1 Vaccines and Related Biological Products Advisory Committee Meeting Clinical Review of Data...

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Vaccines and Related Biological Products Advisory Committee Meeting

Clinical Review of Data Supporting the Immunogenicity, Safety and Effectiveness

of Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted

Andrea James, M.D.FDA/CBER/OVRR/DVRPA

November 14, 2012

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Outline Product Information Q-Pan-H5N1-001 and Q-Pan-002 Immunogenicity Arepanrix™ (Q-Pan-H1N1+AS03A) Effectiveness Study Q-Pan-H5N1-001 and -002 Safety

Solicited reactions Unsolicited, medically attended and serious adverse events

Additional Safety Evaluations Adverse Events of Special Interest (AESI)/potential Immune Mediated

Diseases (pIMDs) Integrated Summaries of Safety (ISS) Post-marketing safety of Arepanrix™ and Pandemrix™ Post-marketing Pharmacovigilance Plan

Discussion topics for the committee

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Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted

GSK’s candidate monovalent, pandemic influenza vaccine

Manufactured in Quebec, Canada using the licensed Flulaval™ process

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Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted

Proper Name: Influenza A (H5N1) Virus Monovalent Vaccine, Adjuvanted

Trade Name: None

Naming Convention: Q(Quebec-manufactured) + Pan (pandemic vaccine) + subtype = “Q-Pan H5N1” This discussion: Assume that the full dose of the

adjuvant (AS03A) is added unless otherwise noted.

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Q-Pan-H5N1

An inactivated, split virion A/H5N1 influenza virus antigen mixed with AS03

AS03: an oil-in-water emulsion adjuvant containing:

Squalene - an unsaturated, metabolizable oil extracted from shark liver

D,L-Alpha-tocopherol (Vitamin E) Polysorbate 80

Thought to enhance both innate and adaptive immune responses by enhancing delivery of antigen to antigen presenting cells.

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Q-Pan H5N1

GSK’s Proposed Indication: Influenza A (H5N1) Virus Monovalent

Vaccine, Adjuvanted is a vaccine indicated for active immunization for the prevention of disease in persons 18 years of age and older at increased risk of exposure to influenza A virus H5N1 subtype contained in the vaccine.

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Q-Pan H5N1

Proposed Dosage: 3.75μg H5N1 HA + AS03 Antigen dose assessed in Study D-Pan-H5N1-007

Dresden manufactured pandemic vaccine (D-Pan) A/Vietnam H5N1 strain Hemagglutinin-inhibiting (HI) antibody responses were

Assessed across doses: 3.75 μg, 7.5 μg,15 μg and 30μg H5N1 HA with and without AS03A

HI antibody responses were low across all doses without AS03A adjuvant

antigen dose-dependent fashion HI antibody responses were high independent of the antigen

dose with AS03A adjuvant

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Q-Pan-H5N1

Vaccine Presentation: Separate vials of H5N1 antigen and AS03

adjuvant Mixed 1:1 volume prior to administration.

Proposed Administration: Two 0.5 mL intramuscular injections administered 21 days apart.

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Studies Q-Pan-H5N1-001 and -002

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Study Q-Pan H5N1-001 and -002Common Trial Elements

Conducted at multiple centers in the U.S. and Canada

Randomized, controlled, single-observer-blind Evaluated immunogenicity and safety Vaccine/Control administered on Days 0, 21 Q-Pan active test arms: A/Indonesia/5/2005 strain Enrolled healthy adult males and females Subjects with prior H5N1 vaccination excluded

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Study Q-Pan-H5N1-001 Design

Phase I/II 10 U.S. and Canada sites Adults 18-64 years old Active control (unadjuvanted H5N1, 3.75

µg HA)

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Study Q-Pan-H5N1-001 Objectives

Demonstrate adjuvant activity by comparing Q-Pan H5N1 adjuvanted with AS03A (full dose) and AS03B (half dose) vs. unadjuvanted H5N1 vaccine

Demonstrate safety of Q-Pan H5N1 vs. unadjuvanted H5N1 vaccine

Demonstrate immunologic equivalence of Q-Pan H5N1 vs. D-Pan H5N1

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Study Q-Pan-H5N1-001Enrollment

680 subjects enrolled 1:2:2:2:2 to: unadjuvanted H5N1 vaccine (n=78) Q-Pan (AS03A) (n=152)

Q-Pan (AS03B) (n=151)

D-Pan (AS03A) (n=151)

D-Pan (AS03B) (n=148)

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Study Q-Pan-H5N1-001 Demographics and Disposition

Mean age: 38.6 years 54.6% of subjects were 18 – 40 years

Women: 57.8% Caucasian: 86.8% Disposition:

97.8% received 2 doses of vaccine 99% completed the study through Day 42. 97.4% completed the study through Day 182.

No subjects withdrew due to an AE

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Study Q-Pan-H5N1-001 Immunogenicity Evaluations and Endpoints

Immunogenicity evaluations: Days 0, 21, 42 and 182

Primary Endpoint Vaccine-homologous virus antibody response in

subjects receiving 2 doses of study vaccine, as demonstrated by the HI antibody titer at Day 42.

Secondary Endpoints HI antibody response after a single dose of vaccine. Persistence of HI antibody response 6 months post

dose 1.

