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					 Vaccines and Related Biological Products
       Advisory Committee Meeting


Influenza Vaccine, Recombinant Hemagglutinin
                    FluBlok
        Protein Sciences Corporation

                 Cynthia Nolletti, MD
               FDA/CBER/OVRR/DVRPA
                 November 19, 2009

                                            1
                 Presentation Outline

   Product Summary
   Regulatory History
   Clinical Overview
   Clinical Trials
      PSC04
      PSC06
      PSC03
      PSC01
   Summary of Efficacy and Immunogenicity
   Overview of Safety
   Overall Conclusions
   Questions for the Committee
                                             2
                     Product Summary
 Product: trivalent recombinant hemagglutinin influenza vaccine
  consisting of three recombinant influenza hemagglutinin antigens
  derived from H1, H3, and B strains, inserted into a baculovirus
  vector, and expressed in Spodoptera frugiperda insect cells.

 Proper name: Influenza Vaccine, Recombinant Hemagglutinin

 Proprietary name: FluBlok

 Proposed Indication: For active immunization of adults 18 years of
  age and older against influenza disease caused by influenza virus
  subtypes A and type B represented in the vaccine.

 Dosage Form and Route of Administration: 135μg influenza HA
  antigen (45μg per influenza virus strain) per 0.5mL dose
  administered as a single dose intramuscularly.
                                                                     3
                     Regulatory History
 October 23, 2004 – original IND filed

 December 11, 2006 - Fast track granted

 September 21, 2007 – Pre-BLA meeting

 April 18, 2008 – Original BLA submission requesting accelerated
  approval.

 August 29, 2008 – Complete Response letter issued.

 April 28, 2009 – Complete Response submitted with additional
  clinical efficacy data. Traditional approval requested.



                                                                    4
                   Clinical Overview
 Data from four clinical trials (one phase 2, three phase 3)
  submitted in support of approval of the 135μg dose

 Two placebo-controlled and two active-controlled trials

 Safety population: 3233 FluBlok recipients
    23% ≥ 50 years of age; 13% ≥ 65 years of age

 Vaccine efficacy population: 2344 FluBlok recipients
    100% 18 to 49 years of age

 Immunogenicity population: 1323 FluBlok recipients
    55% ≥ 50 years of age; 32% ≥ 65 years of age
                                                            5
                     Clinical Trials Overview
 Study/        Phase     Age       FluBlok     Control       Rdm     Blind   Sites
 Date                              n*          n                             (U.S.)

 PSC01         2         18-49      153**      154           1:1:1   MDB     3
 2004-2005                                     Saline
 PSC03         3         ≥65        436        433           1:1     MDB     6
 2006-2007                                     Fluzone
 PSC04         3         18-49     2344        2304          1:1     MDB     24
 2007-2008                                     Saline
 PSC06         3         50-64      300        302           1:1     MDB     6
 2007-2008                                     Fluzone
 Total                             3233        3193

*n=evaluable population for safety and clinical efficacy analyses
**135μg dose group
MDB = modified double-blind, person administering vaccine not blinded.
                                                                                      6
Clinical Overview: Immunogenicity Assessments
  Immunogenicity endpoints were assessed using the hemagglutinin
   inhibition (HAI) assay and FDA criteria for acceptable immune
   responses.*

  Although there is no established immune correlate of protection, the
   HI response may be an acceptable surrogate marker of activity that
   is reasonably likely to predict clinical benefit.

  Previous studies suggest that HI titers of ≥ 1:40 correlate with
   protection against illness.



 * Guidance for Industry: Clinical Data Needed to Support the Licensure of Seasonal
                                                                                      7
 Inactivated Influenza Vaccines (May 2007).
Clinical Overview: Immunogenicity Assessments

  The HAI assay and influenza viral cultures (nasal swab/throat
   swabs) were performed at a single central laboratory.

  A validated assay using BEVS-derived* antigens was used to test
   sera from all treatment groups in the phase 3 studies. Egg-derived
   HA antigens were used in the phase 2 study.




 *BEVS=baculovirus expression vector system
                                                                        8
Clinical Overview: Immune Response Endpoints
 Seroconversion rate (SCR): defined as the proportion of
  subjects with:

    Pre-vaccination HI titer < 1:10 and a post-vaccination titer ≥ 1:40,
     or
    Pre-vaccination HI titer ≥ 1:10 and a minimum 4-fold rise in post-
     vaccination titer.


 Proportion of subjects achieving a post-vaccination HI
  titer ≥ 1:40

    HI titers were drawn on Days 0 and 28 in all studies
                                                                        9
             Clinical Overview
   FDA Immune Response Acceptance Criteria

 For adults < 65 years of age:
    The lower bound of the two-sided 95% CI (LB) for the SCR
     should meet or exceed 40%.
    The LB for the proportion of subjects achieving a post-
     vaccination HI antibody titer ≥ 1:40 should meet or exceed 70%.

 For adults ≥ 65 years of age:
    LB for SCR should be ≥ 30%
    LB for post-vaccination HI ≥ 1:40 should be ≥ 60%.


                                                                   10
                 Clinical Overview
Non-inferiority Endpoints and Acceptance Criteria
  GMT ratio of TIV to FluBlok 28 days post-vaccination for
   each vaccine strain

     The upper bound of the 2-sided 95% CI (UB) on the
      GMT ratio should not exceed 1.5

  The difference between the SCRs of TIV and FluBlok:
   (SCR TIV – SCR FluBlok)

     The UB should not exceed 10%.
                                                          11
                   Clinical Overview
            Clinical Endpoint Assessments
 For the clinical efficacy endpoint, absolute vaccine efficacy (VE)
  relative to placebo was assessed in young healthy adults in studies
  PSC04 and PSC01.

     Vaccine Efficacy (VE) = (1 – RR) x 100 = (1- Pv/Pp) x 100
        RR = relative risk
        Pv=proportion of FluBlok recipients and Pp=proportion of
         Placebo recipients who developed culture-confirmed ILI

 For the active control studies PSC06 and PSC03, the Relative
  Efficacy (RE) (or % Relative Reduction) of FluBlok to Fluzone was
  calculated using descriptive statistics as:

     RE = (1 – RR) x 100.
                                                                      12
Overview: Clinical Endpoint Assessments - ILI

 Influenza-like Illness (ILI) was assessed using a Flu Symptom
  scoring card. Subjects were to contact the clinic if they scored 2 or
  more points:

     1 point: fever ≥ 100ºF oral
     1 point: cough, sore throat, or runny nose/stuffy nose
     1 point: muscle or joint aches, headache,
      chills/sweats, tiredness/malaise

 CDC-ILI was defined as fever of ≥100°F oral accompanied by cough
  and/or sore throat on the same day or on consecutive days.

 ILI was monitored by active and passive surveillance for 6 months
  and/or until the end of the influenza season (EOIS) (whichever was
  longer) in all studies.
                                                                          13
         Study PSC04


Subjects 18 to 49 years of age




                                 14
                Study PSC04 (2007-2008)

 Phase 3 placebo-controlled trial of safety and efficacy in
  healthy young adults 18 to 49 years of age

 Primary Objectives
    Safety: to determine safety relative to placebo
    Efficacy: to determine efficacy relative to placebo

 Secondary Objectives
    Immunogenicity: to assess immune responses to FluBlok
     according to acceptance criteria


                                                               15
                PSC04 (18-49yr): Design

 Phase 3, prospective, randomized, double-blind, placebo-controlled

 4648 healthy adults age 18-49 years at 24 US sites

 Randomized 1:1 FluBlok or placebo

 Immunogenicity subset of 480 FluBlok recipients at 5 sites selected
  for immunogenicity analyses

 Reactogenicity events collected through Day 7, Unsolicited AEs
  through Day 28, and SAEs through Day 180.


