c-1 pentacel ® diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated...

C-1

PENTACELPENTACEL®®

Diphtheria and Tetanus Toxoids and Acellular Pertussis Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and HaemophilusAdsorbed, Inactivated Poliovirus Vaccine and Haemophilus b b

Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined (DTaP-IPV/Hib Combined)(DTaP-IPV/Hib Combined)

Vaccine and Related Biological Products Vaccine and Related Biological Products Advisory CommitteeAdvisory Committee

January 25, 2007January 25, 2007

The vaccines business of sanofi-aventis GroupThe vaccines business of sanofi-aventis Group

C-2

PENTACEL - AgendaPENTACEL - Agenda

IntroductionIntroduction Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs

SafetySafety Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs

Immunogenicity Immunogenicity Michael Decker, MD, MPH Michael Decker, MD, MPH VP Scientific and Medical AffairsVP Scientific and Medical Affairs

Canadian Post-Marketing Canadian Post-Marketing EffectivenessEffectiveness

Scott Halperin, MDScott Halperin, MDProfessor of PediatricsProfessor of PediatricsDalhousie University, Halifax, CanadaDalhousie University, Halifax, Canada

US PerspectiveUS Perspective David Greenberg, MDDavid Greenberg, MDDirector Scientific and Medical AffairsDirector Scientific and Medical Affairs

ConclusionConclusion Luc Kuykens, MD, MPHLuc Kuykens, MD, MPHVP Regulatory AffairsVP Regulatory Affairs

C-3

PENTACEL: First Candidate DTaP-IPV-Hib PENTACEL: First Candidate DTaP-IPV-Hib Combination Vaccine in the USCombination Vaccine in the US

Unique Benefits for Entire Immunization CommunityUnique Benefits for Entire Immunization Community Patient BenefitsPatient Benefits

– Maximum shot reductionMaximum shot reduction

– Well established safety profile; 9 years exclusive useWell established safety profile; 9 years exclusive usein Canadain Canada

Health Care Provider BenefitsHealth Care Provider Benefits– Optimizes implementation of immunization recommendationsOptimizes implementation of immunization recommendations

– Simplifies administrationSimplifies administration

Public Health BenefitsPublic Health Benefits– May improve vaccination coverage rates and timelinessMay improve vaccination coverage rates and timeliness

– Improves combination vaccine supplyImproves combination vaccine supply

C-4

PENTACEL FormulationPENTACEL Formulation

QuadracelQuadracel PENTACELPENTACEL

Tetanus ToxoidTetanus Toxoid 5 Lf5 Lf 5 Lf5 Lf

Diphtheria ToxoidDiphtheria Toxoid 15 Lf15 Lf 15 Lf15 Lf

Pertussis ToxoidPertussis Toxoid 20 20 µgµg 20 20 µµgg

Filamentous HemagglutininFilamentous Hemagglutinin 20 20 µµgg 20 20 µµgg

Pertactin Pertactin 3 3 µµgg 3 3 µµgg

Fimbriae Types 2 and 3Fimbriae Types 2 and 3 5 5 µµgg 5 5 µµgg

IPV Types 1, 2, 3IPV Types 1, 2, 3 40, 8, 32 DAU40, 8, 32 DAU 40, 8, 32 DAU40, 8, 32 DAU

PRP-T (ActHIB)PRP-T (ActHIB) -- 10 10 µµgg

Adjuvant: 0.33 mg aluminum; Adjuvant: 0.33 mg aluminum; 0.6% v/v 0.6% v/v 2-phenoxyethanol2-phenoxyethanol

C-5

Vaccine FormulationVaccine Formulation

PENTACELPENTACEL DaptacelDaptacel AdacelAdacel

Tetanus ToxoidTetanus Toxoid 5 Lf5 Lf 5 Lf5 Lf 5 Lf5 Lf

Diphtheria ToxoidDiphtheria Toxoid 15 Lf15 Lf 15 Lf15 Lf 2 Lf2 Lf

5 Component Pertussis Antigens5 Component Pertussis Antigens

Pertussis ToxoidPertussis Toxoid 20 20 µµgg 10 10 µµgg 2.5 2.5 µµgg

Filamentous HemagglutininFilamentous Hemagglutinin 20 20 µµgg 5 5 µµgg 5 5 µµgg

Pertactin Pertactin 3 3 µµgg 3 3 µµgg 3 3 µµgg

Fimbriae Types 2 and 3Fimbriae Types 2 and 3 5 5 µµgg 5 5 µµgg 5 5 µµgg

IPV Types 1, 2, 3IPV Types 1, 2, 3 40, 8, 32 DAU40, 8, 32 DAU -- --

PRP-TPRP-T 10 10 µµgg -- --


C-6













C-7













C-8

Pertussis Antibody Levels vs ProtectionPertussis Antibody Levels vs Protection

Pattern of Antibodies*Pattern of Antibodies* Protective EfficacyProtective Efficacy††

FIMFIM PRNPRN PTPT %%

LowLow LowLow HighHigh 4646

HighHigh LowLow High or LowHigh or Low 7272

LowLow HighHigh High or LowHigh or Low 7575

HighHigh HighHigh High or LowHigh or Low 8585

*High (*High (>>5 units) or Low (0 to <5 units) levels of antibody before pertussis exposure.5 units) or Low (0 to <5 units) levels of antibody before pertussis exposure.††Efficacy against WHO-defined pertussis. Storsaeter et al. Efficacy against WHO-defined pertussis. Storsaeter et al. Vaccine.Vaccine. 1998;16:1907-16. 1998;16:1907-16.

C-9

PENTACEL Clinical Development ProgramPENTACEL Clinical Development Program

Demonstration of safety and immunogenicityDemonstration of safety and immunogenicity– Comparison to the standard of careComparison to the standard of care

– Comparison of 3 consistency lotsComparison of 3 consistency lots

– Concomitant administration of other Concomitant administration of other recommended vaccinesrecommended vaccines

– Comparison Comparison of a 4of a 4thth dose dose when administered at when administered at 15 to 16 vs 17 to 18 months of age15 to 16 vs 17 to 18 months of age

Immunogenicity of PENTACEL compared to Immunogenicity of PENTACEL compared to Daptacel Daptacel in the in the Sweden I Efficacy StudySweden I Efficacy Study

C-10

PENTACEL Clinical Studies for US LicensurePENTACEL Clinical Studies for US Licensure††

Total number of PENTACEL recipients: Total number of PENTACEL recipients: 71467146

StudyStudy PurposePurpose NN PENTACELPENTACEL

P3T06P3T06 PENTACEL vs Standard of Care (SC) PENTACEL vs Standard of Care (SC) (Daptacel, IPOL, ActHIB) (Daptacel, IPOL, ActHIB) 1939 1939 485 485

494-01494-01 Lot consistency, PENTACEL vs Lot consistency, PENTACEL vs Formulation Equivalent (FE) Formulation Equivalent (FE) (HCPDT, Poliovax, ActHIB)(HCPDT, Poliovax, ActHIB)

35383538 25062506

M5A07M5A07 Interaction with PrevnarInteraction with Prevnar(Infant Series)(Infant Series) 11661166 11661166

494-03494-03 Interaction with Prevnar, MMR and Interaction with Prevnar, MMR and Varivax vaccines (4Varivax vaccines (4thth Dose) Dose) 12071207 12071207

5A99085A9908 Administration at 15-16 vs 17-18Administration at 15-16 vs 17-18months of agemonths of age 17821782 17821782

††All subjects who received at least one doseAll subjects who received at least one dose

C-11

Composition of Studied VaccinesComposition of Studied Vaccines

Standard of Care (SC)Standard of Care (SC) Formulation Equivalent (FE)Formulation Equivalent (FE)

AntigenAntigen PENTACELPENTACEL DaptacelDaptacel IPOLIPOL ActHIBActHIB HCPDTHCPDT†† PoliovaxPoliovax ActHIBActHIB



PTPT 20 20 µµgg 10 10 µµgg 20 20 µµgg

FHAFHA 20 20 µµgg 5 5 µµgg 20 20 µµgg

PRNPRN 3 3 µµgg 3 3 µµgg 3 3 µµgg

FIM FIM 5 5 µµgg 5 5 µµgg 5 5 µµgg

Poliovirus Type 1Poliovirus Type 1 40 DAU40 DAU 40 DAU40 DAU 40 DAU40 DAU



PRP-TPRP-T 10 10 µµgg 10 10 µµgg 10 10 µµgg

††PENTACEL formulation componentPENTACEL formulation component

C-12

SafetySafety ImmunogenicityImmunogenicity††

StudyStudy PENTACELPENTACEL ControlControl PENTACELPENTACEL ControlControl

P3T06P3T06 485485 14541454 374374 11671167

494-01494-01 25062506 10321032 11361136 403403

494-03494-03 12071207 NANA 274274 NANA

M5A07M5A07 NANA NANA 886886 NANA

TotalTotal 41984198 24862486 26702670 15701570

Overall Summary (Infant Series): Overall Summary (Infant Series): Safety and Immunogenicity PopulationsSafety and Immunogenicity Populations

††Per-protocol populationPer-protocol population

C-13

SafetySafety ImmunogenicityImmunogenicity††

StudyStudy PENTACELPENTACEL ControlControl PENTACELPENTACEL ControlControl

P3T06P3T06 431431 418418 371371 349349

494-01494-01 18621862 739739 883883 291291

494-03494-03 958958 NANA 819819 NANA

5A99085A9908 17821782 NANA 735735 NANA

TotalTotal 50335033 11571157 28082808 640640

Overall Summary (4Overall Summary (4thth Dose): Dose): Safety and Immunogenicity PopulationsSafety and Immunogenicity Populations

††Per-protocol populationPer-protocol population

C-14

PENTACEL Key FindingsPENTACEL Key Findings

Comparable immunogenicity to standard of care Comparable immunogenicity to standard of care

Safety profile similar to separate vaccines Safety profile similar to separate vaccines

Can be given concomitantly with other Can be given concomitantly with other recommended vaccinesrecommended vaccines

In Canada, where PENTACEL was introduced in In Canada, where PENTACEL was introduced in 1997 and is used universally1997 and is used universally– Invasive Hib disease remains rareInvasive Hib disease remains rare

– Rates of pertussis have decreased among children Rates of pertussis have decreased among children aged 1-9 yearsaged 1-9 years

C-15









C-16

Safety ObjectivesSafety Objectives

Compare safety of PENTACEL against safety of Compare safety of PENTACEL against safety of control vaccinescontrol vaccines

Assess safety of PENTACEL with or without Assess safety of PENTACEL with or without other recommended vaccinesother recommended vaccines

Safety Population: defined as those who had at Safety Population: defined as those who had at least 1 scheduled dose of study vaccinesleast 1 scheduled dose of study vaccines

C-17

Infant Series and 4Infant Series and 4thth Dose: Safety Profile Dose: Safety Profile

Immediate Reactions Immediate Reactions

– 30 minutes post-vaccination30 minutes post-vaccination

Solicited Local and Systemic ReactionsSolicited Local and Systemic Reactions

Non-Serious Unsolicited Adverse EventsNon-Serious Unsolicited Adverse Events

Events of Special InterestEvents of Special Interest

Serious Adverse EventsSerious Adverse Events

C-18

Infant SeriesInfant Series: Immediate Reactions : Immediate Reactions

Controlled StudiesControlled StudiesNon-controlled Non-controlled

StudiesStudies

PENTACELPENTACEL494-01, P3T06494-01, P3T06

N=2293N=2293SCSC

N=418N=418FEFE

N=739N=739

PENTACELPENTACEL494-03, 5A9908494-03, 5A9908

N=2740N=2740

nn %% nn %% nn %% nn %%

Total participants with at Total participants with at least one reactionleast one reaction 11 <0.1<0.1 33 0.20.2 11 0.10.1 00 0.00.0

