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Vaccines and Related Biological Products Advisory Committee Meeting

Influenza Vaccine, Recombinant Hemagglutinin

FluBlok

Protein Sciences Corporation

Cynthia Nolletti, MDFDA/CBER/OVRR/DVRPA

November 19, 2009

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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

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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.

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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.

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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

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Clinical Trials Overview

*n=evaluable population for safety and clinical efficacy analyses**135μg dose groupMDB = modified double-blind, person administering vaccine not blinded.

Study/

Date

Phase Age FluBlokn*

Controln

Rdm Blind Sites(U.S.)

PSC012004-2005

2 18-49 153** 154Saline

1:1:1 MDB 3

PSC032006-2007

3 ≥65 436 433Fluzone

1:1 MDB 6

PSC042007-2008

3 18-49 2344 2304Saline

1:1 MDB 24

PSC062007-2008

3 50-64 300 302Fluzone

1:1 MDB 6

Total 3233 3193

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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 Inactivated Influenza Vaccines (May 2007).

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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

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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

Clinical Overview: Immune Response Endpoints

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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%.

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Clinical OverviewNon-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%.

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Clinical OverviewClinical 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.

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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.

Overview: Clinical Endpoint Assessments - ILI

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Study PSC04

Subjects 18 to 49 years of age

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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

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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.

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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%

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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.

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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

PSC04 (18-49 yr): Immunogenicity Endpoints

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PSC04 (18-49 yr): Disposition of Subjects Number of Subjects (%)

Treatment Group

Disposition Placebo n (%)

FluBlokn (%)

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 Immunogenicity**

127 448

*Does not include pregnancies**Serology available for immunogenicity analysis. Placebo serologies run as post hoc analysis.

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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

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PSC04 (18-49 yr): Vaccine EfficacyPSC04 (2007-2008) FluBlok

n=2344PlaceboN=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)

*Includes one untyped B strain

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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.

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PSC04 (18-49): Immunogenicity Endpoints

Endpoint Seroconversion rate* % with post-vaccination HI titer ≥ 1:40**

Strain Placebon=127

FluBlokn=448

Placebon=127

FluBlokn=448

H1%95% CI (%)

3(0.9, 7.9)

78(73.5, 81.5)

36(27.9, 45.2)

99(97.1, 99.5)

H3%95% CI (%)

3(0.9, 7.9)

81(77.1, 84.6)

20(13.8, 38.5)

97(94.8, 98.3)

B%95% CI (%)

0(0, 2.9)

52(47.0, 56.5)

37(28.6, 46.0)

96(94.0, 97.8)

All 3 strains met both immunogenicity endpointsAcceptance criteria: *LB 95% CI ≥ 40%; **LB 95% CI ≥ 70%

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Study PSC06

Subjects 50 to <65 Years of Age

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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

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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

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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

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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%

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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)…

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PSC06 (50-64 yr)GMTs and GMT Ratio of Fluzone to FluBlok at Day 28

Visit Antigen H1 H3 B strain

Day 0GMT

Group

Fluzone (n=302) 27.77 18.20 49.18

FluBlok (n=299) 28.71 18.57 48.49

Day 28GMT

Group

Fluzone 139.74 60.88 116.03

FluBlok 181.34 105.41 110.93

Day 28 GMT RatioUB 95%CI*

0.90 0.68 1.14

Meets non-inferioritycriteria?**

YES YES YES

**UB 95%CI ≤ 1.5

*based on Statistical Reviewer’s adjustments for pre-vaccination titer, prior vaccination history, and assay variables.

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PSC06 (50-64yr)Difference in Seroconversion Rates at Day 28

Strain SCR (LB 95% CI)

Difference:SCR Fluzone –SCR FluBlok(95% CI)

MeetsNon-inferiority criteria?*

FluBlokn=299

Fluzonen=302

H1N1 72.2 (66.8)

66.2(60.6)

-6.0(-13.4, 1.4)

YES

H3N2 61.2(55.4)

43.7(38.0)

-17.5(-25.4, -9.5)

YES

B strain 40.8(35.2)

41.1(35.5)

0.3(-7.7, 8.2)

YES

*Acceptance criteria: UB 95%CI ≤ 10%.

