Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed (Boostrix TM ) Ann T. Schwartz, MD CBER, FDA Vaccines and Related Biological.

Tetanus Toxoid, Reduced Diphtheria Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Toxoid and Acellular Pertussis Vaccine, Adsorbed (BoostrixVaccine, Adsorbed (BoostrixTMTM))

Ann T. Schwartz, MDAnn T. Schwartz, MD

CBER, FDACBER, FDA

Vaccines and Related Biological ProductsVaccines and Related Biological ProductsAdvisory Committee MeetingAdvisory Committee Meeting

March 15, 2005March 15, 2005

GlaxoSmithKline BiologicalsGlaxoSmithKline Biologicals

2

OutlineOutline Boostrix vs InfanrixBoostrix vs Infanrix Basis for Licensure Basis for Licensure

Indication: single dose, 10-18 yearsIndication: single dose, 10-18 years

ImmunogenicityImmunogenicity Study Tdap/001Study Tdap/001

Bridge to Pertussis Efficacy Bridge to Pertussis Efficacy

SafetySafety Study Tdap/001 Study Tdap/001 Eleven non-IND studiesEleven non-IND studies

Questions for the CommitteeQuestions for the Committee

3

Boostrix™ formulation per 0.5mL/dose Boostrix™ formulation per 0.5mL/dose comparison with Infanrix®comparison with Infanrix®

COMPONENTCOMPONENT BOOSTRIX™BOOSTRIX™ INFANRIX®INFANRIX®

Tetanus ToxoidTetanus ToxoidDiphtheria ToxoidDiphtheria Toxoid

Pertussis Toxoid (PT)Pertussis Toxoid (PT)Filamentous Filamentous Hemagglutinin (FHA)Hemagglutinin (FHA)Pertactin (PRN)Pertactin (PRN)

AluminumAluminum

PreservativePreservative

5.0 Lf5.0 Lf2.5 Lf2.5 Lf

8.0 µg8.0 µg

8.0 µg8.0 µg2.5 µg2.5 µg

0.3 mg 0.3 mg (as AlOH(as AlOH33))

NoneNone

10 Lf10 Lf25 Lf25 Lf

25 µg25 µg

25 µg25 µg8.0 µg8.0 µg

<< 0.625 mg 0.625 mg (as AlOH(as AlOH33))

2.5 mg 2-PE2.5 mg 2-PE

4

Basis for LicensureBasis for Licensure

Indication: 10-18 years, single dose boosterIndication: 10-18 years, single dose booster

Demonstration of safety Demonstration of safety Demonstration of non-inferiority of anti- Demonstration of non-inferiority of anti-

tetanus and anti-diphtheria seroprotection and tetanus and anti-diphtheria seroprotection and booster response vs. Tdbooster response vs. Td

Demonstration of booster response to Demonstration of booster response to pertussis antigenspertussis antigens

Demonstration of serologic bridge to pertussis Demonstration of serologic bridge to pertussis efficacyefficacy

Demonstration of lot-to-lot consistency ofDemonstration of lot-to-lot consistency of BoostrixBoostrix

5

Pivotal Safety and Pivotal Safety and Immunogenicity Study Tdap/001Immunogenicity Study Tdap/001

Safety, immunogenicity and lot consistency Safety, immunogenicity and lot consistency of Boostrixof Boostrix™™

Comparator vaccine: a U.S.-licensed Td Comparator vaccine: a U.S.-licensed Td vaccine (Massachusetts Public Health vaccine (Massachusetts Public Health Biologic Laboratories) Biologic Laboratories)

6

Tdap/001: Tdap/001: Primary ObjectivesPrimary Objectives To demonstrate: To demonstrate:

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

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

anti-PT, anti-FHA and anti-PRN booster anti-PT, anti-FHA and anti-PRN booster responses in vaccinees administered responses in vaccinees administered Boostrix™Boostrix™

non-inferiority of Boostrix™ vs. Td wrt non-inferiority of Boostrix™ vs. Td wrt Grade 3 pain at the injection siteGrade 3 pain at the injection site

