1

Tetanus Toxoid, Reduced Tetanus Toxoid, Reduced Diphtheria Toxoid and Diphtheria Toxoid and

Acellular Pertussis Acellular Pertussis Vaccine, AdsorbedVaccine, Adsorbed(Tdap, ADACEL™)(Tdap, ADACEL™)

Aventis Pasteur, Ltd.Aventis Pasteur, Ltd.VRBPAC – March 15, 2005VRBPAC – March 15, 2005

ChrisAnna M. Mink, M.D.ChrisAnna M. Mink, M.D.

FDA/OVRR/DVRPAFDA/OVRR/DVRPACC BBEE RR

2

Composition of Study Composition of Study VaccinesVaccines

ComponentADACEL

(Tdap)DAPTACEL

1

(DTaP)

Td2

Tetanus toxoid

5Lf 5 Lf 5 Lf

Diphtheria toxoid

2 Lf 15 Lf 2 Lf

PT 2.5 ug 10 ug -

FHA 5 ug 5 ug -

PRN 3 ug 3 ug -

FIM 2/3 5 ug 5 ug -

Aluminum3 0.33 mg 0.33 mg 0.33mg

Thimerosal - - 0.01%

1DTaP – licensed in U.S. for first 4 doses of primary series; evaluated in Sweden I2Td – manufactured by Aventis Pasteur Inc, U.S. (API)3Aluminum as AlPO4

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Indication SoughtIndication Sought

ADACEL™ is indicated for the ADACEL™ is indicated for the active immunization for the active immunization for the prevention of diphtheria, tetanus prevention of diphtheria, tetanus and pertussis in adolescents and and pertussis in adolescents and adults aged 11 through 64 years as adults aged 11 through 64 years as a booster. a booster.

The dosing schedule is one dose The dosing schedule is one dose

administered intramuscularly (IM).administered intramuscularly (IM).

4

Tdap Trials Submitted to Tdap Trials Submitted to the BLAthe BLA

PivotalPivotal Td506 – Comparative studyTd506 – Comparative study

Serology Bridge for Efficacy (lab study)Serology Bridge for Efficacy (lab study) Td505 – Lot consistencyTd505 – Lot consistency

Non-PivotalNon-Pivotal (Concomitant immunizations) (Concomitant immunizations) Td502 – Tdap with influenza vaccineTd502 – Tdap with influenza vaccine Td501 – Tdap with hepatitis B vaccineTd501 – Tdap with hepatitis B vaccine

Historical TrialsHistorical Trials – 3 abbreviated reports – 3 abbreviated reports Safety DatabaseSafety Database = 6803 Tdap recipients = 6803 Tdap recipients

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Pivotal Trial – Td506Pivotal Trial – Td506 Phase 3, randomized, observer-Phase 3, randomized, observer-

blinded, controlled trial blinded, controlled trial comparing Tdap (ADACEL™) with comparing Tdap (ADACEL™) with Td in adolescents and adults 11-Td in adolescents and adults 11-64 years of age 64 years of age No diphtheria-tetanus-pertussis No diphtheria-tetanus-pertussis

containing vaccines in previous containing vaccines in previous 5 years5 years

Stratified within age groups Stratified within age groups Tdap : Td Tdap : Td 3:2 for 11-17yr 3:2 for 11-17yr

3:1 for 18-64yr 3:1 for 18-64yr One 0.5 mL IM dose of Tdap or Td One 0.5 mL IM dose of Tdap or Td

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Pivotal Trial – Td506Pivotal Trial – Td506 MonitoringMonitoring

Immunogenicity Immunogenicity Randomly selected subset in each age Randomly selected subset in each age stratastrata

Serum - pre-vac and post-vac (35 Serum - pre-vac and post-vac (35 ++ 7 7 days)days)

SafetySafety Immediate adverse events (AEs) – 30 minImmediate adverse events (AEs) – 30 min Solicited AEs – diary card x 14 days Solicited AEs – diary card x 14 days SAEs, new onset medical conditions – 6 SAEs, new onset medical conditions – 6 momo

