prematurely: 111 in the Fluarix group and 86 in the Fluzone group. The most common reason for premature discontinuation was loss to follow-up (N=129); however, 75 of these subjects were lost to follow-up after completing their vaccination(s).

   Reviewer comment: Overall, 5.2% of subjects in the Fluarix group and 7.1% of subjects in the Fluzone group discontinued the study prematurely. The majority of the premature discontinuations were in the group of children younger than 5 years of age; premature discontinuations were reported in 11% of Fluarix subjects and 10% of Fluzone subjects younger than 5 years and in 2% of Fluarix and 2.5% of Fluzone subjects from 5 to 17 years of age. The difference is largely due to the increased number of subjects younger than 5 years of age whose parents withdrew consent or who were lost to follow-up. This may have been related to parental objection to vaccination and/or blood draw among the younger group.

   One study subject discontinued the study prematurely due to a non-serious AE. This subject, a 16 month old male who received only the first dose of Fluarix, had a URI and conjunctivitis on study day 1 and otitis media on day 14. There were no premature study discontinuations due to a serious AE.

   Thirty-four subjects in the Fluarix arm and 37 in the Fluzone arm were excluded from the ATP safety cohort. The reasons for exclusion from the ATP safety cohort are shown in the table below.

   Table 11: Study Fluarix-US-005 – Number of Subjects Excluded from the According-to-Protocol Cohort for Safety by Treatment Arm

   	Fluarix	Fluzone
   Total Vaccinated Cohort	2115	1210
   Administration of protocol forbidden vaccines	4	1
   Randomization failure	8	8
   Study vaccine not administered according to protocol	22	28
   ATP Safety Cohort	2081	1173

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 10, page 50

   Reviewer comment: The percentage of subjects excluded from the ATP safety cohort was small and was similar in the two study arms: 1.6% in the Fluarix arm and 3.1% in the Fluzone arm.

   Because immunogenicity data were obtained for only subjects from 6 months to less than 5 years of age, the distribution of this subgroup is shown separately below.

   Table 12: Study Fluarix-US-005 – Subject Distribution for Subgroup of Subjects from 6 Months to Less than 6 Years of Age by Treatment Arm

   	Fluarix	Fluzone
   Total Vaccinated Cohort	748	748
   Administration of protocol forbidden vaccines	3	1
   Randomization failure	5	2
   Study vaccine not administered according to protocol	22	27
   ATP Safety Cohort	718	718
   Protocol entry criteria violation	2	1
   Non compliance with vaccination schedule	75	61
   Non-compliance with blood sampling schedule	120	118
   Serological data missing	93	91
   Others	2	2
   ATP immunogenicity cohort	426	445

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 11, page 51

   While only 4% of subjects in this age subgroup were excluded from both treatment groups for the ATP cohort for safety, 39% of subjects in the Fluarix group and 36.5% in the Fluzone group were excluded from the ATP immunogenicity cohort. The main reasons for subjects being excluded from the ATP immunogenicity cohort were non-compliance with vaccination schedule, non-compliance with blood sampling schedule, and missing serological data. When GSK noted the large number of subjects who were non-compliant with study windows, they proposed an ad hoc analysis of an extended window cohort (-7 / +7 days); CBER agreed to this analysis (e-mail communication dated September 19, 2007). However, GSK did not include the results for the extended window cohort in the Clinical Study Report. CBER requested the results for the extended window cohort, and these were received July 2, 2009.

   In addition, all 9 subjects from study site 33794 were also excluded when GSK discovered that the investigator at that site had restrictions on his medical license.

   Reviewer comment: The high percentage of subjects excluded from the ATP immunogenicity cohort is concerning. This high percentage may reflect the difficulties of conducting a study in young children.

   Demographics:

   The demographic characteristics of the Total vaccinated cohort are shown in the table below.

   Table 13: Study Fluarix-US-005 – Demographic Characteristics for Total Vaccinated Cohort

   	6 mos - <3 yrs		3 yrs - <5 yrs		5 to <18 yrs		Total
   	Fluarix N=375	Fluzone N=379	Fluarix N=373	Fluzone N=369	Fluarix N=1367	Fluzone N=462	Fluarix N=2115	Fluzone N=1210
   Age (median in years)	1.0	1.0	3.0	3.0	10.0	10.0	7.0	4.0
   % Male	54%	55%	48.5%	45%	51%	54%	51%	52%
   Race*
   White/Caucasian	58%	59%	65%	66%	74.5%	71%	70%	66%
   African/African American	24%	23%	20%	21%	13%	16%	16%	20%
   Other	8.5%	7%	7%	6%	4.5%	4%	6%	6%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 14, page 54
   *Race – only includes racial categories that comprised ≥ 5% of any study arm.

   As shown in the table above, there were a similar percentage of males and females in the study. Most subjects were White / Caucasian; 16% of subjects in the Fluarix arm were of African heritage or African American; 3.7% were American Indian or Alaskan native, and 2.4% were

   Asian. In the Fluzone arm, 52% were White/Caucasian, 20% were African/African American, 3.7% were American Indian/Alaskan Native, and 3.2% were Asian.

   Reviewer comment: The demographic characteristics between the two treatment groups were similar for the overall population and in each age subgroup.

   The demographic characteristics for the ATP cohort for immunogenicity are shown in the table below.

   Table 14: Study Fluarix-US-005 – Demographic Characteristics for ATP Cohort for Immunogenicity

   # of Subjects	6 mos - <3 yrs		3 yrs - <5 yrs		Total
   	Fluarix N=206	Fluzone N=224	Fluarix N=220	Fluzone N=221	Fluarix N=426	Fluzone N=445
   Age (median in years)	1.0	1.0	3.0	3.0	3.0	2.0
   % Male	53%	58%	48%	47%	50%	53%
   Race*
   White/Caucasian	59%	60%	59%	62%	59%	61%
   African/African American	18%	20.5%	22%	21%	20%	21%
   Other	11%	7%	7%	7%	9%	7%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 16, page 56
   *Race – only includes racial categories that comprised ≥ 5% of any study arm.

   Reviewer comment: The demographic characteristics were similar for the Total vaccinated cohort and the ATP cohort for immunogenicity.

   History of influenza vaccination:

   The wphist dataset was analyzed to determine the number of subjects who had previously been vaccinated against influenza. The results are shown in the table below.

   Table 15: Study Fluarix-US-005 – Percentage of Subjects with Previous Influenza Vaccination by Age (Total Vaccinated Cohort)

   Age Subgroup	Fluarix Arm	Fluzone Arm
   6 mos - <3 yrs	37%	35%
   3 yrs - <5 yrs	58.5%	60%
   5 to <18 yrs	55%	56%

   Source: sBLA 125127, SN 319, CSTs for Fluarix-US-005, Dataset wphist

   Reviewer comment: More than one-half of study subjects 3 years of age and older had previously received a vaccine against influenza. More than one-third of subjects younger than 3 years of age had previously been vaccinated. The percentage of subjects who had previously been vaccinated was similar between the two study arms. However, the rates of vaccination were higher than those generally reported in children. (See www.preventchildhoodinfluenza.org/resource/NFID_CIIC_Report.pdf). This may represent enrollment of children at study sites with strong vaccination programs or enrollment at clinical research centers with enrollment of children who have participated in multiple studies over time.

   8.1.9 Efficacy endpoints/outcomes

   Please see Dr. Ahnn’s statistical review.

   Analysis of primary endpoint:

   The non-inferiority of Fluarix to Fluzone was determined by comparison of post-vaccination GMTs of HI antibodies at day 28 or day 49 for each vaccine strain and by comparison of the seroconversion rate post-vaccination. Results for this primary endpoint are shown in the table below.

   Table 16: Study Fluarix-US-005 – Non-Inferiority Comparison of Post-Vaccination Geometric Mean Titers of HI Antibodies by Treatment Arm (ATP immunogenicity Cohort for Subjects from 6 Months to Less than 5 Years of Age)

   	GMTs		Ratio GMTs Fluzone/Fluarix (UL 95% CI*)
   	Fluzone N=443	Fluarix N=425
   A/New Caledonia	128.6	85.6	1.5 (1.77)
   A/Wisconsin	326.1	197.7	1.65 (1.95)
   B/Malaysia	50.2	33.8	1.48 (1.80)

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 22, page 61
   * Upper limit of the 95% confidence interval

   As shown in the table above, the upper limits of the 95% confidence intervals were greater than 1.5 for all three vaccine strains; therefore, the criteria for determining non-inferiority (upper limit of 95% CI ≤ 1.5) were not met for any of the three vaccine strains.

   Table 17: Study Fluarix-US-005 – Non-Inferiority Comparison of Post-Vaccination Seroconversion Rate by Treatment Arm (ATP immunogenicity Cohort for Subjects from 6 Months to Less than 5 Years of Age)

   	GMTs		Ratio Seroconversion Rates Fluzone minus Fluarix (UL 95% CI*)
   	Fluzone N=443	Fluarix N=425
   A/New Caledonia	76%	62%	14% (19.98)
   A/Wisconsin	78%	64%	14% (19.59)
   B/Malaysia	53%	39%	14% (20.93)

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61
   * Upper limit of the 95% confidence interval

   The non-inferiority criteria were also not met for seroconversion rate. The upper limits of the 95% confidence intervals were greater than 10 for all three vaccine strains.

   As shown in the tables below, the results for the Extended window cohort was similar to those for the ATP immunogenicity cohort. Non-inferiority criteria were not met for either cohort.

   Table 18: Study Fluarix-US-005 – Non-Inferiority Comparison of Post-Vaccination Geometric Mean Titers of HI Antibodies by Treatment Arm (Extended Window Cohort for Subjects from 6 Months to Less than 5 Years of Age)

   	GMTs		Ratio GMTs Fluzone/Fluarix (UL 95% CI*)
   	Fluzone N=540	Fluarix N=540
   A/New Caledonia	130.0	84.0	1.55 (1.79)
   A/Wisconsin	325.3	196.9	1.65 (1.92)
   B/Malaysia	54.9	35.3	1.56 (1.85

   Source: sBLA 125127, SN 319.2, Annex 3, Table I.e.1, page 3
   * Upper limit of the 95% confidence interval

   Table 19: Study Fluarix-US-005 – Non-Inferiority Comparison of Post-Vaccination Seroconversion Rate by Treatment Arm (Extended Window Cohort for Subjects from 6 Months to Less than 5 Years of Age)

   	GMTs		Ratio Seroconversion Rates Fluzone minus Fluarix (UL 95% CI*)
   	Fluzone N=540	Fluarix N=540
   A/New Caledonia	78%	62%	15.7% (21.08%)
   A/Wisconsin	78%	64%	14.6% (19.91%)
   B/Malaysia	56%	41%	14.8% (20.65%)

   Source: sBLA 125127, SN 319.2, Annex 3, Table I.e.2, page 4
   * Upper limit of the 95% confidence interval

   Reviewer comment: The primary endpoint for measuring the non-inferiority was comparison of GMTs and of seroconversion rates of Fluarix and Fluzone. Post-vaccination GMTs and seroconversion rates were lower in Fluarix recipients than in Fluzone recipients, and Fluarix was not shown to be non-inferior to Fluzone in the overall age cohort of children 6 months to 5 years of age.

   Analysis of secondary efficacy endpoints:

   Seroconversion rate and Percentage of Subjects with Post-Vaccination HI titer of ≥ 1:40
   The criteria used to evaluate immunogenicity of seasonal influenza vaccines among adults under the regulations for accelerated approval regulations are described in the FDA Guidance for Industry, “Clinical Data Needed to Support the Licensure of Trivalent Inactivated Influenza Vaccines.” Per these guidelines, serum HI antibody responses were considered acceptable for accelerated approval (reasonably likely to predict clinical benefit) if the lower limit of the 95% confidence interval for post-vaccination seroconversion rate is 40% or greater for each vaccine strain, and if the percentage of subjects with post-vaccination HI titers ≥ 1:40 is 70% or greater for each vaccine strain. The seroconversion rate and the percentage of subjects with post-vaccination antibody titers of 1:40 or greater are shown in the table below.