                                                                    16
       PSC04 (18-49 yr): Efficacy Endpoints

 Primary Efficacy Endpoint:
    The proportion of subjects in each treatment group with culture-
     confirmed CDC-ILI associated with isolation of an influenza virus
     antigenically resembling vaccine strains (“matched” strains)

 Vaccine Efficacy (VE) = (1 – RR) x 100

 PSC04 was powered to assess the LB of the two-sided 95% CI (LB)
  of VE around a point estimate of 70%.

 Acceptance criteria: the LB of the 95% CI for VE of FluBlok relative
  to placebo should be ≥ 40%
                                                                     17
      PSC04 (18-49 yr): Efficacy Endpoints


 Secondary and Exploratory Efficacy Endpoints:

    Proportion with culture-confirmed ILI (not necessarily
     CDC-ILI) due to matched strains.

    Proportion with culture-confirmed ILI due to any
     (matched and mismatched) influenza virus strains.




                                                          18
 PSC04 (18-49 yr): Immunogenicity Endpoints


 Immunogenicity Endpoints:

    Seroconversion rate for each vaccine strain

    Proportion of subjects with a Day 28 post-vaccination
     HI titer ≥ 1:40 for each vaccine strain




                                                         19
    PSC04 (18-49 yr): Disposition of Subjects
                                                    Number of Subjects (%)
                                                        Treatment Group
      Disposition                          Placebo                 FluBlok
                                           n (%)                   n (%)
      Randomized                           2325 (100)              2323 (100)
      Vaccinated                           2304 (100)              2344 (100)
      Completed                            2022 (88)               2049 (87)
      Discontinued                           282 (12)                295 (13)
         Due to Death or AE*                   2 (<1)                   2 (<1)
         Lost to follow-up                   251 (11)                295 (13)
      Safety and VE Populations            2304                    2344
      Evaluable Population for               127                     448
      Immunogenicity**

*Does not include pregnancies
**Serology available for immunogenicity analysis. Placebo serologies run as post hoc analysis.
                                                                                                 20
         PSC04 (18-49 yr): Efficacy Results

 646 swabs from 583 subjects obtained during the 180-day
  surveillance period.

 64 (2.7%) FluBlok and 114 (4.9%) placebo had culture-confirmed
  ILI.

 2007-2008 vaccine strains were poorly matched to circulating viral
  strains.
    170 of 178 total isolates antigenically mismatched
    111 of 119 type A isolates antigenically mismatched
    58 of the 59 B isolates mismatched; 1 not typed



                                                                       21
          PSC04 (18-49 yr): Vaccine Efficacy
PSC04 (2007-2008)                FluBlok      Placebo
                                 n=2344       N=2304
Parameter                        #cases (%)   #cases (%)   %Efficacy   (95% CI)
Matched strains (all H3N2)       2 (0.08)     6 (0.26)
1° endpoint CDC-ILI              1 (0.04)     4 (0.2)      75.4        (-148,99.5)
Regardless of match
-all strains                     64 (2.7)     114 (4.9)
-A/H1N1                           3             9
-A/H3N2                          33            58
-A/untyped                        5            12
-B                               23            36*
Any ILI                          64 (2.7)     114 (4.9)    44.8        (24.4,60.0)
Type A ILI                       41 (1.7)      79 (3.4)    49.0        (24.7,65.9)
Type B ILI                       23 (1.0)      36 (1.6)    37.2        (-8.9,64.5)
                                                                                     22
*Includes one untyped B strain
PSC04 (18-49 yr): Summary of Vaccine Efficacy

 VE results for FluBlok against culture-confirmed ILI due
  to antigenically matched strains limited by small numbers
  of cases.

 Point estimate of VE against culture-confirmed ILI for all
  strains regardless of antigenic match was 44.8%.

 LB 95% CI of VE for type A strains was 24.7%, and for
  type B strains included zero.


                                                           23
             PSC04 (18-49): Immunogenicity Endpoints
         Endpoint        Seroconversion rate*        % with post-vaccination
                                                     HI titer ≥ 1:40**
         Strain          Placebo      FluBlok        Placebo        FluBlok
                         n=127        n=448          n=127          n=448
         H1
         %                3           78             36             99
         95% CI (%)      (0.9, 7.9)   (73.5, 81.5)   (27.9, 45.2)   (97.1, 99.5)

         H3
         %                3           81             20             97
         95% CI (%)      (0.9, 7.9)   (77.1, 84.6)   (13.8, 38.5)   (94.8, 98.3)

         B
         %                0           52             37             96
         95% CI (%)      (0, 2.9)     (47.0, 56.5)   (28.6, 46.0)   (94.0, 97.8)


          All 3 strains met both immunogenicity endpoints                          24
Acceptance criteria: *LB 95% CI ≥ 40%; **LB 95% CI ≥ 70%
         Study PSC06


Subjects 50 to <65 Years of Age




                                  25
                  Study PSC06 (50-64 yr)
 Non-inferiority comparison of FluBlok to Fluzone in healthy adults 50
  to 64 years of age.

 Safety Objective:
    to compare the safety and reactogenicity of FluBlok and Fluzone

 Efficacy Objective:
    to compare the relative efficacy of FluBlok and Fluzone in the
      prevention of culture-confirmed ILI

 Immunogenicity Objective:
    to compare the immunogenicity of FluBlok and Fluzone
     according to pre-specified non-inferiority criteria


                                                                      26
              PSC06 (50-64 yr): Design

 Phase 3, prospective, randomized, double-blind, active-
  controlled

 602 subjects at 5 sites in California and Hawaii

 Randomized 1:1 FluBlok or Fluzone

 Reactogenicity events collected through Day 7,
  Unsolicited AEs through Day 28, SAEs through Day 180

                                                        27
     PSC06 (50-64 yr): Efficacy Endpoints

 Proportion with culture-confirmed ILI due to
  matched strains

 Proportion with culture-confirmed ILI regardless
  of antigenic match

 Statistical analyses for the clinical endpoints
  were descriptive


                                                     28
               PSC06 (50-64yr)
           Non-inferiority Endpoints
 GMT ratio of Fluzone to FluBlok 28 days post-
  vaccination for each vaccine strain

   The UB on the GMT ratio should not exceed 1.5


 The difference between the SCRs of Fluzone
  and FluBlok: (SCR Fluzone – SCR FluBlok)

   The UB should not exceed 10%

                                                    29
         PSC06 (50-64 yr): Efficacy Results
 There were no antigenically matched isolates.

 The total numbers of antigenically mismatched isolates was small in
  both groups: FluBlok =7 and Fluzone = 4.

 Case numbers are too small and the confidence intervals are too
  wide to draw meaningful conclusions regarding the relative risk of
  influenza illness in recipients of FluBlok compared to Fluzone in
  healthy adults 50 to 64 years of age.

 Because the clinical endpoint data in this age group was not
  adequate, the immunogenicity data provided an important surrogate
  marker of clinical benefit (next slide)…

                                                                       30
               PSC06 (50-64 yr)
GMTs and GMT Ratio of Fluzone to FluBlok at Day 28
   Visit        Antigen                   H1               H3                 B strain
   Day 0        Group
   GMT          Fluzone (n=302)           27.77            18.20              49.18
                FluBlok (n=299)           28.71            18.57              48.49


   Day 28       Group
   GMT          Fluzone                   139.74           60.88              116.03
                FluBlok                   181.34           105.41             110.93
   Day 28       GMT Ratio                 0.90             0.68               1.14
                UB 95%CI*
   Meets non-inferiority                  YES              YES                YES
   criteria?**
  **UB 95%CI ≤ 1.5
  *based on Statistical Reviewer’s adjustments for pre-vaccination titer, prior          31
  vaccination history, and assay variables.
               PSC06 (50-64yr)
Difference in Seroconversion Rates at Day 28
   Strain      SCR                     Difference:     Meets
               (LB 95% CI)             SCR Fluzone –   Non-
                                       SCR FluBlok     inferiority
                                       (95% CI)        criteria?*
               FluBlok     Fluzone
               n=299       n=302
   H1N1        72.2        66.2          -6.0          YES
               (66.8)      (60.6)      (-13.4, 1.4)

   H3N2        61.2        43.7        -17.5           YES
               (55.4)      (38.0)      (-25.4, -9.5)

   B strain    40.8        41.1          0.3           YES
               (35.2)      (35.5)      (-7.7, 8.2)

     *Acceptance criteria: UB 95%CI ≤ 10%.                           32
  PSC06 (50-64 yr): Immunogenicity Results



 FluBlok met all 6 endpoints establishing non-
  inferiority to Fluzone.