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Tdap/001: Tdap/001: Study DesignStudy Design Prospective, randomized, observer-blinded, Prospective, randomized, observer-blinded,

comparative multi-center study comparative multi-center study Adolescents 10-18 years of ageAdolescents 10-18 years of age Stratified by age before enrollment into two groupsStratified by age before enrollment into two groups

10-14 years of age (N=3000)10-14 years of age (N=3000) 15-18 years of age (N=1000)15-18 years of age (N=1000)

Randomized 1:1:1:1 to four groups:Randomized 1:1:1:1 to four groups: BoostrixBoostrix™™ lot 1 (N=1000) lot 1 (N=1000) BoostrixBoostrix™™ lot 2 (N=1000) lot 2 (N=1000) BoostrixBoostrix™™ lot 3 (N= 1000) lot 3 (N= 1000) TdTdMPHBLMPHBL (N=1000) (N=1000)

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Tdap/001: Tdap/001: Pertinent Inclusion / Exclusion CriteriaPertinent Inclusion / Exclusion Criteria

Completed routine childhood vaccinations Completed routine childhood vaccinations against diphtheria, tetanus and pertussis against diphtheria, tetanus and pertussis diseases (4 or 5 doses)diseases (4 or 5 doses) DTwP doses 1-3DTwP doses 1-3 DTwP or DTaP 4 and/or 5DTwP or DTaP 4 and/or 5

At least 5 years since the receipt of the pre-At least 5 years since the receipt of the pre-school dose of DTP school dose of DTP

Subjects who had received a Td booster Subjects who had received a Td booster within the previous 10 years were excludedwithin the previous 10 years were excluded

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Tdap/001: Study Vaccine Composition per Tdap/001: Study Vaccine Composition per 0.5mL dose0.5mL dose

ComponentComponent BoostrixBoostrix™™ Td Td MPHBLMPHBL

Tetanus toxoidTetanus toxoidDiphtheria toxoidDiphtheria toxoid

Pertussis toxoid (PT)Pertussis toxoid (PT)Filamentous Filamentous hemagglutinin (FHA)hemagglutinin (FHA)Pertactin (PRN)Pertactin (PRN)

AluminumAluminum

PreservativePreservative

5.0 Lf5.0 Lf2.5 Lf2.5 Lf

8.0 8.0 µgµg

8.0 8.0 µgµg2.5 µg2.5 µg

0.3 mg 0.3 mg (as AlOH(as AlOH33))

NoneNone

2.0 Lf2.0 Lf2.0 Lf2.0 Lf

----

--------

0.45 mg 0.45 mg (as (as AlPOAlPO44))

Thimerosal Thimerosal

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Tdap/001:Tdap/001:Safety surveillance and monitoringSafety surveillance and monitoring

Immediate reactionsImmediate reactions 30 minutes post-vaccination30 minutes post-vaccination

Solicited local and systemic adverse events Solicited local and systemic adverse events 0-14 days post-vaccination collected by 0-14 days post-vaccination collected by

diary carddiary card Unsolicited adverse eventsUnsolicited adverse events

Recorded for 6 months post-vaccinationRecorded for 6 months post-vaccination Serious adverse eventsSerious adverse events

Reported and recorded for 6 months post-Reported and recorded for 6 months post-vaccinationvaccination

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Tdap/001:Tdap/001:Overview of Study ProceduresOverview of Study Procedures

10-18 years10-18 years

Visit 1Visit 1 Diary cardDiary card Visit 2Visit 2 Phone call Phone call

Bleed #1/ Bleed #1/

VaccinationVaccination Bleed #2Bleed #2 End studyEnd study

Day 0Day 0 Day 14Day 14 Day 30Day 30 Month 6Month 6

BoostrixBoostrix™™ N = 3000 N = 3000

TdTdMPHBLMPHBL N = 1000 N = 1000

Safety follow-Safety follow-upup

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Tdap/001:Tdap/001:Populations for analysisPopulations for analysis