   Table 20: Study Fluarix-US-005 - Seroconversion Rate and Percentage of Subjects with HI Titer Post-Vaccination of ≥ 1:40 (ATP Cohort for Immunogenicity for Subjects from 6 Months to Less than 5 Years of Age)

   	Fluarix		Fluzone
   	SC* Rate	LL 95% CI#	% ≥ 1:40	LL 95% CI
   A/New Caledonia	62%	58%	76%	72%
   A/Wisconsin	64%	59.5%	78%	74%
   B/Malaysia	38%	34%	53%	48.5%
   	% ≥ 1:40	LL 95% CI	% ≥ 1:40	LL 95% CI
   A/New Caledonia	71%	66%	86%	82%
   A/Wisconsin	77%	73%	94%	91%
   B/Malaysia	40%	35.5%	55%	50%

   *SC=seroconversion, #LL 95% CI=lower limit of 95% confidence interval
   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61

   As shown in the table above, applying the criteria described in the FDA Guidance for Industry, overall study results for Fluarix met these criteria for three of the six endpoints; the Fluzone arm fulfilled these criteria for five of the six endpoints.

   The results for the Extended window cohort were similar; the results for Fluarix met the criteria for demonstration of immunogenicity for three of the six endpoints while the results in the Fluzone arm met the criteria for five of the six endpoints.

   Results for Age subgroups
   Subjects were stratified by age (6 months to 35 months and 36 months to 59 months) as part of the randomization scheme. The analysis of immunogenicity by age subgroups was a secondary endpoint of the study. The results for the 36 to 59 month age group are shown in the tables below.

   Table 21: Study Fluarix-US-005 – Non-Inferiority Comparison of Post-Vaccination Geometric Mean Titers of HI Antibodies for 36-59 Month Age Group and Treatment Arm (ATP immunogenicity Cohort)

   	GMTs		Ratio GMTs Fluzone/Fluarix (UL 95% CI*)
   	Fluzone	Fluarix
   A/New Caledonia	163.7	134.7	0.97 (1.53)
   A/Wisconsin	489.0	453.6	1.08 (1.34)
   B/Malaysia	63.0	55.1	1.14 (1.52)

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61
   * Upper limit of the 95% confidence interval

   Table 22: Study Fluarix-US-005 – Non-Inferiority Comparison of Seroconversion Rates for 36-59 Month Age Group and Treatment Arm (ATP immunogenicity Cohort)

   	GMTs		Ratio Seroconversion Rates Fluzone minus Fluarix (UL 95% CI*)
   	Fluzone	Fluarix
   A/New Caledonia	72.3%	72.7%	-0.45 (7.89)
   A/Wisconsin	70.5%	70.9%	-0.45 (8.05)
   B/Malaysia	55.5%	53.2%	2.27 (11.52)

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61
   Upper limit of the 95% confidence interval

   Reviewer comment: The results for the 35 month to 59 month age group met the pre-defined study criteria for three of the six study endpoints. However, the GMT results for the influenza A/New Caledonia and B/Malaysia strain barely missed the endpoint of 1.5 and the results for seroconversion rate for the B/Malaysia strain were also very close to the predefined non-inferiority margin of 10. The criteria used to define the non-inferiority margin were those typically used by CBER, however, the clinical correlation of these statistical criteria are unknown, and it is unlikely that the small differences in results would be clinically significant.

   The results for the secondary endpoints, seroconversion rate and percentage of subjects with post-vaccination HI titer ≥ 1:40, by age are shown in the tables below.

   Table 23: Study Fluarix-US-005 - Seroconversion rate by Treatment Arm and Age

   	Fluarix		Fluzone
   	SC Rate	LL* 95% CI	SC Rate	LL* 95% CI
   6-35 Months
   A/New Caledonia	51%	44%	80%	74%
   A/Wisconsin	57%	50%	85%	80%
   B/Malaysia	23%	18%	51%	44%
   36-59 Months
   A/New Caledonia	73%	66%	72%	66%
   A/Wisconsin	71%	64%	70.5%	64%
   B/Malaysia	53%	46%	55.5%	49%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 27 and 30, pages 66 and 68
   * Lower limit of the 95% confidence interval

   As shown in the tables above, in the 36 to 59 month age subgroup, the lower bound 95% confidence interval for all three vaccine strains was greater than 40% in both treatment arms, e.g., met criteria described in the FDA Guidance. In the 6 month to 36 month age subgroup, the seroconversion rate was greater than 40% for both influenza A strains in the Fluarix arm and for all three influenza strains in the Fluzone arm.

   Reviewer comment: Although the seroconversion rate in the 6 to 35 month age subgroup, was greater than 40% for the two influenza A antigens, the seroconversion

   rates were considerably lower (-30%) in the Fluarix arm compared to the Fluzone arm. In the older age group, the lower limits of the 95% confidence intervals for all three antigens were similar for all three vaccine strains.

   Table 24: Study Fluarix-US-005 – Percentage of Subjects with Post-Vaccination HI Titer ≥ 1:40 by Treatment Arm and Age

   	Fluarix		Fluzone
   	% ≥ 1:40	LL 95% CI	% ≥ 1:40	LL 95% CI
   6-35 Months
   A/New Caledonia	59%	52%	86%	81%
   A/Wisconsin	65.5%	59%	94%	90%
   B/Malaysia	24%	19%	51%	45%
   36-59 Months
   A/New Caledonia	82%	76%	85.5%	80%
   A/Wisconsin	88%	83%	94%	90%
   B/Malaysia	55%	48%	58%	52%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 28 and 31, pages 66 and 68

   As shown in the table above, the percentage of subjects from 6 months to 35 months of age with post-vaccination antibody titers ≥ 1:40 were considerably higher in Fluzone than in Fluarix recipients.

   Summary of Immunogenicity: The non-inferiority of Fluarix to Fluzone, a licensed vaccine in the U.S., was not demonstrated in children 6 months to 59 months of age. This was largely due to the poor antibody response in children from 6 to 35 months of age who received Fluarix. In children from 36 to 59 months of age, Fluarix was not inferior to Fluzone in three of six endpoints. Of the three endpoints for which non-inferiority was not demonstrated, the non-inferiority margins were only narrowly missed. Therefore, the results in the 36-59 month age group were very close to satisfying the non-inferiority criteria, and any differences are unlikely to be of clinical significance.

   8.1.10 Safety outcomes

   Safety data collected included local and general solicited adverse events, which were monitored for the day of vaccination and the subsequent three days, unsolicited AEs which were monitored for 28 days following the first vaccination and 21 days after the second, and serious adverse events, which were followed for the entire study period (180 days).

   Subjects and their parents/guardians were given a diary card to record solicited adverse events on the day of vaccination and the subsequent three days. Solicited local adverse reactions monitored were pain, redness, and swelling. Parents / guardians were to record the diameter of any redness or swelling at the injection site; reactions from > 0 to ≤ 20 mm were considered Grade 1, reactions > 20 to ≤ 50 mm were considered Grade 2, and reactions > 50 mm were considered Grade 3. The percentage of subjects with any solicited adverse reactions and with Grade 3 solicited local reactions are shown in the table below.

   Table 25: Study Fluarix-US-005 – Percentage of Subjects with One or More Local Solicited Adverse Reactions by Age and Treatment Arm

   	Fluarix	Fluzone
   6-35 months of age
   Any	48%	45%
   Grade 3	3.5%	3.1%
   36-59 months of age
   Any	48%	47%
   Grade 3	2.0%	1.5%
   5-<18 years of age
   Any	63%	60%
   Grade 3	3.1%	1.8%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 41-42, pages 82-83

   Reviewer comment: The percentage of subjects with local solicited adverse reactions was similar between the two treatment arms in each age group. The rate of subjects with Grade 3 solicited adverse reactions was also similar between the two arms for the 6-35 month and 36-59 month age groups, but slightly higher in the 5 to <18 year age group. However, the percentage of subjects with Grade 3 reactions was low in all arms. The higher rate of solicited adverse events was in children 5 to <18 years of age may have been due in part to the ability of older children to verbalized pain.

   The percentage of subjects with each individual solicited local adverse reaction is shown by age group in the table below. For subjects who received two study vaccinations, the percentage is for a reaction after either of the two vaccinations.

   Table 26: Study Fluarix-US-005 – Percentage of Subjects with Individual Local Solicited Adverse Reactions by Age and Treatment Arm

   	6-35 Months		36-59 Months		5-<18 Years
   	Fluarix	Fluzone	Fluarix	Fluzone	Fluarix	Fluzone
   Pain
   Any	41%	36%	39%	41%	59%	57%
   Grade 3	3.2%	2.8%	1.7%	1.5%	1.0%	0.9%
   Redness
   Any	23%	24%	24%	21%	19%	17%
   Grade 3	0	0.3%	0.3%	0	1.1%	0.7%
   Swelling
   Any	14%	11%	15%	15%	15%	14%
   Grade 3	0.3%	0.3%	0	0	1.6%	0.7%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 44-46, pages 85-87

   Reviewer comment: The percentage of subjects with each individual local adverse reaction was similar in the two treatment arms and in each age subgroup. Pain was the most frequently reported local adverse reaction in all study arms and age subgroups. The percentage of subjects reporting pain was highest in the 5 to <17 year age group, which likely reflects an inability of younger children to adequately express pain or an inadequacy of the scale used to capture mild to moderate pain in younger children. Pain was also the most commonly reported Grade 3 local adverse event; Grade 3 pain was most common in younger children. The overall percentage of subjects in the 5 to <17 year old age subgroup with Grade 3 local solicited adverse reactions was slightly higher in the Fluarix arm than in the Fluzone arm. The percentage was higher in Fluarix recipients for all three of the individual local reactions with the largest difference in the rate of Grade 3 swelling. Overall, the rates of Grade 3 local reactions were low and the differences between the two study arms were small.

   The mean size of redness (obtained from information in reaccod dataset) was compared by treatment arm and age group. The mean size of redness in subjects 6 to 35 months of age after the first vaccination was 1.9 mm in both the Fluarix arm and the Fluzone arm. The mean size of redness in subjects from 3 to <5 years in the Fluarix arm was 2.7 mm and in the Fluzone arm was 3.5 mm; in subjects from 5 to 17 years of age, the mean size was 4.8 mm in the Fluarix arm and 3.5 mm in the Fluzone arm. The size of redness at the injection site increased with age group. Size of redness at the injection site was similar between the two treatment arms.

   The mean size of swelling at the injection site was 1.97 mm for reactions in the Fluarix 6-35 month age group and 2.4 mm in the Fluzone 6-35 month age group. The mean size of swelling in the 3 months to < 5 year age group was 2.6 mm in the Fluarix arm and 4.1 mm in the Fluzone arm. In the 5-17 year age group, the mean size of swelling was 7.4 mm in the Fluarix arm and 4.4 mm in the Fluzone arm. In general, the size of swelling at the injection site was similar between the two study arms.

   Solicited general adverse reactions monitored varied by age. In subjects 6 months to < 5 years of age, solicited general adverse reactions were fever, irritability/fussiness, drowsiness, and loss of appetite. In subjects from 5 to < 18 years of age, the solicited general adverse events were fatigue/tiredness, fever, headache, generalized muscle aches, shivering, and joint pain. The exact temperature was also to be recorded; Grade 1 fever was ≥ 38.0 to ≤ 38.5º C, Grade 2 was > 38.6 to < 39.0º C, and Grade 3 was > 39.0º C. The intensity of other solicited adverse events was categorized as Grade 1 if easily tolerated, Grade 2 if interfered with daily activities, and Grade 3 if prevented normal, everyday activities. The percentage of subjects with solicited general adverse reactions is shown in the table below.

