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Summary Basis for Regulatory Action - FluLaval

Date: June 9, 2011

From: Sara Gagneten, Ph.D., Review Committee Chair

BLA/ STN: 125163/176

Applicant Name: ID Biomedical Corporation of Quebec (IDB)/GlaxoSmithKline
Biologicals (GSK)

Date of Submission: August 9, 2010

Proprietary Name/Established Name: Influenza Virus Vaccine/FluLaval®

Indication: FLULAVAL is indicated for active immunization against influenza disease caused by influenza virus subtypes A and type B contained in the vaccine. FLULAVAL is approved for use in persons 18 years of age and older.

Recommended Action: Approval

Signatory Authorities Action: Approval

Offices Signatory Authority: Wellington Sun, M.D., Director, DVRPA
□ I concur with the summary review.
□ I concur with the summary review and include a separate review to add further analysis.
□ I do not concur with the summary review and include a separate review.

Specific Documentation used in
Developing the SBRA 
Reviewer Name 
Clinical ReviewMelisse Baylor, M.D.
Pharmacovigilance ReviewPatricia Rohan, M.D.
Craig Zinderman, M.D.
Statistical Clinical ReviewSang Ahnn, Ph.D.
Bioassay ReviewOlga Zoueva, Ph.D.
Statistical Bioassay ReviewTsai-Lien Lin, Ph.D.
Biomonitoring ReviewCarla Jordan
Janet White
Labeling ReviewsMelisse Baylor, M.D.
Sara Gagneten, Ph.D.
Sang Ahnn, Ph.D.
Maryann Gallagher
Communications and DocumentationKristina Carroll, Ph.D.


FluLaval is a suspension for intramuscular injection. Each 0.5 mL dose of FluLaval is formulated to contain 15 µg hemagglutinin (HA) from each of three influenza viruses from subtypes H1N1 and H3N2 and type B. FluLaval is supplied in a multi-dose vial and contains thimerosal as a preservative. The thimerosal content is 0.01% (25 µg of mercury) per dose.

FluLaval was approved for active immunization against influenza in adults 18 years of age and older on October 5, 2006 under accelerated approval regulations. The approval was based on immunogenicity and safety data from studies using a surrogate marker [hemagglutination inhibition (HI) antibody response] for clinical efficacy.

This supplement was submitted to gain traditional approval for FluLaval based on clinical reports for two studies: Efficacy Clinical Endpoint Study (IDB-707-106) and Non-inferiority Immunogenicity Study (IDB-707-108). However, because the results of the clinical endpoint study did not demonstrate adequate effectiveness of FluLaval, the accelerated approval requirement to verify clinical benefit was not fulfilled. Therefore, the prescribing information was updated to include results from the efficacy and immunogenicity studies and the applicant committed to submit the results of ongoing Study FLU Q-QIV-006, a non-influenza vaccine comparator-controlled clinical endpoint study of FLU Q-QIV (quadrivalent seasonal influenza vaccine produced using the FluLaval process) in persons 3 to 8 years of age.

No manufacturing information was included in this supplement.



Please see information in Section 1. Introduction.












Two pivotal studies were included in this submission:

  • Efficacy Study (IDB-707-106, NCT00216242)

This was a phase 3, randomized, double-blind, placebo-controlled study of the efficacy of FluLaval in the prevention of culture-confirmed influenza illness conducted at 46 sites. The study was conducted during the 2005-2006 and 2006-2007 influenza seasons in healthy adults 18 to 49 years of age.

  • Non-inferiority Study (IDB-707-108, NCT00232947)

This was a phase 3, double-blind, randomized, non-inferiority comparison study of FluLaval versus a US-licensed inactivated split-virion vaccine (Fluzone) conducted at 12 sites in the US. The study was conducted during the 2005-2006 influenza immunization season in medically stable male and female adults 50 years of age or older.

6.1 Efficacy and Immunogenicity

The efficacy of FluLaval was studied in IBD-707-106, a randomized, observer-blind, placebo-controlled study in 7,611 healthy adult volunteers 18 to 49 years of age. During the influenza season, subjects with an influenza-like illness were identified by active and passive surveillance with nasal and throat swabs obtained from these subjects within three days of symptom onset. Specimens were analyzed by viral culture with serologic typing for influenza A subtypes and for type B. The primary evaluation of clinical efficacy was based on cases of culture-confirmed influenza caused by virus strains that matched those contained in the vaccine in the per-protocol efficacy population. According to the prospective analysis plan, the efficacy of FluLaval would be demonstrated if the lower limit of the 1-sided 97.5% confidence interval for vaccine efficacy was above 35%. The sample size was based on the assumption of an influenza attack rate of 2% in placebo recipients and a vaccine efficacy of 72%, to give 80% power to demonstrate vaccine efficacy with a lower limit of the one-sided confidence interval of 97.5% for efficacy greater than 35%. The attack rate and the results for the primary endpoint are shown in the table below.