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PSC06 (50-64 yr): Immunogenicity Results

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

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Study PSC03

Subjects 65 years and older

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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

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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

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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.

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GMT ratio of Fluzone to FluBlok

The difference in SCRs (Fluzone – FluBlok)

PSC03 (≥ 65 yr): Non-inferiority Endpoints

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.

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PSC03 (≥ 65 yr): GMTs and GMT Ratios at Day 28

Strain H1 H3 B strain

Group

Day 0GMT

Fluzone (n=430) 70.2 44.7 80.3

FluBlok (n=431) 69.0 42.7 79.9

Day 28GMT

Fluzone 148.1 199.2 194.8

FluBlok 176.8 338.5 149.6

Day 28 GMT RatioUB 95% CI*

0.96 0.67 1.45

Meets non-inferiorityCriteria?**

Yes Yes Yes

**UB 95% CI on GMT ratio ≤ 1.5

*Based on Statistical Reviewer’s adjustments for pre-vaccination titers and HI assay variables

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PSC03 (≥ 65 yr)Difference in Seroconversion Rates at Day 28

Strain SCR Difference:SCR Fluzone –SCR FluBlok(95% CI)

MeetsNon-inferiority criteria?*

FluBlokn=431

Fluzonen=430

H1N1 43 33 -10.8( -17.3, -4.4)

YES

H3N2 78 58 -20.1(-26.2, -13.9)

YES

B strain 29 39 9.8(3.5, 16.1)

NO

*UB 95% CI for (SCR TIV –SCR FluBlok) should be ≤ 10%

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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.

PSC03 (≥ 65 yr)Immunogenicity Endpoint Results

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Study PSC01

Subjects 18 to 49 Years of Age

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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

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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.

PSC01 (18-49 yr): Efficacy Endpoint

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PSC01 2004-2005 FluBlokn=151

Placebon=153

Parameter #cases(%)

#cases(%)

% VE (95% CI)

Matched Strains 0 0 n/a

All strains regardless of match Any ILI

1 (0.7) 8 (5.2) 87.3 (5.5, 99.7)

-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.

PSC01 (18-49 yr): Vaccine Efficacy Results

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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.

PSC01 (18-49 yr): Vaccine Efficacy

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Clinical Efficacy and Immunogenicity Populations across Studies – FluBlok 135μg

Study Age group Immunogenicitypopulationn* (Control)

Clinical Efficacypopulationn* (Control)

PSC0118-49 yr

150 (151) 151 (153)

PSC03≥65 yr

431 (430) 436 (433)

PSC0418-49 yr

448 (127) 2344 (2304)

PSC0650-64 yr

299 (302) 300 (302)

Total ≥ 18 yr

1328 (833) 3231 (3192)

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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.

Summary: Vaccine Efficacy across Studies

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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.

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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.

Immune Response and Non-inferiority Endpoints across Clinical Studies - FluBlok 135μg

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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.

Immunogenicity Conclusions

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Safety

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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 age

M/F Total

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≥18 yr

2497 300 436 3233

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Safety: DeathsThere 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 embolism94 d post-vax

No

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

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Safety: Serious Adverse Events through Day 180

FluBlok Control

Study SAEs N (E)

Preferred term/Causality*

SAEs N (E)

Preferred term/Causality*

PSC01n=307

2 (2) 2 not related 0

PSC03n=869

36 (45) 36 not related 34 (42) 34 not related

PSC04n=4648

30 (41) 40 not related1 possibly related:Pleuropericarditis

35 (46) 46 not related

PSC06n=602

2 (2) 1 not related1 related:Vasovagal syncope

2 (2) 2 not related

TotalN=6426

70 (90) 1 related1 possibly related

71 (90) None 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

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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

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Summary of SAEs by MedDRA* System Organ Class