   Table 27: Study Fluarix-US-005 – Percentage of Subjects with One or More General Solicited Adverse Reactions by Age and Treatment Arm

   	Fluarix	Fluzone
   6-35 months of age	N=340	N=356
   Any	62%	58%
   Grade 3	7.9%	7.6%
   36-59 months of age	N=350	N=341
   Any	42%	42.5%
   Grade 3	2.6%	4.1%
   5-<18 years of age	N=1349	N=451
   Any	49%	46%
   Grade 3	2.8%	2.9%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 41-42, pages 82-83

   Reviewer comment: The percentage of subjects in each age subgroup reporting general solicited adverse reactions was similar between the two vaccine arms; the percentage of subjects with general adverse reactions was highest in the 6-35 month age group and similar in the other two age groups. The percentage of subjects with Grade 3 general solicited adverse reactions was similar between the two vaccine arms in the 6-35 month and 5-<18 year subgroups, but slightly higher in the Fluzone arm for the 36-59 month age subgroup.

   The percentage of subjects younger than 5 years of age reporting individual general solicited adverse reactions is shown in the table below. Since the individual general solicited adverse reactions monitored differed in the older subgroup, the percentage of subjects from 5 to <18 years of age with each general solicited adverse reaction is shown in a separate table.

   Table 28: Study Fluarix-US-005 – Percentage of Subjects < 5 Years of Age with Individual General Solicited Adverse Reactions by Age and Treatment Arm

   	6-35 Months		36-59 Months
   	Fluarix N=341	Fluzone N=356	Fluarix N=350	Fluzone N=341
   Drowsiness
   Any	33%	30%	14%	20.5%
   Grade 3	3.8%	3.7%	0.6%	0.9%
   Fever
   Any	16%	11%	8.0%	8.8%
   Grade 3	2.9%	1.1%	1.4%	2.1%
   Irritability
   Any	45.5%	46%	22%	24%
   Grade 3	5.0%	4.8%	0.9%	0.3%
   Loss of Appetite
   Any	23.5%	20%	15%	17%
   Grade 3	1.5%	2.8%	1.1%	0.9%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 49-50, pages 90-92

   Reviewer comment: The percentage of subjects with individual general solicited adverse reactions was similar in the two treatment arms. All four general solicited adverse reactions were reported in more than 10% of subjects in the 6-35 month age group with irritability in almost one-half of subjects and drowsiness in one-third. In subjects 36 months of age to < 5 years of age, individual general solicited adverse reactions were reported less commonly; the most frequently reported was irritability, which was reported in 22% of Fluarix recipients and 24% of Fluzone recipients. Grade 3 general solicited adverse reactions were uncommon. Grade 3 fever (>39.0ËšC axillary temperature) was reported in < 3% of subjects in any study arm.

   Table 29: Study Fluarix-US-005 – Percentage of Subjects 5- <18 Years of Age with Individual General Solicited Adverse Reactions by Age and Treatment Arm

   	Fluarix N=1348	Fluzone N=451
   Arthralgia
   Any	6.3%	6.7%
   Grade 3	0.1%	0.2%
   Fatigue
   Any	21%	19.5%
   Grade 3	1.1%	1.3%
   Fever
   Any	5.0%	3.5%
   Grade 3	0.4%	0.2%
   Headache
   Any	16%	17%
   Grade 3	0.6%	0.9%
   Muscle Ache
   Any	30%	29.5%
   Grade 3	0.4%	0.7%
   Shivering
   Any	3.3%	3.8%
   Grade 3	0.1%	0.2%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 48, pages 89

   Reviewer comment: The percentage of subjects with individual general solicited adverse reactions was similar between the two treatment arms. The most commonly reported general solicited adverse reactions were muscle aches followed by fatigue and then headache; arthralgia, fever, and shivering, which were each reported in less than 10% of subjects. Grade 3 solicited general reactions were uncommon, and all were reported in less than 2% of subjects in either arm.

   Fever was the only general solicited event followed in all three age subgroups. The percentage of subjects with fever decreased with increasing age as did the percentage of subjects with Grade 3 fever.

   Information was collected for unsolicited adverse events occurring during the 28 days after the first vaccination and during the 21 days after the second vaccination. The percentage of subjects reporting unsolicited adverse events is shown in the table below.

   Table 30: Study Fluarix-US-005 – Percentage of Subjects with One or More Unsolicited Adverse Reactions by Age and Treatment Arm

   	Fluarix N=375	Fluzone N=379
   6-35 months of age
   Any	48%	50%
   Grade 3	6.4%	7.7%
   36-59 months of age
   Any	36%	37%
   Grade 3	3.8%	3.8%
   5-<18 years of age
   Any	28%	29%
   Grade 3	4.7%	4.1%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 52, page 96

   Reviewer comment: The percentage of subjects with unsolicited adverse events was similar between the two treatment arms in each age subgroup. Unsolicited adverse events and Grade 3 unsolicited AEs were more common in the 6-35 month age subgroup than in the older subgroups.

   The percentage of subjects with unsolicited AEs by organ system class is shown below by organ system classes; organ systems for which 5% or more subjects reported unsolicited AEs in any treatment group were included below.

   Table 31: Study Fluarix-US-005 – Percentage of Subjects with Unsolicited Adverse Reactions by Organ System* (≥ 5% of Subjects in Any Treatment Group with AE)

   	6-35 Months		36-59 Months		5-<18 Years
   	Fluarix N=375	Fluzone N=379	Fluarix N=373	Fluzone N=369	Fluarix N=1367	Fluzone N=462
   Infections and infestations	29%	29%	20%	18%	9.5%	11%
   Respiratory, thoracic, and mediastinal	18%	17%	12%	14%	9%	10%
   Gastrointestinal	11%	12%	6%	6%	7%	5%
   General and administrative site	9%	13%	7.5%	9%	5%	5%
   Skin and subcutaneous tissue	6%	5%	2%	2%	1%	1%

   *Adverse reactions classified by MedDRA system organ class
   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 53-55, pages 97-99

   Reviewer comment: The percentage of subjects with AEs in the organ systems listed in the table was similar between the two treatment arms and in the age groups. The most commonly reported organ system in which unsolicited AEs were reported were infections and infestations and respiratory, thoracic, and mediastinal. The most commonly reported unsolicited AEs in these systems were upper respiratory tract infections, otitis media, cough, rhinorrhea, nasopharyngitis, and pharyngolaryngeal pain. These AEs are consistent with common illnesses in childhood.

   Reviewer comment: The electronic dataset, wunsol, was analyzed for the most common unsolicited adverse events by age. The adverse events reported most commonly in the 6-35 month age group were URI (51 events in Fluarix arm and 49 in Fluzone arm), fever (43 in Fluarix arm and 54 in Fluzone arm), and otitis media (36 in Fluarix arm and 35 in Fluzone arm). The most commonly reported unsolicited AEs in the 3 to <5 year age group were URI (41 events in Fluarix arm and 35 in Fluzone arm), cough (26 in Fluarix arm and 41 in Fluzone arm), and fever (26 in Fluarix arm and 32 in Fluzone arm). The most commonly reported unsolicited AEs in the 5 to 17 year age group were cough (56 events in Fluarix arm and 19 in Fluzone arm), fever (54 in Fluarix arm and 18 in Fluzone arm), and headache (52 in Fluarix arm and 25 in Fluzone arm). In the 6 to 35 month and 36 month to 5 year arms, the number of these individual AEs was similar in the Fluarix and Fluzone arms. After accounting for the 3:1 randomization in the oldest age group, the number of the most common AEs was also similar in the two treatment groups. The types of unsolicited AEs reported most frequently in this study were illnesses or symptoms common to the age groups studied.

   The same electronic dataset was analyzed for the number of subjects with Grade 3 unsolicited events. In the 6-35 month age group, Grade 3 AEs were reported in 27 subjects in the Fluarix arm and in 34 subjects in the Fluzone arm. Grade 3 AEs reported in more than two subjects in the Fluarix arm were fever (7 subjects), diarrhea (5), vomiting (4) and URI (3). Grade 3 AEs reported in more than two subjects in the Fluzone arm were fever (6), gastroenteritis (4), conjunctivitis (3), and otitis media (3). In the 3 to <5 year age group, Grade 3 AEs were reported in 15 subjects in the Fluarix arm and 17 in the Fluzone arm. Grade 3 AEs reported in more than two subjects in this age group were fever (4), vomiting (3), and gastroenteritis (3) in the Fluarix arm and fever (6) in the Fluzone arm. In the 5-17 year age group, there were 68 subjects in the Fluarix arm and 22 in the Fluzone arm with Grade 3 unsolicited AEs; this is consistent with the 3:1 randomization in this age group. Grade 3 AEs reported in this age group for Fluarix recipients were vomiting (18); fever (15); headache; streptococcal pharyngitis and throat pain (7 subjects each); abdominal pain and gastroenteritis (6 subjects each); cough, nausea, and URI (4 subjects each); and diarrhea (3). In the Fluzone arm, vomiting was reported in 4 subjects, fever in 3, and pain in 3. The number of subjects in the two treatment arms with Grade 3 unsolicited AEs was similar between the two arms.

   Cases of influenza-like illness or influenza were not followed by either active or passive surveillance. Influenza was reported as an AE (preferred term of influenza) in 16 subjects: nine (0.4%) of subjects in the Fluarix arm and seven (0.6%) in the Fluzone arm.

   Reviewer comment: On examination of the unsolicited AE dataset, there were an additional seven cases of influenza-like illness in the Fluarix arm and two in the Fluzone arm. The percentage of subjects with either influenza or an influenza-like illness was 1% in each treatment arm. However, since the study was not designed to collect information on influenza or include diagnostic testing of influenza-like illnesses, no conclusions about the percentage of subjects with influenza and/or influenza-like illnesses can be made.

   Parents / guardians were contacted by telephone six months after first study vaccination and asked about new onset chronic diseases. New onset chronic diseases were reported in 11 subjects (0.5%) in the Fluarix arm and in 3 subjects (0.2%) in the Fluzone arm. The only new onset chronic disease reported in more than one study subject was asthma, which was reported in three subjects in the Fluarix arm and one in the Fluzone arm. Other new onset chronic diseases reported in Fluarix recipients were autoimmune thyroiditis, increased cholesterol, increased triglycerides, cardiac murmur cough, allergic rhinitis, alopecia areata, psoriasis, and eczema. The other new onset chronic diseases reported in the Fluzone arm were food allergy and atopic dermatitis.

   Information on serious adverse events was collected for the entire study period (approximately 180 days). A total of 28 serious adverse events were reported in 22 study subjects (11 in each vaccine arm). SAEs were reported for six subjects in the time period from the first vaccination until 21 days after the second vaccination and in 16 subjects during the time from 21 days after the second vaccination until the end of the follow-up period. Of the 22 subjects with SAEs 11 were younger than 3 years of age (5 in Fluarix arm and 6 in Fluzone arm), four were from 3 to < 5 years of age (1 in Fluarix arm and 4 in Fluzone arm), and 7 were 5 to 17 years of age (5 in Fluarix arm and 2 in Fluzone arm). The percentage of subjects with SAEs by treatment arm and age subgroup is shown in the table below.

   Table 32: Study Fluarix-US-005 – Percentage of Subjects with One or More Serious Adverse Event by Age and Treatment Arm

   	Fluarix	Fluzone
   6-35 months of age	1.3%	1.6%
   36-59 months of age	0.3%	0.8%
   5-<18 years of age	0.1%	0.4%

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Tables 37-39, pages 77-79

   The only SAEs reported in more than a single subject in either vaccine arm were pneumonia (3 Fluarix subjects and 2 Fluzone subjects), lymphadenitis (2 Fluarix subjects and none in Fluzone arm), and febrile seizures (1 in Fluarix subject and 2 in Fluzone subject). The SAEs of pneumonia in the Fluarix arm were termed pneumonia, viral pneumonia, and lobar pneumonia. The SAEs of lympadenitis were reported 84 days after the second vaccination in a subject with cellulitis and 158 days after vaccination in a subject with mononucleosis. One SAE was judged as vaccine related. This was a febrile seizure reported four days after the second vaccination in a 13 month old Fluarix recipient; the subject also had a viral upper respiratory infection. The seizure lasted approximately two minutes and the subject was taken to the emergency room afterwards; no electroencephalogram or laboratory studies were done, and the only medication used was ibuprofen. There were no sequelae.