Study IDB-707-106 – Vaccine Attack Rate and Efficacy
(Per-Protocol Efficacy Population)

Attack Rate
FluLaval (N=3714) 0.6%
Placebo (N=3768) 1.2%
Vaccine Efficacy
Point Estimate 46.3%
LB 97.5% CI 9.8%
Source: BLA 125163/ SN 176, CSR for Study IDB-707-106, Table 14, page 78.

Vaccine efficacy for FluLaval was 46.3% with a lower bound one-sided 97.5% confidence interval of 9.8%. This result did not meet the success criteria for demonstration of clinical efficacy as pre-defined in the study protocol. There were twice as many cases of influenza in the placebo arm (N=45) as the FluLaval arm (N=23). The statistical analysis plan had assumed an attack rate in the placebo arm of 2% and the attack rate was actually 1.2%; this may have resulted in an underpowered study. Vaccine efficacy (49.3%, lower bound, one sided confidence interval of 20.3%) was slightly higher against any influenza strain, regardless of vaccine match.

There were 19 cases of vaccine-matched, culture-confirmed influenza in males compared to 26 cases in females. Vaccine efficacy was higher in males (89.0%) than in females (19.4%). The reason for this difference is unclear, and no difference by gender was observed in the immunogenicity subset of the study. The study was not designed or powered to examine efficacy by gender. This finding was unexpected, and there are no known differences in influenza vaccine efficacy by gender. Differences by gender will be analyzed in the ongoing clinical endpoint study.

Immunogenicity analyses were performed in a subset of subjects in IDB-707-106 and in all subjects in Study IDB-707-108. In Study IDB-707-106, the seroconversion rate for FluLaval recipients and the percentage of subjects with HI titers of 1:40 or higher after vaccination with FluLaval met the criteria for demonstration of immunogenicity in FDA Guidance for Industry, “Clinical Data Needed to Support the Licensure of Trivalent Inactivated Vaccines.” Study IDB-707-108 was a randomized, observer-blind, immunogenic and safety study comparing FluLaval to Fluzone in 1,187 adult volunteers 50 years of age and older. In Study IDB-707-108, subjects were randomized in a 1:1 ratio to receive either FluLaval or Fluzone, a U.S.-licensed influenza vaccine. Antibody titers were assessed at baseline and 21 days post-vaccination. The primary object was to demonstrate the non-inferiority of FluLaval to Fluzone; the criteria for successfully meeting this objective were: 1) the lower limit of the two-sided 95% confidence interval of the geometric mean titer (GMT) ratio to be 0.67 or greater for each strain; and 2) the absolute difference in seroconversion rates to be less than 10% for each of the three strains. The results for the primary immunogenicity endpoints are shown in the following table.

Study IBD-707-108 – Non-Inferiority Comparison of FluLaval to Fluzone

Influenza Strain FluLaval
N=592 Fluzone
N=595 Non-Inferiority Comparison
Day 21
GMT Day 21
GMT Geometric Mean Ratio
Point Estimate 95% CI
A/H1N1 113.4 110.2 1.03 0.92, 1.15
A/H3N2 223.9 214.6 1.04 0.89, 1.23
B 82.3 97.1 0.85 0.74, 0.97
SCR SCR Difference in SCR
Point Estimate 95% CI
A/H1N1 34% 32% 2 -3.7, 7.0
A/H3N2 83% 82% 1 -2.6, 6.1
B 53% 56% -3 -8.2, 3.1
Source: BLA 125163/ SN 176, CSR for Study IDB-707-106, Tables 9 and 11, pages 51 and 53.

Immunogenicity of FluLaval as measured by HI titers was shown to be non-inferior to Fluzone in this study.

In the opinion of the clinical reviewer, the results of these two studies support the immunogenicity of FluLaval in adults 18 years of age and older. There is also some evidence of the clinical efficacy of FluLaval; however, the pre-defined criteria for demonstration of efficacy were not met. Therefore, FluLaval is not being granted traditional approval at this time. The applicant is currently conducting a second clinical efficacy trial of FluLaval, and the results of this trial will be submitted to support the traditional approval of FluLaval.

6.2 Biopharmaceutical Assays

Assessments of anti-HA antibody titers were performed in the two clinical studies (IDB-707-106 and IDB-707-108). Immunogenicity analyses were performed in a subset of subjects in IDB-707-106 and in all subjects in Study IDB-707-108. The --(b)(4)-- was performed to test influenza-specific serum antibodies to HA.

• Efficacy study IDB-707-106
Samples from study IDB-707-106 were tested after 2007, when the --------------------------------------------------------------(b)(4)----------------------------------------------------------------------------------------------------------------- for GSK’s various influenza vaccine development projects.