UrticariaUrticaria 11 <0.1<0.1 00 0.00.0 00 0.00.0 00 0.00.0

Allergic reactionAllergic reaction 00 0.00.0 11 0.10.1 00 0.00.0 00 0.00.0

CryingCrying 00 0.00.0 11 0.10.1 00 0.00.0 00 0.00.0

ErythemaErythema 00 0.00.0 11 0.10.1 00 0.00.0 00 0.00.0

DiarrheaDiarrhea 00 0.00.0 00 0.00.0 11 0.10.1 00 0.00.0

IrritabilityIrritability 00 0.00.0 11 0.10.1 00 0.00.0 00 0.00.0

C-19

44thth Dose: Dose: Immediate ReactionsImmediate Reactions

Controlled StudiesControlled StudiesNon-controlled Non-controlled

StudiesStudies


N=2293N=2293SCSC

N=418N=418FEFE

N=739N=739

PENTACELPENTACEL494-03, 5A9908494-03, 5A9908

N=2740N=2740

nn %% nn %% nn %% nn %%

Total participants with at least one reaction 22 0.10.1 11 0.20.2 00 0.00.0 3131 1.11.1

Injection site erythemaInjection site erythema 22 0.10.1 00 0.00.0 00 0.00.0 2424 0.90.9

Injection site bruisingInjection site bruising 00 0.00.0 00 0.00.0 00 0.00.0 22 0.10.1

Injection site burningInjection site burning 00 0.00.0 00 0.00.0 00 0.00.0 11 <0.1<0.1

Injection site indurationInjection site induration 00 0.00.0 11 0.20.2 00 0.00.0 11 <0.1<0.1

Injection site irritationInjection site irritation 00 0.00.0 00 0.00.0 00 0.00.0 11 <0.1<0.1

Local edema upper limbLocal edema upper limb 00 0.00.0 00 0.00.0 00 0.00.0 11 <0.1<0.1

DermatitisDermatitis 00 0.00.0 00 0.00.0 00 0.00.0 11 <0.1<0.1

Mottled skinMottled skin 00 0.00.0 00 0.00.0 00 0.00.0 11 <0.1<0.1

UrticariaUrticaria 00 0.00.0 00 0.00.0 00 0.00.0 11 <0.1<0.1

NasopharyngitisNasopharyngitis 00 0.00.0 00 0.00.0 00 0.00.0 11 <0.1<0.1

TremorTremor 00 0.00.0 00 0.00.0 00 0.00.0 11 <0.1<0.1

C-20



Solicited Local Solicited Local and Systemicand Systemic Reactions Reactions

– Redness, swelling, tenderness, and change in limb Redness, swelling, tenderness, and change in limb circumference (4circumference (4thth dose, only) collected on diary cards, dose, only) collected on diary cards,days 0-7, severity documenteddays 0-7, severity documented




C-21

Infant Series:Infant Series: Solicited Local Reactions After Solicited Local Reactions After PENTACEL, Days 0-7, Any DosePENTACEL, Days 0-7, Any Dose

00

2020

4040

6060

8080

100100

00 11 22 33 44 55 66 77

DaysDays

Per

cen

tP

erce

nt

RednessRedness SwellingSwelling TendernessTenderness

C-22

44thth Dose: Dose: Solicited Local Reactions After Solicited Local Reactions After PENTACEL, Days 0-7PENTACEL, Days 0-7

00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

00 11 22 33 44 55 66 77

DaysDays

RednessRedness SwellingSwelling TendernessTenderness

C-23

Infant Series: Solicited Local Reactions After Infant Series: Solicited Local Reactions After PENTACEL, Days 0-3PENTACEL, Days 0-3, by Dose, by Dose

TendernessTendernessSwellingSwellingRednessRedness

AnyAny 5.7 5.7 4.8 4.8 4.8 4.8 5.6 5.6 3.8 3.8 2.8 2.8 44.2 44.2 36.4 36.4 37.4 37.4

MildMild 3.9 3.9 4.0 4.0 3.9 3.9 3.2 3.2 2.8 2.8 2.1 2.1 25.6 25.6 26.2 26.2 27.3 27.3

ModerateModerate 1.4 1.4 0.6 0.6 0.9 0.9 1.8 1.8 0.8 0.8 0.7 0.7 14.0 14.0 7.9 7.9 8.3 8.3

SevereSevere 0.4 0.4 0.1 0.1 0.1 0.1 0.5 0.5 0.2 0.2 0.0 0.0 4.6 4.6 2.2 2.2 1.9 1.9

5.7 4.8 4.8 5.6 3.8 2.8

44.236.4 37.4

0

20

40

60

80

100

Dose 1

Pe

rce

nt

Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3

Mild Moderate Severe

C-24

Infant Series: Solicited Local Swelling, Infant Series: Solicited Local Swelling, Days 0-3, Comparison to ControlsDays 0-3, Comparison to Controls†† by Dose by Dose

††Percentages are based on the most severe reaction at any of the vaccination sites for the individual control vaccinesPercentages are based on the most severe reaction at any of the vaccination sites for the individual control vaccines

10

20

30

40

50

Per

cen

t

Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3


SCSC

Controlled StudiesControlled Studies

0

AnyAny 5.35.3 3.93.9 2.72.7 6.06.0 5.25.2 7.87.8 7.17.1 4.04.0 3.33.3 6.5 6.5 3.3 3.3 3.13.1

MildMild 3.23.2 3.13.1 2.02.0 3.63.6 4.34.3 6.56.5 5.85.8 3.43.4 3.03.0 3.33.3 2.12.1 2.32.3

ModerateModerate 1.61.6 0.80.8 0.70.7 2.02.0 0.90.9 1.21.2 1.21.2 0.50.5 0.30.3 2.42.4 0.60.6 0.70.7

SevereSevere 0.40.4 0.00.0 0.00.0 0.40.4 0.10.1 0.10.1 0.10.1 0.10.1 0.00.0 0.80.8 0.50.5 0.10.1

3.13.13.3 3.3 6.5 6.5

3.33.34.04.07.17.17.87.8

5.25.26.06.02.72.73.93.9

5.35.3

PENTACELPENTACEL494-03494-03

FEFE


C-25

44thth Dose: Solicited Local Swelling, Dose: Solicited Local Swelling, Days 0-3, Comparison to ControlsDays 0-3, Comparison to Controls††

PENTACEL 494-01, P3T06

SC FE PENTACEL 494-03, 5A9908

0

10

20

30

40

50

Per

cen

t



AnyAny 11.311.3 11.611.6 13.913.9 16.016.0

MildMild 6.96.9 7.77.7 9.29.2 6.66.6

ModerateModerate 3.23.2 2.62.6 3.53.5 7.97.9

SevereSevere 1.21.2 1.31.3 1.31.3 1.61.6

16.016.013.913.9

11.611.611.311.3


C-26

44thth Dose: Change in Limb Circumference, Dose: Change in Limb Circumference,Days 0-3, Comparison to ControlDays 0-3, Comparison to Control††


SC HCPDT PENTACEL 494-03, 5A9908

0

10

20

30

40

50

Per

cen

t



AnyAny 27.027.0 37.537.5 21.721.7 34.434.4

MildMild 22.322.3 28.228.2 18.518.5 26.626.6


SevereSevere 0.30.3 1.11.1 0.00.0 0.80.8

34.434.4

21.721.7

37.537.5

27.027.0


C-27



Solicited Solicited Local andLocal and Systemic Reactions Systemic Reactions

– Fever, less active, crying, fussiness, vomiting, diarrhea, Fever, less active, crying, fussiness, vomiting, diarrhea, anorexia and rash (presence or absence) collected on diary anorexia and rash (presence or absence) collected on diary cards, days 0-7, severity documented cards, days 0-7, severity documented




C-28

Infant Series: Solicited Fever After Infant Series: Solicited Fever After PENTACEL, Day 0-7PENTACEL, Day 0-7, Any Dose, Any Dose

0

10

20

30

40

50

0 1 2 3 4 5 6 7

Days

Per

cen

t

Fever

C-29

Infant Series: Solicited Fever, Days 0-3, Infant Series: Solicited Fever, Days 0-3, Comparison to Controls by DoseComparison to Controls by Dose

10

20

30

40

50

Per

cen

t

0



SCSC FEFE PENTACELPENTACEL494-03494-03


AnyAny 7.77.7 13.713.7 18.718.7 9.39.3 16.116.1 15.815.8 13.813.8 15.715.7 20.620.6 11.5 11.5 16.5 16.5 18.418.4

MildMild 6.26.2 10.410.4 12.912.9 7.77.7 11.811.8 10.710.7 11.511.5 10.810.8 16.016.0 10.010.0 12.712.7 13.913.9

ModerateModerate 1.11.1 3.13.1 5.15.1 1.51.5 3.93.9 4.84.8 2.22.2 4.34.3 3.93.9 1.51.5 3.43.4 4.04.0

SevereSevere 0.40.4 0.20.2 0.70.7 0.10.1 0.40.4 0.30.3 0.10.1 0.60.6 0.70.7 0.00.0 0.40.4 0.50.5

Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3 Dose 1 Dose 2 Dose 3

18.418.416.5 16.5

11.5 11.5

20.620.6

15.715.713.813.8

15.815.816.116.1

9.39.3

18.718.7

13.713.7

7.77.7

PENTACELPENTACEL494-03494-03

C-30

Infant Series: Infant Series: Non-Inferiority of Fever Non-Inferiority of Fever Rates, Rates, Days 0-3, Days 0-3, 90% CI of Difference (PENTACEL minus Control) by Dose90% CI of Difference (PENTACEL minus Control) by Dose

Within LimitWithin Limit Outside LimitOutside Limit

-10-10 -8-8 00 1010 1212 1414-2-2 22 44-4-4-6-6 66 88

P3T06P3T06

1st Dose1st Dose-3.49-3.49

3rd Dose3rd Dose0.560.56

2nd Dose2nd Dose-5.26-5.26

494-01494-01

-1.40-1.402nd Dose2nd Dose

-1.33-1.333rd Dose3rd Dose

1st Dose1st Dose-5.70-5.70

C-31

44thth Dose: Solicited Fever After PENTACEL, Dose: Solicited Fever After PENTACEL, Days 0-7 Days 0-7

0

10

20

30

40

50

0 1 2 3 4 5 6 7

Days

Per

cen

t

Fever

C-32

44thth Dose: Solicited Fever, Days 0-3, Dose: Solicited Fever, Days 0-3,Comparison to ControlsComparison to Controls


SC FE PENTACEL 494-03, 5A9908

0

10

20

30

40

50

Per

cen

t


AnyAny 11.211.2 8.78.7 13.113.1 14.514.5

MildMild 8.18.1 5.55.5 9.19.1 9.39.3


SevereSevere 0.60.6 0.80.8 0.50.5 0.80.8

14.514.513.113.1

8.78.711.211.2


C-33

44thth Dose: Dose: Non-Inferiority of Fever Non-Inferiority of Fever Rates, Rates, Days 0-3, Days 0-3, 90% CI of Difference (PENTACEL minus Control)90% CI of Difference (PENTACEL minus Control)

Within LimitWithin Limit Outside LimitOutside Limit

-10-10 -8-8 00 1010 1212 1414-2-2 22 44-4-4-6-6 66 88

494-01494-01-2.42-2.42

P3T06P3T064.664.66

C-34


Immediate ReactionsImmediate Reactions



– Any non-serious Any non-serious unsolicited unsolicited event, event, days 0-7, days 0-7, severity documentedseverity documented