   Reviewer comment: There was no increase in a single type of SAE or increase of SAEs in a single organ system in either vaccine arm. The SAEs observed in this study were consistent with the ages studied: 8 of the 11 subjects with SAEs in the 6 to 35 month old cohort had infections as did four of the subjects in the 36 to 59 month cohort. The SAEs in the 5 to 17 year old cohort were from various causes including suicide attempt, appendicitis, head injury, and spontaneous abortion.

   The percentage of subjects receiving concomitant medications during the study was 39% in the Fluarix arm and 45% in the Fluzone arm. Prophylactic antipyretics were administered to 3.1% of subjects in the Fluarix arm and in 3.6% of subjects in the Fluzone arm. Twenty-five percent of subjects in the Fluarix arm and 28% in the Fluzone arm received a pyretic during the study.

   Reviewer comment: On analysis of the electronic dataset, antiyr, the percentage of subjects who received concomitant medications during the seven days post-vaccination was similar between the two treatment arms. In the 6 to 35 month age group, 45% of subjects in the Fluarix arm and 46% in the Fluzone arm received medications. Concomitant medication usage was lower in the older age groups during the week after vaccination. In the 3 to 5 year age group, 33.5% of subjects in the Fluarix arm and 37% in the Fluzone arm received concomitant medication(s), and in the 5 to 17 year age group, 21% of subjects in the Fluarix arm and 17.5% in the Fluzone arm received medications. The most common type of medication received in all age groups was antipyretics.

   There were no deaths in the study.

   8.1.11 Comments & Conclusions

   The primary objective of this study was to demonstrate the non-inferiority of Fluarix to Fluzone in children from 6 months to 59 months of age. Non-inferiority of Fluarix to Fluzone, a licensed vaccine in this age group in the U.S., was not demonstrated in the entire cohort of children, but this was largely due to the poor antibody response in Fluarix recipients from 6 to 35 months of age. In children from 36 to 59 months of age, Fluarix was not inferior to Fluzone in three of six endpoints. Of the three endpoints for which non-inferiority was not demonstrated, the non-inferiority margin was only narrowly missed. Therefore, the results were very close to satisfying the non-inferiority criteria, and any differences are unlikely to be of clinical significance. In addition, the antibody responses as measured by seroconversion rate and percentage of subjects with post-vaccination HI titers of ≥ 1:40 met the CBER criteria used for accelerated approval in adults. Furthermore, the evaluation of immunogenicity of the subgroup of study subjects from 36 to 59 months of age is valid, because study subjects were stratified by age and evaluation of immunogenicity by age was a secondary endpoint. Therefore, in the opinion of this reviewer, the results of Study Fluarix-US-005 support the effectiveness of Fluarix in children from 36 months to 59 months of age.

   Local solicited adverse reactions were reported commonly in study subjects with pain reported in at least one-third of all subjects in each age subgroup. Redness and swelling at the injection site were reported in more than 10% of subjects in each subgroup. However, Grade 3 local adverse reactions were uncommon. Solicited general adverse reactions were reported more frequently in the youngest age subgroup. In subjects from 6 months to 35 months of age, irritability was reported in 45%, drowsiness in 33%, and decreased appetite in 23.5%. These AEs were reported less frequently in subjects from 36 to 59 months of age with irritability reported in 22%, drowsiness in 14%, and decreased appetite in 15%. Grade 3 general solicited events were also reported uncommonly. Reactogenicity events reported in subjects from 5 to 17 years of age were similar to those reported in adults; pain, redness, and swelling at injection site as well as fatigue, muscle aches, and headache reported in more than 10% of subjects. The unsolicited adverse events and serious adverse events reported in this study reflected common illnesses in the age groups studied, and no safety signal was observed by this reviewer.

   8.2 FLU-056

   A phase III double-blind, randomized, multicenter, comparative vaccination study of the immunogenicity and reactogenicity of a thiomersal-free formulation of Influsplit SSW® 2003/2004 versus the standard formulation of Influsplit SSW® 2003/2004 in children aged from 6 months to <6 years.

   This study was not conducted under a U.S. IND.

   Reviewer comment: The study was conducted in Germany, where Fluarix is marketed as Influsplit SSW.

   8.2.1 Objective/Rationale

   The primary objective of Study Flu-056 was to investigate the humoral immune response in children aged from 6 months to <6 years administered thimerosal-free formulation Fluarix compared to the antibody response in children receiving a thimerosal-reduced formulation of Fluarix. At the time of that the study was conducted, the thimerosal-reduced formulation of Fluarix was the formulation licensed for use in the U.S. However, the currently licensed formulation of Fluarix is thimerosal free.

   The secondary objective was to investigate the safety and reactogenicity of thimerosal-free Fluarix compared to thimerosal-reduced Fluarix in children 6 months to <6 years of age.

   8.2.2 Design Overview

   Study FLU-056 was a phase III, multicenter, trial comparing thimerosal-free and thimerosal-reduced Fluarix in pediatric subjects from 6 months to < 6 years of age. Study subjects were stratified by age (6-35 months and 36-71 months) and randomized in a 1:1 ratio into one of the two vaccine groups. The study was designed to enroll 220 with 110 subjects in each age group.

   The subjects, investigators, and GSK medical monitors were blinded to treatment assignment.

   All subjects received two doses of study vaccine on Day 0 and Day 28. A 0.5 mL dose was administered to children 36 to 71 months of age, and a 0.25 ml dose was administered to children ages 6-35 months of age. Subjects were monitored for 30 minutes immediately following vaccination.

   Subjects were seen at the study site on Day 0, Day 28 (window +/- 2 days), on Day 49 (window +/- 2 days), Month 4, and Month 7. Subjects and their parents/guardians were given a diary card to record temperature and specific local and systemic adverse events for 3 days post-vaccination, with instructions to call the investigator immediately for any adverse events perceived as serious. Solicited local adverse events were pain, redness, and swelling/induration at the injection site. The size of redness or swelling/induration was recorded using a stencil aid; the intensity was defined as Grade 1 for reactions >0 to <10 mm, Grade 2 for >10 to ≤ 30 mm, and Grade 3 for reactions > 30 mm. Pain was graded as Grade 1 (minor reaction to touch), Grade 2 (cries or protests on touch), and Grade 3 (cries when arm is moved or spontaneously moves arm). Solicited systemic events were fever/temperature increase (measured nightly), irritability/fussiness, drowsiness, and loss of appetite. The temperature in degrees Celsius was recorded; the temperature was to be measured rectally in children 6 to 35 months of age and axillary in children 36 to 71 months of age. Temperature measured rectally was Grade 1 if 38.0º-38.5 º C, Grade 2 if 38.6 º -39.5 º C, and Grade 3 if greater than 39.5 º C. Axillary temperatures were Grade 1 if 37.5 º -38.0 º C, Grade 2 if 38.1 º -39.0 º C, and Grade 3 if greater than 39.0 º C. Other systemic adverse events were assessed as Grade 1 (easily tolerated with no effect on normal activity), Grade 2 (interferes with normal activity), and Grade 3 (prevents normal activity). All solicited adverse events were considered related to study vaccination.

   Information about unsolicited adverse events was collected between Days 0 and 58.

   8.2.3 Population

   Study subjects were excluded if they had previously received a vaccine for influenza prevention. Subjects were excluded or vaccine administration was delayed for acute disease at the time of enrollment or of vaccination. Acute disease was defined as the presence of a moderate or severe illness with or without fever. Vaccines could be administered to children with a minor illness such as diarrhea, mild upper respiratory infection with or without low-grade febrile illness, e.g, oral temperature <37.5°C (99.5°F) / axillary temperature <37.5°C (99.5°F). Subjects did not receive the second vaccine if they had an allergic reaction after the first vaccination that might have been caused by any ingredient of the vaccine or an anaphylactic reaction after the first study vaccine.

   8.2.4 Products mandated by the protocol

   The study vaccines used were two formulations of FluarixÒ for the Northern Hemisphere 2003-2004, which contained hemagglutinin (HA) from three influenza strains for a total HA content of 45 µg. Each study vaccine contained 15 µg of each of the following influenza antigens:
   A/New Caledonia/20/99 (H1N1-like),
   A/Moscow/10/99 (H3N2-like), and
   B/Hong Kong/330/2001-like.

   The study vaccines were supplied in ready-to-use syringes containing a single 0.5 mL dose. Thimerosal-reduced Fluarix contained 0.0025 mg of thimerosal per 0.5 mL dose.

   8.2.5 Endpoints

   The primary endpoint was the description of post-vaccination geometric mean titers (GMTs) of serum hemagglutination-inhibiting antibodies (HAI) for each vaccine strain on Day 21. Blood draws for antibody determination were obtained on Day 0, Day 49, Month 4, and Month 7.

   Safety outcomes were also evaluated in the study.

   8.2.6 Statistical considerations

   The primary endpoint was the description of antibody response post-vaccination by geometric mean titers (GMTs) of HI antibodies for each vaccine strain on Day 21. The GMT of HI antibodies at Day 0 and post-vaccination was calculated by taking the anti-log of the mean of the log titer transformations (titers below the cut-off 1:10 will be given the arbitrary value of half the cut off for calculation purpose). The antibody response would also be used to calculate the following:

   • seroconversion factor (defined as the quotient of the GMT after the second vaccination divided by the GMT before vaccination, which corresponds to the ratio of the antibody concentration after two vaccinations to that before any vaccinations),
   • seroconversion rate (defined as the proportion of subjects who were either seronegative before vaccination with a post-vaccination antibody titer of ≥ 1:40 or who were seropositive before vaccination and had a four fold or greater increase in titer after the second vaccination),
   • seroprotection rate (defined as the proportion of subjects with an antibody titer ≥ 1:40 after the second vaccination), and
   • seroprotection power (defined as the proportion of subjects with an antibody titer <1:40 on day 0 and an antibody titer of ≥ 1:40 after the second vaccination).

   The 95% confidence intervals were calculated for each analysis.

   The secondary endpoints were:

   • Occurrence, intensity and relationship to vaccination of solicited local and general signs and symptoms during a 4-day follow-up period (i.e. day of vaccination and 3 subsequent days) after each vaccination.
   • Occurrence, intensity and relationship to vaccination of unsolicited local and general signs and symptoms during follow-up period(s) after each vaccination within 28 days after the first vaccination and within 30 days after the second.
   • Occurrence, severity, and relationship to vaccination of serious adverse events during the entire study.
   • Descriptive comparison of the percentage of subjects receiving any new concomitant medication, any new antipyretics, and prophylactic antipyretics between Days 0 and 27 after the first vaccination and between Days 28 and 57 after the second vaccination.
   • Descriptive comparison of the antibody response at Month 3 or Month 6 after the second vaccination.

   The sample size was based on the requirements for annual licensing in Europe in adults, which stipulates a minimum of 50 subjects per age group.

   The Total vaccinated cohort included all subjects with data available for the analysis in question. The analysis of safety was based primarily on the total vaccinated cohort. The “According to Protocol” (ATP) cohort was defined as subjects who met all entry criteria, had been vaccinated in accordance with the randomization schedule, had received the correct dose of the planned vaccine, and in whom the randomization code had not been prematurely broken. The analysis of immunogenicity was based primarily on the ATP cohort.