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Study Q-Pan-H5N1-001Immunogenicity Success Criteria

Demonstration of AS03 adjuvant activity Supported if on Day 42 after two doses of study

vaccine:

Lower bound of 95% CI of the difference in (Q-pan H5N1 – unadjuvanted H5N1) seroconversion rates (SCR)1 > 15% AND

Lower bound of 95% CI around the geometric mean titer (GMT) ratio (Q-Pan H5N1/unadjuvanted H5N1) > 2

1. SCR = % of subjects with a pre-vaccination HI titer <10 and a post-vaccination titer ≥40 or with a pre-vaccination HI titer (Day 0) ≥10 and a fold-increase (post/pre) ≥4.

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Study Q-Pan-H5N1-001Immunogenicity Analysis Population

According-To-Protocol Cohort for Analysis of Immunogenicity (ATP-I) population: Met all eligibility criteria Complied with protocol procedures No elimination criteria met Provided a complete set of immunogenicity

endpoint measures at Day 0 and Day 42 Received the correct vaccine

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Study Q-Pan-H5N1-001Primary Immunogenicity Results: Day 42

Activity of AS03 demonstrated Difference in SCRs

79.9% (95% CI = 69.4-87.3%) Exceeded pre-specified difference of Q-Pan H5N1

(AS03A) – unadjuvanted H5N1 LBs > 15

Adjusted GMT ratio 43.4 (95% CI = 29.9-62.9) Exceeded pre-specified difference of Q-Pan H5N1

(AS03A)/unadjuvanted H5N1 LB of > 2

Study Q-Pan-H5N1-001Secondary HI Immunogenicity Results

Treatment Group

N n % SCR(95% CI)

% of Subjects with HI titer > 1:40

(95% CI)

GMT(95% CI)

Day 21

H5N1unadjuvanted

75 13 6.7

(2.2, 14.9)

6.7 (2.2, 14.9)

6.1 (5.2, 7.1)

Q-Pan (AS03A) 144 140 41.7

(33.5, 50.2)

41.7

(33.5, 50.2)

22.5

(17.8, 28.6)

Day 42

H5N1unadjuvanted

75 13 17.3(9.6, 27.8)

17.3 (9.6, 27.8)

10.5 (8.2, 13.5)

Q-Pan (AS03A) 144 140 97.2 (93, 99.2)

97.2 (93, 99.2)

464.7 (383.4, 563.4)

Day 182

H5N1unadjuvanted

74 2 2.7 (0.3, 9.4)

2.7 (0.3, 9.4)

5.6 (5.1, 6.2)

Q-Pan (AS03A) 141 77 54.6 (46, 63)

54.6 (46, 63)

27.8 (22.8, 33.8)

N = number of subjects with available data

n = number of responders

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Q-Pan-H5N1-001 GSK’s post hoc Immunogenicity Analysis

Adjuvant effect of AS03A vs. AS03B By age strata 18-40 yrs vs. 41-64 yrs. AS03B performed less well in the older cohort

Lower GMTs as compared to AS03A

AS03A: 364.1 (299.2, 443.1) vs. AS03B: 209.7 (160.4, 274.2)

Results supported moving forward with AS03A in the adult population.

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Q-Pan-H5N1-001 Immunogenicity Conclusion

-001 Immunogenicity data supported: Selected antigen dose: 3.75 μg Selected adjuvant dose: AS03A

Need for two doses of vaccine to produce an adequate HI antibody response

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Study Q-Pan-H5N1-002 Design

Phase III 40 U.S. and Canada sites Adults > 18 years old Control: saline placebo Immunogenicity evaluations: Days 0, 21,

42 and 182

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Study Q-Pan-H5N1-002 Enrollment

Total N = 4,561 Stratified by age: 18 – 64 and > 64 years Randomization 3:1

Q-Pan H5N1 (N = 3422) Saline placebo (N = 1139)

Immunogenicity subset: N=2,083 Lot consistency subset: N=1,260

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Study Q-Pan-H5N1-002 Objectives

Demonstrate an immune response that met CBER’s suggested immunogenicity criteria to support accelerated approval of a pandemic influenza vaccine

Demonstrate lot consistency for 3 antigen and 3 adjuvant lots*

Demonstrate the safety of Q-Pan vs. saline placebo

*Lot consistency was met

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Study Q-Pan-H5N1-002 Demographics and Disposition

Mean age: 39 years (18 – 64 years) 72 years (> 64 years)

Women: 56% Caucasian:

86% (18-64 years) 94% (> 64 years)

Disposition: 97% received 2 doses of vaccine 98% completed the study through Day 42 95.2% completed the study through Day 182 76.2% completed the study through Day 364*

*Study Q-Pan-H5N1-002 was amended to add a safety evaluation on Day 364 and subjects needed to be reconsented.

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Q-Pan-H5N1-002Immunogenicity Endpoints

Primary endpoints (D42 - 21 days post Dose 2) Vaccine-homologous virus HI seroconversion rates Proportion of subjects with vaccine-homologous virus

HI reciprocal titers ≥ 40 The GMT ratio of vaccine-homologous virus

reciprocal HI titers with 2-sided 95% CIs within 0.67 to 1.5 for lot consistency

Secondary endpoints included Persistence of HI antibody response through 6

months post Dose 1

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Immunogenicity Success Criteria1

Age Group

% of Subjects Achieving SCR2 % of Subjects Achieving HI antibody titer > 1:40

18-64 years

Lower bound of 95% CI > 40%


> 64 years



These criteria and the 1:40 HI antibody titer are borrowed from seasonal influenza.