– Any non-seriousAny non-serious event requiring healthcare provider event requiring healthcare provider contact,contact, days 8-60, severity documented days 8-60, severity documented



C-35

Infant Series and 4Infant Series and 4thth Dose: Dose: Non-serious Non-serious Unsolicited Adverse EventsUnsolicited Adverse Events

No difference in rates between PENTACEL No difference in rates between PENTACEL and control groups for frequently reported and control groups for frequently reported and rare eventsand rare events

Most events were common childhood Most events were common childhood conditions such as URI, otitis media, teething conditions such as URI, otitis media, teething and nasal congestionand nasal congestion

Majority assessed as non-related by Majority assessed as non-related by the investigatorsthe investigators

C-36






– Hypotonic-hyporesponsive episode (HHE), hypotonia, Hypotonic-hyporesponsive episode (HHE), hypotonia, non-febrile seizure, febrile seizure, and possible seizure non-febrile seizure, febrile seizure, and possible seizure collected days 0-60, severity documentedcollected days 0-60, severity documented


C-37

Infant Series: Events of Special Interest, Infant Series: Events of Special Interest, Days 0-7, Comparison to Controls After Any DoseDays 0-7, Comparison to Controls After Any Dose

P3T06P3T06 494-01494-01 494-03494-03

PENTACELPENTACELN=485N=485

StandardStandardof Careof CareN=1454N=1454


Formulation Formulation EquivalentEquivalent

N=1032N=1032PENTACELPENTACEL

N=1207N=1207

nn %% nn %% nn %% nn %% nn %%

HHEHHE 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0

HypotoniaHypotonia 00 0.00.0 11 0.10.1 33 0.10.1 00 0.00.0 11 0.10.1

Non-Febrile SeizureNon-Febrile Seizure 00 0.00.0 11 0.10.1 11 <0.1<0.1 11 0.10.1 00 0.00.0

Febrile SeizureFebrile Seizure 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0

Possible SeizurePossible Seizure 00 0.00.0 00 0.00.0 11 <0.1<0.1 00 0.00.0 00 0.00.0

C-38

44thth Dose Dose: : Events of Special Interest, Events of Special Interest, Days 0-7, Comparison to ControlDays 0-7, Comparison to Control

P3T06P3T06 494-01494-01 494-03494-03 5A99085A9908


Standard Standard of Careof CareN=418N=418





N=1782N=1782

nn %% nn %% nn %% nn %% nn %% nn %%

HHEHHE 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0

HypotoniaHypotonia 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0

Non-Febrile Non-Febrile SeizureSeizure 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0

Febrile SeizureFebrile Seizure 00 0.00.0 00 0.00.0 00 0.00.0 22 0.30.3 00 0.00.0 22 0.10.1

Possible SeizurePossible Seizure 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0 00 0.00.0

C-39







– Any serious adverse event during the study through Day 60 Any serious adverse event during the study through Day 60 post-dose 3 or post-dose 4 (Day 180 for P3T06), post-dose 3 or post-dose 4 (Day 180 for P3T06), severity documentedseverity documented

C-40

Infant Series: Serious Adverse Events, Infant Series: Serious Adverse Events, Days 0-60, Comparison to Control After Any DoseDays 0-60, Comparison to Control After Any Dose

P3T06P3T06 494-01494-01 494-03494-03






N=1207N=1207

nn %% nn %% nn %% nn %% nn %%

Total participants with at least one SAE 2525 5.25.2 7575 5.25.2 3838 1.51.5 1717 1.61.6 4949 4.14.1

Total participants with at least one related SAE elated SAE

00 0.00.0 11 0.10.1 00 0.00.0 00 0.00.0 00 0.00.0

C-41

Infant Series: Related Serious Adverse Events Infant Series: Related Serious Adverse Events After Any DoseAfter Any Dose

No SAEs were reported as related to PENTACELNo SAEs were reported as related to PENTACEL

A 7-week-old female (Study P3T06) experienced non-A 7-week-old female (Study P3T06) experienced non-febrile seizure with apnea 12 hours post-Dose 1 of febrile seizure with apnea 12 hours post-Dose 1 of Daptacel, ActHIB, IPOL. Recombivax and Prevnar were Daptacel, ActHIB, IPOL. Recombivax and Prevnar were co-administered. The event was considered probably co-administered. The event was considered probably related to vaccinationrelated to vaccination

C-42

Infant Series: DeathsInfant Series: Deaths

A total of 3 deaths occurred during the Infant Series:A total of 3 deaths occurred during the Infant Series:– A 2-month-old female (Study 494-03, PENTACEL) died following A 2-month-old female (Study 494-03, PENTACEL) died following

an automobile accident, 22 days post-Dose 1an automobile accident, 22 days post-Dose 1

– A 4-month-old male (Study 494-03, PENTACEL) died 52 days A 4-month-old male (Study 494-03, PENTACEL) died 52 days post-Dose 1. Cause of death reported as Sudden Infant post-Dose 1. Cause of death reported as Sudden Infant Death SyndromeDeath Syndrome

– An 8-month-old female (Study P3T06, SC) developed symptoms An 8-month-old female (Study P3T06, SC) developed symptoms 54 days post-Dose 3 and was diagnosed with ependymoma. 54 days post-Dose 3 and was diagnosed with ependymoma. Death occurred 222 days post-Dose 3; primary cause of death Death occurred 222 days post-Dose 3; primary cause of death reported as aspirationreported as aspiration

All deaths were considered unrelated to vaccinationAll deaths were considered unrelated to vaccination

C-43

44thth Dose: Serious Adverse EventsDose: Serious Adverse Events

P3T06P3T06 494-01494-01 494-03494-03 5A99085A9908




FormulationFormulationEquivalentEquivalent



N=1782N=1782

nn %% nn %% nn %% nn %% nn %% nn %%

0-60 days0-60 days 99 2.12.1 77 1.71.7 77 0.40.4 44 0.50.5 1111 1.11.1 2929 1.61.6

61-180 days61-180 days 99†† 2.12.1 22 0.50.5 NANA NANA NANA NANA

No SAEs were reported as related to PENTACEL or No SAEs were reported as related to PENTACEL or Control vaccinesControl vaccines

††Upper respiratory infections (3), congenital malformations (2), reaction to antibiotic, Upper respiratory infections (3), congenital malformations (2), reaction to antibiotic, reaction to insect bite, post-infection cerebellar ataxia, seizurereaction to insect bite, post-infection cerebellar ataxia, seizure

C-44

44thth Dose: Deaths Dose: Deaths

One death occurred after Day 60 of the Infant Series One death occurred after Day 60 of the Infant Series and before the administration of the 4and before the administration of the 4thth dose dose– A 9-month-old male (Study 494-01, PENTACEL) developed A 9-month-old male (Study 494-01, PENTACEL) developed

symptoms 95 days post-Dose 3. Subject was later diagnosed symptoms 95 days post-Dose 3. Subject was later diagnosed with neuroblastoma, which eventually led to death 256 days with neuroblastoma, which eventually led to death 256 days post-Dose 3post-Dose 3

One death occurred after administration of the 4th doseOne death occurred after administration of the 4th dose– A 15-month-old male (Study P3T06, PENTACEL) died 9 days A 15-month-old male (Study P3T06, PENTACEL) died 9 days

post-Dose 4. Cause of death reported as suffocationpost-Dose 4. Cause of death reported as suffocation

Both deaths were considered unrelated to vaccinationBoth deaths were considered unrelated to vaccination

C-45

Canadian Canadian Post-Marketing Safety Post-Marketing Safety

Experience with PENTACEL Experience with PENTACEL

C-46

Canadian Post-Marketing Safety Experience Canadian Post-Marketing Safety Experience

Introduced in May 1997, exclusively used Introduced in May 1997, exclusively used since 1998since 1998

More than 12 million doses distributedMore than 12 million doses distributed

Similar dosing schedule as proposed for USSimilar dosing schedule as proposed for US

Passive surveillance data from spontaneous Passive surveillance data from spontaneous reports to sanofi pasteurreports to sanofi pasteur

C-47

Canadian Post-Marketing Safety Experience: Canadian Post-Marketing Safety Experience: Reported Events Reported Events

288 reports received from May 1997 through 288 reports received from May 1997 through April 2006April 2006– 221 were non-serious221 were non-serious

Most commonly reported adverse events were Most commonly reported adverse events were injection site reactions injection site reactions

C-48

Post-marketing Experience: Most Frequently Reported Post-marketing Experience: Most Frequently Reported Adverse Events Following PENTACEL VaccinationAdverse Events Following PENTACEL Vaccination

MedDRA AE Preferred TermMedDRA AE Preferred Term11 Number of AEs Number of AEs 22

Injection site reactionInjection site reaction 6565

PyrexiaPyrexia 6464

CryingCrying 5151

Injection site inflammationInjection site inflammation 3535

IrritabilityIrritability 3131

UrticariaUrticaria 2525

VomitingVomiting 2424

RashRash 2020

ConvulsionConvulsion33 1919

Injection site massInjection site mass 1616

1MedDRA coding dictionary version 9.02AE: adverse event. Includes both medically-confirmed and consumer cases3Includes MedDRA PT terms of Convulsion, Febrile convulsion, Status epilepticus and Convulsion local

C-49

Distribution of Spontaneously Reported Events Distribution of Spontaneously Reported Events of Special Interest*of Special Interest*

Total reports Total reports received received

N=288**N=288**

Post-Post-Dose 1Dose 1




Post-Post-Any DoseAny Dose

nn nn nn nn nn

HHEsHHEs1,41,4 88 44 00 00 1212

All SeizuresAll Seizures2,42,4 33 66 22 88 1919

Febrile SeizuresFebrile Seizures44 00 00 00 22 22

EncephalopathyEncephalopathy44 11 11 00 11 33

Fatal ReportsFatal Reports3,43,4 1010 11 00 33 1414

* For the period 1 May 1997 and 30 April 2006.**Medically-confirmed and consumer reports1Reported as HHE, or where the symptoms reported corresponded to the definition used for an HHE2MedDRA PT terms of Convulsion, Febrile convulsion, Status epilepticus and Convulsion local3Includes SIDS, Death Due to Unknown cause, and Death Due to Known Cause4For instances where dose information was not provided, the dose number was assumed based on the patient’s age and the latency to the event.