TVC for safetyTVC for safety Vaccinated subjects with safety dataVaccinated subjects with safety data

TVC for immunogenicityTVC for immunogenicity Vaccinated subjects with serologic dataVaccinated subjects with serologic data

ATP for immunogenicityATP for immunogenicity Vaccinated subjects complying with Vaccinated subjects complying with

protocol with serologic dataprotocol with serologic data

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ResultsResults

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Tdap/001:Tdap/001:Demographics Total Vaccinated CohortDemographics Total Vaccinated Cohort(N= 4114)(N= 4114) 52.1% males and 47.9% females52.1% males and 47.9% females EthnicityEthnicity

85.7% Caucasian85.7% Caucasian 5.6% African-Americans 5.6% African-Americans 5.7% Hispanics5.7% Hispanics 0.8% Asians0.8% Asians ~ 2% Other ~ 2% Other

Mean age: 12.9 yearsMean age: 12.9 years 75.2% subjects 10-14 years of age 75.2% subjects 10-14 years of age 24.8% subjects 15-18 years24.8% subjects 15-18 years

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Tdap/001Tdap/001

IMMUNOGENICITY IMMUNOGENICITY

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Tdap/001:Tdap/001:ImmunogenicityImmunogenicity Definitions, endpoints and results Definitions, endpoints and results

Diphtheria and Tetanus toxoidsDiphtheria and Tetanus toxoids• Seroprotection Seroprotection • Pre-vaccinationPre-vaccination• Booster responseBooster response• ResultsResults

Pertussis antigensPertussis antigens• Booster responseBooster response• ResultsResults

Serologic Bridge to Infanrix pertussis antigensSerologic Bridge to Infanrix pertussis antigens

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Tdap/001: Seroprotection and Booster Tdap/001: Seroprotection and Booster response to diphtheria and tetanusresponse to diphtheria and tetanus toxoids one month post-vaccinationtoxoids one month post-vaccination

SeroprotectionSeroprotection >> 0.1 IU/mL 0.1 IU/mL

Booster responseBooster response

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

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

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

AntigenAntigenBoostrix™Boostrix™

N=2466-2471N=2466-2471TdTdMPHBLMPHBL

N=814-817N=814-817

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

DiphtheriaDiphtheria 0.1 IU/mL 0.1 IU/mL

85.8 (84.3, 87.1)85.8 (84.3, 87.1) 84.8 (82.1, 87.2)84.8 (82.1, 87.2)

1.0 IU/mL1.0 IU/mL 17.1 (15.6, 18.6)17.1 (15.6, 18.6) 19.5 (16.9, 22.4)19.5 (16.9, 22.4)

TetanusTetanus 0.1 IU/mL 0.1 IU/mL

97.7 (97.1, 98.3)97.7 (97.1, 98.3) 96.8 (95.4, 97.9)96.8 (95.4, 97.9)

1.0 IU/mL 1.0 IU/mL 36.8 (34.9, 38.7)36.8 (34.9, 38.7) 39.9 (36.5, 43.4)39.9 (36.5, 43.4)

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Tdap/001: Primary Immunogenicity Tdap/001: Primary Immunogenicity Endpoints and Non-inferiority Criteria Endpoints and Non-inferiority Criteria (Boostrix™ vs Td(Boostrix™ vs TdMPHBLMPHBL))