Historical data suggest that at a titer of 1:40 ~50% of subjects may be protected from illness due to seasonal influenza virus.

1Clinical Data Needed to Support the Licensure of Pandemic Influenza Vaccines (2007)2SCR = % of subjects with a pre-vaccination HI titer <10 and a post-vaccination titer ≥40

or with a pre-vaccination HI titer (Day 0) ≥10 and a fold-increase (post/pre) ≥4.

Study Q-Pan-H5N1-002 Primary Immunogenicity Results

Treatment Group N n % of SCR(95% CI)

% of Subjects with HI titer > 1:40(95% CI)

GMT(95% CI)

Day 42

Q-Pan 18-64 yrs

1571 1427 90.8 (89.3, 92.2)

90.8 (89.3, 92.2)

249 (231.8, 267.5)

Placebo 18-64 yrs

76 1 1.3 (0, 7.1)

1.3 (0, 7.1)

5.1 (4.9, 5.4)

Q-Pan >64 years

396 295 74 (69.4, 78.2)

74 (69.4, 78.2)

81.9 (69.7, 96.2)

Placebo>64 years

40 1 2.5 (0.1, 13.2)

2.5 (0.1, 13.2)

5.5 (4.5, 6.8)

N – Number of subjects with both pre- and post- vaccination results available

n – number of responders

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Q-Pan-H5N1-002 Day 182 Immunogenicity Results

Treatment Group

N n % of SCR(95% CI)

% of Subjects with HI titer > 1:40

(95% CI)

GMT(95% CI)

Day 182

Q-Pan 18-64 yrs

366 255 61.5 (56.3, 66.5)

61.5 (56.3, 66.5)

36.2 (31, 42.2)

Placebo 18-64 yrs

37 1 2.7 (0.1, 17.8)

2.7 (0.1, 17.8)

5.5 (4.8, 6.5)

Q-Pan >64 years

91 59*60**

64.8 (54.1, 74.6)

65.9 (55.3, 75.5)

44.8 (33.3, 60.4)

Placebo>64 years

19 0 0 (0, 17.6)

0 (0, 17.6)

5.4 (4.6, 6.3)

N – Number of subjects with both pre- and post- vaccination results available

n – number of responders•number of seroconverters

** number of subjects w/ HI titer > 1:40

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Summary of Q-Pan-H5N1 Immunogenicity

Q-Pan H5N1 Antigen dose sparing (3.75 μg/dose) Two doses of vaccine are needed

Achieve an adequate HI antibody response Exceed CBER’s suggested immunogenicity

criteria.

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Vaccine Effectiveness

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ArepanrixTM (H1N1+AS03A) Effectiveness Study

“A Test-negative Case-Control Study to Evaluate the Effectiveness of GSK Biologicals’ Adjuvanted Monovalent Inactivated H1N1 Influenza Vaccine (ArepanrixTM) in Young Children (6 months to < 10 years of age)”

Sponsored by: New Brunswick Department of Health Canada

Conducted by: Dr. Van Buynder, et al

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Arepanrix (H1N1+AS03A) Effectiveness Study

GSK did not participate in the study conduct

CBER did not provide input into the study design

Safety data were not collected Arepanrix evaluated at a single, 0.25 mL

dose (1.9μg H1N1 HA+ AS03B)

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Arepanrix (1.9 H1N1+AS03B) Effectiveness Study Population

Of the ~73,000 children aged 6 months to 9 years in New Brunswick 116 (0.16% of total population) were tested for

H1N1 Eligible for the study (n=116) 91 children met study criteria and agreed to

participate 28 cases -- PCR confirmed H1N1+ nasal swabs 63 controls -- PCR negative for H1N1

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Arepanrix (1.9 H1N1+AS03B) Effectiveness Results

When subjects were vaccinated > 14 days prior to symptom onset: Estimated vaccine effectiveness (VE) = 100%

(95% CI: 79.5,100)

When subjects were vaccinated > 10 days prior to symptom onset: Estimated VE = 96% (95% CI: 66, 99.4)

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Arepanrix (1.9 μg H1N1+AS03B) Effectiveness Study

Limitations of the study Small sample size Large percentage of subjects excluded from the

effectiveness analysis Potential for bias e.g. selection, reporting Retrospective study design

Conclusions: Study suggests a single, 0.25mL dose of Arepanrix

H1N1 was effective against H1N1 influenza virus in this small, study in children

Given limitations, CBER is unable to use the results of this study to confirm effectiveness of Q-Pan H5N1

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Safety Results of Studies Q-Pan-H5N1-001 and -002

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Studies Q-Pan-H5N1-001 and -002Primary Safety Population

Total Vaccinated Cohort (TVC) Received at least 1 dose of vaccine Any post-vaccination data Based on treatment actually received.