C-50

Safety ConclusionsSafety Conclusions

Safety profile of PENTACEL is similar to that of the Safety profile of PENTACEL is similar to that of the separate administration of standard of care vaccines separate administration of standard of care vaccines (Daptacel, IPOL, and ActHIB) or formulation-equivalent (Daptacel, IPOL, and ActHIB) or formulation-equivalent component vaccines (HCPDT, Poliovax, and ActHIB) component vaccines (HCPDT, Poliovax, and ActHIB)

PENTACEL is safe when administered alone or PENTACEL is safe when administered alone or concomitantly with other age-recommended vaccinesconcomitantly with other age-recommended vaccines

No unexpected safety signals were identified in the No unexpected safety signals were identified in the Canadian post-marketing safety experience, which Canadian post-marketing safety experience, which confirms conclusions from clinical trialsconfirms conclusions from clinical trials

C-51









C-52

Immunological Endpoints and AnalysesImmunological Endpoints and Analyses

Geometric Mean Titers (GMT)Geometric Mean Titers (GMT)– A primary endpoint for all antigensA primary endpoint for all antigens

4-Fold Rise (from pre-Dose 1)4-Fold Rise (from pre-Dose 1)– A primary endpoint for pertussis antigensA primary endpoint for pertussis antigens

Seroprotection (Seroprotection (post-Dose threshold)post-Dose threshold)– A primary endpoint for Diphtheria, Tetanus, Hib, PolioA primary endpoint for Diphtheria, Tetanus, Hib, Polio

Vaccine Response (Vaccine Response (cutoff point and cutoff point and baseline)baseline)– All pertussis antigensAll pertussis antigens

Reverse Cumulative Distribution Curves (RCDC)Reverse Cumulative Distribution Curves (RCDC)– All antigensAll antigens

Serological bridge to efficacySerological bridge to efficacy– All pertussis antigensAll pertussis antigens

C-53

Immunogenicity Presentation Sequence Immunogenicity Presentation Sequence

Pertussis ImmunogenicityPertussis Immunogenicity

Hib (PRP) ImmunogenicityHib (PRP) Immunogenicity

Diphtheria and Tetanus ImmunogenicityDiphtheria and Tetanus Immunogenicity

Polio ImmunogenicityPolio Immunogenicity

Co-Administration with Other Licensed VaccinesCo-Administration with Other Licensed Vaccines

C-54

P3T06: PENTACEL vs US Standard of Care Vaccines P3T06: PENTACEL vs US Standard of Care Vaccines Study CharacteristicsStudy Characteristics

Multi-center, randomized, controlled, Multi-center, randomized, controlled, open-label studyopen-label study – 1939 infants 1939 infants

– Vaccinated at 2, 4, 6, and 15-16 months of ageVaccinated at 2, 4, 6, and 15-16 months of age

PENTACEL vaccine (n=484) vs Daptacel (3 lots), PENTACEL vaccine (n=484) vs Daptacel (3 lots), IPOL, ActHIB (n=1455)IPOL, ActHIB (n=1455)– All subjects received concomitant Recombivax HB All subjects received concomitant Recombivax HB

and Prevnarand Prevnar

ObjectiveObjective– Demonstrate non-inferiority of PENTACEL vs USDemonstrate non-inferiority of PENTACEL vs US

standard of care vaccines Daptacel, IPOL, ActHIBstandard of care vaccines Daptacel, IPOL, ActHIB

C-55

P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Pertussis GMTs

PENTACELPENTACEL Daptacel, IPOL, ActHIBDaptacel, IPOL, ActHIB

00

2020

4040

6060

8080

100100

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

00

5050

100100

150150

200200

250250

300300

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

PTPT FHAFHA PRNPRN FIMFIM

PENTACELPENTACEL 90.090.0 73.773.7 36.136.1 268.2268.2

ControlControl 63.863.8 29.229.2 43.343.3 267.2267.2

C-56

P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 3: Pertussis 4-Fold Rise Rates


ControlControl 86.186.1 60.960.9 75.475.4 86.386.3


00

2020

4040

6060

8080

100100


Per

cen

tP

erce

nt

C-57

P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 3: Pertussis Non-Inferiority ComparisonsNon-Inferiority Comparisons

Non-inferiority is based on 90% confidence intervals.

C-58

P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: Pertussis GMTs


ControlControl 168.5168.5 64.064.0 186.1186.1 513.5513.5

PENTACELPENTACEL Daptacel and ActHIBDaptacel and ActHIB

00

4040

8080

120120

160160

200200

PTPT FHAFHA PRNPRN00

100100

200200

300300

400400

500500

600600

FIMFIM

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

C-59

P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 4: Pertussis 4-Fold Rise Rates


ControlControl 97.197.1 79.379.3 98.398.3 91.691.6


00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt


C-60

P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 4: Pertussis Non-Inferiority ComparisonsNon-Inferiority Comparisons


C-61

P3T06: PENTACEL vs US Standard of Care VaccinesPost-Dose 4: 4-Fold Rise Responses to Multiple Pertussis Antigens

PENTACELPENTACEL 0.90.9 99.199.1 98.298.2 94.394.3 79.879.8

ControlControl 0.40.4 99.699.6 98.798.7 94.894.8 73.373.3


NoneNone Any 1 of 4Any 1 of 4 Any 2 of 4Any 2 of 4 Any 3 of 4Any 3 of 4 All 4All 400

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

C-62

PENTACEL Bridge to EfficacyPENTACEL Bridge to EfficacyP3T06 vs Sweden I Efficacy TrialP3T06 vs Sweden I Efficacy Trial

NIH-sponsored efficacy trial in Sweden 1992-1995NIH-sponsored efficacy trial in Sweden 1992-1995– Infants received Daptacel at 2, 4, 6 months of ageInfants received Daptacel at 2, 4, 6 months of age

– 85% efficacy vs WHO-defined classic pertussis85% efficacy vs WHO-defined classic pertussis

– 78% efficacy vs any pertussis (lab-confirmed, 78% efficacy vs any pertussis (lab-confirmed, 1 day of cough)1 day of cough)

Pertussis antibody levels in Sweden I Efficacy Trial Pertussis antibody levels in Sweden I Efficacy Trial were compared to those following 4 doses of were compared to those following 4 doses of PENTACEL in US pivotal trials P3T06 and 494-01PENTACEL in US pivotal trials P3T06 and 494-01

Sera from P3T06, 494-01 and the Sweden I Efficacy Sera from P3T06, 494-01 and the Sweden I Efficacy Trial were tested contemporaneously in same Trial were tested contemporaneously in same laboratory, under same conditions, using the same laboratory, under same conditions, using the same validated assayvalidated assay

C-63

P3T06: PENTACEL vs Sweden I (Bridge to Efficacy) GMTs


Sweden ISweden I 87.587.5 40.740.7 111.3111.3 339.3339.3

PENTACELPENTACEL Sweden ISweden I

00

4040

8080

120120

160160

200200

PTPT FHAFHA PRNPRN00

100100

200200

300300

400400

500500

600600

FIMFIM

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

C-64

P3T06: PENTACEL vs Sweden I (Bridge to Efficacy) Non-Inferiority Analyses

Non-inferiority is based on 90% confidence intervals for GMTs and VR; 95% for 4-fold rise.

C-65

494-01: Lot Consistency494-01: Lot ConsistencyPENTACEL vs ControlPENTACEL vs Control

Multi-center, randomized, controlled, open-label Multi-center, randomized, controlled, open-label lot-consistency studylot-consistency study– 3538 infants 3538 infants

– Vaccinated at 2, 4, 6, and 15 months of ageVaccinated at 2, 4, 6, and 15 months of age

PENTACEL (3 lots, n=2506) vs HCPDT, Poliovax, PENTACEL (3 lots, n=2506) vs HCPDT, Poliovax, ActHIB given separately (n=1032)ActHIB given separately (n=1032)– All subjects received concomitant Recombivax HBAll subjects received concomitant Recombivax HB

– Most subjects received concomitant PrevnarMost subjects received concomitant Prevnar

ObjectivesObjectives– Lot consistencyLot consistency

– Non-inferiorityNon-inferiority

C-66

494-01: Lot Consistency, 494-01: Lot Consistency, Post-Dose 3Post-Dose 3, , Pertussis Pertussis

Lot consistency is based on 90% confidence intervals.

C-67

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis GMTs


ControlControl 84.584.5 69.269.2 38.638.6 246.0246.0

00

2020

4040

6060

8080

100100

PTPT FHAFHA PRNPRN FIMFIM00

5050

100100

150150

200200

250250

300300

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

PENTACELPENTACEL HCPDT, Poliovax, ActHIBHCPDT, Poliovax, ActHIB

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

C-68

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis 4-Fold Rise Rates


ControlControl 89.789.7 78.078.0 78.678.6 87.087.0


00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt


C-69

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 3: Pertussis Non-Inferiority Analyses


C-70

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis GMTs


ControlControl 188.6188.6 128.3128.3 129.9129.9 350.3350.3


00

2525

5050

7575

100100

125125

150150

175175

200200

225225

00

5050

100100

150150

200200

250250

300300

350350

400400

450450

500500

550550

GM

T (

EU

/mL

)G

MT

(E

U/m

L)


GM

T (

EU

/mL

)G

MT

(E

U/m

L)

C-71

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis 4-Fold Rise Rates


ControlControl 94.494.4 86.386.3 92.892.8 87.987.9


0

20

40

60

80

100

Per

cen

t

PT FHA PRN FIM

C-72

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4: Pertussis Non-Inferiority Analyses


C-73

494-01: PENTACEL vs Sweden I (Bridge to Efficacy) 494-01: PENTACEL vs Sweden I (Bridge to Efficacy) GMTsGMTs


00

4040

8080

120120

160160

200200

00

100100

200200

300300

400400

500500

600600

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

GM

T (

EU

/mL

)G

MT

(E

U/m

L)



Sweden ISweden I 87.587.5 40.740.7 111.3111.3 339.3339.3

C-74

494-01: PENTACEL vs Sweden I (Bridge to Efficacy) 4-Fold Rise Rates


Sweden ISweden I 86.386.3 68.868.8 98.898.8 86.386.3


00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt


C-75

494-01: PENTACEL vs Sweden I (Bridge to Efficacy) Non-Inferiority Analyses

Non-inferiority is based on 90% confidence intervals for GMTs and VR; 95% for 4-fold rise.

C-76

494-01: PENTACEL vs Sweden I (Bridge to Efficacy) Box Plot of 2-Month Baseline PRN Antibody LevelsBox Plot of 2-Month Baseline PRN Antibody Levels

Per

tact

in (

EU

/mL

)P

erta

ctin

(E

U/m

L)

494-01 Stage I (n=507) Sweden I (n=80)

0

20

40

80

60

100

120

140

160

180

200

12: 11% (65/507)12: 11% (65/507) 12: 1% (1/80)12: 1% (1/80)

C-77

PENTACEL PENTACEL Post-Dose 4Post-Dose 4 vs Sweden I vs Sweden I RCDCs: PTRCDCs: PT

PENTACEL, P3T06PENTACEL, M5A07PENTACEL, 494-01PENTACEL, 494-03PENTACEL, 5A9908Daptacel, SWEDEN I

C-78

PENTACEL PENTACEL Post-Dose 4Post-Dose 4 vs Sweden I vs Sweden I RCDCs: FHARCDCs: FHA


C-79

PENTACEL PENTACEL Post-Dose 4Post-Dose 4 vs Sweden I vs Sweden I RCDCs: PRNRCDCs: PRN


C-80

PENTACEL PENTACEL Post-Dose 4Post-Dose 4 vs Sweden I vs Sweden I RCDCs: FIMRCDCs: FIM

FIM Antibody (EU/mL)FIM Antibody (EU/mL)


C-81

55thth Dose Follow-up Studies to 494-01, P3T06: Dose Follow-up Studies to 494-01, P3T06: P3T10 and P3T11 (Studies Currently Underway)P3T10 and P3T11 (Studies Currently Underway)

Both studies were multi-center, randomized, Both studies were multi-center, randomized, open-labelopen-label

Solicited all PENTACEL or Daptacel recipients Solicited all PENTACEL or Daptacel recipients in P3T06 and 494-01 to participatein P3T06 and 494-01 to participate

Sample size for pertussis immunogenicitySample size for pertussis immunogenicity– 259 in P3T10259 in P3T10

– 363 in P3T11 (89 primed with PENTACEL, 363 in P3T11 (89 primed with PENTACEL, 274 primed with Daptacel)274 primed with Daptacel)

Blood obtained for serology immediately prior Blood obtained for serology immediately prior to 5to 5thth dose dose