ContinuedMedical Dictionary for Regulatory Activities

FB=FluBlok; PBO=placebo; E = # of events

PSC04 PSC06 PSC03 PSC01

SOC FBE

PBOE

FBE

TIVE

FBE

TIVE

FBE

PBOE

Blood and lymphatic system disorders

1 1 1

Cardiac disorders 3 2 8 8

Congenital, familial and genetic disorders

0 1

Eye disorders 0 1

Gastrointestinal disorders 3 3 1 0 5 3

General disorders and Administration site conditions

1 2 1

Hepatobiliary disorders 1 1 1 2

Infections and infestations 4 13 4 5

Injury, poisoning and procedural complications

6 3 2 5

Metabolism and nutrition disorders

0 3 3

Musculoskeletal and connective tissue disorders

2 2 3 3

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Summary of SAEs by MedDRA System Organ Class (cont)

PSC04 events PSC06 PSC03 PSC01

SOC FBE

PBOE

FBE

TIVE

FBE

TIVE

FBE

PBOE

Neoplasms benign,malignant and unspecified

3 1 0 1 4 4

Nervous system disorders 1 1 1 1 7 5 2 0

Pregnancy, puerperium and perinatal conditions

0 2

Psychiatric disorders 4 5 1 1

Renal and urinary disorders 1 1 2

Reproductive system and breast disorders

7 4 1

Respiratory, thoracic and mediastinal disorders

3 0 2 2

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

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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.

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Unsolicited AE byMedDRA Preferred Term

FluBlokN=3233

PlaceboN=2188

Fluzonen=735

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 - -

Safety Results of Search for Hypersensitivity-type Events

Rash: Rates lower in FluBlok group compared to Fluzone. None in the FluBlok recipients were serious or severe. Majority appeared unrelated to FluBlok.

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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.

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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.

Hypersensitivity-Type Events (continued)

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

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

Hypersensitivity-Type Events: (Continued)

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Safety: Reactogenicity Events across Trials Most frequent events in FluBlok subjects: local pain, headache, fatigue and myalgia. Rates

similar to Fluzone:

Diary Card FluBlokN= 3233

Fluzone N=735

Placebo 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%)

66

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

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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.

68

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.

69

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?

70

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

Questions for the Committee

71

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

Questions for the Committee

72

Backup Slides

73

Clinical Overview: Race and Ethnicity across Studies

Race/Ethnicity

PSC01%

PSC03%

PSC04%

PSC06%

USPopulation*

White/Caucasian

85 99 67 73 81.3

Black/African/American

6 <1 18 4 13.0

Latino/Hispanic **

3 <1 11 8 7.4

Asian 3 0 3 12 4.5

American Indian/Alaska Native

1 0 <1 0 1.0

Native Hawaiian/Pacific Islander

1 0 <1 <1 0.2

Other 2 <1 1 4

*July 2007 census **Hispanic origin is considered an ethnicity, not a race; Hispanics may be any race.

74

Demographic Characteristics across StudiesEvaluable Population for Immunogenicity

Study Age Group

n* Mean Age

M/F%

Prior yearFlu 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.

75

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.

76

PSC04 (18-49 yr): Vaccine EfficacyPSC04 (2007-2008) FluBlok

n=2344PlaceboN=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

77

PSC06 – ResultsDisposition of Subjects

Number of Subjects (%)

Disposition* FluBlokn (%)

Fluzonen (%)

Overall 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

78

Strain % post-vaccination HI titer ≥ 1:40*

FluBlokn=299

Fluzonen=302

H1N1 % HI ≥1:40 95% CIMeets LB ≥ 70%?

96(93.5, 98.1)yes

96(92.8, 97.7)yes

H3N2 % HI ≥1:40 95% CIMeets LB ≥ 70%?

85(80.8, 89.1)yes

75(69.9, 79.9)no

B Strain % HI ≥1:40 95% CIMeets LB ≥ 70%?

93(89.5, 95.6)yes

94(91.1, 96.7)yes

PSC06: Other Immune Response Endpoints

Proportion of subjects with Post-vaccination HI titer ≥ 1:40

*Immune response acceptance criteria: LB 95% CI should be ≥ 70%

79

PSC06: Other Immune Response Endpoints

Strain Seroconversion Rate* (95% CI)

FluBlokN=299

Fluzonen=302

H1N1 % 95%CI Meets acceptance criteria?*

72.2(66.8, 77.2)Yes

66.2(60.6, 71.5)Yes

H3N2 % 95%CI Meets acceptance criteria?

