GlaxoSmithKline Biologicals

Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (BoostrixTM)
Vaccines and Related Biological Products Advisory Committee Meeting March 15, 2005
Ann T. Schwartz, MD CBER, FDA

Outline
Boostrix vs Infanrix Basis for Licensure

Indication: single dose, 10-18 years

Study Tdap/001

Immunogenicity

Bridge to Pertussis Efficacy Safety

Study Tdap/001 Eleven non-IND studies

Questions for the Committee

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Boostrix formulation per 0.5mL/dose comparison with Infanrix

COMPONENT Tetanus Toxoid Diphtheria Toxoid Pertussis Toxoid (PT) Filamentous Hemagglutinin (FHA) Pertactin (PRN) Aluminum BOOSTRIX INFANRIX 5.0 Lf 10 Lf 2.5 Lf 25 Lf 8.0 g 8.0 g 2.5 g 0.3 mg (as AlOH3) 25 g 25 g 8.0 g < 0.625 mg (as AlOH3)

Preservative

None

2.5 mg 2-PE

Basis for Licensure

Indication: 10-18 years, single dose booster
Demonstration of safety Demonstration of non-inferiority of anti-

tetanus and anti-diphtheria seroprotection and booster response vs. Td Demonstration of booster response to pertussis antigens Demonstration of serologic bridge to pertussis efficacy Demonstration of lot-to-lot consistency of Boostrix
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Pivotal Safety and Immunogenicity Study Tdap/001

Safety, immunogenicity and lot consistency

of Boostrix

Comparator vaccine: a U.S.-licensed Td

vaccine (Massachusetts Public Health Biologic Laboratories)

Tdap/001: Primary Objectives

To demonstrate:

non-inferiority of Boostrix vs. Td wrt antiD and anti-T seroprotection rates non-inferiority of Boostrix vs. Td wrt antiD and anti-T booster response rates

anti-PT, anti-FHA and anti-PRN booster responses in vaccinees administered Boostrix non-inferiority of Boostrix vs. Td wrt Grade 3 pain at the injection site
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Tdap/001: Study Design

Prospective, randomized, observer-blinded,

comparative multi-center study Adolescents 10-18 years of age Stratified by age before enrollment into two groups 10-14 years of age (N=3000) 15-18 years of age (N=1000) Randomized 1:1:1:1 to four groups: Boostrix lot 1 (N=1000) Boostrix lot 2 (N=1000) Boostrix lot 3 (N= 1000) TdMPHBL (N=1000)
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Tdap/001: Pertinent Inclusion / Exclusion Criteria

Completed routine childhood vaccinations

against diphtheria, tetanus and pertussis diseases (4 or 5 doses)

DTwP doses 1-3 DTwP or DTaP 4 and/or 5

At least 5 years since the receipt of the pre-

school dose of DTP

Subjects who had received a Td booster

within the previous 10 years were excluded

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Tdap/001: Study Vaccine Composition per 0.5mL dose

Component Tetanus toxoid Diphtheria toxoid Pertussis toxoid (PT) Filamentous hemagglutinin (FHA) Pertactin (PRN) Aluminum Preservative Boostrix 5.0 Lf 2.5 Lf 8.0 g Td MPHBL 2.0 Lf 2.0 Lf --

8.0 g 2.5 g
0.3 mg (as AlOH3) None

--0.45 mg (as AlPO4) Thimerosal

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Tdap/001: Safety surveillance and monitoring

Immediate reactions

30 minutes post-vaccination Solicited local and systemic adverse events 0-14 days post-vaccination collected by diary card Unsolicited adverse events Recorded for 6 months post-vaccination Serious adverse events Reported and recorded for 6 months postvaccination

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Tdap/001: Overview of Study Procedures

10-18 years Boostrix N = 3000

TdMPHBL N = 1000

Safety follow-up

Visit 1 Bleed #1/ Vaccination Day 0

Diary card

Visit 2 Bleed #2

Phone call End study Month 6

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Day 14

Day 30

Tdap/001: Populations for analysis

TVC for safety Vaccinated subjects with safety data TVC for immunogenicity Vaccinated subjects with serologic data ATP for immunogenicity Vaccinated subjects complying with protocol with serologic data
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Results

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Tdap/001: Demographics Total Vaccinated Cohort (N= 4114)

52.1% males and 47.9% females Ethnicity

85.7% Caucasian 5.6% African-Americans 5.7% Hispanics 0.8% Asians ~ 2% Other 75.2% subjects 10-14 years of age 24.8% subjects 15-18 years

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Mean age: 12.9 years

Tdap/001

IMMUNOGENICITY

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Tdap/001: Immunogenicity
Definitions, endpoints and results

Diphtheria and Tetanus toxoids Seroprotection Pre-vaccination Booster response Results Pertussis antigens Booster response Results Serologic Bridge to Infanrix pertussis antigens