C-82

Percent Seropositive* at Percent Seropositive* at Pre-Dose 5Pre-Dose 5, , By Study and Pertussis AntigenBy Study and Pertussis Antigen

**LOQ: PT, 5; FHA, 3; PRN, 3; FIM, 17 LOQ: PT, 5; FHA, 3; PRN, 3; FIM, 17

75.375.3

89.689.6 89.689.6

77.677.674.274.2 74.274.2

87.687.6

68.568.5

58.858.8 59.359.3

95.395.3

54.754.7

Per

cen

t P

erce

nt

LO

Q L

OQ

PENTACEL (P3T10)PENTACEL (P3T10) PENTACEL (P3T11)PENTACEL (P3T11) Daptacel (P3T11)Daptacel (P3T11)

00

2020

4040

6060

8080

100100


C-83







C-84

P3T06: PENTACEL vs US Standard of Care VaccinesPost-Doses 3 and 4: Hib Seroprotection Rates


PENTACELPENTACEL 92.392.3 72.172.1 97.897.8

ControlControl 93.393.3 70.870.8 95.995.9

Per

cen

tP

erce

nt

Post-Dose 4Post-Dose 4Post-Dose 3Post-Dose 3

00

2020

4040

6060

8080

100100

0.15 0.15 µg/mLµg/mL 1.0 1.0 µg/mLµg/mL 1.0 1.0 µg/mLµg/mL

C-85

P3T06: PENTACEL vs US Standard of Care VaccinesPost-Doses 3 and 4: Hib GMTs


PENTACELPENTACEL 2.312.31 17.7117.71

ControlControl 2.292.29 20.4920.49

GM

T (

µg

/mL

)G

MT

(µ

g/m

L)

Post-Dose 3Post-Dose 3 Post-Dose 4Post-Dose 400

11

22

33

00

55

1010

1515

2020

2525

GM

T (

µg

/mL

)G

MT

(µ

g/m

L)

C-86

P3T06: Non-inferiority Testing of Hib Seroprotection Rates P3T06: Non-inferiority Testing of Hib Seroprotection Rates (Control-PENTACEL) and GMT Ratios (Control/PENTACEL)(Control-PENTACEL) and GMT Ratios (Control/PENTACEL)

% % 0.15 0.15 µg/mLµg/mL

% % 1.0 1.0 µg/mLµg/mL

% % 1.0 1.0 µg/mLµg/mL

C-87

% 1.0 µg/mL

% 0.15 µg/mL

494-01: Lot Consistency, 494-01: Lot Consistency, Post-Dose 3Post-Dose 3: Hib: Hib

Lot consistency is based on 90% confidence intervals.

C-88

494-01: GMTs and Seroprotection Rates, PENTACEL Lots at Post-Dose 3: Hib

Lot 1Lot 1 Lot 2Lot 2 Lot 3Lot 3

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.5

3.03.0

3.53.5

4.04.0

GM

T (

GM

T (

µµg

/mL

)g

/mL

)

00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

94.594.5

78.578.5

95.095.0

77.277.2

96.796.7

81.781.7

0.15 0.15 µµg/mLg/mL 1.0 1.0 µµg/mLg/mL

3.13.12.92.9

3.63.6

C-89

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Doses 3 and 4: Hib Seroprotection Rates


ControlControl 98.398.3 88.888.8 99.099.0


00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

0.15 0.15 µg/mLµg/mL 1.0 1.0 µg/mLµg/mL


1.0 1.0 µg/mLµg/mL

C-90

P3T06 and 494-01: Comparison of Hib GMTs P3T06 and 494-01: Comparison of Hib GMTs Post-Doses 3 and 4Post-Doses 3 and 4

PENTACELPENTACEL 3.193.19

ControlControl 6.236.23

PENTACELPENTACEL ControlControl

0

1

2

3

4

5

6

7

494-01

Post-Dose 3

0

5

10

15

20

25

30

35

40

494-01

Post-Dose 4

24.1224.12

35.9035.90

GM

T (

GM

T (

µµg

/mL

)g

/mL

)

GM

T (

GM

T (

µµg

/mL

)g

/mL

)

C-91





00

11

22

33

44

55

66

77

P3T06P3T06 494-01494-01

GM

T (

GM

T (

µµg

/mL

)g

/mL

)

P3T06P3T06 494-01494-01

17.7117.71 24.1224.12

20.4920.49 35.9035.90

GM

T (

GM

T (

µµg

/mL

)g

/mL

)


00

55

1010

1515

2020

2525

3030

3535

4040

C-92

494-01: Non-inferiority Testing of Hib Seroprotection Rates 494-01: Non-inferiority Testing of Hib Seroprotection Rates (Control-PENTACEL) and GMT Ratios (Control/PENTACEL)(Control-PENTACEL) and GMT Ratios (Control/PENTACEL)


% % 0.15 0.15 µg/mLµg/mL

% % 1.0 1.0 µg/mLµg/mL

% % 1.0 1.0 µg/mLµg/mL

C-93





00

11

22

33

44

55

66

77

P3T06P3T06 494-01494-01

GM

T (

GM

T (

µµg

/mL

)g

/mL

)

P3T06P3T06 494-01494-01

17.7117.71 24.1224.12

20.4920.49 35.9035.90

GM

T (

GM

T (

µµg

/mL

)g

/mL

)


00

55

1010

1515

2020

2525

3030

3535

4040

C-94

US and Canadian PENTACEL Licensure Trials: US and Canadian PENTACEL Licensure Trials: Post-Dose 3: Post-Dose 3: Hib GMTs by TrialHib GMTs by Trial

PENTACEL Studies: 494-01, P3T06, M5A07, 494-03, M5A03, PB9502, PB9601PENTACEL Studies: 494-01, P3T06, M5A07, 494-03, M5A03, PB9502, PB9601ActHIB Studies: P3T07, 494-01, P3T06, PB9502ActHIB Studies: P3T07, 494-01, P3T06, PB9502

00

11

22

33

44

55

66

77

88

PENTACELPENTACEL ActHIBActHIB

GM

T (

GM

T (

µµg

/mL

)g

/mL

)

494-01494-01

C-95

PENTACEL Studies: 494-01, P3T06, 5A9908, 494-03, M5A03, PB9502, PB9601PENTACEL Studies: 494-01, P3T06, 5A9908, 494-03, M5A03, PB9502, PB9601ActHIB Studies: 494-01, P3T06, PB9502ActHIB Studies: 494-01, P3T06, PB9502

US and Canadian PENTACEL Licensure Trials: US and Canadian PENTACEL Licensure Trials: Post-Dose 4: Post-Dose 4: Hib GMTs by TrialHib GMTs by Trial

494-01494-01

00

55

1010

1515

2020

2525

3030

3535

4040

4545

GM

T (

GM

T (

µµg

/mL

)g

/mL

)


C-96

P3T06: Hib GMTs by Study Site P3T06: Hib GMTs by Study Site ((10 Subjects), 10 Subjects), Post-Dose 3Post-Dose 3

00

11

22

33

44

55

66

77


GM

T (

GM

T (

µµg

/mL

)g

/mL

)

C-97

P3T06: Hib GMTs by Study Site P3T06: Hib GMTs by Study Site Post-Dose 3:Post-Dose 3: PENTACEL vs Control by Site PENTACEL vs Control by Site

Shows only sites with Shows only sites with 10 PENTACEL subjects per group10 PENTACEL subjects per group

00

11

22

33

44

55

66

77


GM

T (

GM

T (

µµg

/mL

)g

/mL

)

C-98

Hib GMTs at Hib GMTs at Post-Dose 3Post-Dose 3, By Study, By StudyPENTACELPENTACEL ActHIB Given SeparatelyActHIB Given Separately

4.44.4

7.17.1

3.23.22.82.8

2.32.3

3.03.03.53.5

3.83.8

6.26.2

2.32.3

3.03.0

00

11

22

33

44

55

66

77

88


GM

T (

GM

T (

µµg

/mL

)g

/mL

)

PB9502PB9502 PB9601PB9601 494-01494-01 494-03494-03 P3T06P3T06 M5A03M5A03 M5A07M5A07 494-01494-01 P3T06P3T06 P3T07P3T07PB9502PB9502

C-99

Hib GMTs at Hib GMTs at Pre-Dose 4Pre-Dose 4, By Study, By Study

0.420.42

0.600.60

0.380.38

0.310.31

0.560.56

0.290.29 0.300.300.370.37

0.560.56

0.250.250.250.25

0.500.50

0.750.75

1.001.00

GM

T (

GM

T (

µµg

/mL

)g

/mL

)

ControlControl

PENTACELPENTACEL ActHIB Given SeparatelyActHIB Given Separately

0.320.32

PB9502PB9502 PB9601PB9601 5A99085A9908 494-01494-01 494-03494-03 P3T06P3T06 M5A03M5A03 PB9502PB9502 494-01494-01 P3T06P3T06M5A07M5A07

PENTACELPENTACEL

00

C-100

Hib GMTs at Hib GMTs at Post-Dose 4Post-Dose 4, By Study, By StudyPENTACELPENTACEL ActHIB Given SeparatelyActHIB Given Separately

1010

2020

3030

4040

30.130.1

PB9502PB9502

39.839.8

PB9601PB9601

32.532.5

5A99085A9908

24.124.1

494-01494-01

36.736.7

494-03494-03

17.717.7

P3T06P3T06

25.625.6

M5A03M5A03

27.127.1

PB9502PB9502

35.935.9

494-01494-01

20.520.5

P3T06P3T06

GM

T (

GM

T (

µµg

/mL

)g

/mL

)

24.124.1

M5A07M5A07

ControlControlPENTACELPENTACEL

00

C-101

Hib GMTs at Pre-Dose 5, By Study

2.062.06

1.481.481.391.39

GM

T (

GM

T (

μμg

/mL

)g

/mL

)

00

0.50.5

1.01.0

1.51.5

2.02.0

2.52.52.522.52

PENTACELPENTACEL Separate VaccinesSeparate Vaccines

ActHIBActHIBTD508TD508P3T10P3T10 P3T11P3T11


C-102

Hib Seroprotection (Hib Seroprotection (1.0 1.0 µg/mLµg/mL) ) at at Post-Dose 3Post-Dose 3, By Study, By Study


84.784.7

95.595.5

79.179.175.675.6

72.172.178.578.5 78.478.4

88.988.9 88.888.8

70.870.875.775.7

Per

cen

tP

erce

nt

00

2020

4040

6060

8080

100100

PB9502PB9502 PB9601PB9601 494-01494-01 494-03494-03 P3T06P3T06 M5A03M5A03 M5A07M5A07 494-01494-01 P3T06P3T06 P3T07P3T07PB9502PB9502


C-103

Hib Seroprotection (Hib Seroprotection (0.15 0.15 µg/mLµg/mL) ) at at Pre-Dose 4Pre-Dose 4, By Study, By Study


75.475.4

84.884.8

73.073.068.668.6

83.883.8

65.465.4 67.767.773.173.1

80.880.8

60.760.7

69.169.1


Per

cen

tP

erce

nt

00

2020

4040

6060

8080

100100


C-104

Hib Seroprotection (Hib Seroprotection (1.0 1.0 µg/mLµg/mL) ) at at Post-Dose 4Post-Dose 4, By Study, By Study


99.099.0 100.0100.0 98.898.8 98.298.2 99.199.1 97.897.8 97.397.3 100.0100.0 99.099.095.995.997.997.9

Per

cen

tP

erce

nt

00

2020

4040

6060

8080

100100



C-105

Hib Seroprotection (≥0.15 Hib Seroprotection (≥0.15 µg/mLµg/mL) at ) at Pre-Dose 5Pre-Dose 5, By Study, By Study