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Td506 - ObjectivesTd506 - Objectives Tdap vs. TdTdap vs. Td

To compare safety To compare safety To assess the immune To assess the immune

responses to diphtheria (dip) responses to diphtheria (dip) and tetanus (tet)and tetanus (tet)

Tdap vs. DTaP (DAPTACEL®)Tdap vs. DTaP (DAPTACEL®) To compare the immune To compare the immune

response to pertussis antigensresponse to pertussis antigens

Separate assessments for Separate assessments for adolescentsadolescents

(11-17 yrs) and adults (18-64 yrs)(11-17 yrs) and adults (18-64 yrs)

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Td506 Results: Td506 Results: EnrollmentEnrollment

Vaccine Group

PopulationTdap

NTdN

TotalN

Adolescents(11-17 years)

1225 818 2053

Adults(18-64 years)

1807 600 2427

Total(11-64 years)

3032 1418 4480*

* 19 were not vaccinated

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Td506 Results: PopulationsTd506 Results: Populations Demographic characteristicsDemographic characteristics

Similar for Tdap and Td groupsSimilar for Tdap and Td groups Populations for analysisPopulations for analysis

Intent-to-treat, safety (ITTS) – all Intent-to-treat, safety (ITTS) – all randomized and received study vaccine randomized and received study vaccine (Tdap or Td)(Tdap or Td)

ITT, Immunogenicity (ITTI) – ITT, Immunogenicity (ITTI) – randomized, vaccinated and bledrandomized, vaccinated and bled

Per-Protocol Immunogenicity (PPI) – Per-Protocol Immunogenicity (PPI) – ITTI subset with no major protocol ITTI subset with no major protocol violationsviolations

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Td506: Endpoints - Dip and Td506: Endpoints - Dip and Tet Immune ResponsesTet Immune Responses

Tdap vs. Td, % of subjects achieving Tdap vs. Td, % of subjects achieving response non-inferior if lower limit (LL) response non-inferior if lower limit (LL) of 2-sided 95% CI of the difference (of 2-sided 95% CI of the difference () ) in rates is > -10%in rates is > -10% Seroprotective levelsSeroprotective levels

Defined Defined >> 0.1 IU/mL 0.1 IU/mL Booster responsesBooster responses

Defined as 4-fold rise if pre-vac level Defined as 4-fold rise if pre-vac level below cut-off and 2-fold rise if above the below cut-off and 2-fold rise if above the cut-off level (2.56 IU/mL for dip and 2.7 cut-off level (2.56 IU/mL for dip and 2.7 IU/mL for tet)IU/mL for tet)

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Td506 Results: Dip and TetTd506 Results: Dip and TetSeroprotective Levels in Seroprotective Levels in

AdolescentsAdolescentsTdap

N=527%

TdN=516

% Diff % (95% CI)

Diphtheria

> 0.1 IU/mL (pre) 72.5 70.7 1.8 (-3.7, 7.3)

> 0.1 IU/mL (post) 99.8 99.8 0.0 (-0.5, 0.5)

> 1.0 IU/mL (pre) 15.7 17.3 -1.5 (-6.0, 3.0)

> 1.0 IU/mL (post) 98.7 98.4 0.3 (-1.2, 1.7)

Tetanus

> 0.1 IU/mL (pre) 99.6 99.2 0.4 (-0.5, 1.3)

> 0.1 IU/mL (post) 100 100 0.0 (0.0, 0.0)

> 1.0 IU/mL (pre) 44.6 43.8 0.8 (-5.2, 6.8)

> 1.0 IU/mL (post) 99.6 99.4 0.2 (-0.6, 1.0)

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Td506 Results: Dip and TetTd506 Results: Dip and TetSeroprotective Levels in AdultsSeroprotective Levels in Adults

TdapN=741

%

TdN=506

% Diff % (95% CI)