61.2(55.4, 66.8)Yes

43.7(38.0, 49.5)NO

B Strain % 95%CI Meets acceptance criteria?

40.8(35.2, 46.6)NO

41.0(35.5, 46.8)NO

*Acceptance criteria: LB ≥ 40%.

Seroconversion Rate

80

PSC03: Disposition of Subjects

Disposition FluBlokN=436 (%)

Fluzonen=434 (%)

Randomized 436 (100) 434 (100)

Vaccinated 436 (100) 433 (100)

Completed 428 (98) 426 (98)

Discontinued - due to AE

8 (2) 0

8 (2) 1

Safety Population 436 433

Efficacy Population 431 430

81

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.

82

% 4-fold rise in HI* % with post-vaccination HI titer ≥ 1:40**

Strain Fluzonen=430

FluBlokn=431

Fluzonen=430

FluBlokn=431

H1%LB 95% CI Meets criteria?

3328.1No

4338.7Yes

9592.4Yes

9592.1Yes

H3%LB 95% CI Meets criteria?

5852.8Yes

7873.5Yes

9389.7Yes

9794.3Yes

B%LB 95% CI Meets criteria?

3934.4Yes

2925.0No

9795.2Yes

9288.6Yes

PSC03: Immune Response Endpoints

*Acceptance criteria = LB 95% CI for %4-fold rise must be ≥ 30%.

**Acceptance criteria = LB 95% CI for % HI ≥1:40 must be ≥ 60%.

83

PSC03: Other Immune Response EndpointsProportion with Day 28 HI Titer ≥ 1:40

Strain % post-vaccination HI ≥ 1:40 Day 28*

FluBlok n=431

Fluzone n=430

H1 n (%) LB 95% CI *

408 (95) 92.1

408 (95) 92.4

H3 n(%) LB 95% CI

416 (97) 94.3

398 (93) 89.7

B strain n(%) LB 95% CI

395 (92) 88.6

418 (97) 95.2

*Acceptance criteria: LB 95% CI for % HI ≥1:40 should be ≥ 60%

84

PSC03: Seroconversion/4-fold Rise in HI Titer

*Acceptance criteria = LB 95% CI for %4-fold rise must be ≥ 30%.

85

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.

86

PSC01: Disposition of Subjects

Disposition

Number (%) of Subjects

Study Treatment

OverallN=460

FluBlok 75µg N=153

FluBlok 135µg N=153

PlaceboN=154

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

87

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.

PSC01 (18-49 yr): Immunogenicity Results

88

Seroconversion rate* % with post-vaccination HI titer ≥ 1:64**

Strain Placebon=151

FluBlok 135µgn=150

Placebon=151

FluBlok 135 µgn=150

H1 LB of 95% CI Meets criteria?

0no

51.7yes

32.5no

80.9yes

H3 LB of 95% CI Meets criteria?

5.2no

69.1yes

57.4no

97.6yes

B Strain LB of 95% CI Meets criteria?

0no

55.1yes

3.2no

57.1NO

PSC01 (18-49 yr): Immunogenicity Results

*LB 95% CI for SCR must be at least 40%

**LB 95% CI for % HI ≥ 1:64 must be at least 70%

89

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.

90

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.

Considerations in the Evaluation of Vaccine Efficacy in the Presence of Antigenic Mismatch

(cont)

91

Treatmentgroup

Season VE vs Placebo% Point estimate (LB 95% CI)

Comments

VE Fluzone FluMist

Healthy 18-49 yrs

2004-20051

n=1247

Overall Type AType B

75 (42)69 ( 7)83 (26)

48 (0)47 (0)49 (0)

A/H3N2 drifted;B 60% mismatch

Attack rate 7.8%

2005-20062

n=2058Overall 16 (0) 8 (0)

96% H3N2 drifted.4% B, no match.

Attack rate 1.8%,Wide 95% CIs

2007-20083

n= 1952

Overall Type AType B

68 (46)72 (49)Too few

36 (0)29 (0)Too few

90% A/H3N2 drifted; 10% B, no match;

Attack rate 10.8%

Randomized Placebo-Controlled Trials of Vaccine EfficacyOhmit SE, Monto A, et al, University of Michigan

1Ohmit SE, et al. N Eng J Med 2006;355:2513-22.2Ohmit SE, et al. J Infect Dis 2008; 198:312-7.3Monto A, et al. N Eng J Med 2009; 361:1260-7.