96.596.591.791.7 94.394.3

P3T11P3T1100

2020

4040

6060

8080

10010098.498.4

TD508TD508P3T10P3T10 P3T11P3T11


Per

cen

tP

erce

nt

C-106

P3T07: Daptacel+IPOL+ActHIB - No Concomitant Prevnar M5A07: PENTACEL - No Concomitant Prevnar Post-Dose 3: Hib Seroprotection Rates and GMTs

≥≥0.15 0.15 μμg/mLg/mL ≥≥1.0 1.0 μμg/mLg/mL


Daptacel, IPOL, ActHIBDaptacel, IPOL, ActHIB 93.593.5 73.273.2 2.72.7


00

11

22

33

44

55

00

2020

6060

8080

100100

4040Per

cen

tP

erce

nt

GM

T (

GM

T (

μμg

/mL

)g

/mL

)

C-107

P3T07: Daptacel+IPOL+ActHIB - with Concomitant Prevnar M5A07: PENTACEL - with Concomitant Prevnar Post-Dose 3: Hib Seroprotection Rates and GMTs

PENTACEL, PrevnarPENTACEL, Prevnar 95.895.8 77.177.1 3.33.3

Daptacel, IPOL, ActHIB, PrevnarDaptacel, IPOL, ActHIB, Prevnar 94.494.4 80.380.3 3.83.8

PENTACEL, PrevnarPENTACEL, Prevnar Daptacel, IPOL, ActHIB, PrevnarDaptacel, IPOL, ActHIB, Prevnar

00

11

22

33

44

55

00

2020

6060

8080

100100

4040Per

cen

tP

erce

nt

≥≥0.15 0.15 μμg/mLg/mL ≥≥1.0 1.0 μμg/mLg/mL

GM

T (

GM

T (

μμg

/mL

)g

/mL

)

C-108

PENTACEL vs Standard of CarePENTACEL vs Standard of CarePost-Dose 3:Post-Dose 3: Hib RCDCs Hib RCDCs

Hib Antibody (Hib Antibody (µg/mL)µg/mL)

C-109







C-110

P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Diphtheria, Tetanus Seroprotection Rates


ControlControl 100.0100.0 98.598.5 100.0100.0 100.0100.0


0.01 IU/mL0.01 IU/mL 0.1 IU/mL0.1 IU/mL

DiphtheriaDiphtheria TetanusTetanus0.01 IU/mL0.01 IU/mL 0.1 IU/mL0.1 IU/mL

00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

C-111

P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 4: Diphtheria, Tetanus Seroprotection Rates


ControlControl 100.0100.0 95.795.7 100.0100.0 99.499.4




00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

C-112

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB494-01: PENTACEL vs HCPDT, Poliovax, ActHIBPost-Dose 3Post-Dose 3: Diphtheria, Tetanus Seroprotection Rates: Diphtheria, Tetanus Seroprotection Rates


ControlControl 99.799.7 92.292.2 100.0100.0 100.0100.0




00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

C-113

494-01: PENTACEL vs HCPDT, Poliovax, ActHIB 494-01: PENTACEL vs HCPDT, Poliovax, ActHIB Post-Dose 4Post-Dose 4: Diphtheria, Tetanus Seroprotection Rates: Diphtheria, Tetanus Seroprotection Rates


ControlControl 99.799.7 95.195.1 100.0100.0 98.698.6


00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt



C-114

PENTACEL Non-inferiority, P3T06 and 494-01:PENTACEL Non-inferiority, P3T06 and 494-01:Diphtheria and Tetanus Seroprotection RatesDiphtheria and Tetanus Seroprotection Rates


% % 0.1 0.1 IU/mLIU/mL% % 0.01 0.01 IU/mLIU/mL








C-115







C-116

P3T06 and 494-01: PENTACEL vs ControlPolio Seroprotection Rates (1:8)

PENTACELPENTACEL 99.499.4 100.0100.0 100.0100.0 99.799.7 100.0100.0 100.0100.0 100.0100.0 100.0100.0 100.0100.0

ControlControl 100.0100.0 100.0100.0 100.0100.0 100.0100.0 100.0100.0 100.0100.0 100.0100.0 100.0100.0 100.0100.0

Polio 1Polio 1 Polio 2Polio 2 Polio 3Polio 300

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

PENTACELPENTACEL Daptacel, IPOL and ActHIBDaptacel, IPOL and ActHIB HCPDT, Poliovax, ActHIBHCPDT, Poliovax, ActHIB

Polio 1Polio 1 Polio 2Polio 2 Polio 3Polio 3 Polio 1Polio 1 Polio 2Polio 2 Polio 3Polio 3

494-01 Post-Dose 3494-01 Post-Dose 3 494-01 Post-Dose 4494-01 Post-Dose 4P3T06 Post-Dose 3P3T06 Post-Dose 3

C-117

Polio 1 % 1:8

Polio 2 % 1:8

Polio 3 % 1:8

Polio 1 % 1:8

Polio 2 % 1:8

Polio 3 % 1:8

Polio 1 % 1:8

Polio 2 % 1:8

Polio 3 % 1:8

PENTACEL Non-inferiority, P3T06 and 494-01:PENTACEL Non-inferiority, P3T06 and 494-01:Polio Seroprotection RatesPolio Seroprotection Rates


C-118







C-119

P3T06: PENTACEL vs US Standard of Care Vaccines Post-Dose 3: Pneumococcal Seroprotection Rates

PENTACELPENTACEL 100.0100.0 98.198.1 92.592.5 81.081.0 99.799.7 94.494.4 100.0100.0 96.396.3 100.0100.0 98.198.1 97.597.5 94.794.7 98.198.1 92.892.8

ControlControl 100.0100.0 98.998.9 91.491.4 80.780.7 99.399.3 96.796.7 99.399.3 97.497.4 99.599.5 97.897.8 97.997.9 95.695.6 96.996.9 91.391.3

PENTACELPENTACEL Daptacel, IPOL and ActHIBDaptacel, IPOL and ActHIB

00

2020

4040

6060

8080

100100

0.150.15 0.500.50

44 6B6B 9V9V 1414 18C18C 19F19F 23F23F

Per

cen

tP

erce

nt

0.150.15 0.500.50 0.150.15 0.500.50 0.150.15 0.500.50 0.150.15 0.500.50 0.150.15 0.500.50 0.150.15 0.500.50

C-120

494-03: Co-Administration With Other 494-03: Co-Administration With Other Recommended VaccinesRecommended Vaccines

Multi-center, randomized, open-label studyMulti-center, randomized, open-label study– PENTACEL 4PENTACEL 4thth dose dose†† given at 15 to 16 months of age given at 15 to 16 months of age

concomitantly with, or separately from, MMR, concomitantly with, or separately from, MMR, Varivax, and PrevnarVarivax, and Prevnar

– Only 4Only 4thth dose data are presented (n=958) dose data are presented (n=958)

Objective: Objective: – Determine the effect of PENTACEL on Determine the effect of PENTACEL on

co-administered vaccinesco-administered vaccines

††PENTACEL was previously administered at 2, 4, and 6 months of agePENTACEL was previously administered at 2, 4, and 6 months of age

C-121

494-03: Effect of PENTACEL on Concomitant VaccinesPrevnar 4th Dose

PENTACEL+PrevnarPENTACEL+Prevnar 100.0100.0 98.798.7 97.497.4 95.595.5 100.0100.0 98.798.7 100.0100.0 99.499.4 100.0100.0 98.798.7 100.0100.0 97.497.4 98.798.7 95.595.5

MMR+Varivax+PrevnarMMR+Varivax+Prevnar 100.0100.0 99.499.4 99.499.4 97.597.5 100.0100.0 99.499.4 100.0100.0 100.0100.0 99.499.4 98.798.7 99.499.4 96.296.2 98.798.7 95.695.6

PENTACEL+PrevnarPENTACEL+Prevnar MMR+Varivax+PrevnarMMR+Varivax+Prevnar

00

2020

4040

6060

8080

100100

0.150.15 0.500.50

44 6B6B 9V9V 1414 18C18C 19F19F 23F23F

Per

cen

tP

erce

nt

0.150.15 0.500.50 0.150.15 0.500.50 0.150.15 0.500.50 0.150.15 0.500.50 0.150.15 0.500.50 0.150.15 0.500.50

C-122

00

2525

5050

7575

100100

125125

150150

00

5050

100100

150150

200200

250250

300300


GM

T (

EU

/mL

)G

MT

(E

U/m

L)

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

M5A07: PENTACEL+Prevnar vs PENTACELPost-Dose 3: Pertussis GMTs

PENTACEL+PrevnarPENTACEL+Prevnar 103.6103.6 82.482.4 45.745.7 272.5272.5


PENTACELPENTACELPENTACEL+PrevnarPENTACEL+Prevnar

C-123

M5A07: PENTACEL+Prevnar vs PENTACELM5A07: PENTACEL+Prevnar vs PENTACELPost-Dose 4Post-Dose 4 Pertussis GMTs Pertussis GMTs

00

4040

8080

120120

160160

200200

00

100100

200200

300300

400400

500500

GM

T (

EU

/mL

)G

MT

(E

U/m

L)

GM

T (

EU

/mL

)G

MT

(E

U/m

L)


PENTACEL+PrevnarPENTACEL+Prevnar 189.7189.7 116.2116.2 98.298.2 456.3456.3



C-124

M5A07: PENTACEL+Prevnar vs PENTACELPost-Dose 3: Hib Seroprotection Rates and GMTs

PENTACEL+PrevnarPENTACEL+Prevnar 95.895.8 77.177.1


3.323.32

3.603.60

00

2020

4040

6060

8080

100100

0.15 0.15 µµg/mL g/mL 1.0 1.0 µµg/mLg/mL

Per

cen

tP

erce

nt

GM

T (

µg

/mL

)G

MT

(µ

g/m

L)

00

11

22

33

44

55

66


C-125

M5A07: PENTACEL+Prevnar vs PENTACEL Post-Dose 4: Hib Seroprotection Rates and GMTs

1.0 1.0 µµg/mLg/mL


PENTACEL+PrevnarPENTACEL+Prevnar 97.797.7

PENTACELPENTACEL 98.298.2

00

2020

4040

6060

8080

100100

Per

cen

tP

erce

nt

00

55

1010

1515

2020

2525

3030

21.721.7

26.726.7

GM

T (

µg

/mL

)G

MT

(µ

g/m

L)

C-126

Overall Immunogenicity ConclusionsOverall Immunogenicity Conclusions

PENTACEL efficacy against Pertussis can be concluded PENTACEL efficacy against Pertussis can be concluded based on favorable serological comparison to the based on favorable serological comparison to the Sweden I Efficacy Trial Sweden I Efficacy Trial

PENTACEL produced Pertussis GMTs and PENTACEL produced Pertussis GMTs and seroresponse rates comparable to those seen with seroresponse rates comparable to those seen with separately administered vaccines separately administered vaccines

Good similarity of responses demonstrated across all Good similarity of responses demonstrated across all the US licensure trials (RCDCs)the US licensure trials (RCDCs)

Good antibody persistence up to 4-6 years of ageGood antibody persistence up to 4-6 years of age

PENTACEL produced Diphtheria, Tetanus, and PENTACEL produced Diphtheria, Tetanus, and Poliovirus seroprotection rates comparable to those Poliovirus seroprotection rates comparable to those seen with separately administered vaccinesseen with separately administered vaccines