                                                  33
       Study PSC03


Subjects 65 years and older




                              34
                Study PSC03 (2006-2007)

 Non-inferiority comparison of FluBlok to Fluzone in adults 65 years
  and older

 Safety Objective:
    To compare the safety and reactogenicity of FluBlok and
     Fluzone

 Efficacy Objective:
    To compare the relative efficacy of FluBlok and Fluzone in the
      prevention of culture-confirmed ILI

 Immunogenicity Objective:
    To compare the immunogenicity of FluBlok and Fluzone
                                                                        35
              PSC03 (≥ 65 yr): Design

 Phase 3, prospective, randomized, double blind, active-
  controlled

 870 medically stable adults ≥ 65 years of age at 6 US
  study sites

 Randomized 1:1 FluBlok or Fluzone

 Reactogenicity events through Day 7, Unsolicited AEs
  through Day 28, and SAEs through Day 180

                                                            36
            PSC03 (≥ 65 yr): Endpoints

 Efficacy
    Proportion of subjects in each vaccine group who
     experienced culture-confirmed CDC-ILI

    Proportion who experienced any culture-confirmed
     medically attended acute respiratory illness

    Descriptive statistics were used to calculate a
     Relative Efficacy of FluBlok to Fluzone:
       RE = (1 – RR) x 100.

                                                        37
  PSC03 (≥ 65 yr): Non-inferiority Endpoints


 GMT ratio of Fluzone to FluBlok


 The difference in SCRs (Fluzone – FluBlok)




                                               38
   PSC03 (≥ 65 yr): Clinical Efficacy Results



 Of 53 sets of cultures, only 3 were positive, 2 Fluzone
  and 1 FluBlok, all three for influenza Type A.

 The case numbers are too small and the confidence
  intervals are too wide to draw meaningful conclusions
  from study PSC03 regarding the relative risk of influenza
  illness in recipients of FluBlok compared to Fluzone in
  adults 65 years of age and older.
         PSC03 (≥ 65 yr): GMTs and GMT Ratios at Day 28
                       Strain                             H1              H3              B strain
                       Group
      Day 0            Fluzone (n=430)                    70.2            44.7            80.3
      GMT
                       FluBlok (n=431)                    69.0            42.7            79.9


      Day 28           Fluzone                            148.1           199.2           194.8
      GMT
                       FluBlok                            176.8           338.5           149.6

      Day 28           GMT Ratio                          0.96            0.67            1.45
                       UB 95% CI*
                       Meets non-inferiority               Yes              Yes             Yes
                       Criteria?**
**UB 95% CI on GMT ratio ≤ 1.5
                                                                                                     40
*Based on Statistical Reviewer’s adjustments for pre-vaccination titers and HI assay variables
               PSC03 (≥ 65 yr)
Difference in Seroconversion Rates at Day 28
   Strain     SCR                 Difference:      Meets
                                  SCR Fluzone –    Non-
                                  SCR FluBlok      inferiority
                                  (95% CI)         criteria?*
              FluBlok   Fluzone
              n=431     n=430
   H1N1       43        33          -10.8          YES
                                  ( -17.3, -4.4)
   H3N2       78        58         -20.1           YES
                                  (-26.2, -13.9)
   B strain   29        39           9.8           NO
                                  (3.5, 16.1)

  *UB 95% CI for (SCR TIV –SCR FluBlok) should be ≤ 10%          41
               PSC03 (≥ 65 yr)
        Immunogenicity Endpoint Results

 FluBlok met 5 of the 6 primary endpoint criteria for
  demonstrating non-inferiority to Fluzone.

 H1 and H3 antigens met both non-inferiority endpoints.

 B strain demonstrated non-inferiority to Fluzone by the
  GMT ratio, but not by SCR criteria.


                                                            42
        Study PSC01


Subjects 18 to 49 Years of Age




                                 43
                   Study PSC01 (2004-2005)
   Phase 2 dose-finding safety, immunogenicity and efficacy study in
    healthy adults 18 to 49 years of age

   Safety Objective:
      To determine safety relative to placebo

   Immunogenicity Objective:
      To compare the immunogenicity of two dose levels of FluBlok,
       75µg versus 135µg total HA antigen*

   Efficacy Objective:
      To determine clinical efficacy in the prevention culture-confirmed
        ILI.

*FluBlok 75µg = 15µg H1, 45µg H3, 15µg B strain
 FluBlok 135μg = 45μg per strain                                        44
      PSC01 (18-49 yr): Efficacy Endpoint


 Clinical Efficacy
   Proportion with culture-confirmed ILI

 The study was not powered to test formal null
  hypotheses. Descriptive statistics were used to
  detect trends between the treatment groups.



                                                    45
  PSC01 (18-49 yr): Vaccine Efficacy Results
 PSC01 2004-2005             FluBlok     Placebo
                             n=151       n=153
 Parameter                   #cases      #cases      % VE      (95% CI)
                             (%)         (%)
 Matched Strains             0           0                     n/a
 All strains regardless of   1 (0.7)     8 (5.2)     87.3      (5.5, 99.7)
 match Any ILI
 -A/H1N1                     0           0
 -A/H3N2 (n=151)             0           6           100       (29.7, 100)
 -B                          1           2           49.3      (-873, 99.1)
 -A/H3N2 (n=301)*            4           6           66.1      (-29.8, 92.6)
 Any ILI all strains*        5 (1.7)     8 (5.2)     68.2      (-10.1, 91.8)

*Blue shade: For these parameters both FluBlok dose group results (n=151 +
150) are included because both doses contained 45μg of the predominant
H3N2 strain.                                                              46
         PSC01 (18-49 yr): Vaccine Efficacy
 Antigenically dissimilar H3N2 virus predominated

 VE of the 135μg dose was 87.3% (LB 5.5%) against all culture-
  positive ILI and against all strains regardless of match.

 Because H3N2 predominated and because both the 75 and 135µg
  dose groups contained 45µg of H3 antigen, if all cases from subjects
  who received the 75μg dose are included in the analysis, VE
  decreased to 68.2% (LB -10.1%).

 The estimates of VE in study PSC01 suggest a favorable trend.
  However, this study was not powered to test a formal null hypothesis
  of vaccine efficacy and it is limited by the overall small sample size
  and wide confidence intervals.


                                                                      47
Clinical Efficacy and Immunogenicity Populations
          across Studies – FluBlok 135μg
   Study      Age group   Immunogenicity   Clinical Efficacy
                          population       population
                          n* (Control)     n* (Control)
   PSC01                   150   (151)      151     (153)
              18-49 yr
   PSC03                   431   (430)      436    (433)
              ≥65 yr
   PSC04                   448   (127)     2344 (2304)
              18-49 yr
   PSC06                   299   (302)      300    (302)
              50-64 yr
   Total                  1328   (833)     3231 (3192)
    ≥ 18 yr
                                                               48
    Summary: Vaccine Efficacy across Studies
   PCS04 (18-49 yr)
      Despite antigenic mismatch, overall VE against culture-confirmed illness
       due to any strain was 44.8% (LB 24.4%).

