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Tetanus Toxoid, Reduced Diphtheria

Toxoid and Acellular Pertussis

Vaccine, Adsorbed (BoostrixTM)

Ann T. Schwartz, MD

CBER, FDA

Vaccines and Related Biological Products

Advisory Committee Meeting

March

15, 2005

GlaxoSmithKline Biologicals

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Outline

Boostrix vs Infanrix

Basis for Licensure

Indication: single dose, 10-18 years

Immunogenicity Study Tdap/001

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 BOOSTRIX INFANRIX

Tetanus Toxoid

Diphtheria Toxoid

Pertussis Toxoid (PT)

Filamentous

Hemagglutinin (FHA)

Pertactin (PRN)

Aluminum

Preservative

5.0 Lf

2.5 Lf

8.0 g

8.0 g

2.5 g

0.3 mg

(as AlOH3)

None

10 Lf

25 Lf

25 g

25 g

8.0 g

< 0.625 mg

(as AlOH3)

2.5 mg 2-PE

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Basis for Licensure

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

Demonstration of non-inferiority of anti-tetanus and anti-diphtheria seroprotection andbooster response vs. Td

Demonstration of booster response topertussis antigens

Demonstration of serologic bridge to pertussisefficacy

Demonstrat ion o f lot -to-lo t con sis tency ofBoost r ix

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Pivotal Safety and Immunogenicity StudyTdap/001 Safety, immunogenicity and lot consistency

of Boostrix

Comparator vaccine: a U.S.-licensed Tdvaccine (Massachusetts Public Health

Biologic Laboratories)

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Tdap/001:

Primary Objectives

To demonstrate:

non-inferiority of Boostrix vs. Td wrt anti-D and anti-T seroprotection rates

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

anti-PT, anti-FHA and anti-PRN boosterresponses in vaccinees administered

Boostrix

non-inferiority of Boostrix vs. Td wrtGrade 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 twogroups 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 doseComponent Boostrix Td MPHBL

Tetanus toxoidDiphtheria toxoid

Pertussis toxoid (PT)

Filamentoushemagglutinin (FHA)Pertactin (PRN)

Aluminum

Preservative

5.0 Lf2.5 Lf

8.0 g

8.0 g2.5 g

0.3 mg(as AlOH3)

None

2.0 Lf2.0 Lf

--

----

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 bydiary card

Unsolicited adverse events

Recorded for 6 months post-vaccination Serious adverse events

Reported and recorded for 6 months post-

vaccination

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Tdap/001:

Overview of Study Procedures

10-18 years

Visit 1 Diary card Visit 2 Phone call

Bleed #1/

Vaccination Bleed #2 End study

Day 0 Day 14 Day 30 Month 6

Boostrix N = 3000

TdMPHBL N = 1000

Safety follow-up

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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

Mean age: 12.9 years 75.2% subjects 10-14 years of age 24.8% subjects 15-18 years

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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 Boosterresponse to diphtheria and tetanustoxoids one month post-vaccination

Seroprotection > 0.1 IU/mL

Booster response

Pre: < 0.1 IU/mL Post: > 0.4 IU/mL

Pre: > 0.1 IU/mL Post: Four-fold rise

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

AntigenBoostrix

N=2466-2471TdMPHBL

N=814-817

% (95% CI) % (95% CI)

Diphtheria 0.1 IU/mL 85.8 (84.3, 87.1) 84.8 (82.1, 87.2) 1.0 IU/mL 17.1 (15.6, 18.6) 19.5 (16.9, 22.4)Tetanus 0.1 IU/mL 97.7 (97.1, 98.3) 96.8 (95.4, 97.9)

1.0 IU/mL 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

anti-diphtheria%

0.1 IU/mL

UL 95% CI

10%

% booster UL 95% CI 10%anti-tetanus % 0.1 IU/mL UL 95% CI 10%

% booster UL 95% CI 10%

2-sided 95% CI

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Tdap/001: Differences in anti-diphtheriaresponse rates between Boostrix andTdMPHBL one month post vaccination

(ATP cohort for immunogenicity)

Endpoint Boostrix TdMPHBL Td - Boostrix

(95% CI)(%) (%) % 0.1 IU/mL 99.9 99.9 0.0 (-0.6, 0.3)**

Booster

response

90.6 95.9 5.3 (3.4, 7.0)**

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

Td /001 Diff i ti t t

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Endpoint Boostrix TdMPHBL Td- Boostrix

(95% CI)

(%) (%) % 0.1 IU/mL 100 100 0.0 (-0.4, 0.2)**

Boosterresponse

89.7 92.5 2.9 (0.6, 4.9)**

1.0 IU/mL 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

Tdap/001: Differences in anti-tetanusresponse rates between Boostrix andTdMPHBL one month post vaccination

(ATP cohort for immunogenicity)

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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 Post: > 20 EU/mL

Pre: > 5 EU/mL< 20 EU/mL Post: 4-fold rise

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

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Tdap/001: Primary Immunogenicity