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Studies Q-Pan-H5N1-001 and -002Safety Evaluations

Safety evaluations: Days 0-6 diary card solicited reactogenicity

events Days 0-84 unsolicited adverse events (AEs) Days 0 – 182 medically attended and serious

AEs (-001) Days 0 - 364 medically attended and serious

AEs (-002)

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Studies Q-Pan-H5N1-001 and -002Solicited AE Grading

Severity grading Mild (Grade 1) – no interference with normal

activities Moderate (Grade 2) – some interference with

normal activities Severe (Grade 3) – prevented normal activity

Redness and swelling Grade 3 -- > 100 mm

Study Q-Pan-H5N1-001: Local Reactions By Subject for Dose 1 or Dose 2

Local Symptom, n (%)

Group AUnadjuvanted H5N1

N=78

Group BQ-Pan H5N1 (AS03A)

N=152

Any Pain 18 (23.1) 133 (87.5)

Gr 3 Pain 1 (1.3) 9 (5.9)

Any Redness 0 7 (4.6)

Gr 3 Redness 0 0

Any Swelling 0 12 (7.9)

Gr 3 Swelling 0 0

N = number of subjects with at least one documented dose

n = number of subjects reporting AE at least once

Any = any grade

Gr 3 - Grade 3, severe

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Study Q-Pan-H5N1-001: Systemic Reactions By Subject for Dose 1 or Dose 2

GeneralSymptom, n (%)


N=78


N=152

Any Myalgia 15 (19.2) 74 (48.7)

Gr 3 Myalgia 1 (1.3) 9 (5.9)

Any Headache 25 (32.1) 71 (46.7)

Gr 3 Headache 1 (1.3) 10 (6.6)

Any Fatigue 16 (20.5) 64 (42.1)

Gr 3 Fatigue 2 (2.6) 6 (3.9)

Any Arthralgia 12 (15.4) 49 (32.2)

Gr 3 Arthralgia 1 (1.3) 7 (4.6)



Any = any grade


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Study Q-Pan-H5N1-001: Systemic Reactions By Subject for Dose 1 or Dose 2

GeneralSymptom, n (%)


N=78


N=152

All Sweating 6 (7.7) 23 (15.1)

Gr 3 Sweating 0 3 (2.0)

All Shivering 4 (5.1) 18 (11.8)

Gr 3 Shivering 0 5 (3.3)

All Temperature > 38 º C 0 4 (2.6)

Temperature > 39 º C 0 0




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Study Q-Pan-H5N1-001:Reactogenicity Event Outcomes

Antipyretics required : 32% of Q-Pan H5N1 (AS03A) subjects vs.

21% unadjuvanted H5N1subjects

Q-Pan H5N1 (AS03A) subjects Resolved in a median of: 3 days No medical attention needed

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Study Q-Pan-H5N1-001: AEs and MAEs Unsolicited AEs reported (by subject)

Day 42: Q-Pan H5N1 (AS03A) – 44% and unadjuvanted H5N1 -- 39% Day 84: Q-Pan H5N1 (AS03A) – 51% and unadjuvanted H5N1 -- 45%

Events occurring exclusively in Q-Pan (AS03A) subjects (2 – 3%) Diarrhea, anemia, lymphadenopathy, dizziness, muscle spasms and

sinusitis

MAEs reported (by subject) Day 42: Q-Pan H5N1 (AS03A) – 7% and unadjuvanted H5N1 -- 12% Day 182: Q-Pan H5N1 (AS03A) – 19% and unadjuvanted H5N1 -- 21%

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Study Q-Pan-H5N1-001:SAEs

SAEs (through Day 182) 3 SAEs in 2 Q-Pan H5N1 (AS03A) subjects

Cholelithiasis and pancreatitis(1) and Chest pain (1)

Deemed vaccine unrelated by investigators

No deaths were reported.

Study Q-Pan-002: Local Reactions By Subject, Dose 1 or Dose 2

Local Symptom n (%)

Q-Pan H5N1N = 3376

Saline PlaceboN = 1122

Any Pain 2808 (83.2) 224 (20.0)

Gr > 2 Pain 1244 (36.8) 43 (3.8)

Gr 3 Pain 156 (4.6) 8 (0.7)

Any Redness, 287 (8.5) 8 (0.7)

Gr3 Redness 4 (0.1) 0

Any Swelling, 351 (10.4) 8 (0.7)

Gr 3 Swelling 4 (0.1) 0


n = number of subjects reporting reaction at least once

Any = any grade

Gr > 2 – at least moderate, Grade 2


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Study Q-Pan-002: Systemic Reactions By Subject, Dose 1 or Dose 2

General Symptom, n (%)

Q-Pan H5N1N = 3375


Any Myalgia 1526 (45.2) 231 (20.6)

Gr 3 Myalgia 109 (3.2) 21 (1.9)

Any Headache 1179 (34.9) 312 (27.8)

Gr 3 Headache 97 (2.9) 27 (2.4)

Any Fatigue 1148 (34) 253 (22.5)

Gr 3 Fatigue 107 (3.2) 26 (2.3)

Any Arthralgia 853 (25.3) 136 (12.1)

Gr 3 Arthralgia 63 (1.9) 10 (0.9)N = number of subjects with at least one documented dose


Any = any grade



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Study Q-Pan-002 Safety: Systemic Reactions By Subject, Dose 1 or Dose 2 (cont)

General Symptom, n (%)

Q-Pan H5N1N = 3375


All Shivering 563 (16.7) 109 (9.7)