Diphtheria

> 0.1 IU/mL (pre)

62.6 63.3 -0.70 (-6.2, 4.8)

> 0.1 IU/mL (post)

94.1 95.1 -1.0 (-3.6, 1.5)

> 1.0 IU/mL (pre) 14.3 16.0 -1.7 (-5.7, 2.4)

> 1.0 IU/mL (post)

78.0 79.9 -0.9 (-3.5, 1.7)

Tetanus

> 0.1 IU/mL (pre)

97.3 95.9 1.4 (-0.7, 3.5)

> 0.1 IU/mL (post)

100 99.8 0.2 (-0.2, 0.6)

> 1.0 IU/mL (pre) 73.0 70.3 2.7 (-2.5, 7.7)

> 1.0 IU/mL (post)

97.8 98.2 -0.1 (-1.0, 0.8)

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Td506 Results: Dip and TetTd506 Results: Dip and TetBooster Response RatesBooster Response Rates

Adolescents Adults

BoosterRespons

e*

TdapN=52

7%

TdN=5

16%

Diff %(95%

CI)

TdapN=7

41%

TdN=50

6%

Diff %(95%

CI)

Diphtheria

95.1 95.0 0.1 (-2.5,

2.8)

87.4 83.4 4.0 (0.0,

8.0)

Tetanus 91.7 91.3 0.4 (-3.0,

3.8)

63.1 66.8 -3.7 (-9.0,

1.6)*Defined as 4-fold rise if pre-vac level below *Defined as 4-fold rise if pre-vac level below cut-off and 2-fold rise if above the cut-off level cut-off and 2-fold rise if above the cut-off level (2.56 IU/mL for dip and 2.7 IU/mL for tet)(2.56 IU/mL for dip and 2.7 IU/mL for tet)

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Td506: Endpoints - Pertussis Td506: Endpoints - Pertussis Immune Responses for Efficacy Immune Responses for Efficacy

BridgeBridge Tdap vs. DTaP (DAPTACEL®)Tdap vs. DTaP (DAPTACEL®)

DTaP ~85% efficacy against DTaP ~85% efficacy against B. B. pertussis pertussis infection with 21 days of infection with 21 days of paroxysmal cough in Sweden I paroxysmal cough in Sweden I Efficacy TrialEfficacy Trial

Geometric mean concentrations Geometric mean concentrations (GMCs) for each antigen (PT, FHA, (GMCs) for each antigen (PT, FHA, PRN and FIM), non-inferior if:PRN and FIM), non-inferior if: LL of 2-sided 95% CI ratio of LL of 2-sided 95% CI ratio of GMC (Tdap/DTaP) > 0.67GMC (Tdap/DTaP) > 0.67

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Serologic Bridge to EfficacySerologic Bridge to Efficacy DTaP (DAPTACEL®) Samples from DTaP (DAPTACEL®) Samples from

Sweden ISweden I 80 of original 181 paired samples available 80 of original 181 paired samples available

(not randomized)(not randomized) Samples obtained pre- and 1 mo post-3Samples obtained pre- and 1 mo post-3rdrd

dose from infants immunized at 2, 4 and 6 dose from infants immunized at 2, 4 and 6 mo of agemo of age

Laboratory Laboratory Assayed concurrently with Tdap samples Assayed concurrently with Tdap samples

from adolescents in Td505 using ELISA in from adolescents in Td505 using ELISA in 2002 at APL2002 at APL

Antibody values for comparisons with Antibody values for comparisons with adolescents adolescents andand adults in Td506 (primary adults in Td506 (primary comparisons for efficacy bridge)comparisons for efficacy bridge)

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Tdap and DTaP Tdap and DTaP Pertussis Post-Vaccination Pertussis Post-Vaccination

GMC*GMC*

*GMC = geometric mean concentration (ELISA Units/mL)‡ 1 month after 3 doses (2, 4 and 6 mo) in Sweden I Efficacy Trial