      Point estimates against all type A and all type B influenza were 49.0%
       and 37.2% respectively.

      Failed to meet primary endpoint against antigenically matched strains
       because mismatched circulating virus predominated.

   PCS01 (18-49 yr)
      Antigenic mismatch predominated. Descriptive statistics demonstrated a
       favorable trend towards VE: 87.3% (LB 5.5%) against all culture-
       confirmed ILI.

   PCS03 and PSC06 (≥ 50 yr)
      Unable to assess RE because of very small numbers of cases.
                                                                                49
             Efficacy Conclusions

 In healthy adults (18 to 49 years), the VE of
  FluBlok against culture-confirmed influenza due
  to antigenically mismatched strains was 44.8%
  (LB 24.4%).

   The efficacy data is driven by study PSC04
    (adults 18 to 49 years of age) where the
    sample size and the attack rate were
    adequate to assess absolute vaccine efficacy
    (VE) against placebo.

                                                    50
Immune Response and Non-inferiority Endpoints
   across Clinical Studies - FluBlok 135μg
   H1 and H3 strains met both immune response endpoints in adults 18-49
    years of age (PSC04 and PSC01).

   H1 and H3 strains met both criteria for non-inferiority to Fluzone in older
    adults in the two studies that evaluated non-inferiority endpoints, PSC03
    and PSC06.

   The B strain met both immune response endpoints in the largest and pivotal
    study, PSC04, of young healthy adults.

   B strain met both criteria for non-inferiority to Fluzone in study PSC06,
    adults 50-64 years of age.

   B strain met the GMT ratio endpoint, but failed the seroconversion endpoint
    for non-inferiority to Fluzone in study PSC03, adults ≥ 65 years of age.

                                                                                  51
           Immunogenicity Conclusions


 FluBlok is immunogenic in young adults 18-49 years.
  The FluBlok H1 and H3 antigens also elicited a robust
  immune response that was non-inferior to Fluzone in
  adults 50 years of age and older.

 The B antigen failed to demonstrate non-inferiority in
  elderly adults ≥ 65 years of age. Similar weak
  responses to the B strain have been noted in studies of
  older adults using currently licensed TIVs.


                                                            52
Safety




         53
             Overview of Safety Across Trials
   The safety database for FluBlok 135μg consisted of 3233 subjects 18 to
    over 65 years of age.

   23% of subjects were ≥ 50 years of age; 13% were ≥ 65 years of age

   Females and Caucasians represented the majority of subjects.

    Study    Dose    18-49yr    50-64yr   ≥65yr   Mean     M/F     Total
                                                  age

    PSC01    135µg    153                         31.3     37/63    153
    PSC03    135µg                        436     72.9     48/52    436
    PSC04    135µg   2344                         32.5     41/59   2344
    PSC06    135µg              300               55.9     38/62    300
    Total            2497       300       436                      3233
    ≥18 yr

                                                                             54
                                Safety: Deaths
There were a total of six deaths across the four studies, 2 occurring in young previously
healthy adults (PSC04) and 4 occurring in subjects > 65 years of age (PSC03). The deaths
were balanced, 3 in FluBlok recipients, 3 in control groups, and none appeared related to the
study vaccines.

    Study     Subject                   Treatment Group                       Related?*
                           FluBlok                   Control
    PSC04     04-02568     Pulmonary embolism                                 No
                           94 d post-vax
              05-03291                               MVA 171 d post-vax       No
    PSC06     None
    PSC03      3027        Perforated diverticulum                            No
               1017        Pontine hemorrhage                                 No
               1166                                  Cardiac arrest           No
               1589                                  Coronary heart disease   No
    PSC01     None

*assessed by investigator and Reviewer as not related because of lack of
temporal relationship and/or biologic plausibility                                        55
      Safety: Serious Adverse Events through Day 180
                             FluBlok                                       Control
Study            SAEs           Preferred term/                SAEs            Preferred term/
                N (E)           Causality*                     N (E)           Causality*

PSC01            2   (2)          2 not related                 0
n=307

PSC03           36 (45)         36 not related                 34 (42)         34 not related
n=869
PSC04           30 (41)         40 not related                 35 (46)         46 not related
n=4648                          1 possibly related:
                                Pleuropericarditis
PSC06            2   (2)        1 not related                   2   (2)         2 not related
n=602                           1 related:
                                Vasovagal syncope
Total           70 (90)         1 related                      71   (90)       None related
N=6426                          1 possibly related

N= # subjects who experienced an SAE, counted only once regardless of number of events per
individual
E= # events overall including more than one SAE per individual
*Causality assessed by site investigator                                                         56
       SAE’s Assessed as Possibly Related or
                Related to FluBlok
   PSC04 Subject 05-03221 - Pleuropericarditis

      47 year-old male, history of hypertension, onset within 11 days of
       vaccination with FluBlok
      Extensive evaluation: no specific etiology
      Discharge diagnosis: possible viral pleuropericarditis
      Investigator assessment: possibly related

   PSC06 Subject 01-0036 - Vasovagal syncope

      57 year old male, onset within 15 minutes of phlebotomy and receipt of
       FluBlok
      Report not suggestive of an anaphylactic or hypersensitivity reaction
      Event compatible with vasovagal syncope associated with phlebotomy
       and/or intramuscular injection
      Investigator assessment: related
                                                                            57
   Summary of SAEs by MedDRA* System Organ Class
                                         PSC04         PSC06         PSC03           PSC01
SOC                                      FB      PBO   FB      TIV   FB      TIV     FB        PBO
                                         E       E     E       E     E       E       E         E
Blood and lymphatic                      1       1                   1
system disorders
Cardiac disorders                        3       2                   8       8
Congenital, familial and                 0       1
genetic disorders
Eye disorders                            0       1
Gastrointestinal disorders               3       3     1       0     5       3
General disorders and                    1       2                   1
Administration site conditions
Hepatobiliary disorders                  1       1                   1       2
Infections and infestations              4       13                  4       5
Injury, poisoning and                    6       3                   2       5
 procedural complications
Metabolism and nutrition                 0       3                           3
disorders
Musculoskeletal and                      2       2                   3       3
connective tissue disorders
 Medical Dictionary for Regulatory Activities                                                    58
 FB=FluBlok; PBO=placebo; E = # of events                                          Continued
      Summary of SAEs by MedDRA System Organ Class (cont)

                              PSC04 events   PSC06         PSC03         PSC01
SOC                           FB     PBO     FB      TIV   FB      TIV   FB      PBO
                              E      E       E       E     E       E     E       E
Neoplasms benign,             3      1       0       1     4       4
malignant and unspecified
Nervous system disorders      1      1       1       1     7       5     2       0
Pregnancy, puerperium and     0      2
perinatal conditions
Psychiatric disorders         4      5                     1       1
Renal and urinary disorders   1      1                     2
Reproductive system and       7      4                     1
breast disorders
Respiratory, thoracic and     3      0                     2       2
mediastinal disorders
Surgical/medical procedures                                        1
Vascular disorders                                         3

# subjects with SAEs          30     35      2       2     36      34    2       0
TOTAL # SAE events            41     46      2       2     45      42    2       0
                                                                                     59
             Safety: Hypersensitivity Events
 As part of the safety review, the data was evaluated for
  hypersensitivity events across studies.

 Electronic datasets from each of the four studies
  (FluBlok n=3233) were searched for hypersensitivity-
  type reactions using MedDRA preferred terms.* The
  Applicant was asked to provide case narratives, case
  report forms, and consulting physicians’ notes for all
  hypersensitivity-type events.
* Preferred terms included immune system disorders, hypersensitivity, drug
  hypersensitivity, adverse drug reaction, allergy, anaphylaxis, hives, urticaria,
  serum sickness, vasculitis, swelling, angioedema, allergic asthma, anemia,
  lymphadenopathy, thrombocytopenia, immune thrombocytopenia,
  arthralgia, myalgia, synovitis, rash, and rash pruritic.