AntigenAntigen

EndpointEndpoint Td -Boostrix Td -Boostrix ™™

anti-diphtheriaanti-diphtheria % % 0.1 IU/mL 0.1 IU/mL UL 95% CI UL 95% CI

10%10%

% booster% booster UL 95% CI UL 95% CI

10%10%

anti-tetanusanti-tetanus % % 0.1 IU/mL 0.1 IU/mL UL 95% CI UL 95% CI

10%10%

% booster% booster UL 95% CI UL 95% CI

10%10%

2-sided 95% CI2-sided 95% CI

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Tdap/001: Differences in anti-diphtheria Tdap/001: Differences in anti-diphtheria response rates between Boostrix™ and response rates between Boostrix™ and TdTd

MPHBLMPHBL one month post vaccination one month post vaccination (ATP cohort for immunogenicity)(ATP cohort for immunogenicity)

EndpointEndpoint BoostrixBoostrix™™ TdTdMPHBLMPHBL Td - BoostrixTd - Boostrix™™ (95% CI)(95% CI)

(%)(%) (%)(%) %%

0.1 0.1 IU/mL IU/mL

99.999.9 99.999.9 0.0 (-0.6, 0.3)**0.0 (-0.6, 0.3)**

BoosterBoosterresponseresponse

90.690.6 95.995.9 5.3 (3.4, 7.0)**5.3 (3.4, 7.0)**

1.0 1.0 IU/mL IU/mL

97.397.3 99.399.3 2.0 (1.0, 2.8)2.0 (1.0, 2.8)§§Boostrix: N= 2463-2516, Td: N=814-834Boostrix: N= 2463-2516, Td: N=814-834** Non-inferiority criterion met** Non-inferiority criterion met

§ Non-inferiority criteria were not pre-specified§ Non-inferiority criteria were not pre-specified

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EndpointEndpoint Boostrix™Boostrix™ TdTdMPHBLMPHBL TdTd - Boostrix- Boostrix™™ (95% CI) (95% CI)

(%)(%) (%)(%) %%

0.1 IU/mL 0.1 IU/mL 100100 100100 0.0 (-0.4, 0.2)**0.0 (-0.4, 0.2)**

BoosterBoosterresponseresponse

89.789.7 92.592.5 2.9 (0.6, 4.9)**2.9 (0.6, 4.9)**

1.0 IU/mL 1.0 IU/mL 99.599.5 99.899.8 0.3 (-0.4, 0.7) 0.3 (-0.4, 0.7) §§

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

** Non-inferiority criterion met** Non-inferiority criterion met

§ Non-inferiority criteria were not pre-specified§ Non-inferiority criteria were not pre-specified

Tdap/001: Differences in anti-tetanus Tdap/001: Differences in anti-tetanus response rates between Boostrix™ and response rates between Boostrix™ and TdTd

MPHBLMPHBL one month post vaccination one month post vaccination (ATP cohort for immunogenicity)(ATP cohort for immunogenicity)

22

Tdap/001: Booster response to pertussis Tdap/001: Booster response to pertussis components one month post- components one month post- vaccinationvaccination

Booster response to PT, FHA, PRNBooster response to PT, FHA, PRN

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

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

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

23

Tdap/001: Primary Immunogenicity Tdap/001: Primary Immunogenicity Endpoints Endpoints (Boostrix(Boostrix™™pertussis antigens)pertussis antigens)

AntigensAntigens EndpointEndpoint Evaluation criteriaEvaluation criteria LL of 2-sided 95% CILL of 2-sided 95% CI

anti-PTanti-PT % booster% booster 80%80% anti-FHAanti-FHA % booster% booster 80%80% anti-PRNanti-PRN % booster% booster 80%80%

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

Antigen Antigen BR Rate (%)BR Rate (%) 95% CI95% CI

PT PT 84.584.5 (83.0, 85.8)**(83.0, 85.8)**

FHA FHA 95.195.1 (94.2, 95.9)**(94.2, 95.9)**

PRN PRN 95.495.4 (94.5, 96.1)**(94.5, 96.1)**

Boostrix™ N = 2677 – 2752Boostrix™ N = 2677 – 2752

**Primary endpoint met**Primary endpoint met

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Serologic bridge to pertussis efficacy study Serologic bridge to pertussis efficacy study