C-127

Overall Immunogenicity ConclusionsOverall Immunogenicity Conclusions

PENTACEL produced Hib GMTs and seroprotection PENTACEL produced Hib GMTs and seroprotection rates that were:rates that were:– Comparable to separately administered US standard of Comparable to separately administered US standard of

care vaccinescare vaccines

– Similar across the full range of PENTACEL studiesSimilar across the full range of PENTACEL studies

– Very high following the 4Very high following the 4thth dose dose

– Persisted into the pre-school booster age Persisted into the pre-school booster age

PENTACEL can be co-administered with other routinely PENTACEL can be co-administered with other routinely recommended infant and toddler vaccinesrecommended infant and toddler vaccines

With respect to immune responses, PENTACEL is a With respect to immune responses, PENTACEL is a suitable replacement for separately administered suitable replacement for separately administered Daptacel, IPOL, and ActHIBDaptacel, IPOL, and ActHIB

C-128






Scott Halperin, MDScott Halperin, MDProfessor of Pediatrics Professor of Pediatrics Dalhousie University, Halifax, CanadaDalhousie University, Halifax, Canada



C-129

Canadian Post-Marketing ExperienceCanadian Post-Marketing Experience

Licensed May 1997Licensed May 1997

Introduced nationally 1997-1998Introduced nationally 1997-1998

Universal and exclusive useUniversal and exclusive use

As of April 2006, more than 12 million dosesAs of April 2006, more than 12 million doses

Canadian schedule: 2, 4, 6, and 18 monthsCanadian schedule: 2, 4, 6, and 18 months

Quadracel (DTaP-IPV; PENTACEL without Hib) Quadracel (DTaP-IPV; PENTACEL without Hib) at 4-6 yearsat 4-6 years

C-130

Pertussis Incidence Rates, Canada, Pertussis Incidence Rates, Canada, 1924 – 20001924 – 2000

Source: Canadian Immunization Guide, 6Source: Canadian Immunization Guide, 6 thth ed., 2005:169. ed., 2005:169.

C-131

Age-specific Rates of Pertussis, Canada, Age-specific Rates of Pertussis, Canada, 1988 – 20051988 – 2005††

††Provisional data for 2003-2005.Provisional data for 2003-2005.Source: http://dsol-smed.hc-sc.gc.ca/dsol-smed/ndis/c_time_e.html and Notifiable Diseases Reporting System, Source: http://dsol-smed.hc-sc.gc.ca/dsol-smed/ndis/c_time_e.html and Notifiable Diseases Reporting System, Public Health Agency of CanadaPublic Health Agency of Canada

Year

0

50

100

150

200

250

300

Rat

e p

er 1

00,0

00R

ate

per

100

,000

88 90 92 94 96 98 00 02 04†

PENTACEL Introduced

<1 yr 1-4 yr 5-9 yr

C-132

Canadian IMPACT Surveillance NetworkCanadian IMPACT Surveillance Network

12 pediatric hospitals throughout Canada12 pediatric hospitals throughout Canada

90% of tertiary care pediatric beds 90% of tertiary care pediatric beds

Referrals from all provinces and territoriesReferrals from all provinces and territories

Children from birth through 16 years of ageChildren from birth through 16 years of age

Surveillance conducted by nurse monitor at Surveillance conducted by nurse monitor at each siteeach site

C-133

Annual Number of Hospitalized Cases of Annual Number of Hospitalized Cases of Pertussis, IMPACT Centers, 1993 – 2005Pertussis, IMPACT Centers, 1993 – 2005

Source: Bettinger et al., 6th Canadian Immunization Conference, Montreal, Quebec, Dec 5-8, 2004.Source: Bettinger et al., 6th Canadian Immunization Conference, Montreal, Quebec, Dec 5-8, 2004.Bettinger et al., Pediatr Infect Dis J. 2007;26:31-5.Bettinger et al., Pediatr Infect Dis J. 2007;26:31-5.

PENTACEL EraPENTACEL IntroductionWhole Cell Era

PENTACELUsed Nationally

0

50

100

150

200

250

300

350

93 94 95 96 97 98 99 00 01 02 03 04 05

Year

Nu

mb

er o

f C

ases

C-134

Number of Pertussis Cases by Age Group, Number of Pertussis Cases by Age Group, Northwest TerritoriesNorthwest Territories

Age (years)

Nu

mb

er o

f C

ases

1010

2020

3030

4040

5050

< 1 1-4 5-9

1993-1996Whole Cell

1997-2000PENTACEL

2001-2004PENTACEL

0

Source: Kandola K, et al. Source: Kandola K, et al. Can J Infect Dis Med Microbiol.Can J Infect Dis Med Microbiol. 2005;16:271-4. 2005;16:271-4.

C-135

Incidence of Invasive Hi* Disease in Children Incidence of Invasive Hi* Disease in Children Aged <5 Years, Canada, 1989 – 2005Aged <5 Years, Canada, 1989 – 2005

Data for 2003-2005 are provisional.Data for 2003-2005 are provisional.Source: Public Health Agency of Canada, 2006.Source: Public Health Agency of Canada, 2006.*Not all *Not all Haemophilus influenzaeHaemophilus influenzae were confirmed as type b. were confirmed as type b.

Year

PENTACEL Introduced

0

4

8

12

16

20

24

89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05

Rat

e p

er 1

00,0

00

C-136

0

100

200

300

400

500

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05

Year

Nu

mb

er o

f C

ases

Invasive Hib Disease Among Children Admitted to Hospitals Invasive Hib Disease Among Children Admitted to Hospitals in the IMPACTin the IMPACT†† Surveillance Network, 1985 – 2005 Surveillance Network, 1985 – 2005

††Immunization Monitoring Program, ActiveImmunization Monitoring Program, ActiveSource: Source: Can Med Assoc J.Can Med Assoc J. 1996;154:1041-1047 and 2005;172:53-6; 1996;154:1041-1047 and 2005;172:53-6;

Can Commun Dis Rep.Can Commun Dis Rep. 1998;24:105-108; 2000;26:93-96; 2001;27:149-150; 1998;24:105-108; 2000;26:93-96; 2001;27:149-150; Paediatr Child Health.Paediatr Child Health. 2005;10:314; and David Scheifele, IMPACT. 2005;10:314; and David Scheifele, IMPACT.

PENTACELIntroduced

C-137

Invasive Hib Disease, Children Aged <5 YearsInvasive Hib Disease, Children Aged <5 YearsIMPACT Surveillance Network, 2001 – 2005IMPACT Surveillance Network, 2001 – 2005

Only 34 cases during 2001 Only 34 cases during 2001 – – 20052005

Of these, 11 occurred among native children Of these, 11 occurred among native children (Aboriginal – First Nation and Inuit)(Aboriginal – First Nation and Inuit)– 2 unvaccinated2 unvaccinated

– 7 partially vaccinated (1 or 2 doses)7 partially vaccinated (1 or 2 doses)

– 2 received 3 doses (1 with recurrent 2 received 3 doses (1 with recurrent pneumonia history)pneumonia history)

Only 2 breakthrough cases during 5-year periodOnly 2 breakthrough cases during 5-year period

C-138

International Circumpolar Surveillance International Circumpolar Surveillance PHAC, Canada and CDC, USPHAC, Canada and CDC, US

CanadaCanada USUS

RegionsRegionsYukon, Northwest Territories, Yukon, Northwest Territories, Nunavut, northern Labrador Nunavut, northern Labrador

and Quebecand QuebecAlaskaAlaska

Total populationTotal population 137,000137,000 664,000664,000

Native populationNative population 75,000 (55%)75,000 (55%) 120,000 (18%)120,000 (18%)

SurveillanceSurveillance 5 years (2000-2004)5 years (2000-2004) 5 years (2002-2006)5 years (2002-2006)

VaccineVaccine PENTACELPENTACEL PRP-OMPPRP-OMP

Hib cases <5 y/o Hib cases <5 y/o 4 (3 Native)4 (3 Native) 7 (6 Native)7 (6 Native)

Ages (Doses)Ages (Doses) 1.6 mo (0)1.6 mo (0)

3.7 mo (unknown)3.7 mo (unknown)

3.9 mo (partial)3.9 mo (partial)

1.4 yr (partial)1.4 yr (partial)

0.4 mo (2)0.4 mo (2)

0.5 mo (0)0.5 mo (0)

0.8 mo (2)0.8 mo (2)

1.1 yr (2)1.1 yr (2)

2.4 yr (3)2.4 yr (3)

2.6 yr (3)2.6 yr (3)

3.6 yr (3)3.6 yr (3)

C-139

2007 NACI Recommendations for 2007 NACI Recommendations for Use of Combination Vaccines in CanadaUse of Combination Vaccines in Canada

““Combination vaccines against diphtheria, Combination vaccines against diphtheria, pertussis, polio, tetanus and…Hib infections pertussis, polio, tetanus and…Hib infections have become the standard for routine primary have become the standard for routine primary immunization of infants in Canada.”immunization of infants in Canada.”

““Like its monovalent constituent vaccines, Like its monovalent constituent vaccines, PENTACEL has been highly successful in PENTACEL has been highly successful in controlling these infectious diseases in Canada controlling these infectious diseases in Canada but has the additional benefit of fewer but has the additional benefit of fewer injections.”injections.”

NACI = Canadian National Advisory Committee on ImmunizationNACI = Canadian National Advisory Committee on ImmunizationCCDR 2007;33(ASC-1):1-14CCDR 2007;33(ASC-1):1-14

C-140

Conclusions: Effectiveness of PENTACEL Conclusions: Effectiveness of PENTACEL Against Pertussis and Invasive Hib DiseaseAgainst Pertussis and Invasive Hib Disease

9 years of clinical experience with more than 9 years of clinical experience with more than 12 million doses of PENTACEL in Canada12 million doses of PENTACEL in Canada

Multiple surveillance systems confirm very low Multiple surveillance systems confirm very low rates of pertussis and Hib disease rates of pertussis and Hib disease

PENTACEL provides sustained protection PENTACEL provides sustained protection against pertussis through 9 years of age against pertussis through 9 years of age

PENTACEL provides excellent protection PENTACEL provides excellent protection against invasive Hib diseaseagainst invasive Hib disease– Hib cases are rare among vaccinated children, Hib cases are rare among vaccinated children,

including high risk populationsincluding high risk populations

C-141









C-142

US PerspectiveUS Perspective

US ExperienceUS Experience– Pertussis and Hib epidemiology Pertussis and Hib epidemiology

– Comparison to Canadian experienceComparison to Canadian experience

Benefits of PENTACEL VaccineBenefits of PENTACEL Vaccine– Patient, healthcare provider, public healthPatient, healthcare provider, public health

– Immunization scheduleImmunization schedule

– Coverage rates and timelinessCoverage rates and timeliness

C-143

0

50

100

150

200

250

300

20 30 40 50 60 70 80 90 00Year

Ca

se

s (

Th

ou

sa

nd

s)

Epidemiology of Pertussis: Epidemiology of Pertussis: United States, 1922 United States, 1922 – – 20052005

CDC. CDC. MMWR.MMWR. 2002;51:73-76; 2002;51:73-76;CDC. Summary of notifiable diseases, US, 2003. Published Apr 22, 2005, MMWR 2003:52(54):72-76;CDC. Summary of notifiable diseases, US, 2003. Published Apr 22, 2005, MMWR 2003:52(54):72-76;CDC. Summary of notifiable diseases, US, 2004. Published June 16, 2006, MMWR 2004:53(53):19;CDC. Summary of notifiable diseases, US, 2004. Published June 16, 2006, MMWR 2004:53(53):19;CDC. CDC. MMWR.MMWR. 2005;55:890. 2005;55:890.