Gr 3 Shivering 66 (2.0) 12 (1.1)

All Sweating 362 (10.7) 82 (7.3)

Gr 3 Sweating 28 (0.8) 13 (1.2)

All Temperature > 38 ºC 156 (4.6) 38 (3.4)

Temperature > 39 ºC 31 (0.9) 10 (0.9)

Temperature > 40 ºC 4 (0.1) 4 (0.4)





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Study Q-Pan-H5N1-002: Unsolicited AEs

Day 42: Q-Pan H5N1 (38%) and saline placebo (35%)

Day 84: Q-Pan H5N1(43.4%) and saline placebo (39.6%) Imbalances in unsolicited adverse events

Most common imbalances (by subject) occurred in the preferred terms

Injection site pruritus: Q-Pan 1.64% (n=64) vs. placebo 0.35% (n=4)

Injection site warmth: Q-Pan 1.34% (n=46) vs. placebo 0.18% (n=2)

Insomnia: Q-Pan 0.4% (n=14) vs. placebo 0.09% (n=1)

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Study Q-Pan-H5N1-002: MAEs and SAEs MAEs – at least 1 event

Day 42: Q-Pan subjects (9%) and placebo subjects (10%)

Day 182: Q-Pan subjects (23%) and placebo subjects (22%)

Day 364: Q-Pan and placebo subjects (30%)

SAEs – at least 1 event Day 42: 18 subjects (0.4% Q-Pan, 0.3% placebo) Day 182: 82 subjects (1.8% Q-Pan, 1.7% placebo) Day 364: 160 subjects (3.2% Q-Pan, 4% placebo)

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Study Q-Pan-H5N1-002: SAEs

Day 182: SAEs occurring exclusively in the Q-Pan group (> 3:1 ratio)

Myocardial infarction (MI) (n=5) Intestinal obstruction (n=4) Pulmonary embolism (n=3)

Day 364: Two MIs occurred in the placebo group Intestinal obstruction (n=4) Pulmonary embolism (n=3) Thyroid cancer (n=3) Convulsion (n=3)

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Study Q-Pan-H5N1-002: SAEs Occurring Exclusively in the Q-Pan H5N1 Group

SAE Day(s) of Onset Vaccine Dose Gender/Age Medical

History

Outcome

Intestinal obstruction

19 2 M/68 HTN Recovered


22 2 M/66 Colostomy Recovering


110132

2 F/53 Obese, multiple prior abd surgeries Recovered w/ sequelae


124 2 F/71 Polyps, Diverticulosis Recovered

PE 21 1 M/59 None Not recovered

PE 113 2 M/76 HTN, MV regurg, PVD Recovered

PE 142 2 F/78 HTN,hypothyroid Not recovered

Convulsion 35 2 F/25 - Recovered

Convulsion 252 2 M/69 - Recovered

Convulsion 346 2 M/34 Irritable bowel Not recovered

Thyroid CA 21 2 F/68 Seizure disorder Not recovered

Thyroid CA 29 2 M/72 CAD, insomnia, eczema Recovered

Thyroid CA 223 2 F/32 ↑Cholesterol, insomnia, joint pains Not recovered

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Study Q-Pan-H5N1-002 Non-Fatal SAEs All SAEs were deemed unrelated to vaccine by the investigator

Four SAEs per the CBER reviewer have a strong temporal relationship to vaccination and/or lack an alternate, plausible cause

Cerebrovascular accident x 2 65 y.o. female with a history of hypertension not stated to be uncontrolled or

requiring medication. SAEs on Day 1 and Day 9 post the 2nd dose of active vaccine. Ischemic infarcts confirmed via CT Resolved with sequelae 4 and 10 days, respectively, after onset.

Pulmonary embolism (PE) 59 y.o. male without recorded past medical history PE Day 21 post Dose 1

Corneal transplant rejection 52 y.o. female s/p corneal transplant 18 yrs prior Left corneal transplant rejection Day 103 post dose 2

Cecitis 63 y.o. male with right sided abdominal pain requiring exploratory surgery on Day

143 post dose 2 Pathology c/w inflammatory changes and thickening of the cecum

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Study Q-Pan-H5N1-002 Deaths

Deaths 1 death through Day 42

Q-Pan H5N1 – 59 y.o. male w/ PMH of diabetes and hypercholesterolemia.

Fatal MI 17 days post one dose of Q-Pan. No autopsy. Deemed unrelated by investigator.

11 deaths through Day 364 4 Q-Pan H5N1 – metastatic ovarian CA, unknown CA,

cirrhotic liver disease and GI bleed in addition to fatal MI 7 saline placebo – malignant brain neoplasm, cardiomegaly,

MVA s/p cardiac event, death NOS, fatal gunshot wound, tongue CA, pneumonia

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Q-Pan-H5N1-001 and -002 Safety Summary

Q-Pan-H5N1 More frequent local and systemic reactogenicity More severe reactogenicity

Locally in both -001 and -002 Systemically in -001

Imbalances in reported AEs Expected: Injection site reactions Unexpected: Insomnia, PEs, bowel obstruction, convulsion,

thyroid cancer Randomization 3:1 Frequency of all events is small Clinical relevance uncertain

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Additional Safety Evaluations

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AESI/pIMDs GSK screened safety databases for selected neuroinflammatory,

musculoskeletal, gastrointestinal, metabolic, skin and autoimmune disorders Adverse Events of Special Interest (AESI)/potential Immune Mediated

Diseases (pIMDs)

AESI - defined in the European Medicines Agency’s (EMA) Committee for Medicinal Products for Human Use (CHMP) Risk Management Plan for Pandemic Vaccines for safety monitoring (2009)

GSK included additional preferred terms (PTs) and Standardized MedDRA Queries (SMQs) in a list of pIMDs.