26

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

Non-inferiority to InfanrixNon-inferiority to Infanrix®®,, administered as a administered as a 3-dose primary series 3-dose primary series

GMCs one month post Boostrix compared GMCs one month post Boostrix compared to GMCs one month after completing infant to GMCs one month after completing infant series with Infanrixseries with Infanrix®®

27

Serologic bridge: APV-039 and APV-050Serologic bridge: APV-039 and APV-050

Study APV-039Study APV-039 Safety, immunogenicity and lot consistency Safety, immunogenicity and lot consistency

study of Infanrixstudy of Infanrix®® 3-dose series at 3, 4, and 5 months of age3-dose series at 3, 4, and 5 months of age Pop. for household contact study APV-050Pop. for household contact study APV-050

Study APV-050Study APV-050 Efficacy 89% (95% CI: 77- 95%) against WHO-Efficacy 89% (95% CI: 77- 95%) against WHO-

defined pertussisdefined pertussis• >> 21 days of paroxysmal cough with 21 days of paroxysmal cough with

positive culture and/or serologic testingpositive culture and/or serologic testing

28

Serologic bridge: Testing of study Serologic bridge: Testing of study samplessamples

TVC of APV-039 TVC of APV-039 Subjects who had serologic data for at least Subjects who had serologic data for at least

one pertussis antigenone pertussis antigen Majority had anti-PT toxoid serological data Majority had anti-PT toxoid serological data

onlyonly APV-039 Serologic assays performed in 1994APV-039 Serologic assays performed in 1994 Tdap/001 Serologic assays performed in 2003Tdap/001 Serologic assays performed in 2003

Used same assays and same laboratoryUsed same assays and same laboratory

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Endpoints for serologic bridgeEndpoints for serologic bridge

Pertussis Pertussis antigensantigens

EndpointEndpoint (EU/mL)(EU/mL)

RatioRatio InfanrixInfanrix®®/Boostrix/Boostrix™™

anti-PTanti-PT GMCGMC UL 95% CI < 1.5UL 95% CI < 1.5

anti-FHAanti-FHA GMCGMC UL 95% CI < 1.5UL 95% CI < 1.5

anti-PRNanti-PRN GMCGMC UL 95% CI < 1.5UL 95% CI < 1.5

30

Ratios of GMCs between Boostrix™ and Ratios of GMCs between Boostrix™ and Infanrix® one month post-vaccination (TVC)Infanrix® one month post-vaccination (TVC)

AntigenAntigen InfanrixInfanrix®® BoostrixBoostrix™™ Infanrix®/Infanrix®/ **** BoostrixBoostrix™™

NN GMC*GMC* NN GMC*GMC* Ratio (95% CI)Ratio (95% CI)

anti-PTanti-PT 28842884 45.745.7 29412941 86.986.9 0.53 (0.50,0.55)0.53 (0.50,0.55)

anti-FHAanti-FHA 685685 83.683.6 29792979 614.8614.8 0.14 (0.13,0.15)0.14 (0.13,0.15)

anti-PRNanti-PRN 631631 112.3112.3 29782978 470.7470.7 0.24 (0.21,0.27)0.24 (0.21,0.27)

* ELISA units / mL* ELISA units / mL

** pre-specified non-inferiority criteria met** pre-specified non-inferiority criteria met

31

SafetySafety

32

Overall Safety DatabaseOverall Safety Database

3289 subjects, age 10-18 years, received a 3289 subjects, age 10-18 years, received a single dose of Boostrixsingle dose of Boostrix™ (Studies Tdap/001 ™ (Studies Tdap/001 and Tdap/029)and Tdap/029)