Infants Adolescents Adults

Post GMCDTaP‡N=80

Tdap – 505N=1053

Tdap - 506N=526

TdapN=741

PT 86.6 338.1 309.3 178.8

FHA 39.9 265.5 214.8 192.9

FIM 341.1 1804.8 1792.4 852.7

PRN 108.1 367.3 344.5 341.9

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Efficacy Bridge: Tdap vs. Efficacy Bridge: Tdap vs. DTaP DTaP

Post-Vaccination GMC Post-Vaccination GMC RatiosRatios

Antigen

AdolescentsTdap/DTaPGMC Ratio(95% CIs)

AdultsTdap/DTaPGMC Ratio(95% CIs)

PT 3.6 (2.8, 4.5) 2.1 (1.6, 2.7)

FHA 5.4 (4.5, 6.5) 4.8 (3.9, 5.9)

FIM 5.3 (3.9, 7.1) 2.5 (1.8, 3.5)

PRN 3.2 (2.5, 4.1) 3.2 (2.6, 4.4)

All lower limits of 95% CI for GMC ratios for Tdap/DTaP for adolescents and adults exceeded 0.67 criterion

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Td506: Endpoints – Td506: Endpoints – Pertussis Booster Pertussis Booster

Responses Responses Tdap vs. Historical limits for TdapTdap vs. Historical limits for Tdap

Booster Responses - % of subjects Booster Responses - % of subjects achieving booster response achieving booster response compared to acceptable rate for compared to acceptable rate for each antigen determined in each antigen determined in historical studies, non-inferior if the historical studies, non-inferior if the LL 95% CI > acceptable rate (~80%) LL 95% CI > acceptable rate (~80%)

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Td506 Results: Td506 Results: Pertussis Booster Pertussis Booster

ResponsesResponses

*Rates in historical trials used to define rate for each antigen Non-inferiority demonstrated, LL of 95% CIs > acceptable rate for each antigen

Adolescents

Adults

Antigen

N=524% (95% CI)

N=739% (95% CI)

Pre-definedAcceptable

Rate*

PT 92.0 (89.3, 94.2)

84.4 (81.6, 87.0)

81.2

FHA 85.6 (82.3, 88.4)

82.7 (79.8, 85.3)

77.6

FIM 94.9 (92.6, 96.6)

95.9 (83.2, 88.4)

82.4

PRN 94.5 (92.2, 96.3)

93.8 (91.8, 95.4)

86.4

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Td506: Endpoints - SafetyTd506: Endpoints - Safety

Tdap vs. Td – SafetyTdap vs. Td – Safety Safety comparisons for Safety comparisons for

erythema, swelling, pain erythema, swelling, pain and fever from Days 0-14and fever from Days 0-14

Rates of events, non-Rates of events, non-inferior if upper limit inferior if upper limit (UL) of 2-sided 95% CI (UL) of 2-sided 95% CI < 10%< 10%

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Td506: Safety EndpointTd506: Safety EndpointComparisons in AdolescentsComparisons in Adolescents

Adolescents

“Any” IntensitySolicited AEs (Days

0-14)

TdapN=11

75%

TdN=78

7%

Diff % (95% CI)

Erythema 20.8 19.7 1.1 (-2.6, 4.7)

Swelling 20.7 18.3 2.6 (-0.9, 6.2)

Pain 77.8 71.0 6.8 (2.8, 10.7)

Fever (> 38oC/100.4oF)

4.9 2.7 2.2 (0.6, 3.9)Non-inferiority was demonstrated for all comparisons, except pain

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Td506: Safety EndpointTd506: Safety EndpointComparisons in AdultsComparisons in Adults

Adults

“Any” IntensitySolicited AEs (Days 0-14)

TdapN=16

98%

TdN=56

1%

Diff % (95% CI)

Erythema 24.7 21.6 3.2 (-0.8, 7.1)

Swelling 21.0 17.3 3.7 (0.0, 7.4)