Overlap exists between the two lists.

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AESIs/pIMDs Neuroinflammatory disorders (optic neuritis, multiple sclerosis,

demyelinating disease, transverse myelitis, Guillain-Barre syndrome, myasthenia gravis, encephalitis, neuritis, Bell’s palsy)

Musculoskeletal disorders (systemic lupus erythematosus, cutaneous lupus, Sjogren’s syndrome, scleroderma, dermatomyositis, polymyositis, rheumatoid arthritis, juvenile rheumatoid arthritis, polymyalgia rheumatica, reactive arthritis,psoriatic arthropathy, ankylosing spondylitis, spondylarthropathy)

Gastrointestinal disorders (Crohn’s disease, ulcerative colitis, celiac disease)

Metabolic diseases (autoimmune thyroiditis, Grave's or Basedow’s disease, Hashimoto thyroiditis, insulin-dependent diabetes mellitus [IDDM], Addison’s disease)

Skin disorders (psoriasis, vitiligo, Raynaud’s phenomenon, erythema nodosum, autoimmune bullous skin diseases)

Others (autoimmune hemolytic anemia, idiopathic thrombocytopenic purpura, antiphospholipid syndrome, vasculitis, temporal arteritis, Behcet's syndrome, pernicious anemia, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune glomerulonephritis, autoimmune uveitis, autoimmune cardiomyopathy, sarcoidosis, Stevens-Johnson syndrome).

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Q-Pan-H5N1-002 AESI/pIMDs

A total of 15 subjects (14 Q-Pan-H5N1 subjects, 1 placebo subject) reported 16 AESI/pIMDs. GSK and CBER agreed that the following Q-

Pan-H5N1 cases had alternate plausible causes: polymyalgia rheumatica (PMR), lumbar radiculitis, rheumatoid arthritis, Crohn’s disease, celiac disease and rheumatoid lung (n = 1 each)

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Study-Q-Pan-002: AESI/pIMDsTreatment Diagnosis Subject Age,

Gender and Significant Past Medical History

AESI OnsetDays Post

Last Vaccine

Dose

Dose Alternate PlausibleCause per

GSK

Alternate PlausibleCause per

CBER

AdditionalComments

Q-Pan H5N1

CN IV Palsy 77 y.o. M w/ hypertension

22 2 Y N GSK consideredhypertension a likely cause.CBER considered a hyperinflammatory vaccine response

Q-Pan H5N1

PMR 84 y.o. F w/ legpain.

82 2 _ N PI considered fibromyalgiaSubject w/ new onset back pain 2 days post Dose 1 and new onset neck and shoulder pain w/ ↑ESR .

Q-Pan H5N1

Autoimmune hepatitis (AIH)

28 y.o. M 40 2 Y N mild to mod ↑liver enzymes, TBili – 2.6. antiSMA+ 1:5120, Bx suggestive of AIH.Baseline sera tested after diagnosis antiSMA + 1:320, LFTs nl.

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Study-Q-Pan-002 AESI/pIMDsTreatment Diagnosis Subject Age,


AESI OnsetDays Post

Last Vaccine

Dose

Dose Alternate Plausible

Cause perGSK

Alternate Plausible

Cause perCBER

AdditionalComments

Q-Pan H5N1

Psoriasis 48 y.o. F 5 2 N N

Q-Pan H5N1

Erythema Nodosum

35 y.o. F 40 2 N N

Q-Pan H5N1

Temporal arteritis

72 y.o. F 196 2 N N Patient diagnosed w/ PMR on Day 81.

Q-Pan H5N1

Facial Palsy 62 y.o. F 78 2 N N

Q-Pan H5N1

Systemic LupusErythematosus

54 y.o. F 137 2 N N Osteoporosis and hypothyroidism diagnosed on the same date

Q-Pan H5N1

Vasculitis, cutaneous

50 y.o. F 22 1 N N

Placebo Psoriasis 68 y.o. M 226 2 N N

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Integrated Summaries of Safety (ISS)

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ISS GSK performed two integrated summaries of safety

ISS-1 (2009) Safety data from eight Q-Pan and D-Pan H5N1 controlled and

uncontrolled studies. Included 12,281 adult subjects 9,873 received H5N1+AS03 vaccine and 2,408 received either

active (unadjuvanted H5N1/Fluarix) or saline placebo control (4:1 ratio)

ISS-2 (2011) Safety data from 24 Q-Pan and D-Pan H5N1 and H1N1 controlled

and uncontrolled studies. Included 22,521 adult subjects 16,160 received H5N1 or H1N1+AS03 vaccine and 6,361 received

an active (unadjuvanted H5N1/Fluarix/Flulaval) or saline placebo control (2.5:1 ratio)

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ISS-1 Results Solicited adverse events were reported similarly to

events in the pivotal clinical trials Frequency and severity

Mild temperature elevations occurred twice as frequently in H5N1+AS03 subjects vs control subjects.