                                                                                60
                      Safety
Results of Search for Hypersensitivity-type Events
     Unsolicited AE by        FluBlok      Placebo     Fluzone
     MedDRA Preferred         N=3233       N=2188      n=735
     Term
                              n (%)        n (%)       n (%)
     Pleuropericarditis       1            -           -
     Hypersensitivity         4 ( 0.1)     1 (0.04)    -
     Urticaria                1            -           -
     Rash                     9 ( 0.3)     3 (0.1)     6 (0.8)
     Swelling face            1            -           -

   Rash:
      Rates lower in FluBlok group compared to Fluzone.
      None in the FluBlok recipients were serious or severe.
      Majority appeared unrelated to FluBlok.                   61
   Hypersensitivity-Type Events (continued)

 Of the remaining hypersensitivity-type events in FluBlok
  recipients, there were 2 events across studies that were
  either serious or severe and may have been related to
  FluBlok:

    one case of pleuropericarditis (already discussed);

    one case of swelling of the lips and tongue.




                                                           62
        Hypersensitivity-Type Events (continued)

 PSC04 Subject 19731 – Hypersensitivity

    22 y.o. female history of seasonal allergic rhinitis, exercise-
     induced symptoms (bronchiolar constriction, facial edema,
     edema of extremities, rash, itchiness, and swelling of the
     tongue), mild asthma, and headaches.

    Abrupt onset of swollen lips and tongue 10 hours and 20 minutes
     following vaccination.

    Self-medicated with Claritin (loratidine)10mg and Benadryl
     25mg. Symptoms resolved by Study Day 2.

    Investigator assessed event as moderate and possibly related to
     the study vaccine.

                                                                       63
  Hypersensitivity-Type Events: (Continued)


 The safety database did not reveal other
  hypersensitivity-type safety signals.

 The data did not reveal large imbalances in
  these events between treatment groups.




                                                64
            Safety: Reactogenicity Events across Trials
   Most frequent events in FluBlok subjects: local pain, headache, fatigue and myalgia.
    Rates similar to Fluzone:
     Diary Card                  FluBlok           Fluzone            Placebo
                                 N= 3233           N=735              N= 2458
     LOCAL
     Pain                        1192 (37%)        265 (36%)          207 (8%)

     Redness                      167   (5%)        79 (11%)           50 (2%)
     Swelling                     163   (5%)        88 (12%)           47 (2%)
     Bruising                     116   (4%)        36   (5%)          65 (3%)
     SYSTEMIC
     Headache                     519 (16%)        104 (14%)          417 (17%)
     Fatigue                      445 (14%)        104 (14%)          361 (15%)
     Tiredness, lack of energy    105   (3%)        65   (9%)          51 (2%)
     Muscle pain                  342 (10%)         79 (11%)          173 (7%)
     Joint pain                   134   (4%)        44   (6%)          91 (4%)
     Nausea                       174   (5%)        30   (4%)         119 (5%)
     Chills/shivering             102   (3%)        31   (4%)          74 (3%)
     Fever                         23 ( 1%)         1 (<1%)            14 (1%)         65
          Safety: Unsolicited Adverse Events
   Unsolicited AEs:
      Rates were similar between FluBlok and Control groups.
      Most frequent across studies: headache (0.3-8.4%) and symptoms
       of respiratory infection (0-5.9%)*
      Most assessed as not related to study vaccines; most mild to
       moderate.

   No other unusual trends, patterns or safety signals were observed.

   No reports of Guillain Barre Syndrome or other autoimmune type
    events.

   Frequency of Unsolicited AEs similar to licensed TIVs.

   Analysis of individuals over 65 years of age did not reveal safety
    issues unique to this age group.
*Symptoms of URI: cough, pharyngolaryngeal pain, nasal congestion, URI,
nasopharyngitis                                                           66
                      Safety Conclusions
   The safety database for FluBlok 135μg consisted of 3233 subjects 18
    to over 65 years of age.

   Deaths were few (6 total), balanced, and appeared unrelated to the
    study vaccines.

   The vast majority of SAEs occurred in subjects older than 65 years of
    age, and were assessed as unrelated to the study vaccines.

   Two SAEs in FluBlok recipients were related or possibly related to the
    vaccine: vasovagal syncope and pleuropericarditis.

   There was no large imbalance of hypersensitivity events.

   No other unusual trends, patterns or safety signals were observed.

   Overall, the type and frequency of adverse events experienced by
    FluBlok subjects was similar to those reported for other trivalent
    influenza vaccines.
                                                                          67
                 Overall Conclusions
 FluBlok demonstrated an absolute vaccine efficacy of
  44.8% (LB 24.4%) against antigenically mismatched
  influenza strains in healthy adults 18 to 49 years of age.

 FluBlok elicited robust immune responses to H1 and H3
  and somewhat weaker responses to B antigen in older
  adults.

 Safety data did not reveal unexpected trends or safety
  signals.

 The type and frequency of adverse events experienced
  by FluBlok subjects was similar to those reported for
  other TIVs.
                                                           68
             Questions for the Committee
1.    Do the available clinical data support effectiveness of
      FluBlok in the prevention of influenza disease caused
      by influenza subtypes A and type B included in the
      vaccine in adults:

     a. 18 to 49 years of age;

     b. 50 to 64 years of age;

     a. 65 years and older?

                                                                69
         Questions for the Committee


2. Do the available safety data support the safety
   of FluBlok in adults 18 years and older?




                                                 70
         Questions for the Committee


3. Please comment on what additional studies, if
   any, should be requested post-licensure.




                                                   71
Backup Slides




                72
Clinical Overview: Race and Ethnicity across
                   Studies
  Race/                    PSC01      PSC03     PSC04      PSC06     US
  Ethnicity                %          %         %          %         Population*
  White/                   85         99        67         73        81.3
  Caucasian
  Black/                   6          <1        18          4        13.0
  African/American
  Latino/                  3          <1        11          8        7.4
  Hispanic **
  Asian                    3          0          3         12        4.5
  American Indian/         1          0         <1          0        1.0
  Alaska Native
  Native Hawaiian/         1          0         <1         <1        0.2
  Pacific Islander
  Other                    2          <1        1          4


 *July 2007 census
                                                                                       73
**Hispanic origin is considered an ethnicity, not a race; Hispanics may be any race.
   Demographic Characteristics across Studies
    Evaluable Population for Immunogenicity
Study          Age            n*          Mean           M/F         Prior year
               Group                      Age            %           Flu vaccine %
                                                                     FluBlok        Control
PSC01          18-49            150       31             37/63       n/a            n/a

PSC03          ≥65              431       72.9           48/52       83             84

PSC04          18-49            448       32.9           45/55       21             n/a**

PSC06          50-64            299       55.9           38/62       69             70

Total                         1328

*n=Evaluable Population **This variable was not evaluated in the post hoc placebo group analyses
The majority of subjects across studies were Caucasian. The demographic
characteristics of the total Evaluable Population for Clinical Efficacy and of the Safety
Population across studies were almost identical to those presented above.                          74
                   PSC04: Populations
 Safety Analysis – Safety Population
    All randomized subjects who received Study Vaccine
     categorized according to actual treatment received

 Efficacy Analysis – Evaluable Population

    Immunogenicity – all subjects who met eligibility criteria, were
     randomized, had no major protocol violations, and had HI titers
     taken at Day 0 and Day 28, categorized based on actual
     treatment received.