Epidemiology of Pertussis; Canada, 1924-2000

C-144

Pertussis Incidence, US, 2005Pertussis Incidence, US, 2005

Rates per 100,000 persons; Rates per 100,000 persons; National Center for Immunization and Respiratory Diseases, CDC. Pertussis Surveillance Reports for 2005.National Center for Immunization and Respiratory Diseases, CDC. Pertussis Surveillance Reports for 2005.

0

10

20

30

40

50

160

<6 mos 6-11 mos 1-4 yrs 5-9 yrs 10-19 yrs 20+ yrs

Inci

den

ce p

er 1

00,0

00

140

C-145

00

0.10.1

0.20.2

0.30.3

0.40.4

0.50.5

9494 9595 9696 9797 9898 9999 0000 0101 0202 0303 0404 0505

YearYear

Hib: Invasive Disease in US Children <5 Years Hib: Invasive Disease in US Children <5 Years National Data, 1994 National Data, 1994 – – 20052005

Note: Rates per 100,000 persons; Only cases confirmed as type b are shown.Note: Rates per 100,000 persons; Only cases confirmed as type b are shown.Source: Source: MMWRMMWR 1995;44:545-50; 1996;45:901-6; 1998;47:993-8; 2001;50:48; 2002:51:16; 2002;51:234-7; 2004;53:691; 1995;44:545-50; 1996;45:901-6; 1998;47:993-8; 2001;50:48; 2002:51:16; 2002;51:234-7; 2004;53:691; 2005;54:775; and 2006;55:887. 2005;54:775; and 2006;55:887.

Rat

e p

er 1

00,0

00R

ate

per

100

,000

C-146

0.0

0.2

0.4

0.6

0.8

1.0

1.2

1.4

94 95 96 97 98 99 00 01 02 03 04 05

Year

Inci

den

ce R

ate

Hib: Invasive Disease in US Children <5 Years Hib: Invasive Disease in US Children <5 Years ABCs Data, 1994 ABCs Data, 1994 – – 20052005

Note: Rates per 100,000 persons; Note: Rates per 100,000 persons; 2005 data are provisional2005 data are provisionalSource: http://www.cdc.gov/ncidod/dbmd/abcs/reports.htmSource: http://www.cdc.gov/ncidod/dbmd/abcs/reports.htm

0

5

10

15

20

25

94 95 96 97 98 99 00 01 02 03 04 05Year

Ca

se

s

IMPACT Surveillance NetworkIMPACT Surveillance Network

C-147

0

10

20

30

40

50

60

96 97 98 99 00 01 02 03 04 05

Year

Per

cen

t o

f M

arke

t S

har

eActHIB Vaccine Market Share in the US, ActHIB Vaccine Market Share in the US, 1996 1996 – – 2005 2005

Note: Assumed market of 15.2 million Hib conjugate vaccine doses per year; includes TriHIBitNote: Assumed market of 15.2 million Hib conjugate vaccine doses per year; includes TriHIBit ®®..Source: Data on file, sanofi pasteur.Source: Data on file, sanofi pasteur.

C-148

Summary of US and Canadian ExperiencesSummary of US and Canadian Experiences

Pertussis epidemiology is similar in US and Canada Pertussis epidemiology is similar in US and Canada – In Canada, PENTACEL has led to sustained protection against In Canada, PENTACEL has led to sustained protection against

pertussis through 9 years of agepertussis through 9 years of age

The epidemiology of invasive Hib disease is similar in The epidemiology of invasive Hib disease is similar in US and CanadaUS and Canada– ActHIB is the dominant Hib vaccine used in the USActHIB is the dominant Hib vaccine used in the US

– ActHIB, in PENTACEL, is the exclusive Hib vaccine used ActHIB, in PENTACEL, is the exclusive Hib vaccine used in Canada in Canada

In light of these data, PENTACEL is expected to perform In light of these data, PENTACEL is expected to perform as well in US as it has in Canada as well in US as it has in Canada

C-149

2007 Recommended Childhood Immunization 2007 Recommended Childhood Immunization Schedule: Birth Schedule: Birth – 18 Months– 18 Months

C-150

ACIP, AAP, AAFP Recommendations:ACIP, AAP, AAFP Recommendations:Combination VaccinesCombination Vaccines

““To minimize the number of injections children To minimize the number of injections children receive, parenteral combination vaccines receive, parenteral combination vaccines should be used, if licensed and indicated for the should be used, if licensed and indicated for the patient’s age, instead of their equivalent patient’s age, instead of their equivalent component vaccines.”component vaccines.”

““The use of licensed combination vaccines is The use of licensed combination vaccines is preferred over separate injection of their preferred over separate injection of their equivalent component vaccines.”equivalent component vaccines.”

Centers for Disease Control and Prevention (CDC). Centers for Disease Control and Prevention (CDC). MMWR.MMWR. 1999;48(No. RR-5):1-2. 1999;48(No. RR-5):1-2.

C-151

CDC: Timeliness of Childhood Immunizations, CDC: Timeliness of Childhood Immunizations, United StatesUnited States

2003 National Immunization Survey (n=14,810)2003 National Immunization Survey (n=14,810)

Only 17% of 24-35 month old children were Only 17% of 24-35 month old children were immunized on time for 6 vaccinesimmunized on time for 6 vaccines

Undervaccinated by mean of 172 daysUndervaccinated by mean of 172 days

37% undervaccinated >6 months for 37% undervaccinated >6 months for 1 vaccine1 vaccine– IPV IPV 9% 9%

– DTaP DTaP 16% 16%

– HibHib 21%21%

Luman et al. Luman et al. JAMA.JAMA. 2006;293:1204-11. 2006;293:1204-11.

C-152

0

20

40

60

80

100

4 DTaP 3 Hep B 3 IPV

Per

cen

t o

f C

hil

dre

n

Separate Vaccine Cohort (n=1990) Combination Cohort (n=1990)

Improved Coverage Rates, 2 Years of Age Improved Coverage Rates, 2 Years of Age Georgia Medicaid 2003Georgia Medicaid 2003

Marshall et al. 40th National Immunization Conference, Atlanta, GA, March 2006.

All comparisons, P<0.001

C-153

Improved Coverage Rates, 15 Months of Age Improved Coverage Rates, 15 Months of Age Germany, 1996 Germany, 1996 –– 2003 2003

00

1010

2020

3030

4040

5050

Per

cen

t F

ull

y Im

mu

niz

ed

Per

cen

t F

ull

y Im

mu

niz

ed

by

15 M

on

ths

of

Ag

eb

y 15

Mo

nth

s o

f A

ge

HibHib IPVIPV Hepatitis BHepatitis B

MonovalentMonovalent19961996

DTaP-HibDTaP-Hib1997-19981997-1998

DTaP-IPV-HibDTaP-IPV-Hib1998-20001998-2000

DTaP-IPV-Hib-HepBDTaP-IPV-Hib-HepB2001-20032001-2003

Kailies et al. Kailies et al. Pediatr Infect Dis J.Pediatr Infect Dis J. 2006;25:507-12. 2006;25:507-12.N=2701 children with immunization booklets availableN=2701 children with immunization booklets available

C-154

2007 Recommended Childhood Immunization 2007 Recommended Childhood Immunization Schedule: Birth Schedule: Birth – 18 Months– 18 Months

C-155

Reduction of the Number of Injections Through Reduction of the Number of Injections Through 18 Months of Age with Combination Vaccines18 Months of Age with Combination Vaccines

23

-10

-5

0

5

10

15

20

25

Total # of Shots

Single Entity

20

-3

Comvax

18

-5

Pediarix

16

-7

PENTACEL

22

-1

TriHIBit

Shot Reduction vs Single Entity

C-156

PENTACEL: First Candidate DTaP-IPV-Hib PENTACEL: First Candidate DTaP-IPV-Hib Combination Vaccine in the USCombination Vaccine in the US

Patient BenefitsPatient Benefits– Maximum shot reductionMaximum shot reduction

– Safety profile encourages complianceSafety profile encourages compliance

Healthcare Provider BenefitsHealthcare Provider Benefits– Optimizes implementation of immunization recommendationsOptimizes implementation of immunization recommendations

– Simplifies administrationSimplifies administration

Public Health BenefitsPublic Health Benefits– Expected to improve vaccination coverage rates and timelinessExpected to improve vaccination coverage rates and timeliness

– Facilitates optimal HepB scheduleFacilitates optimal HepB schedule

– Improves combination vaccine supply for infant seriesImproves combination vaccine supply for infant series

C-157





Canadian Post-Marketing Canadian Post-Marketing ExperienceExperience


US ExperienceUS Experience David Greenberg, MDDavid Greenberg, MDDirector Scientific and Medical AffairsDirector Scientific and Medical Affairs


C-158

PENTACEL Clinical Safety ConclusionsPENTACEL Clinical Safety Conclusions

Safety profile of PENTACEL similar to that of Safety profile of PENTACEL similar to that of separate administration of US standard of care separate administration of US standard of care vaccines (Daptacel, IPOL, and ActHIB)vaccines (Daptacel, IPOL, and ActHIB)

PENTACEL is safe when administered alone or PENTACEL is safe when administered alone or concomitantly with other age-recommended concomitantly with other age-recommended vaccinesvaccines

C-159

PENTACEL Immunogenicity ConclusionsPENTACEL Immunogenicity Conclusions

PENTACEL efficacy against Pertussis can be PENTACEL efficacy against Pertussis can be concluded based on favorable serological concluded based on favorable serological comparison to the Sweden I Efficacy Trialcomparison to the Sweden I Efficacy Trial

PENTACEL produced Hib GMTs and PENTACEL produced Hib GMTs and seroprotection rates that were comparable to seroprotection rates that were comparable to separately administered US standard of separately administered US standard of care vaccinescare vaccines

Immune responses were similar when PENTACEL Immune responses were similar when PENTACEL was administered alone or concomitantly with was administered alone or concomitantly with other vaccinesother vaccines

C-160

PENTACEL BenefitsPENTACEL Benefits

Proven safety record after 9 years of exclusive use Proven safety record after 9 years of exclusive use in Canadain Canada

Proven effective in controlling pertussis and Hib Proven effective in controlling pertussis and Hib disease in Canadadisease in Canada– Similar epidemiology of pertussis and Hib in Canada and US Similar epidemiology of pertussis and Hib in Canada and US

predicts similar success with PENTACELpredicts similar success with PENTACEL

Patient benefits with maximum shot reductionPatient benefits with maximum shot reduction

Provider benefits with simplified administrationProvider benefits with simplified administration

Public health benefits through potential improvement of Public health benefits through potential improvement of vaccination timeliness and coveragevaccination timeliness and coverage

C-161

PENTACELPENTACEL®®

Diphtheria and Tetanus Toxoids and Acellular Pertussis Diphtheria and Tetanus Toxoids and Acellular Pertussis Adsorbed, Inactivated Poliovirus Vaccine and HaemophilusAdsorbed, Inactivated Poliovirus Vaccine and Haemophilus b b

Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined Conjugate (Tetanus Toxoid Conjugate) Vaccine Combined (DTaP-IPV/Hib Combined)(DTaP-IPV/Hib Combined)

Vaccine and Related Biological Products Vaccine and Related Biological Products Advisory CommitteeAdvisory Committee

January 25, 2007January 25, 2007

The vaccines business of sanofi-aventis GroupThe vaccines business of sanofi-aventis Group

c-1 pentacel ® diphtheria and tetanus toxoids and acellular pertussis adsorbed, inactivated...

Documents