   The definition of the ATP cohort was revised post-hoc to allow for wider windows for each study visit. According to the sponsor, use of the time windows pre-defined in the study protocol would have severely limited the number of evaluable subjects. The pre-defined windows and revised windows are shown below.

   Table 33: Study FLU-056 - Acceptable Intervals (Windows) Between Study Visits

   	Protocol Interval	Revised Interval for Strict ATP Analysis	Revised Interval for Less Strict Analysis
   Visit 1 → Visit 2	28 +/- 2 days	26-30 days	22-44 days
   Visit 2 → Visit 3	21 +/- 2 days	19-23 days	17-25 days
   Visit 3 → Phone contact	9 +/- 5 days	9-14 days	Any interval
   Visit 2 → Visit 4	3 months +/- 7 days	83-97 days	Any interval
   Visit 2 → Visit 5	6 months +/- 7 days	173-187 days	Any interval

   Source: sBLA 125127, SN 319, CSR for FLU-056, Table 2, page 30

   8.2.7 Results

   The first subject was enrolled in the study on October 8, 2003 and the last study visit for the last subject was August 27, 2004. The study was conducted at 12 centers in Germany.

   8.2.8 Populations enrolled/analyzed/demographics

   Subject distribution and Demographics

   A total of 157 subjects were enrolled in the study: 153 were included in the ATP safety cohort, 131 in the ATP immunogenicity cohort, and 100 in the strict ATP immunogenicity cohort. The disposition of subjects is shown in the table below.

   Table 34: Study FLU-056 - Number of Subjects Enrolled in Study FLU-056 and Subject Disposition by Age Cohort

   	6-35 Months	36-71 Months
   Total enrolled	88	69
   Total vaccinated	88 (100%)	69 (100%)
   Received protocol-forbidden vaccines	2	1
   Study dose not administered per protocol	0	1
   ATP safety cohort	86 (98%)	67 (97%)
   Non-compliance with new windows Visit 1→2 and Visits 2→3	12	10
   ATP immunogenicity cohort	74 (84%)	57 (83%)
   Non-compliance with vaccination schedule, blood sampling, and/ or serology data missing	21	10
   Strict ATP immogenicity cohort	53 (60%)	47 (68%)

   Source: sBLA 125127, SN 319, CSR for FLU-056, Table 8, page 51

   As shown in the table above, fewer subjects than planned were enrolled and the percentage of subjects who strictly followed the study was small: 60% of the younger cohort and 68% of the older cohort.

   Reviewer comment: As a result of the small number of subjects in the strict ATP immunogenicity cohort, it is difficult to reach any conclusions about vaccine immunogenicity from this study.

   Eighty-eight children from 6 months to < 3 years of age, and 69 subjects from 3 years to < 6 years of age were enrolled in the Total vaccinated cohort. Subjects were almost evenly divided by gender with a slight increase in females (52%) in the 6 month to <3 year age group and in males in the 3 years to <6 years age group (56.5%). The majority of subjects were White (N=148 or 94%); there was one Black, 4 North African/Arabic, and 4 Other.

   In the ATP cohort for immunogenicity, 74 subjects from 6 months to < 3 years of age, and 57 subjects from 3 years to < 6 years of age were enrolled. Fifty-three percent of the younger age group and 54% of the older age group were male. Ninety-three percent of all subjects were White.

   8.2.9 Efficacy endpoints/outcomes

   Please see Dr. Ahnn’s statistical review.

   Analysis of primary endpoint

   Immunogenicity was described by the change in GMT of HI antibodies. The primary cohort for analysis of immunogenicity was the ATP cohort. In the 6 to 35 month age groups, the proportion of subjects who were seropositive (e.g., had detectable serum HI antibody) for each of the vaccine strains was similar at baseline for all subjects. In 6-35 month age subjects who received the thimerosal-free vaccine, 100% of subjects had measurable serum HI antibody to all three strains after two vaccine doses. After two doses of the thimerosal-reduced vaccine, 81% of subjects were seropositive for the H1N1 strain, 94% for the H3N2 strain, and 86% for the B strain. The GMTs were higher in the thimerosal-free group for H1N1 and B strains; the post-vaccination serum antibody titers for the H3N2 strain were also higher in the thimerosal-free group, but the 95% confidence intervals (CIs) for this strain were overlapping.

   In the cohort of subjects 36 to 71 months of age, baseline titers for the H3N2 and B influenza strains were similar; however, for the H1N1, A/New Caledonia strain, 43.5% of subjects in the thimerosal-free arm were seropositive at baseline compared to 15% in the thimerosal-reduced arm. After two doses of study vaccine, the percentage of subjects with detectable serum antibody HI titers for each strain was the same in both arms: 96% for the H1N1 strain and 100% for the other two strains. All 95% CIs were overlapping.

   All subjects had detectable serum HI antibody titers through Month 7 of the study.

   Reviewer comment: Antibody response, as measured by detectable serum HI antibody, was observed to all three influenza antigens in both the thimerosal-free and Fluarix (thimerosal-reduced) arms. However, this endpoint is not commonly used by CBER to determine vaccine immunogenicity, and the clinical significance of this finding is not clear.

   Other analyses of vaccine immunogenicity

   The percentage of subjects with post-vaccination HI titers of 1:40 or greater and the seroconversion rate are shown in the table below.

   Table 35: Study FLU-056 - Seroconversion Rate and Percentage of Subjects with HI Titers ≥ 1:40 Post-Vaccination (with Lower Limit of 95% Confidence Interval)

   Influenza Strain	Percentage with HI Titers ≥ 1:40				Seroconversion Rate
   	6-35 Months		36-71 Months		6-35 Months		36-71 Months
   	TF* N=34	TR# N=36	TF N=23	TR N=27	TF N=34	TR N=36	TF N=23	TR N=27
   H1N1	73.5% (56%)	50% (33%)	78% (56%)	85% (66%)	73.5% (56%)	47% (30%)	74% (52%)	85% (66%)
   H3N2	97% (85%)	61% (43.5%)	96% (78%)	96% (81%)	94% (80%)	58% (41%)	78% (56%)	89% (71%)
   B	85% (69%)	64% (46%)	87% (66%)	89% (71%)	82% (65.5%)	64% (46%)	87% (66%)	89% (71%)

   *TF=thimerosal-free, #TR=thimerosal-reduced or Fluarix
   Source: sBLA 125127, SN 319, CSR for FLU-056, Table 16, page 63

   In all subjects who received the thimerosal-free vaccine (regardless of age group), the point estimate for the percentage of subjects with post-vaccination HI titers ≥ 1:40 was greater than 70% as recommended by the EMEA for annual studies of influenza vaccine. However, CBER recommends the use of the lower limit of the 95% CI to measure the percentage of subjects with HI titers ≥ 1:40 when this endpoint is used, as described in the FDA Guidance for Industry, “Clinical Data Needed to Support the Licensure of Trivalent Inactivated Influenza Vaccines.” These criteria were met in both age groups of thimerosal-free vaccine recipients for the antibody response to the H3N2 strain only. The point estimates for the percentage of Fluarix (thimerosal-reduced) subjects with post-vaccination titers ≥ 1:40 was greater than 70% for all three strains in the 36-71 month age group but less than 70% for all three strains in the 6-35 month age group. The lower bound 95% CI was greater than 70% for Fluarix recipients 36-71 months of age to the H3N2 and B influenza antigens.

   The point estimates for seroconversion rates were greater than 40% as recommended by the EMEA for all strains, all ages, and both vaccines. The lower bound 95% CI was greater than 40% for all except for one group: antibody response to H1N1 in Fluarix subjects 6-35 months of age.

   Reviewer comment: This study was not designed or powered to meet the CBER criteria. In spite of this, the CBER criteria were met for four of the six endpoints in both age groups for subjects who received the thimerosal-free vaccine, which is the currently marketed formulation of Fluarix in the United States.

   The seroprotection power was similar in all age groups, to all strains, and for both vaccines with one exception; the seroprotection power was statistically significantly higher to the H3N2 strain in subjects 6-35 months of age who received the thimerosal-reduced formulation.

   According to the CHMP criteria for subjects 18 to 60 years of age, influenza vaccines should induce a seroconversion factor greater than 2.5. This was achieved in both age groups, for both vaccines, and for all three strains.

   8.2.9 Safety outcomes

   In the 6-35 month age group, adverse events (AEs) were reported in 82% of subjects in the thimerosal-free vaccine arm and in 60.5% of those in the Fluarix arm. In the 36-71 month age group, 62.5% of subjects who received the thimerosal-free vaccine and 70% who received Fluarix reported at least one AE during the study. The percentage of subjects with general adverse reactions was slightly higher than with local adverse reactions in both treatment arms: 63% in the thimerosal-free arm and 52.5% in the Fluarix arm reported a general AE, while 45% in the thimerosal-free arm and 35% in the Fluarix arm reported a local AE.

   Local and general solicited adverse event

   The percentage of subjects with local solicited events after either the first or second vaccination is shown in the following table.

   Table 36: Study FLU-056 - Percentage of Subjects with Local Solicited Adverse Events

   	Thimerosal-Free		Fluarix
   	6-35 Months	36-71 Months	6-35 Months	36-71 Months
   Pain	36%	28%	21%	40.5%
   Redness	27%	19%	19%	22%
   Swelling/Induration	23%	22%	16%	16%

   Source: sBLA 125127, SN 319, CSR for FLU-056, Table 24, page 80

   In subjects 6-35 months of age, a greater percentage reported local solicited events in the thimerosal-free arm than in the Fluarix arm. This was not observed in the 36-71 month age group. In subjects 36-71 months of age, pain was much more common in Fluarix recipients than in recipients of the thimerosal-free vaccine; there were no Grade 3 pain events in thimerosal-free vaccine recipients, while Grade 3 pain was reported in 4% of Fluarix subjects. Redness was also observed more frequently in older subjects receiving Fluarix compared to those receiving the thimerosal-free vaccine; however, swelling was more common in recipients of the thimerosal-free vaccine.

   Reviewer comment: In the younger age group, there were fewer local solicited adverse reactions after vaccination with the thimerosal-reduced vaccine compared to vaccination with the thimerosal-free vaccine. In the older age group, the reverse was observed. Therefore, it is impossible to reach any conclusions about the effect of a reduced amount of thimerosal on local solicited adverse reactions.

   The percentage of subjects with systemic solicited events after either the first or second dose of study vaccine is shown in the table below. Overall, systemic solicited AEs were reported more frequently in the younger age group than in the older age group.

   Table 37: Study FLU 056 - Percentage of Subjects with Systemic Solicited Adverse Events

   	Thimerosal-Free		Fluarix
   	6-35 Months N=44	36-71 Months N=32	6-35 Months N=43	36-71 Months N=37
   Drowsiness	34%	25%	21%	27%
   Fever	34%	16%	33%	27%
   Irritability	39%	12.5%	26%	16%
   Loss of appetite	34%	19%	30%	16%

   Source: sBLA 125127, SN 319, CSR for FLU-056, Table 26, pages 85-87

   Overall, systemic solicited symptoms were observed more commonly in thimerosal-free vaccine recipients than in Fluarix recipients. The only exception was the increased rate of drowsiness in the older age group receiving Fluarix. Grade 3 systemic solicited events were uncommon. Grade 3 fever was observed in three recipients of the thimerosal-free vaccine and in four recipients of Fluarix. The only other Grade 3 systemic solicited events were one event of drowsiness and one of loss of appetite; both reported in the Fluarix arm.

   Reviewer comment: In general, the percentage of subjects with individual systemic solicited adverse events was higher in the 36-71 month age group. There was no correlation between the frequency of solicited general adverse reactions and thimerosal content of the vaccine.