    Clinical Efficacy – all subjects who met eligibility criteria, were
     randomized, had no major protocol violations, and completed at
     least 50% of follow-up telephone contacts, including the end of
     influenza season (EOIS) call, categorized based on actual
     treatment received.
                                                                        75
               PSC04 (18-49 yr): Vaccine Efficacy
PSC04 (2007-2008)                FluBlok      Placebo
                                 n=2344       N=2304
Parameter                        #cases (%)   #cases (%)   %Efficacy   (95% CI)
Matched strains (allH3N2)        2 (0.08)     6 (0.26)
1° endpoint CDC-ILI              1 (0.04)     4 (0.2)      75.4        (-148,99.5)
2° endpoint Any ILI              2 (0.1)      6 (0.3)      67.2        (-83.2,96.8)
Regardless of match
-all strains                     64 (2.7)     114 (4.9)
-A/H1N1                           3             9
-A/H3N2                          33            58
-A/untyped                        5            12
-B                               23            36*
CDC-ILI                          44 (1.9)      78 (3.4)    44.6        (18.8,62.6)
Any ILI                          64 (2.7)     114 (4.9)    44.8        (24.4,60.0)
Type A ILI                       41 (1.7)      79 (3.4)    49.0        (24.7,65.9)
Type B ILI                       23 (1.0)      36 (1.6)    37.2        (-8.9,64.5)

*Includes one untyped B strain                                                        76
                   PSC06 – Results
                Disposition of Subjects
                         Number of Subjects (%)

Disposition*             FluBlok      Fluzone      Overall
                         n (%)        n (%)        n (%)
Enrolled                                           602 (100)
Randomized               300 (49.8)   302 (50.2)   602 (100)
Vaccinated               300 (49.8)   302 (50.2)   602 (100)
Safety Population        300 (49.8)   302 (50.2)   602 (100)
Evaluable Population     299          302          601
Completed                298          300          598
*Complete Study Report
                                                               77
  PSC06: Other Immune Response Endpoints
 Proportion of subjects with Post-vaccination HI titer ≥ 1:40
        Strain     % post-vaccination   FluBlok        Fluzone
                   HI titer ≥ 1:40*     n=299          n=302


        H1N1       % HI ≥1:40            96            96
                   95% CI               (93.5, 98.1)   (92.8, 97.7)
                   Meets LB ≥ 70%?      yes            yes
        H3N2       % HI ≥1:40           85             75
                   95% CI               (80.8, 89.1)   (69.9, 79.9)
                   Meets LB ≥ 70%?      yes            no
        B Strain   % HI ≥1:40           93             94
                   95% CI               (89.5, 95.6)   (91.1, 96.7)
                   Meets LB ≥ 70%?      yes            yes

*Immune response acceptance criteria: LB 95% CI should be ≥ 70%
                                                                      78
PSC06: Other Immune Response Endpoints
          Seroconversion Rate
  Strain                          Seroconversion Rate*
                                  (95% CI)
                                  FluBlok         Fluzone
                                  N=299           n=302
  H1N1
    %                             72.2            66.2
    95%CI                         (66.8, 77.2)    (60.6, 71.5)
    Meets acceptance criteria?*   Yes             Yes
  H3N2
    %                             61.2            43.7
    95%CI                         (55.4, 66.8)    (38.0, 49.5)
    Meets acceptance criteria?    Yes             NO
  B Strain
     %                            40.8            41.0
     95%CI                        (35.2, 46.6)    (35.5, 46.8)
     Meets acceptance criteria?   NO              NO
   *Acceptance criteria: LB ≥ 40%.                               79
         PSC03: Disposition of Subjects
Disposition           FluBlok     Fluzone
                      N=436 (%)   n=434 (%)

Randomized            436 (100)   434 (100)

Vaccinated            436 (100)   433 (100)

Completed             428 (98)    426 (98)

Discontinued            8   (2)     8   (2)
   - due to AE          0           1
Safety Population     436         433

Efficacy Population   431         430

                                              80
         PSC03: Analysis Populations

 Safety Population: all randomized subjects who
  received any dose of study medication

 Evaluable Population
   for Immunogenicity: all randomized subjects who
    received the correct dose of vaccine and had titers
    taken at baseline and at Day 28

   for Relative Risk (Relative Efficacy): All subjects who
    received the correct dose of vaccine.
                                                          81
            PSC03: Immune Response Endpoints
                    % 4-fold rise in HI*       % with post-vaccination
                                               HI titer ≥ 1:40**
  Strain            Fluzone        FluBlok     Fluzone        FluBlok
                    n=430          n=431       n=430          n=431
  H1
  %                 33             43          95             95
  LB 95% CI         28.1           38.7        92.4           92.1
  Meets criteria?   No             Yes         Yes            Yes
  H3
  %                 58             78          93             97
  LB 95% CI         52.8           73.5        89.7           94.3
  Meets criteria?   Yes            Yes         Yes            Yes
  B
  %                 39             29          97             92
  LB 95% CI         34.4           25.0        95.2           88.6
  Meets criteria?   Yes            No          Yes            Yes

 *Acceptance criteria = LB 95% CI for %4-fold rise must be ≥ 30%.
                                                                         82
**Acceptance criteria = LB 95% CI for % HI ≥1:40 must be ≥ 60%.
    PSC03: Other Immune Response Endpoints
      Proportion with Day 28 HI Titer ≥ 1:40
       Strain         % post-vaccination HI ≥ 1:40
                               Day 28*
                      FluBlok           Fluzone
                      n=431             n=430
       H1
        n (%)         408 (95)          408 (95)
        LB 95% CI *        92.1              92.4
       H3
        n(%)          416 (97)          398 (93)
        LB 95% CI         94.3               89.7
       B strain
        n(%)          395 (92)          418 (97)
        LB 95% CI          88.6              95.2

*Acceptance criteria: LB 95% CI for % HI ≥1:40 should be ≥ 60%   83
     PSC03: Seroconversion/4-fold Rise in HI Titer




*Acceptance criteria = LB 95% CI for %4-fold rise must be ≥ 30%.   84
          PSC01: Statistical Considerations
 Sample Size
    The study was not powered to test formal null hypotheses, but
     descriptive statistics were used to detect trends between the
     treatment groups.

 Seroconversion: A sample size of 450 subjects, 150 per treatment
  group was selected to ensure that a 15% or greater difference in the
  seroconversion rate between treatment groups would be detected
  with an α=0.05 and 80% power. This assumed that 60-80% of
  subjects would have a 4-fold rise in HI titer.

 Clinical Efficacy: The Applicant calculated that, for a placebo group
  attack rate of 5%, a sample size of 150 subjects per arm would
  detect a minimum difference of 13.4% in cases of culture-confirmed
  ILI between treatment groups with 80% power.

                                                                      85
             PSC01: Disposition of Subjects
                                      Number (%) of Subjects
                                    Study Treatment
                                          FluBlok
                       FluBlok 75µg        135µg      Placebo     Overall
Disposition               N=153            N=153       N=154      N=460

Vaccinated               151 (99)        153 (100)    154 (100)   458 (99)

Completed                148 (97)        151 (99)     152 (99)    451 (98)
Discontinued               5 (3)           2   (1)      2   (1)    9    (2)
  -Due to AE               0               0            0               0
Safety Population       151              153          154         458
Evaluable Population
(Clinical Efficacy)        150              151         153         454

                                                                              86
   PSC01 (18-49 yr): Immunogenicity Results

 The 135μg dose was more immunogenic than the 75μg dose and
  was selected for further clinical development.

 The HAI assay for this study was validated, but used a different
  dilution series (LOD 1:4 instead of 1:10) than for the other clinical
  trials of FluBlok. More stringent acceptance criteria using HI titer
  thresholds of ≥ 1:64 were applied to the SCR and % HI ≥ 1:40
  endpoints.