92

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:

93

Vaccine Efficacy and Antigenic Characterization from Recently Published Literature

Study/Design

Season Population/Age

Efficacy/Effectiveness*

Comments TIV/LAIV

CDC-MarshfieldClinic

Observational Case-control

Acute resp or febrile illness

2007-2008

(interimresults 1/21/08 to2/8/08)

≥6mos with or w/o indication

All typeA 58%All typeB 35%

Overall 44%

Mismatched H3N1 predominated;

Type B allmismatched

Fluzone

Healthy 5-49year old subset

All typeA 68%All typeB 33%

Overall 54%

Belongia, et al and CDC,

Marshfield, WI

Case control Acute resp illness

2004-2005 ≥6mos with Indication

10% overall VE 5% matched overall Fluzone

2005-2006 21% overall VE 5% matched overall

2006-2007 52% overall VE 91% matched 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; RPCT=randomized placebo-control trial

94

Study/Design

Season Population/Age

Efficacy/Effectiveness*

Comments TIV/LAIV

Skowronski, et alCanadianSentinelSurveillance

Case control

2006-2007

Children and adults ≥9yrs

(8% ≥65 yrs)

Overall VE 46%H1N1 VE 92%H3N2 VE 41%B strain VE 12%(adjusted for age andchronic conditions)

H1N1 matched; H3N2 50% matched;B no match

80%GSKFluviral

Ohmit,Monto, et al

RPCT: TIV, LAIV, and PBO

2004-2005

Healthy 18-49 yrs

Fluzone/FluMist**Overall VE 75/48%Type A VE 69/47%Type B VE 83/49%

A/H3N2 moderatemismatch;B 60% mismatchAttack rate 7.8%

Fluzone/FluMist

2005-2006

Fluzone/FluMist:**Overall VE 16/8%%

No match,Attack rate 1.8%,Wide 95% CIs

Fluzone/FluMist

2007-2008

Fluzone/FluMist**Overall VE 68/36%Type A VE 72/29%Type B VE – too few

cases

A/H3N2 predominated and matched; B no match;Attack rate 10.8%

Fluzone/FluMist

Vaccine Efficacy and Antigenic Characterization from Recently Published Literature (cont)

Adapted from Jackson LA. J Infect Dis 2009; 199:155-158 *point estimates, by strain if known; red type indicates matched strains

95

Immune Response and Non-inferiority Endpoints across Studies – FluBlok 135μg

PSC01 n=150Age 18-49

PSC03 n=431Age ≥ 65

PSC04 n=448Age 18-49

PSC06 n=299Age 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)

*PSC01 used a higher HI threshold of ≥ 1:64

96

Immune Response and Non-inferiority Endpoints across Studies – FluBlok 135μg

PSC01 n=150Age 18-49

PSC03 n=431Age ≥ 65

PSC04 n=448Age 18-49

PSC06 n=299Age 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)

*PSC01 used a higher HI threshold of ≥ 1:64

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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.

98

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

99

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.

Hypersensitivity-Type Events (continued)

100

Overview of Safety: Pregnancy Outcomes

Study PSC04 PSC01

FluBlokN=1391

PBON=1349

FluBlokN=96

PBON=89

Total Pregnancies

20 (1.4%) 17 (1.3%) 3 (3.1%) 0

CompleteFollow-up*

15 (75%) 15 (88%) 3 (100%)

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

101

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(FluBlok)

Onset Post-vax

Severity Causality Comments

12-08876 1 d Mild unrelated axilla

13-09825 27 d Mild unrelated thorax, associated URI

16-12140 4 d Mild unrelated back

16-12475 2 d 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.

102

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.

103

Safety: Discontinuations Due to AEs – PSC04*

*PSC01 and PSC06: No discontinuations due to AEs.PSC03: One Fluzone recipient discontinued due to cerebral hemorrhage.

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

104

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.