2163 additional subjects, 4-78 years of age, 2163 additional subjects, 4-78 years of age, analyzed for safety after receipt of a single analyzed for safety after receipt of a single dose of Tdap (0.5 mg Al) in eleven non-IND dose of Tdap (0.5 mg Al) in eleven non-IND studiesstudies

33

Tdap/001:Tdap/001:SafetySafety

Primary Safety EndpointPrimary Safety Endpoint Non-inferiority of Boostrix™ vs. Td wrt Non-inferiority of Boostrix™ vs. Td wrt

Grade 3 pain at the injection siteGrade 3 pain at the injection site Solicited local adverse eventsSolicited local adverse events

72 hours and 15 days72 hours and 15 days Solicited systemic adverse eventsSolicited systemic adverse events

72 hours and 15 days72 hours and 15 days Unsolicited adverse eventsUnsolicited adverse events Serious adverse eventsSerious adverse events

34

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

Event Event EndpointEndpoint BoostrixBoostrix™™ -- TdTd

Grade 3 pain*Grade 3 pain* %% UL 95% CI UL 95% CI 4% 4%

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

35

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

IntensityIntensity BoostrixBoostrix™™%%

TdTdMPHBLMPHBL

%%

Boostrix – TdBoostrix – Td % (95% CI)% (95% CI)

AnyAny 75.375.3 71.771.7 3.66 (0.55,6.89)3.66 (0.55,6.89)

Grade Grade >>22 51.251.2 42.542.5 8.67 (5.13,12.17)8.67 (5.13,12.17)

Grade 3Grade 3 4.64.6 4.04.0 0.54 (-1.01, 1.87)§0.54 (-1.01, 1.87)§

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

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

36

Tdap/001: Incidence of local symptoms Tdap/001: Incidence of local symptoms in subjects 10-18 years within 72 hours of in subjects 10-18 years within 72 hours of vaccination (TVC)vaccination (TVC)

EventEvent IntensityIntensity BoostrixBoostrix™™ (%)(%)

Td Td MPHBL MPHBL

(%)(%)RednessRedness Any Any 21.921.9 19.519.5

> 20 mm> 20 mm 4.04.0 3.83.8>> 50 mm 50 mm 1.61.6 1.51.5

SwellingSwelling Any Any 20.220.2 19.819.8> 20 mm> 20 mm 5.05.0 4.84.8>> 50 mm 50 mm 2.42.4 3.23.2

Increased arm Increased arm circumferencecircumference

>5 mm >5 mm 21.421.4 23.223.2> 20 mm> 20 mm 1.61.6 1.51.5>> 40 mm 40 mm 0.30.3 0.30.3

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Tdap/001: Incidence of solicited systemic Tdap/001: Incidence of solicited systemic symptoms within 15 days following symptoms within 15 days following administration of Boostrixadministration of Boostrix™™ or Td or TdMPHBL MPHBL (TVC)(TVC)

EventEvent IntensityIntensity BoostrixBoostrix™ (%)™ (%)N = 3030N = 3030

Td Td MPHBL MPHBL (%)(%)N = 1013N = 1013

FeverFever(oral/axillary)(oral/axillary)

>> 37.5 37.5°C°C 13.413.4 13.113.1

> 38> 38°C°C 5.05.0 4.74.7

> 39> 39°C°C 1.41.4 1.01.0

HeadacheHeadacheAny Any 43.143.1 41.541.5

Grade Grade 22 15.715.7 12.712.7

Grade 3Grade 3 3.73.7 2.72.7

FatigueFatigueAny Any 37.037.0 36.736.7

Grade Grade 22 14.414.4 12.912.9

Grade 3Grade 3 3.73.7 3.23.2

GI GI SymptomsSymptoms

Any Any 26.026.0 25.825.8

Grade Grade 22 9.89.8 9.79.7

Grade 3Grade 3 3.03.0 3.23.2

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Tdap/001: Occurrence of Serious Tdap/001: Occurrence of Serious Adverse eventsAdverse events