H5N1+AS03 subjects reported more unsolicited injection site reaction, injection site warmth, injection site

pruritus, malaise, nausea, insomnia and dizziness All reported pIMDs were in the H5N1+AS03 arm (n=17)

Captured in -002 AESI/pIMD report (5): polymyalgia rheumatica (2), CN IV palsy (1), psoriasis (1), erythema nodosum (1),

12 ISS-1 unique cases: Grave’s disease (1); uveitis (1), polymalgia rheumatica (2), facial palsy (3), facial paresis (1), neuritis (1), multiple sclerosis (1), sclerodema (1), psoriasis (1)

66

ISS-1 AESI/pIMDsTreatment Diagnosis Subject Age,


AESI Onset

Days Post Last

Vaccine Dose


Cause per

GSK


CBER

Comments

Q/D-Pan+AS03

Facial paresis 38 y.o. F w/ h/o HA on the day of vaccination

0(8 hrs)

1 Y N GSK believes time to event too short and patient successfully rechallenged. Subject continued to have symptoms for 39 days (19 days post Dose 2.)

Q/D-Pan+AS03

Neuritis 48 y.o. F no relevant PMH

0 1 Y N Severe arm pain within hrs of injection. Persisted for 83 days. CBER considered dx c/w brachial plexus neuritis

67

ISS-1 AESI/pIMDsTreatment Diagnosi

sSubject Age, Gender and

Significant Past Medical History

AESI Onset

Days Post Last

Vaccine Dose

Dose Alternate PlausibleCause per

GSK

Alternate Plausible

Cause per

CBER

Comments

Q/D-Pan+AS03

PMR 59 y.o. F w/ h/o fibromyalgia

13 2 N N Qualitatively worse symptoms, ↑CRP, ↑ESR. Treated w/ steroids w/ relief of symptoms

Q/D-Pan+AS03

PMR 70 y.o. F w/out h/o rheumatic dz

38 2 N N New onset scapular and pelvic girdle pain

Q/D-Pan+AS03

Grave’s Disease

40 y.o. F w/ h/o Chronic Hep C and depression

33 2 N N Antithyroglobulin ab were positive 22 months post diagnoisis. Tx’d w/ total thyroidectomy.

Q/D-Pan+AS03

Uveitis 47 y.o. F no relevant PMH

91 2 N N

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ISS-1 AESI/pIMDsTreatment Diagnosis Subject Age, Gender

and Significant Past Medical History

AESI Onset

Days Post Last

Vaccine Dose


Cause per

GSK


CBER

Comments

Q/D-Pan+AS03

Scleroderma 61 y.o. F w/ h/o htn and hypothyroidism

23 2 N N Skin tightening over her trunk, dyspnea and esophageal reflux. Skin bx + for scleroderma

Q/D-Pan+AS03

Facial palsy 37 y.o. F no relevant PMH

30 1 N N

Q/D-Pan+AS03

Bell’s palsy 62 y.o. F no relevant PMH

78 2 N N

Q/D-Pan+AS03

Facial weakness

54 y.o. F w/out PMH

113 2 N N

Q/D-Pan+AS03

Psoriasis 49 y.o. F w/ a h/o Gilbert’s dz and HUS

5 2 N N

Q/D-Pan+AS03

Multiple Sclerosis

36 y.o. F ~304 2 N N

69

ISS-2 AESI/pIMDs

Additional Reports of Diagnoses Previously Discussed facial palsy/paresis/CN paralysis

(n=4) PMR or Temporal Arteritis (n=3) Psoriasis (n=4) Celiac Disease (n=2) Radiculitis/Radiculopathy (n=3) MS (n=2) Rheumatoid Arthritis Uveitis (n=1) SLE (n=1)

Reports of Diagnoses Not Previously Discussed Autoimmune thyroiditis

(n=4) Thrombocytopenia (n=3) Ulcerative colitis (n=2) CN III and VI paralysis,

optic neuritis, ankylosing spondylitis, Raynaud’s phenomenon, Stevens-Johnson Syndrome (n=1, each)

70

Treatment Diagnosis Subject Age, Gender and

Significant Past Medical History

AESI OnsetDays Post

Last Vaccine Dose


Cause per

GSK


CBER

Comments

Q/D-Pan+AS03

MS 34 y.o. M ~240 2 N N

Q/D-Pan+AS03

ITP 52 y.o. M w/ remote h/o

gross hematuria

18 2 N N Platelet count went from 173K at baseline to 97K. Remained asymptomatic

Q/D-Pan+AS03

Ulcerative colitis

65 y.o. M ~165 1 N N Presented as rectal bleeding

Q/D-Pan+AS03

Ankylosing Spondylitis

37 y.o. M ~130 2 N N Dx w/ colitis and R knee arthrosis.

Q/D-Pan+AS03

Raynaud’s

Phenomenon

31 y.o. F 12 1 N N Two episodes lasting 15-30 minutes

Q/D-Pan+AS03

Autoimmune

Thyroiditis

31 y.o. F > 730 2 N N

Q/D-Pan+AS03

Basedow’s

Disease

40 y.o. F w/ Hepatitis C

33 2 N N

ISS-2 AESI/pIMDs

71

Post Marketing Safety Experience with Related Products

72

PandemrixTM H1N1 and Arepanrix H1N1TM Pandemic Vaccines

GSK’s H1N1 pandemic vaccines – not licensed in the U.S. Pandemrix H1N1

Manufactured using the Fluarix® (Dresden, Germany) manufacturing process.