 The 135μg dose met 5 of the 6 immune response endpoints. 57.1%
  (LB 95% CI) of subjects met the criteria for a post-vaccination HI
  titer of ≥ 1:64. If the post-vaccination threshold was changed to ≥
  1:32, 76.4% (LB) of subjects met the endpoint.


                                                                          87
   PSC01 (18-49 yr): Immunogenicity Results
                    Seroconversion rate*           % with post-vaccination
                                                   HI titer ≥ 1:64**

Strain              Placebo    FluBlok 135µg       Placebo   FluBlok 135 µg
                    n=151      n=150               n=151     n=150
H1
 LB of 95% CI       0          51.7                32.5      80.9
 Meets criteria?    no         yes                 no        yes
H3
 LB of 95% CI       5.2        69.1                57.4      97.6
 Meets criteria?    no         yes                 no        yes
B Strain
 LB of 95% CI       0          55.1                3.2       57.1
 Meets criteria?    no         yes                 no        NO

 *LB 95% CI for SCR must be at least 40%
**LB 95% CI for % HI ≥ 1:64 must be at least 70%                              88
 Considerations in the Evaluation of Vaccine
Efficacy in the Presence of Antigenic Mismatch
   VE is influenced by the degree of antigenic match between vaccine strains
    and circulating virus. Low attack rates and small sample sizes may also
    contribute to unreliable or variable estimates of efficacy.

   Estimates of efficacy in young healthy adults have ranged from 70% to 90%
    when the vaccine and circulating viruses are well-matched. These
    estimates are limited by the relative lack of randomized, placebo-controlled
    trials (RPCT).

   Studies conducted during seasons where the vaccine and circulating strain
    are poorly matched have demonstrated lower efficacy.

   Because variability in attack rates and/or antigenic drift can make
    assessments of VE over a single season difficult, multiple seasons may
    provide a more accurate estimate of VE.

                                                                              89
 Considerations in the Evaluation of Vaccine
Efficacy in the Presence of Antigenic Mismatch
                     (cont)
 To put the efficacy data from PSC04 in perspective, we examined
  results from a series of 3 annual RPCTs conducted by Monto A,
  Ohmit, SE, and others at the University of Michigan.

 These studies estimated the absolute and relative efficacies of
  licensed TIV and LAIV in healthy adults 18-49 years of age.

 Three influenza seasons were studied: 2004-2005; 2005-2006; and
  2007-2008; results are summarized in the next slide.



                                                                    90
         Randomized Placebo-Controlled Trials of Vaccine Efficacy
             Ohmit SE, Monto A, et al, University of Michigan

 Treatment      Season               VE vs Placebo             Comments
 group                        % Point estimate (LB 95% CI)
                              VE          Fluzone    FluMist
 Healthy        2004-         Overall     75 (42)    48 (0)    A/H3N2 drifted;
 18-49 yrs      20051         Type A      69 ( 7)    47 (0)    B 60% mismatch
                              Type B      83 (26)    49 (0)
                n=1247                                         Attack rate 7.8%
                2005-20062                                     96% H3N2 drifted.
                              Overall     16 (0)     8 (0)     4% B, no match.
                n=2058
                                                               Attack rate 1.8%,
                                                               Wide 95% CIs
                2007-20083    Overall     68 (46)    36 (0)    90% A/H3N2 drifted;
                              Type A      72 (49)    29 (0)    10% B, no match;
                n= 1952       Type B      Too few    Too few
                                                               Attack rate 10.8%

1Ohmit SE, et al. N Eng J Med 2006;355:2513-22.
2Ohmit SE, et al. J Infect Dis 2008; 198:312-7.                                      91
3Monto A, et al. N Eng J Med 2009; 361:1260-7.
 Estimates of Vaccine Efficacy in the Literature
 where Antigenic Characterization is Available

 Although it is difficult to make direct comparisons because of
  differences in study design and methodology, the following table,
  adapted from Jackson L, et al, JID 2009, presents results of some
  recently published studies of VE against culture-confirmed influenza
  with antigenic characterization:




                                                                    92
  Vaccine Efficacy and Antigenic Characterization from
             Recently Published Literature
Study/                 Season          Population/       Efficacy/           Comments             TIV/
Design                                 Age               Effectiveness*                           LAIV

CDC-Marshfield         2007-2008       ≥6mos with or     All typeA 58%       Mismatched           Fluzone
Clinic                                 w/o indication    All typeB 35%       H3N1
                       (interim                                              predominated;
Observational          results                           Overall 44%
Case-control           1/21/08 to                                            Type B all
                       2/8/08)         Healthy 5-49      All typeA 68%       mismatched
Acute resp or                          year old subset   All typeB 33%
febrile illness
                                                         Overall 54%

Belongia, et al and    2004-2005       ≥6mos with        10% overall VE      5% matched overall   Fluzone
    CDC,                               Indication
Marshfield, WI         2005-2006                         21% overall VE      5% matched overall

Case control           2006-2007                         52% overall VE      91% matched
Acute resp illness                                                               overall

    Adapted from Jackson LA. J Infect Dis 2009; 199:155-158
  *point estimates, by strain if known; red type indicates matched strains
 **VE based on both culture and real-time PCR-confirmed cases;                                           93
              RPCT=randomized placebo-control trial
  Vaccine Efficacy and Antigenic Characterization from
          Recently Published Literature (cont)
Study/           Season     Population/     Efficacy/                Comments              TIV/
Design                      Age             Effectiveness*                                 LAIV
Skowronski,      2006-      Children and    Overall VE 46%           H1N1 matched;         80%
et al            2007       adults ≥9yrs    H1N1 VE 92%              H3N2 50% matched;     GSK
Canadian                                    H3N2 VE 41%              B no match            Fluviral
Sentinel                    (8% ≥65 yrs)    B strain VE 12%
Surveillance                                (adjusted for age and
                                            chronic conditions)
Case control
Ohmit,Monto,     2004-      Healthy         Fluzone/FluMist**        A/H3N2 moderate       Fluzone/
et al            2005       18-49 yrs       Overall VE 75/48%        mismatch;             FluMist
                                            Type A VE 69/47%         B 60% mismatch
RPCT:                                       Type B VE 83/49%         Attack rate 7.8%
TIV, LAIV,
                 2005-                      Fluzone/FluMist:**       No match,             Fluzone/
and PBO
                 2006                       Overall VE 16/8%%        Attack rate 1.8%,     FluMist
                                                                     Wide 95% CIs
                 2007-                      Fluzone/FluMist**        A/H3N2 predominated   Fluzone/
                 2008                       Overall VE 68/36%        and matched;          FluMist
                                            Type A VE 72/29%         B no match;
                                            Type B VE – too few      Attack rate 10.8%
                                                 cases
  Adapted from Jackson LA. J Infect Dis 2009; 199:155-158
*point estimates, by strain if known; red type indicates matched strains                              94
      Immune Response and Non-inferiority Endpoints
             across Studies – FluBlok 135μg
          PSC01 n=150             PSC03 n=431              PSC04 n=448   PSC06 n=299
          Age 18-49               Age ≥ 65                 Age 18-49     Age 50-64
 % 4-fold increase in HI titer Point estimate (LB 95%CI)
 H1       64   (41.1)                                      78   (73.5)
 H3       81   (73.4)                                      81   (77.1)
 B        49   (41.1)                                      52   (47.0)
 % HI ≥ 1:40 Point estimate (LB 95% CI)*
 H1       87   (80.9)                                      99   (97.1)
 H3       100 (97.6)                                       97   (94.8)
 B        65   (57.1)*                                     96   (94.0)
 Difference in SCRs (TIV – FluBlok) – UB of the 95% CI
 H1                                -4.4                                  1.4
 H3                               -13.9                                  -9.5
 B                                16.1                                   8.2
 GMT ratio (GMT TIV/GMT FluBlok) – (UB of the 95% CI)
 H1                               0.85    (0.96)                         0.77 (0.90)
 H3                               0.58    (0.67)                         0.58 (0.68)
 B                                1.30    (1.45)                         1.00 (1.14)   95
*PSC01 used a higher HI threshold of ≥ 1:64
     Immune Response and Non-inferiority Endpoints
            across Studies – FluBlok 135μg
        PSC01 n=150             PSC03 n=431               PSC04 n=448   PSC06 n=299
        Age 18-49               Age ≥ 65                  Age 18-49     Age 50-64
% 4-fold increase in HI titer Point estimate (LB 95%CI)
H1      64   (41.1)             43     (38.7)             78   (73.5)   72     (66.8)
H3      81   (73.4)             78     (73.5)             81   (77.1)   61     (55.4)
B       49   (41.1)             29     (25.0)             52   (47.0)   41     (35.2)
% HI ≥ 1:40 Point estimate (LB 95% CI)*
H1      87   (80.9)             95     (92.1)             99   (97.1)   96     (93.5)
H3      100 (97.6)              97     (94.3)             97   (94.8)   85     (80.8)
B       65   (57.1)*            92     (88.6)             96   (94.0)   93     (89.5)
Difference in SCRs (TIV – FluBlok) – UB of the 95% CI
H1                               -4.4                                   1.4
H3                              -13.9                                   -9.5
B                                16.1                                   8.2
GMT ratio (GMT TIV/GMT FluBlok) – (UB of the 95% CI)
H1                              0.85    (0.96)                          0.77 (0.90)
H3                              0.58    (0.67)                          0.58 (0.68)
B                               1.30    (1.45)                          1.00 (1.14)     96
*PSC01 used a higher HI threshold of ≥ 1:64
                  PSC04: Deaths
 Death from Pulmonary Embolism - Subject
  02568: a 47 y.o. female vaccinated on
  September 9, 2007. No concomitant
  vaccinations. On Jan 1, 2008 (94 days post-
  vaccination), the subject was hospitalized and
  died from a PE.