Endpoints

(Boostrixpertussis antigens)

Antigens EndpointEvaluation criteria

LL of 2-sided 95% CIanti-PT % booster 80%anti-FHA % booster 80%anti-PRN % booster 80%

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Tdap/001: Booster response (BR) to pertussisantigens one month post-Boostrix in 10-18years old (ATP cohort for immunogenicity)

Antigen BR Rate (%) 95% CI

PT 84.5 (83.0, 85.8)**FHA

95.1 (94.2, 95.9)**

PRN95.4 (94.5, 96.1)**

Boostrix N = 2677 2752

**Primary endpoint met

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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 WHO-

defined 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 dataonly

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

Pertussisantigens

Endpoint(EU/mL)

RatioInfanrix/Boostrix

anti-PT GMC UL 95% CI < 1.5

anti-FHA GMC UL 95% CI < 1.5

anti-PRN GMC UL 95% CI < 1.5

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Ratios of GMCs between Boostrix andInfanrix one month post-vaccination (TVC)

Antigen Infanrix Boostrix Infanrix/ **Boostrix

N GMC* N GMC* Ratio (95% CI)anti-PT 2884 45.7 2941 86.9 0.53 (0.50,0.55)

anti-FHA 685 83.6 2979 614.8 0.14 (0.13,0.15)

anti-PRN 631 112.3 2978 470.7 0.24 (0.21,0.27)

* ELISA units / mL

** 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-INDstudies

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Tdap/001:

Safety

Primary Safety Endpoint

Non-inferiority of Boostrix vs. Td wrtGrade 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 Endpoint Boostrix-Td

Grade 3 pain* % UL 95% CI 4%

*Grade 3 pain = spontaneously painful and/or

prevented normal activity

Td /001 I id f P i ithi 15

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

Intensity Boostrix

%

TdMPHBL%

Boostrix Td

% (95% CI)Any 75.3 71.7 3.66 (0.55,6.89)

Grade >2 51.2 42.5 8.67 (5.13,12.17)

Grade 3 4.6 4.0 0.54 (-1.01, 1.87)

Any pain = painful on touchGrade 2 pain = painful when limb movedGrade 3 pain = spontaneously painful and/or prevented normal activity

non-inferiority criterion met (upper limit 95% CI on the difference 4%)

Td /001 I id f l l t

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Tdap/001: Incidence of local symptoms

in subjects 10-18 years within 72 hours of

vaccination (TVC)

Event Intensity Boostrix(%)

Td MPHBL(%)

Redness Any 21.9 19.5

> 20 mm 4.0 3.8> 50 mm 1.6 1.5

Swelling Any 20.2 19.8

> 20 mm 5.0 4.8

> 50 mm 2.4 3.2Increased armcircumference

>5 mm 21.4 23.2

> 20 mm 1.6 1.5

> 40 mm 0.3 0.3

Td /001 I id f li it d t i

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Tdap/001: Incidence of solicited systemicsymptoms within 15 days followingadministration of Boostrix or TdMPHBL (TVC)

Event Intensity Boostrix (%)N = 3030

Td MPHBL (%)N = 1013

Fever(oral/axillary)

> 37.5C 13.4 13.1

> 38C 5.0 4.7

> 39C 1.4 1.0

Headache

Any 43.1 41.5

Grade 2 15.7 12.7Grade 3 3.7 2.7

Fatigue

Any 37.0 36.7

Grade 2 14.4 12.9Grade 3 3.7 3.2

GISymptoms

Any 26.0 25.8

Grade 2 9.8 9.7Grade 3 3.0 3.2

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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 post-

vaccination

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Study Tdap/001: SAEs within 6 months post-vaccination with Boostrix or TdMPHBL

Wounds/fractures (4)

Overdose/drugabuse(3)

Depression/ADHD (2)

Cholecystitis (1)

Headache (1)

Spontaneous AB (1) Menorrhagia (1)

Sinusitis w/

migraine(1)

Pleural effusion withpneumothorax

status-post surgery

for repair of pectus

excavatum(1) Appendicitis (1/Td)

Tooth abscess (1/Td)

Td /001 P t f bj t (10 18

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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)

AE Type

Boostrix (%)

N = 3005

TdMPHBL (%)

N = 1003

n (%) n (%)Chronic illness 22 0.7 9 0.9

ER visit 101 3.4 25 2.5

Non-routinemedical visit

52 1.7 16 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 14 / F Alcohol

intoxication

21

Non-US

formulation

Boostrix

13 / M Syncope 28

11 / F Diabetic

hypoglycemia /

seizure

37

11 / F Diabetes 20

10 / F Appendicitis 23

12 / F LOC immediate

49 / F Uveitis 7

6 / F Polypectomy 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 supportthe efficacy of Boostrix in individuals 10-18years of age?

VOTE

2. Are the available data adequate to supportthe safety ofBoostrix when administered toindividuals 10-18 years of age?

VOTE

3. Please identify any issues which should beaddressed, including post-licensure studies.

Discussion