   Unsolicited Adverse Events

   Overall unsolicited AEs were reported in 43 subjects (57%) who received the thimerosal-free vaccine and in 52 (65%) who received Fluarix. Unsolicited AEs were reported slightly more often in children 6-35 months of age (50 subjects) compared to those 36-71 months of age (45). The organ system most commonly involved was the respiratory tract, which, as the sponsor notes, is not surprisingly given that the study was conducted during fall and winter. The majority of respiratory AEs was infectious and included bronchitis, ear infection, and rhinitis.

   There were two Grade 3 unsolicited AEs in the Fluarix group (fever and gastroenteritis); neither was judged to be vaccine-related. There were no Grade 3 unsolicited AEs in the thimerosal-free vaccine group.

   Reviewer comment: The unsolicited adverse events reported in Study FLU-056 were consistent with common childhood illnesses observed in winter and fall.

   No unsolicited AEs were judged as vaccine-related.

   There were three serious AEs: brain trauma, gastroenteritis, and constipation. None were considered to be vaccine related.

   There were no adverse events resulting in premature study discontinuation. There were no deaths.

   8.2.10 Comments & Conclusions

   Study FLU-056 was a randomized, Phase III study comparing thimerosal-free Fluarix, which is the currently licensed formulation with the previously licensed, thimerosal-reduced formulation of Fluarix in children from 6 months of age to 71 months of age. The study was small and lacked the statistical power to identify the more immunogenic of the two vaccines or to determine the immunogenicity of the study vaccines using CBER accelerated approval criteria. There were trends for higher antibody titers post-vaccination in the thimerosal-free arm compared to the thimerosal-reduced vaccine arm. The CBER criteria were met for all three strains and for both study vaccines in children 36 to 71 months of age. In the same age group, the CBER criteria for the rates of subjects with post-vaccination titers ≥ 1:40 were met for one of the three influenza strains in the thimerosal-free arm and for two of the strains in the thimerosal-reduced arm. The antibody responses were lower in the 6 month to 35 month age group, particularly in the thimerosal-reduced vaccine arm.

   Pain at the injection site and irritability were the most frequently observed solicited adverse reactions post-vaccination in both treatment arms. Grade 3 adverse reactions were uncommon with either vaccine. Unsolicited events were not attributed to study vaccine by the investigator, and most of the unsolicited AEs were consistent with childhood illnesses typically observed in fall and winter.

   Overall, this was a small study that was underpowered to show any statistically significant difference between the two vaccines. Not surprisingly, anti-HI levels post-vaccination did not meet all of the CBER criteria recommended to demonstrate vaccine immunogenicity in adults. In addition, both vaccines were fairly well tolerated and no serious safety concerns were identified.

   8.3 Fluarix- 062

   An open, phase IV study on the immunogenicity and tolerability of Influsplit SSW® 2005/2006 in children aged 6-13 years

   Reviewer comment: The study was conducted in Germany, where Fluarix is marketed as Influsplit SSW.

   8.3.1 Objective/Rationale

   The primary objective of Study Fluarix-062 was to describe the post-vaccination geometric mean titers (GMTs) of the HI antibody response and the seroconversion rates against the three influenza strains in Fluarix after vaccination in children between 6 and 9 years of age.

   The secondary objectives were: 1) to describe the post-vaccination GMTs and seroconversion rate after vaccination with Fluarix in children 10-13 years of age, and 2) to evaluate the incidence, type, and severity of local and general reactogenicity events and serious adverse events after vaccination with Fluarix.

   8.3.2 Design Overview

   Study Fluarix-062 was an open-label, immunogenicity and safety study of Fluarix in children from 6 to 13 years of age. Study subjects were stratified by age (6-9 years and 10-13 years). The study enrolled children who had not been vaccinated against influenza. Subjects from 6 to 9 years of age received two doses of Fluarix, administered four weeks apart. Subjects from 10 to 13 years of age were vaccinated once.

   Subjects from 6 to 9 years of age, who received two doses of study vaccine, were seen at the study site on days 0, 28, and 49. Subjects from 10 to 13 years of age, who received a single dose of study vaccine, were seen in study clinic on days 0 and 21. All subjects were contacted by telephone 30 days after the last study visit. The study intervals are provided in the table below.

   Table 38: Study Fluarix-062 – Intervals between Study Visits

   Subjects 6-9 Years of Age		Subjects 10-13 Years of Age
   Study Period	Duration of Interval	Study Period	Duration of Interval
   Visit 1→Visit 2	28 ± 2 days	Visit 1→Visit 2	21 ± 2 days
   Visit 2→Visit 3	21 ± 2 days	Visit 2→Telephone contact	30 ± 5 days
   Visit 3→Telephone contact	58 ± 5 days

   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Tables 3-4, page 27

   Demographic data, medical history including influenza vaccination history, height and weight measurement, urine pregnancy test for female subjects of childbearing potential, and baseline body temperature were performed before vaccination. The health record was reviewed prior to vaccination. Fluarix was administered as an intramuscular injection into the non-dominant arm. Subjects were observed in clinic for at least 30 minutes afterwards.

   Reviewer comment: There is no mention in the Clinical Study Report or protocol that physical examinations were performed in the study, which may have resulted in fewer adverse events being detected. Information on unsolicited AEs and SAEs were collected, but it must be assumed that any signs or symptoms resulting in these AEs triggered a targeted physical examination.

   Subjects and their parents/guardians were given a diary card to record temperature, any local and/or general adverse events occurring on the day of vaccination (day 0) and during the next 3 subsequent days (days 1-3). Solicited local adverse reactions monitored in the diary card were pain, redness, and swelling. Solicited general adverse reactions monitored were fever, headache, chills, fatigue, sweating, myalgia, and arthralgia. Parents / guardians were to record the diameter of any redness or swelling at the injection site; reactions from > 0 to ≤ 20 mm were considered Grade 1, reactions > 20 to ≤ 50 mm were considered Grade 2, and reactions > 50 mm were considered Grade 3. The exact axillary temperature was also to be recorded; Grade 1 fever was 37.5 to 38.0º C, Grade 2 was 38.1 to 39.0º C, and Grade 3 was > 39.0º C. The intensity of other solicited adverse events was categorized as Grade 1 if easily tolerated, Grade 2 if interfered with daily activities, and Grade 3 if prevented normal, everyday activities.

   Information was collected for unsolicited adverse events and for serious adverse events occurring from the time of vaccination until 30 days after the last vaccination: days 0-58 for subjects 6 to 9 years of age and days 0-30 for subjects 10 to 13 years of age.

   HI antibody titers were measured at baseline, day 28, and day 49 in subjects who received two doses of study vaccine and at baseline and day 21 in subjects who received a single dose of study vaccine.

   8.3.3 Population

   The study enrolled children from 6 to 13 years of age. Eligible children could be healthy or at risk of influenza complications, with underlying diseases such as those with asthma; chronic obstructive pulmonary disease; chronic cardiovascular, hepatic, and renal disease; diabetes, and other metabolic diseases.

   Children, who were previously vaccinated against influenza or who had a history of influenza disease as confirmed by a laboratory test, were excluded. Children were also excluded for acute illness, multiple sclerosis, immunodeficiency, or known allergic reactions to a vaccine component.

   Study subjects from 6 to 9 years of age with an acute illness at the time of the second vaccination or an allergic reaction to the first vaccination did not receive a second vaccination.

   8.3.4 Products mandated by the protocol

   Fluarix was provided as pre-filled syringes with an injectable volume of 0.5 mL. The influenza antigens used were those recommended for the Northern Hemisphere 2005-2006 influenza season. Each 0.5 mL contained 15 µg of the following antigens (45 µg total):
   A/New Caledonia/20/99 (H1N1),
   A/New York/55/2004 (H3N2), and
   B/Jiangsu/10/2003.
   The Fluarix formulation used contained trace amounts of thimerosal (≤ 1 µg of mercury per 0.5 mL dose, maximum of 0.0025 mg/dose).

   8.3.5 Endpoints

   The primary immunogenicity endpoint was HI antibody titers to the three influenza strains contained in the study vaccine. Blood samples for antibody levels were collected at baseline for all subjects. Blood samples for post-vaccination antibody titers were collected on Day 28 for subjects who received a single dose of study vaccine and were collected on Day 28 and Day 49 for subjects who received two doses of study vaccine. HI titers were assayed at GSK Biologics in Dresden, Germany.

   8.3.6 Statistical considerations

   Immunogenicity results were analyzed using descriptive statistics. The primary immunogenicity endpoint was the post-vaccination HI antibody response in children 6 to 9 years of age. One of the secondary endpoints was the post-vaccination antibody response in children 10-13 years of age. Antibody titers were assessed using GMTs, seroconversion rate, seroconversion factors. Seroconversion rate was defined as the proportion of subjects with a four fold or higher increase in HI antibody titers post-vaccination. The seroconversion factor was defined as the mean increase in GMT or the quotient of the post-vaccination GMT divided by the pre-vaccination GMT. The results were compared to the CHMP criteria for adults 18 to 60 years of age. Other immunogenicity analyses included seroprotection rate, defined as the proportion of subjects having a post-vaccination HI antibody titer of 1:40 or greater, and seroprotection power, defined as the proportion of subjects who had a pre-vaccination HI titer <1:40 and a post-vaccination HI titer of 1:40 or greater.

   Reviewer comment: The study was not designed to meet prespecified immunogenicity criteria.

   The safety analyses were performed using descriptive statistics. All solicited local adverse reactions were considered vaccine-related. The vaccine relatedness for all other AEs was determined by the investigator.

   Reviewer comment: The study was open-label and single arm, which limits the interpretation of the safety results.

   The study populations were:

   • Total vaccinated cohort for immunogenicity – all vaccinated subjects for whom pre- and post-vaccination blood samples were available,
   • Total vaccinated cohort for safety – all vaccinated subjects for whom a diary card was available,
   • ATP cohort for analysis of immunogenicity – all subjects for whom laboratory immunogenicity analysis was available, who met all entry criteria, who received the correct dose of the planned vaccine, and for whom the correct sampling intervals were kept, and
   • ATP cohort for the analysis of reactogenicity – all subjects for whom the respective analysis was available, who received the correct dose of the planned vaccine, and who properly completed and submitted the diary card. 8.3.7 Results

   Study Fluarix-062 was conducted at 18 study centers in Germany. The first subject was enrolled on November 17, 2005, and the last subject follow-up was March 28, 2006.

   8.3.8 Populations enrolled/analyzed

   Subject Disposition

   A total of 224 subjects (110 in the 6 to 9 year age group and 114 in the 10 to 13 year age group) were enrolled in the study. Of these, 221 completed the study, and three subjects prematurely discontinued the study. Two subjects in the 6 to 9 year age group were lost to follow-up; one received both vaccinations and the other received a single vaccination. One subject in the 10 to 13 year age group was lost to follow-up between the Day 28 visit and the Day 30 telephone contact.

   Subject disposition by age is shown in the table below.

   Table 39: Study Fluarix-062 – Subject Disposition by Age

   	Number of Subjects
   	6-9 Years of Age	10-13 Years of Age	Total
   Total Vaccinated Cohort	110	114	224
   Vaccine not administered according to protocol	1	0	1
   ATP safety cohort	109	114	223
   Violation of entry criteria	0	2	2
   Non-compliance with blood sampling schedule	12	6	18
   ATP cohort for immunogenicity	97	106	203

   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Table 13, page 45

   As shown in the table above, 99% of subjects vaccinated were included in the ATP safety cohort and 91% of subjects vaccinated were included in the ATP cohort for immunogenicity. The most common reason (18 subjects) for exclusion from the ATP cohort for immunogenicity was blood sampling outside of the schedule interval. Two subjects were excluded from the ATP cohort for immunogenicity due to receipt of vaccines (history of influenza vaccination in one subject and vaccination against hepatitis A and B in the other subject) prohibited in the study protocol.

   Reviewer comment: The majority of subjects were eligible for the ATP cohorts for safety and for immunogenicity. Therefore, it appears that the study was well conducted.