The SOP for the ---(b)(4)--- method followed in the -------(b)(4)------- and the validation report comparing the ---------(b)(4)---------- laboratories for the --(b)(4)-- method was provided in the original submission. Validation information for the (b)(4) procedure performed in the -------(b)(4)------- was provided in Amendment 1 (January 13, 2011).

• Non-inferiority Immunogenicity Study IDB-707-108
The objectives of this study were to evaluate seroconversion rates (SCRs) and geometric mean (GMTs) for each of the 3 viral antigens of FluLaval compared to Fluzone. Immunogenicity was assessed at day 21 by analysis of serum HI antibody specific for the 3 viruses included in the vaccines.

Sera from study IDB-707-108 were tested by the ------(b)(4)------ prior to 2007 by IDB’s (b)(4) Method. The --(b)(4)-- description and validation report were submitted in the original BLA for FluLaval (BLA 125163, Approved October 5, 2006).

Influenza Virus Culture and Subtyping Assays

6.3 Pediatric Research Equity Act Requirements

Under the Pediatric Research Equity Act (21 U.S.C. 355c), all applications for new active ingredients, new indications, new dosage forms, new dosing regimens, or new routes of administration are required to contain an assessment of the safety and effectiveness of the product for the claimed indication in pediatric patients unless this requirement is waived, deferred, or inapplicable. This application does not contain any of the changes listed above and therefore, was not presented to the Pediatric Research Committee.

6.4 Bioresearch Monitoring (BIMO) Inspection

----------------------------------With-Held Per Privacy Act---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------


7.1 Safety Data from Clinical Studies and Postmarketing Experience

Results of the two trials were submitted to support the safety of FluLaval. The most common adverse events associated with FluLaval in the studies were pain at the injection site, tiredness, headache, and muscle and joint aches. Adverse reactions reported in more than 10% of FluLaval recipients in either study were pain, redness, and swelling at the injection site; tiredness; headache; muscle or joint aches; and malaise. The frequency of solicited adverse reactions was higher in FluLaval recipients than in placebo recipients in Study IDB-707-106, and was similar to the frequency reported in Fluzone recipients in Study IDB-707-108. The percentage of serious adverse events was low in both studies (1% in IDB-707-106 and 3% in IDB-707-108). There were three deaths in FluLaval recipients, all in Study IDB-707-108. These three deaths occurred more than one month after FluLaval administration in elderly subjects with underlying chronic diseases, and none were judged by the study investigator or the FDA clinical reviewer as related to the study vaccine. Overall, the safety findings were consistent with those previous described in the prescribing information for FluLaval and for other trivalent inactivated influenza vaccines. No new safety signals were identified in the review of this supplemental BLA. In summary, the safety profile of FluLaval was acceptable for approval of this application.

7.2 Pharmacovigilance Plan and Pregnancy Registry

The proposed pharmacovigilance and pregnancy registry plans were found to be adequate.



It was determined that presentation of the supplement to the Vaccines and Related Biological Products Advisory Committee (VRBPAC) was not required because of the existing experience with the currently licensed FluLaval vaccine. Furthermore, because our review of information submitted in the supplement, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion, it was agreed that presentation of this supplement to the VRBPAC was not necessary.



There are no other relevant regulatory issues of note



Revisions were made to the prescribing information to include the results of Studies IDB-707-106 and IDB-707-108. These revisions primarily involved Section 6.0 Adverse Reactions and Section 14.0 Clinical Studies, which were revised to include the results of both trials. Additional revisions were made, where appropriate, to harmonize the FluLaval label with other influenza vaccine labels were included in Section 2 Dosage and Administration, Section 4 Contraindications, and Section 7 Drug Interactions.

After negotiations with the sponsor, it was determined by the committee that the prescribing information submitted in Amendment 9 (June 8, 2011) is acceptable.



Because the results of the clinical endpoint study did not demonstrate adequate effectiveness of FluLaval, the accelerated approval commitment to verify clinical benefit was not fulfilled. Therefore, there was one post-marketing study requirement related to the approval of this supplement. Under the accelerated approval of biological products regulations, 21 CFR 601.41, we required that FluLaval be further evaluated to verify and describe its clinical benefit. GSK committed to complete ongoing Study FLU Q-QIV-006, a non-influenza vaccine comparator-controlled clinical endpoint study of FLU Q-QIV (quadrivalent seasonal influenza vaccine produced using the FluLaval process) in persons 3 to 8 years of age.

In summary, the relevant safety, immunogenicity and clinical efficacy data from studies submitted in this supplement BLA will be included in the prescribing information. FluLaval will not be granted traditional approval at this time and an additional study will be conducted to satisfy the requirement to verify and describe clinical benefit of biological products approved under the accelerated approval provisions, as specified in 21 CFR 601.41.

The committee recommends approval of this BLA supplement.