   Applicant reported that details were not available
    because husband did not have authority to sign for
    reports.

   Investigator assessed event as not related.

                                                         97
    Hypersensitivity-Type Events (continued)

 Of the remaining hypersensitivity-type events in FluBlok recipients:

     2 were either serious or severe and may have been caused by
      FluBlok;

     2 were mild and/or probably unrelated to FluBlok;

     2 were suggestive of seasonal allergies or infection-related
      rhinitis, were not temporally related to vaccination, appeared
      unrelated.

     1 was a dermatitis due to topical use of neomycin


                                                                         98
     Hypersensitivity-Type Events (continued)
   PCS04 Subject 12074 – Hypersensitivity/facial swelling
      35 y.o. female
      Grade 1 injection site pain on Day 0, then no complaints.
      Day 16: dizziness, nausea, pruritis and facial swelling.
      Private MD evaluation on Day 16: red puffy eyes and puffy upper lip,
       otherwise unremarkable.
      Labs normal except for mildly elevated ESR 34 (nl 0-20).
      Resolved without specific treatment.
      Investigator assessed as not related.

   PSC06 Subject 0266 – Urticaria
      52 yo female experienced corneal abrasion, sinus pain and hives four
       days post-vaccination.
      Hives assessed as non-serious, mild in intensity and possibly related to
       the study vaccine.                                                     99
       Overview of Safety: Pregnancy Outcomes

   Study                          PSC04                          PSC01
                                  FluBlok        PBO             FluBlok        PBO
                                  N=1391         N=1349          N=96           N=89
   Total                          20 (1.4%)      17 (1.3%)       3 (3.1%)       0
   Pregnancies
   Complete                       15 (75%)       15 (88%)        3 (100%)
   Follow-up*
   Normal term birth**            12 (80%)       11 (65%)        1
   Congenital Anomalies            0               0             0
   Elective Termination            2               3             2
   Spontaneous abortion            1               1
   Complications/AE’s*             4               5             0

*FluBlok: hyperemesis, pulmonary embolism, staph infection, miscarriage;
Fluzone: kidney stone, appendicitis, hypertension, ectopic pregnancy, miscarriage      100
                          Safety: Rash – PSC04
    Rash: 4 FluBlok and 1 Placebo subject in PSC04 reported rash. One
     FluBlok subject had a moderate intensity rash assessed as possibly related
     to the study vaccine, but that resolved without sequelae. The remainder
     were mild, non-serious, and assessed as not related to study vaccines.

  Subject        Onset        Severity      Causality      Comments
  (FluBlok)      Post-vax
  12-08876        1d          Mild          unrelated      axilla
  13-09825       27 d         Mild          unrelated      thorax, associated URI
  16-12140        4d          Mild          unrelated      back
  16-12475        2d          Mod           ? related      face, neck, back, shoulder

#12475: 34 year old female vaccinated with FluBlok on Sept 19, 2007. PMH included
seasonal allergies and allergy to “mycins”. On Days 2-4 she experienced left leg and back
bruising, felt not related to the vaccine, and rash on the face, neck, chest and shoulder. The
rash was described as moderate, required no treatment, and resolved without sequelae. The
rash was assessed as possibly related to the study vaccine because of the temporal
relationship between vaccination and onset.                                                101
     Safety: Rash in FluBlok Recipients (cont)
   PSC06: Urticaria: Subject #0266 was vaccinated with FluBlok on Oct 23,
    2007. Four days post-vaccination, the subject reported hives. Assessed as
    non-serious, mild in intensity and possibly related to the study vaccine.
    Resolved without sequelae after treatment with medication on October 27,
    2007.

   PSC03: Five total, none serious or severe. Two FluBlok subjects had
    rashes that were ongoing at the time of the interim analysis (Day 28).
    Subject #0572 experienced a facial rash that was considered mild, non-
    serious, and not related to the vaccine. FluBlok Subject #1086 had
    eczema, also non-serious, mild, and assessed as not related to the vaccine.
    Remaining 3: ingrown toenail, sebaceous cyst, and blisters from topical
    antibiotic.

   PSC01: Rash occurred in two subjects, both in the FluBlok 75µg group.
    Subject 2401 experienced rash in the left axillary area 22 days post-
    vaccination. Subject 2441 experienced a rash in the left antecubital area 4
    days post-vaccination. Neither was considered serious, both were
    assessed as mild and unrelated to the study vaccine, and both resolved
    without sequelae.                                                         102
   Safety: Discontinuations Due to AEs – PSC04*
        Treatment       Subject       Reason for discontinuation
        FluBlok
                        04-02568      Pulmonary embolism/death
                        05-03321      Pleuropericardial effusion
                        19-14659      Pregnancy - miscarriage
                        19-14567      Pregnancy
                        19-14509      Pregnancy
                        17-10859      Pregnancy
        Placebo
                        05-03291      MVA/death
                        11-08096      Multiple fractures
                        15-11410      Pregnancy
                        19-14587      Pregnancy
                        08-05715      Pregnancy
*PSC01 and PSC06: No discontinuations due to AEs.
PSC03: One Fluzone recipient discontinued due to cerebral hemorrhage.   103
    Safety: Questionable Case of Bell’s Palsy
 Possible Bell’s Palsy: Subject 17759 was a 35 y.o. female with a
  history of prior episodes of Bell’s Palsy

 In 1988, during pregnancy, and in March 2007: characterized by
  numbness in her cheek. Treated with a steroid injection in March
  2007.

 Subject experienced similar prodromal symptoms of recurrence
  (watery eyes) one day prior to vaccination, and was symptomatic
  (numbness of the cheek) within one hour of vaccination on Day 0.

 Symptoms resolved without treatment or sequelae by Day 3, and did
  not recur by the end of the study.

 Event described as mild, not serious, not related to the study
  vaccine.
                                                                     104

				
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