~173 million doses were distributed Estimated 31 million people received Pandemrix

Arepanrix H1N1 Manufactured using the Flulaval® (Quebec, Canada)

manufacturing process. ~171 million doses were distributed Estimated 59 million people received Arepanrix

* Distribution data presented with permission by GSK

73

Summary of Pandemrix and Arepanrix Post Marketing Safety Analyses

GSK conducted specific analyses to assess postmarketing safety of Pandemrix and Arepanrix for a number of safety outcomes: Thrombocytopenia, anaphylaxis, arthropathies, pain

in extremity, convulsions, dysgeusia/ageusia, facial palsy/paresis, Guillain-Barré Syndrome (GBS), narcolepsy, pregnancy outcomes, stillbirth, safety data from pediatric subjects, solid organ transplant rejection, events with fatal outcomes

74

Summary of Arepanrix and Pandemrix H1N1

Post Marketing Safety Analyses Results Febrile convulsion – Arepanrix H1N1

Most common SAE reported after Arepanrix vaccination in children 0 – 2 years of age (event rate of 1/1 million vaccinated) 3 – 9 years of age (event rate of 0.5/1 million vaccinated)

Febrile convulsion was added to the Arepanrix H1N1 Reference Safety Information (RSI).

Guillain-Barré Syndrome (GBS) – Arepanrix H1N1 Observed number of cases > expected number of

cases (from literature and Arepanrix exposure data) Guillain-Barré syndrome was relocated in the RSI to

be listed as “reported with Arepanrix H1N1”.

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Narcolepsy and Pandemrix H1N1

Increased postmarketing reports of narcolepsy post Pandemrix H1N1 vaccination Studies in Finland, Sweden and Ireland identified

6-13 fold increased risk of narcolepsy in children and adolescents post vaccination

3 - 7 excess cases/100,000 vaccinated

Added to the “Warnings” and “Undesirable Effects” of the Pandemrix EU Summary of Product Characteristics Restricted its use in persons < 20 years old

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Narcolepsy: General Information A disorder of sleep-wake control in which elements of

sleep intrude into wakefulness and elements of wakefulness intrude into sleep. Sleep maintenance insomnia is common Narcoleptics can be misdiagnosed as insomniacs

Manifests as daytime sleepiness with or without cataplexy – emotionally triggered, transient muscle weakness hypnagogic hallucinations sleep paralysis

Narcolepsy with cataplexy Estimated prevalence in the U.S. 25-50/100,000 persons1

Estimated incidence in the U.S. 0.74/100,000 person-years1

Typically diagnosed in teens and early twenties Narcolepsy may be triggered by immune activation and

has a strong HLA association (DQB1*0602)1

1Sleep. 2007;30 (1):13

77

Pharmacovigilance Plan

78


Passive surveillance (pre-pandemic and pandemic period) Routine data collection on all adverse event reports Global literature review, periodic distribution and

safety reports Disproportionality analysis (signal detection) –

monthly (pre-pandemic), weekly (pandemic) Close monitoring of the following AEs: Bell's palsy,

convulsion, demyelinating disorders, encephalitis, Guillain-Barré syndrome (GBS), neuritis, vasculitis, vaccination failure, narcolepsy, AIH and increased concentrations of transaminases.

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Active surveillance (during the pandemic period) Pandemic cohort safety study in one EU

country Data will be shared with U.S.

Pregnancy registry GSK has committed to working with the US

government to evaluate safety.

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Q-Pan H5N1 Summary Slide Proportion of subjects achieving seroconversion

and HI titers > 1:40 after 2 doses of Q-Pan-H5N1, 21 days apart Exceeds CBER’s suggested immunogenicity criteria

for accelerated approval of a pandemic vaccine. Significant local and systemic reactogenicity

Pain was the most frequent solicited event Transient, not requiring medical attention

Imbalance in reporting frequency of unsolicited AEs, SAEs, and AESI/pIMDs Significance of these imbalances are unclear due to

Rarity of events both in the studies and in the general population.

Size of the study populations

81

Thank you!

Q-Pan review team DVRPA management OVRR management OBE reviewers

82

Questions for the Committee

83

Questions for the Committee

1. Do the immunogenicity data support licensure of the Q-Pan H5N1 vaccine for use in adults at increased risk of exposure or during a pandemic?

Please vote yes or no

84

Discussion Topics for the Committee

2. Do the safety data support licensure of the Q-Pan H5N1 vaccine for use in adults at increased risk of exposure or during a pandemic?

Please vote yes or no

85

Discussion Topic for the Committee

Please discuss the following two approaches to confirm the effectiveness of Q-Pan H5N1 for “traditional” approval.

1. To confirm the clinical benefit of Q-Pan H5N1 with efficacy data generated with a US-licensed seasonal influenza virus vaccine made according to the same manufacturing process.

2. To confirm the clinical benefit of Q-Pan H5N1 by conducting an effectiveness study (or studies) during an H5N1 influenza virus pandemic.

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