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Tdap/001: Seroprotection and Booster response to diphtheria and tetanus

toxoids one month post-vaccination

Seroprotection
Booster response

> 0.1 IU/mL

Pre: < 0.1 IU/mL Pre: > 0.1 IU/mL

Post: > 0.4 IU/mL Post: Four-fold rise

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Tdap/001: Pre-vaccination anti-toxoid levels (ATP cohort for immunogenicity)

Boostrix

Antigen
Diphtheria 0.1 IU/mL 1.0 IU/mL Tetanus 0.1 IU/mL 1.0 IU/mL

N=2466-2471
% (95% CI)

N=814-817
% (95% CI)

TdMPHBL

85.8 (84.3, 87.1) 84.8 (82.1, 87.2) 17.1 (15.6, 18.6) 19.5 (16.9, 22.4) 97.7 (97.1, 98.3) 96.8 (95.4, 97.9) 36.8 (34.9, 38.7) 39.9 (36.5, 43.4)
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Tdap/001: Primary Immunogenicity Endpoints and Non-inferiority Criteria (Boostrix vs TdMPHBL)

Antigen Endpoint Td -Boostrix UL 95% CI 10%
UL 95% CI 10% UL 95% CI 10% UL 95% CI 10%

anti-diphtheria % 0.1 IU/mL

% booster anti-tetanus % 0.1 IU/mL % booster 2-sided 95% CI

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Tdap/001: Differences in anti-diphtheria response rates between Boostrix and TdMPHBL one month post vaccination (ATP cohort for immunogenicity)
Endpoint Boostrix (%) 99.9 90.6 TdMPHBL (%) 99.9 95.9 Td - Boostrix (95% CI) % 0.0 (-0.6, 0.3)** 5.3 (3.4, 7.0)**

0.1 IU/mL
Booster response 1.0 IU/mL

97.3

99.3

2.0 (1.0, 2.8)

Boostrix: N= 2463-2516, Td: N=814-834

** Non-inferiority criterion met Non-inferiority criteria were not pre-specified
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Tdap/001: Differences in anti-tetanus response rates between Boostrix and TdMPHBL one month post vaccination
(ATP cohort for immunogenicity)
Endpoint Boostrix TdMPHBL
(%) 100 89.7 (%) 100 92.5

0.1 IU/mL Booster response 1.0 IU/mL

Td - Boostrix (95% CI) % 0.0 (-0.4, 0.2)**

2.9 (0.6, 4.9)**

99.5

99.8

0.3 (-0.4, 0.7)

Boostrix: N= 2463-2516, Td: N=814-834

** Non-inferiority criterion met Non-inferiority criteria were not pre-specified
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Tdap/001: Booster response to pertussis components one month post- vaccination

Booster response to PT, FHA, PRN

Pre: < 5 EU/mL Pre: > 5 EU/mL< 20 EU/mL Pre: > 20 EU/mL

Post: > 20 EU/mL Post: 4-fold rise Post: > 2-fold rise

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Tdap/001: Primary Immunogenicity Endpoints (Boostrixpertussis antigens)

Evaluation criteria LL of 2-sided 95% CI

Antigens

Endpoint

anti-PT anti-FHA anti-PRN

% booster % booster % booster

80% 80% 80%

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Tdap/001: Booster response (BR) to pertussis antigens one month post-Boostrix in 10-18 years old (ATP cohort for immunogenicity)
Antigen PT BR Rate (%) 84.5 95% CI (83.0, 85.8)**

FHA
PRN
Boostrix N = 2677 2752 **Primary endpoint met

95.1
95.4

(94.2, 95.9)**
(94.5, 96.1)**

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Serologic bridge to pertussis efficacy study

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Serologic bridge to clinical efficacy Study:Tdap/001 and APV/039, APV/050

Non-inferiority to Infanrix, administered as a

3-dose primary series GMCs one month post Boostrix compared to GMCs one month after completing infant series with Infanrix

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Serologic bridge: APV-039 and APV-050

Study APV-039

Safety, immunogenicity and lot consistency study of Infanrix 3-dose series at 3, 4, and 5 months of age Pop. for household contact study APV-050 Study APV-050 Efficacy 89% (95% CI: 77- 95%) against WHOdefined pertussis > 21 days of paroxysmal cough with positive culture and/or serologic testing

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Serologic bridge: Testing of study samples

TVC of APV-039

Subjects who had serologic data for at least one pertussis antigen Majority had anti-PT toxoid serological data only APV-039 Serologic assays performed in 1994 Tdap/001 Serologic assays performed in 2003 Used same assays and same laboratory

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Endpoints for serologic bridge

Pertussis antigens anti-PT anti-FHA anti-PRN Endpoint (EU/mL) GMC GMC GMC Ratio Infanrix/Boostrix UL 95% CI < 1.5 UL 95% CI < 1.5 UL 95% CI < 1.5

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Ratios of GMCs between Boostrix and Infanrix one month post-vaccination (TVC)
Antigen Infanrix
N GMC*

Boostrix
N

Infanrix/ ** Boostrix
0.53 (0.50,0.55)