   Demographics

   The mean age of subjects in the study was 9.4 years (7.4 years in the 6-9 year age group and 11.3 in the 10-13 year age group). There were slightly more females (57%) than males (43%) enrolled. Race and ethnicity were not provided.

   Medical history

   Current medical conditions were reported for 34% of subjects. Current medical conditions were more common in older subjects (43%) than in younger (19%).

   A total of 60% of subjects had pre-existing medical symptoms. These most commonly were respiratory, thoracic, or mediastinal (observed in 23% of subjects from 6 to 9 years of age and in

   Reviewer comment: In the general medical history dataset (wgenmd), diagnoses were listed as current, past, or both. Current conditions or conditions that were both current and past were reported in 93 subjects (41.5%). Using MedRA terms, the most commonly involved organ system was respiratory, thoracic, and mediastinal (34 conditions), which included 16 subjects with asthma. Other current conditions were varied and ranged from 19 subjects with environmental allergies to five subjects with obesity. Past medical conditions or conditions listed as both past and current were reported in 70 subjects (31%). The most commonly involved organ system in past conditions was also respiratory, thoracic, and mediastinal. Seven subjects had asthma. Other past medical conditions ranged from neurodermatitis (eight subjects) to allergic conjunctivitis (5 subjects).
   Although a large percentage of subjects had pre-existing conditions, the types of pre-existing conditions were varied and not necessarily conditions increasing the risk of influenza disease severity. Therefore, this study was not adequate to explore the immunogenicity of influenza vaccine in subjects with pre-existing disease that predispose subjects to severe influenza disease.

   8.3.9 Efficacy endpoints/outcomes

   Please see also Dr. Sang Ahnn’s statistical review.

   The primary endpoints were the antibody response to the three influenza antigens contained in the study vaccine in 6 to 9 year old subjects as measured by GMTs, seroconversion rate and seroconversion factor. At baseline, 47% of subjects in this age group were seropositive for the influenza A/H1N1 strain, 78% for the influenza A/H3N2 strain, and 37% for the influenza B strains. Immunogenicity results are shown in the table below.

   Table 40: Study Fluarix-062 – Immunogenicity Results for Subjects from 6 to 9 Years of Age after Two Doses of Fluarix (ATP Cohort for Immunogenicity)

   Influenza Strain	GMT		Seroconversion Rate		Seroconversion Factor
   	Baseline	Post- Vaccination	%	LL 95% CI*	Value	LL 95% CI*
   A/H1N1	17.3	719.2	98%	92.6%	41	32.6
   A/H3N2	25.6	393.9	84%	75%	15	11.9
   B	11.5	301.8	97%	91.0	26	21.4

   *LL 95% CI = lower limit of the 95% confidence interval
   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Table 17, 18, and 20, pages 49-52

   As shown in the table above, the GMTs increased substantially after vaccination for all three strains. The seroconversion rates were greater than 80% for all three strains, and the post-vaccination antibody levels ranged from 15 to 41 fold higher than pre-vaccination levels.

   Reviewer comment: In the FDA Guidance for Industry, “Clinical Data Needed to Support the Licensure of Trivalent Inactivated Influenza Vaccines” seroconversion rate and the percentage of subjects with post-vaccination HI titers ≥ 1:40 are used to evaluate immunogenicity under accelerated approval in non-comparative studies in adults. The lower bound 95% confidence interval for seroconversion rate should be greater than 40% for all three strains to establish immunogenicity of a vaccine. In this study the lower bound of the 95% confidence interval for the percentage of subjects with seroconversion was well above 40% for all three strains. The seroconversion factor has not been used by FDA for regulatory decisions relating to influenza vaccines and this outcome is not described in the Guidance.

   Secondary Immunogenicity Endpoints

   HI antibody titers pre- and post-vaccination, seroconversion rate, and seroconversion factor were also analyzed for subjects from 10 to 13 years of age and are shown in the table below.

   Table 41: Study Fluarix-062 – Immunogenicity Results for Subjects from 10-13 Years of Age after a Single Dose of Fluarix (ATP Cohort for Immunogenicity)

   Influenza Strain	GMT		Seroconversion Rate		Seroconversion Factor
   	Baseline	Post- Vaccination	%	LL 95% CI*	Value	LL 95% CI*
   A/H1N1	26.4	1326.6	85%	76.6%	50.2	36.2
   A/H3N2	29.3	300.6	78%	69.2%	10.3	8.2
   B	17.4	218.9	85%	76.6%	12.6	10.4

   *LL 95% CI = lower limit of the 95% confidence interval
   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Tables 17, 18, and 20, pages 49-52

   At baseline, 75.5% of subjects in the 10-13 year old age group had HI antibodies to influenza A/H1N1 at a level of 1:10 or higher, 77% had antibodies to influenza A/H3N2, and 66% had antibodies to influenza B. HI antibody titers increased substantially post-vaccination in this age group also.

   The percentage of subjects with post-vaccination HI titers of 1:40 and the seroprotection power are shown in the table below.

   Table 42: Study Fluarix-062 – Percentage of Subjects with Post-Vaccination HI Antibody Titers ≥ 1:40 and the Seroprotection Power (SPP) (ATP Cohort for Immunogenicity)

   	6-9 Years of Age				10-13 Years of Age
   Influenza Strain	% with HI Titers ≥ 1:40		SPP		% with HI Titers ≥ 1:40		SPP
   	%	LL 95% CI*	Value	LL 95% CI*	%	LL 95% CI*	Value	LL 95% CI*
   A/H1N1	98%	92.6%	97%	88.1%	86%	77.7%	69%	53.7%
   A/H3N2	96%	89.6%	93%	82.7%	95%	89.3%	91%	80.7%
   B	99%	94.3%	99%	92.5%	88%	79.9%	83%	72.2%

   *LL 95% CI = lower limit of the 95% confidence interval
   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Tables 19 and 21, pages 51 and 53

   Reviewer comment: According to the FDA Guidance, the lower bound 95% confidence interval for the percentage of subjects with post-vaccination HI antibody titers ≥ 1:40 should be 70% or higher for all three strains. The results for this study met those criteria. The applicant defines seroprotection power as the percentage of subjects with baseline titers <1:40 and post-vaccination HI titers of ≥ 1:40. There is no correlate for that analysis in the FDA Guidance.

   Reviewer comment: The immunogenicity results for subjects with chronic diseases compared to healthy children were not provided. However, because of the varied nature of the underlying diseases, this analysis is not likely to be helpful.

   Results of the immunogenicity analyses performed using the total vaccinated cohort instead of the ATP cohort for immunogenicity were similar.

   8.3.10 Safety outcomes

   There were 228 subjects in the Total vaccinated cohort for analysis of safety: 110 in the 6 to 9 year age group and 114 in the 10 to 13 year age group. The percentage of subjects with any solicited adverse event is shown in the table below.

   Table 43: Study Fluarix-062 - Number and Percentage of Subjects with Solicited Adverse Reactions

   	Any Solicited Adverse Reaction	Solicited General Adverse Reactions	Solicited Local Adverse Reactions
   Subjects 6-9 Years of Age (Either Dose)	96 (87%)	64 (58%)	85 (77%)
   Subjects 6-9 Years of Age (After 1st Dose)	84 (76%)	54 (49%)	69 (63%)
   Subjects 6-9 Years of Age (After 2nd Dose)	80 (74%)	39 (36%)	74 (68.5%)
   Subjects 10-13 Years of Age	78% (68%)	39 (34%)	67% (59%)

   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Table 27, page 59

   Reviewer comment: Solicited adverse reactions were reported more frequently in the 6 to 9 year age group than in the 10 to 13 year age group. Although there were fewer solicited general adverse reactions after the second dose compared to the first, the percentage of subjects with any solicited AE or a solicited local adverse reaction was similar between the first and second doses in children 6-9 years of age.

   Most of the solicited adverse events were mild in severity. Grade 2 or 3 adverse reactions were reported in 18% of subjects in the 6-9 year age group after the first dose, in 24% after the second dose, and in 21% of subjects in the 10-13 year age group.

   The percentage of subjects with individual types of solicited local adverse reactions is shown in the table below. The adverse reactions for the 6 to 9 year old age group shown in the table are those reported after either the first or second vaccination.

   Table 44: Study Fluarix-US-062 – Percentage of Subjects with Individual Solicited Local Adverse Reactions

   	6-9 Years of Age N=110	10-13 Years of Age N=114
   Pain	74.5%	47%
   Redness	35.5%	21%
   Swelling	40%	34%

   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Table 29, page 61-62

   Pain was the most commonly reported solicited local adverse reaction in both age groups. Grade 3 solicited local adverse reactions were reported for one subject in each group; both reported Grade 3 pain. Four subjects in the 6-9 year age group and five in the 10-13 year age group reported solicited local adverse reactions that were ongoing after the four day period for collection of solicited reactions. The solicited local adverse reactions resolved within eight days for all nine subjects.

   Reviewer comment: The percentage of subjects reporting each individual local solicited adverse reaction was higher in the 6 to 9 year age group than in the 10 to 13 year age group. The reason for this is unclear.

   The percentage of subjects with individual solicited general adverse reactions is shown in the table below.

   Table 45: Study Fluarix-US-062 – Percentage of Subjects with Individual Solicited General Adverse Reactions

   	6-9 Years of Age	10-13 Years of Age
   Headache	34.5%	17%
   Fatigue	27%	19%
   Myalgia	25.5%	11%
   Shivering	15.5%	7%
   Arthralgia	6%	5%
   Fever	6%	3%
   Sweating	4.5%	3.5%

   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Table 30, page 63-64

   In the 6 to 9 year old age group, Grade 3 solicited general adverse reactions were reported for two subjects with headache, two with myalgia, and one each with fatigue, shivering, and arthralgia. In the 10 to 13 year old age group, Grade 3 solicited general adverse reactions were reported for one subject with headache, one with shivering, and one with arthralgia.

   Reviewer comment: The most commonly reported solicited general adverse events were headache, fatigue, and myalgia. This is consistent with the other pediatric studies of Fluarix. Fever was uncommon, and no subject reported a temperature of 40Ëš C or higher. Each of the individual solicited general adverse reactions was reported more frequently in the 6 to 9 year age group than in the 10 to 13 year age group; the reason for this is unclear.

   Unsolicited adverse events were followed for 58 days (30 days after the last vaccination) for subjects in the 6 to 9 year age group and for 30 days in the 10 to 13 year age group. There were 105 unsolicited AEs reported in 52 (47%) subjects in the 6 to 9 year age group; 48 unsolicited AEs were reported in 30 subjects (26%) in the 10 to 13 year age group. Upper respiratory tract infection was the most commonly reported unsolicited AE in the study.

   Reviewer comment: On review of the unsolicited adverse events (wunsol), unsolicited AEs were reported in 70 subjects. The unsolicited AEs reported in five or more subjects were upper respiratory infection (20 adverse events), cough (12 AEs), rhinitis (10 AEs), vomiting, abdominal pain, and diarrhea (7 AEs each), enteritis (6 AEs), fever (5 AEs), and pharyngeal pain (5 AEs). These adverse events are consistent with common illnesses observed in children.

   Grade 3 unsolicited AEs were reported in four subjects: three in the 6 to 9 year old age group (2.7% of subjects) (enteritis in one and streptococcal infections in two) and one subject in the 10 to 13 year old age group (0.9% of subjects) (cough).

   Serious AEs were reported in three subjects, all of whom were in the 6 to 9 year age group. One subject was diagnosed with enteritis that began on study day 23 and resolved after two days. One subject was diagnosed with tonsillitis and lymphadenopathy with onset on day 26. The third subject had hematuria with onset on study day 19 and was diagnosed with hereditary fructose intolerance. None of the serious AEs were judged by the investigator as vaccine related.

   Reviewer comment: In the opinion of this reviewer, it is unlikely that any of these serious AEs were related to study vaccine.

   There were no pregnancies in study participants. There were no premature discontinuations due to adverse events. There were no study deaths.