Serious adverse events occurring during the Serious adverse events occurring during the

6 month post vaccination:6 month post vaccination: 0.5% (15) events in the Boostrix™ group 0.5% (15) events in the Boostrix™ group

0.2% (2) events in the Td0.2% (2) events in the TdMPHBLMPHBL group group

No SAEs reported during days 0-30 post-No SAEs reported during days 0-30 post-

vaccinationvaccination

39

Study Tdap/001: SAEs within 6 months post-Study Tdap/001: SAEs within 6 months post-vaccination with vaccination with Boostrix™ or TdBoostrix™ or Td

MPHBLMPHBL

Wounds/fractures (4)Wounds/fractures (4) Overdose/drug Overdose/drug

abuse(3)abuse(3) Depression/ADHD (2)Depression/ADHD (2) Cholecystitis (1)Cholecystitis (1) Headache (1)Headache (1) Spontaneous AB (1)Spontaneous AB (1) Menorrhagia (1)Menorrhagia (1)

Sinusitis w/ Sinusitis w/ migraine(1)migraine(1)

Pleural effusion with Pleural effusion with pneumothorax status-pneumothorax status-post surgery for post surgery for repair of pectus repair of pectus excavatum(1)excavatum(1)

Appendicitis (1/Td)Appendicitis (1/Td) Tooth abscess (1/Td)Tooth abscess (1/Td)

40

Tdap/001: Percentage of subjects (10-18 Tdap/001: Percentage of subjects (10-18 years old) reporting AEs during the 5 month years old) reporting AEs during the 5 month follow-up period by type (TVC)follow-up period by type (TVC)

AE TypeAE Type

BoostrixBoostrix™ (%)™ (%)

N = 3005N = 3005

TdTdMPHBL MPHBL (%)(%)

N = 1003N = 1003

nn (%)(%) nn (%)(%)

Chronic illnessChronic illness 2222 0.70.7 99 0.90.9

ER visitER visit 101101 3.43.4 2525 2.52.5

Non-routine Non-routine medical visitmedical visit

5252 1.71.7 1616 1.61.6

41

Occurrence of Serious adverse events in Occurrence of Serious adverse events in eleven additional studies post-vaccinationeleven additional studies post-vaccinationVaccine Vaccine

N= 2372N= 2372

Age/GenderAge/Gender EventEvent Onset Onset (days)(days)

BoostrixBoostrix™™ 14 / F14 / F Alcohol Alcohol intoxicationintoxication

2121

Non-USNon-US

formulationformulation

BoostrixBoostrix

13 / M13 / M SyncopeSyncope 2828

11 / F11 / F Diabetic Diabetic hypoglycemia / hypoglycemia / seizureseizure

3737

11 / F11 / F DiabetesDiabetes 2020

10 / F10 / F AppendicitisAppendicitis 2323

12 / F12 / F LOCLOC immediateimmediate

49 / F49 / F UveitisUveitis 77

6 / F6 / F PolypectomyPolypectomy 2929

42

SummarySummary

Primary immunogenicity endpoints: all met Primary immunogenicity endpoints: all met

Primary safety endpoint: metPrimary safety endpoint: met

No unexpected adverse events or serious No unexpected adverse events or serious

safety concernssafety concerns

Serologic Bridge: Non-inferiority criteria metSerologic Bridge: Non-inferiority criteria met

43

Questions and discussion items for the Questions and discussion items for the committeecommittee1. Are the available data adequate to support 1. Are the available data adequate to support the efficacy of Boostrix™ in individuals the efficacy of Boostrix™ in individuals 10-18 years of age? 10-18 years of age?

VOTEVOTE2. Are the available data adequate to support 2. Are the available data adequate to support the safety of the safety of Boostrix™ when administered to when administered to individuals 10-18 years of age?individuals 10-18 years of age?

VOTEVOTE

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

DiscussionDiscussion