GMC* Ratio (95% CI)

anti-PT

2884 45.7 83.6

2941 86.9

anti-FHA 685
anti-PRN 631
* ELISA units / mL

2979 614.8 0.14 (0.13,0.15)

112.3 2978 470.7 0.24 (0.21,0.27)

** pre-specified non-inferiority criteria met

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Safety

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Overall Safety Database

3289 subjects, age 10-18 years, received a

single dose of Boostrix (Studies Tdap/001 and Tdap/029)

2163 additional subjects, 4-78 years of age,

analyzed for safety after receipt of a single dose of Tdap (0.5 mg Al) in eleven non-IND studies

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Tdap/001: Safety
Primary Safety Endpoint

Non-inferiority of Boostrix vs. Td wrt Grade 3 pain at the injection site Solicited local adverse events 72 hours and 15 days Solicited systemic adverse events 72 hours and 15 days Unsolicited adverse events Serious adverse events

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Tdap/001: Primary Safety Endpoint and Non-inferiority criterion

Event
Grade 3 pain*

Endpoint
%

Boostrix - Td
UL 95% CI 4%

*Grade 3 pain = spontaneously painful and/or prevented normal activity

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Tdap/001: Incidence of Pain within 15 days post-vaccination in subjects 10-18 years of age (TVC)
Intensity Boostrix TdMPHBL
% %

Boostrix Td
% (95% CI)

Any

75.3

71.7

3.66 (0.55,6.89)

Grade >2
Grade 3

51.2
4.6

42.5
4.0

8.67 (5.13,12.17)
0.54 (-1.01, 1.87)

Any pain = painful on touch Grade 2 pain = painful when limb moved Grade 3 pain = spontaneously painful and/or prevented normal activity non-inferiority criterion met (upper limit 95% CI on the difference 4%)
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Tdap/001: Incidence of local symptoms in subjects 10-18 years within 72 hours of vaccination (TVC)
Event Redness Intensity Any > 20 mm > 50 mm Any > 20 mm > 50 mm >5 mm > 20 mm > 40 mm Boostrix (%) 21.9 4.0 1.6 20.2 5.0 2.4 21.4 1.6 0.3 Td MPHBL (%) 19.5 3.8 1.5 19.8 4.8 3.2 23.2 1.5 0.3
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Swelling

Increased arm circumference

Tdap/001: Incidence of solicited systemic symptoms within 15 days following administration of Boostrix or TdMPHBL (TVC)
Event Intensity > 37.5C > 38C > 39C Any Grade 2 Grade 3 Any Grade 2 Grade 3 Any Grade 2 Grade 3 Boostrix (%) N = 3030 13.4 5.0 1.4 43.1 15.7 3.7 37.0 14.4 3.7 26.0 9.8 3.0 Td MPHBL (%) N = 1013 13.1 4.7 1.0 41.5 12.7 2.7 36.7 12.9 3.2 25.8 9.7 37 3.2

Fever
(oral/axillary)

Headache

Fatigue

GI Symptoms

Tdap/001: Occurrence of Serious Adverse events

Serious adverse events occurring during the

6 month post vaccination:

0.5% (15) events in the Boostrix group

0.2% (2) events in the TdMPHBL group

No SAEs reported during days 0-30 postvaccination

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Study Tdap/001: SAEs within 6 months postvaccination with Boostrix or TdMPHBL Wounds/fractures (4) Overdose/drug abuse(3) Depression/ADHD (2) Cholecystitis (1) Headache (1) Spontaneous AB (1) Menorrhagia (1)

Sinusitis w/ migraine(1) Pleural effusion with pneumothorax status-post surgery for repair of pectus excavatum(1) Appendicitis (1/Td) Tooth abscess (1/Td)

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Tdap/001: Percentage of subjects (10-18 years old) reporting AEs during the 5 month follow-up period by type (TVC)
Boostrix (%) N = 3005 n (%) 22 0.7 101
52

AE Type Chronic illness

TdMPHBL (%) N = 1003 n (%) 9 0.9 25

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ER visit
Non-routine medical visit

3.4
1.7

2.5
1.6

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Occurrence of Serious adverse events in eleven additional studies post-vaccination

Vaccine N= 2372 Age/Gender Event Onset (days)

Boostrix
Non-US formulation Boostrix

14 / F
13 / M 11 / F

Alcohol intoxication
Syncope Diabetic hypoglycemia / seizure Diabetes Appendicitis LOC Uveitis Polypectomy

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28 37

11 / F 10 / F 12 / F 49 / F 6/F

20 23 immediate 7 29
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Summary
Primary immunogenicity endpoints: all met Primary safety endpoint: met No unexpected adverse events or serious

safety concerns
Serologic Bridge: Non-inferiority criteria met

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Questions and discussion items for the committee

1. Are the available data adequate to support the efficacy of Boostrix in individuals 10-18 years of age? VOTE 2. Are the available data adequate to support the safety of Boostrix when administered to individuals 10-18 years of age? VOTE

3. Please identify any issues which should be addressed, including post-licensure studies. Discussion
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