   Concomitant medication use was documented in 36% of subjects in the 6 to 9 year age group and in 15% of subjects in the 10 to 13 year old age group. The use of antipyretics in the 30 days post-vaccination was reported in 10% of 6 to 9 year olds and in 2.6% of 10 to 13 year olds.

   Reviewer comment: On review of the electronic dataset for concomitant medication use (wmedic), the most condition for which medications were used was URI (17 episodes), asthma (16), and cough (10). Seventeen subjects received antibiotics. The reasons for antibiotic use included streptococcal infection (3 subjects), bronchitis (3 subjects), tonsillitis (2 subjects), Crohn’s disease (2 subjects); other reasons for antibiotic use were for one subject only. Seventeen subjects received antipyretics; the reasons for antipyretic use, which were reported in more than one subject, were fever (4 subjects) and abdominal pain (2 subjects).

   8.3.11 Comments & Conclusions

   The results of Study Fluarix-062 support the immunogenicity of Fluarix in children from 6 to 13 years of age. Although there was not an active comparator in the study, the immunogenicity results met the CBER criteria recommended for demonstration of immunogenicity. The usefulness of the safety results was limited due to the open-label design of the study. However, no new safety signal was observed in this reviewer’s analysis of the safety results.

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9. Overview of Effectiveness Across Trials

    

   The conclusions about the immunogenicity and safety of Fluarix in children 3 years of age and older were primarily based on the results of Study Fluarix-US-005. Study Fluarix-US-005 was a Phase III, randomized, observer-blind study to evaluate the immunogenicity and safety of Fluarix compared with Fluzone® (Sanofi Pasteur) in healthy children 6 months and older. Subjects were stratified by age (6 months to < 3 years, 3 to < 5 years, and 5 to < 18 years), then randomized to receive either Fluarix or Fluzone. Subjects in the two younger age subgroups (6 months to < 3 years, 3 to < 5 years) were randomized in a 1:1 ratio to Fluarix or Fluzone. Subjects in the 5 to < 18 year cohort were randomized in a 3:1 ratio to Fluarix or Fluzone. Children ages 6 months to 9 years who had not previously received a seasonal influenza vaccine received two doses, at day 0 and at approximately one month. Children who had previously received a seasonal influenza vaccine received one dose, and children ages 9-18 years regardless of history of previous seasonal influenza vaccine received one dose. The primary immunogenicity objective was to demonstrate the immunological non-inferiority of Fluarix compared to Fluzone in children 6 months to < 5 years of age. The secondary immunogenicity objectives were to compare the post-vaccination geometric mean titers (GMTs) of Fluarix and Fluzone and to compare the seroconversion rate and percentage of subjects with HI titers ≥ 1:40 post-vaccination in subgroups of children 6 months to < 36 months of age to those in children 3 to < 5 years of age.

   The non-inferiority of Fluarix to Fluzone was determined by comparison of post-vaccination GMTs of HI antibodies and by comparison of seroconversion rate. The non-inferiority margins were not met for any of the three vaccine strains when compared by GMTs or when compared by seroconversion rate. However, on analysis by pre-defined and stratified age groups, lower serum HI antibody titers were noted in the 6 month to 35 month age group. The non-inferiority comparison for subjects in the older age group is shown in the tables below.

   Table 46: Study Fluarix-US-005 – Non-Inferiority Comparison of Post-Vaccination Geometric Mean Titers of HI Antibodies for 36-59 Month Age Group and Treatment Arm (ATP immunogenicity Cohort)

   	GMTs		Ratio GMTs Fluzone/Fluarix (UL 95% CI*)
   	Fluzone	Fluarix
   A/New Caledonia	163.7	134.7	0.97 (1.53)
   A/Wisconsin	489.0	453.6	1.08 (1.34)
   B/Malaysia	63.0	55.1	1.14 (1.52)

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61

   Table 47: Study Fluarix-US-005 – Non-Inferiority Comparison of Seroconversion Rates for 36-59 Month Age Group and Treatment Arm (ATP immunogenicity Cohort)

   	GMTs		Ratio Seroconversion Rates Fluzone minus Fluarix (UL 95% CI*)
   	Fluzone	Fluarix
   A/New Caledonia	72.3%	72.7%	-0.45 (7.89)
   A/Wisconsin	70.5%	70.9%	-0.45 (8.05)
   B/Malaysia	55.5%	53.2%	2.27 (11.52)

   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61

   According to the study protocol, non-inferiority would be demonstrated if the upper bound of the 95% confidence interval for the ratio of GMTs was ≤ 1.5 and if the upper bound of the 95% confidence interval for the comparison of seroconversion rates was ≤ 10. The results for the 35 month to 59 month age group met these pre-defined study criteria for three of the six study endpoints, and narrowly missed the other three endpoints. Although the criteria used to define the non-inferiority margin were those typically used by CBER, the clinical correlation of these statistical criteria are unknown, and it is unlikely that the small differences in results and pre-defined margins would be clinically significant. In addition, immunogenicity in subjects 36 months to 59 months of age was also demonstrated in the secondary endpoint analyses in which seroconversion rates and percentage of subjects with post-vaccination titers ≥ 1:40 were compared to those recommended by CBER as the basis for accelerated approvals in adults in the FDA Guidance for Industry ““Clinical Data Needed to Support the Licensure of Trivalent Inactivated Influenza Vaccines.” These results are shown in the table below.

   Table 48: Study Fluarix-US-005 – Seroconversion (SC) Rate and Percentage of Subjects with HI Titer Post-Vaccination of ≥ 1:40 (ATP Cohort for Immunogenicity)

   Seroconversion Rate	Value	LL 95% CI#
   A/New Caledonia	62%	58%
   A/Wisconsin	64%	59.5%
   B/Malaysia	38%	34%
   % of Subjects with HI titer ≥ 1:40	Value	LL 95% CI
   A/New Caledonia	71%	66%
   A/Wisconsin	77%	73%
   B/Malaysia	40%	35.5%

   *SC=seroconversion, #LL 95% CI=lower limit of 95% confidence interval
   Source: sBLA 125127, SN 319, CSR for Fluarix-US-005, Table 23, page 61

   According to the CBER guidelines, post-vaccination seroconversion rate should be 40% or greater for each vaccine strain and the percentage of subjects with post-vaccination HI titers ≥ 1:40 should be 70% or greater for each vaccine strain. These criteria were met for both influenza A strains, but not for the influenza B strain.

   Immunogenicity in children three years of age and older was further demonstrated by the results from Study FLU-056. In this study, a thimerosal-free formulation was compared to a thimerosal-reduced formulation of Fluarix in children from 6 months to 71 months. Study subjects were stratified by age into two subgroups: 6 months to 35 months and 36 months to 71 months. Immunogenicity results are shown in the table below.

   Table 49: Study FLU-056 - Seroconversion Rate and Percentage of Subjects with HI Titers ≥ 1:40 Post-Vaccination (with Lower Limit of 95% Confidence Interval)

   	Seroconversion Rate		% of Subjects with HI ≥ 1:40
   	Thim Free	Thim Reduc	Thim Free	Thim Red
   H1N1	74% (52%)	85% (66%)	78% (56%)	85% (66%)
   H3N2	78% (56%)	89% (71%)	96% (78%)	96% (81%)
   B	87% (66%)	89% (71%)	87% (66%)	89% (71%)

   Source: sBLA 125127, SN 319, CSR for FLU-056, Table 16, page 63

   The immunogenicity of Fluarix in older children (6 to 13 years of age) was demonstrated in Study Fluarix-062. In this open-label study, subjects were stratified by age into two cohorts: 6 to 9 years and 10 to 13 years. Immunogenicity results for both age groups are shown below.

   Table 50: Study Fluarix-062 – Immunogenicity Results (ATP Cohort for Immunogenicity)

   Influenza Strain	Seroconversion Rate		Seroconversion Factor
   	%	LL 95% CI*	Value	LL 95% CI*
   Subjects 6-9 Years of Age
   A/H1N1	98%	92.6%	41	32.6
   A/H3N2	84%	75%	15	11.9
   B	97%	91.0	26	21.4
   Subjects 10-13 Years of Age
   A/H1N1	85%	76.6%	50.2	36.2
   A/H3N2	78%	69.2%	10.3	8.2
   B	85%	76.6%	12.6	10.4

   *LL 95% CI = lower limit of the 95% confidence interval
   Source: sBLA 125127, SN 319, CSR for Fluarix-062, Table 17, 18, and 20, pages 49-52

   As shown above, seroconversion rates ranged from 78% to 98% and the lower 95% confidence limit exceeded 60% all three influenza strains and for both age groups.

   The totality of these immunogenicity data demonstrates the immunogenicity of Fluarix in children 3 years of age and older. Post-vaccination serum HI antibody titers were similar in children from 36 months to 59 months after vaccination with Fluarix or Fluzone. The antibody response in children from 35 months to 71 months met pre-defined study criteria for demonstration of immunogenicity in Study FLU-052. The results for Study Fluarix-062 in subjects 6 years to 13 years of age met the CBER HI antibody response criteria used for accelerated approval for adults.

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10. Overview Overview of Safety Across Trials

    The results from all three studies included in the license supplement were provided to support the safety of Fluarix. However, the usefulness of the results from Studies FLU-056 and Fluarix-062 are limited due to the lack of a comparator and the open-label, single arm design of Fluarix-062. In Study Fluarix-US-005, local solicited adverse reactions, particularly pain, were commonly observed in children. Pain was reported in more than one-third of subjects. Redness and swelling at the injection site were reported in more than 10% of children. In children from 36 months to 59 months, drowsiness, irritability, and decreased appetite were observed in more than 10% of subjects. Fever was reported in 8% of children in the younger age group. In older children, 5 years to 17 years, pain (59% of subjects) was more common than in younger children. Redness and swelling at the injection site were reported in more than 10% of the older subgroup. In subjects from 5 to 17 years of age, myalgia, fatigue, and headache were all reported in more than 10% of subjects.

    Unsolicited adverse reactions were consistent with those illnesses commonly reported during childhood. Serious adverse events were uncommon in all three studies, and no serious AE was judged by the investigator or by this reviewer as vaccine-related. There were no deaths in any of the studies.

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11. Dose Regimens and Administration

    Fluarix is available as 0.5 mL single-dose prefilled syringes. Fluarix is administered as a single 0.5 mL injection by the intramuscular route preferably into the region of the deltoid muscle of the upper arm.

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12. Conclusions - Overall

    The clinical data submitted in the supplemental BLA support the effectiveness and safety of Fluarix when administered to children 3 years of age and older. Study FLU-005, a randomized, active-controlled trial of 441 healthy children from 6 months to less than 5 years of age provided the primary evaluation of effectiveness. In this study, immunologic non-inferiority to a U.S.-licensed comparator vaccine was demonstrated in the age group of children from 3 to less than 5 years of age. In the opinion of this reviewer, the use of the safety and immunogenicity from this age subgroup is valid since the study was stratified by age and examination of immunogenicity by age was a study objective. Effectiveness in children from 36 months to 71 months is further supported by the post-vaccination serum HI antibody responses in Study FLU-056, and for children from 6 to 13 years of age by the HI antibody responses in Study Fluarix-062.

    The safety concerns are primarily mild to moderate local injection site reactions. Irritability, drowsiness, and decreased appetite were reported commonly post-vaccination in children from 36 months to < 5 years of age, while myalgia, fatigue, and headache were reported in children from 5 years to 17 years of age.

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• Recommendations

   

  This clinical reviewer recommends that Fluarix be approved for the indication of active immunization of children three years of age and older against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine.

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• Labeling

   

  The indication was revised to include approval for use of Fluarix in children 3 years of age and older. Other changes to the package insert included the results of Study Fluarix-US-005 in Section 6.1 Clinical Trials Experience, Section 8.4 Pediatric Use, and Section 14 Clinical Studies.

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