Pain 65.7 62.9 2.7 (-1.9, 7.3)

Fever (> 38oC/100.4oF)

1.4 1.1 0.3 (-0.7, 1.4)

Non-inferiority was demonstrated for all comparisons

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Td506 Results: Safety Td506 Results: Safety OverviewOverview

Adolescents Adults

Safety EventSafety Event

TdapN=117

5%

TdN=79

2%

TdapN=175

2%

TdN=57

3%

Immediate AEs 0.5 0.6 0.2 0.2

Any Local AEs1 Day 0-14

80.4 74.0 68.4 67.0

Any Systemic AEs2

Day 0-14

65.5 61.0 50.3 47.6

SAEs 0.9 1.0 1.9 1.91 Local AE – pain, swelling, erythema; axillary node swelling2 Systemic – fever, chills, headache, nausea, vomiting, bodyache, lethargy, rash, sore/swollen joints

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Td506 Results: Safety Td506 Results: Safety Immediate AEs – no anaphylaxis eventsImmediate AEs – no anaphylaxis events Solicited systemic AE rates similar in Solicited systemic AE rates similar in

Tdap and Td groupsTdap and Td groups Sore/swollen joints reported by ~11.5% Sore/swollen joints reported by ~11.5%

Tdap and Td adolescent groups; 9.1% Tdap and Td adolescent groups; 9.1% in Tdap and 7% in Td adult groupsin Tdap and 7% in Td adult groups

Unsolicited AEs (Days 0-28) – no pattern Unsolicited AEs (Days 0-28) – no pattern Trend for higher rate of local AEs in Tdap Trend for higher rate of local AEs in Tdap

and Td vaccinees in young adolescents and Td vaccinees in young adolescents (11-14 yrs)(11-14 yrs)

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Td506 Results: SafetyTd506 Results: Safety SAEsSAEs

83 events in 63 participants 83 events in 63 participants Rate of 1.5% in both Tdap and Td groups Rate of 1.5% in both Tdap and Td groups

No deaths reportedNo deaths reported 2 neuropathic events in adults2 neuropathic events in adults

1 day post-Tdap, 26yo female hospitalized 1 day post-Tdap, 26yo female hospitalized for migraine and unilateral facial paralysis; for migraine and unilateral facial paralysis; ↑BP (160/100) at time of vaccination ↑BP (160/100) at time of vaccination

12 days post-Tdap, 49yo female 12 days post-Tdap, 49yo female hospitalized for dysasthesia in neck and hospitalized for dysasthesia in neck and left arm; evaluated for myocardial left arm; evaluated for myocardial infarction and diagnosed as “nerve infarction and diagnosed as “nerve compression”compression”

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Td506 – Trial SummaryTd506 – Trial Summary Safety and immunogenicity Safety and immunogenicity

endpoints were met for both endpoints were met for both adolescents and adults:adolescents and adults: SafetySafety

Non-inferiority was Non-inferiority was demonstrated for AE rates demonstrated for AE rates after ADACEL™ as compared after ADACEL™ as compared to AE rates after Td (except to AE rates after Td (except “any” pain in adolescents)“any” pain in adolescents)

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Td506 – Trial Summary, Td506 – Trial Summary, cont.cont.

Immunogenicity for dip and tetImmunogenicity for dip and tet

Non-inferiority was Non-inferiority was demonstrated for dip and tet demonstrated for dip and tet following ADACEL™ as following ADACEL™ as compared to Td for:compared to Td for:Seroprotective ratesSeroprotective ratesBooster responses Booster responses

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Td506 – Trial Summary, Td506 – Trial Summary, cont.cont.

Immunogenicity for pertussis Immunogenicity for pertussis antigensantigens Non-inferiority was demonstrated Non-inferiority was demonstrated

for the immune responses to the for the immune responses to the pertussis antigens following pertussis antigens following ADACEL™ as compared to the ADACEL™ as compared to the immune responses following 3 immune responses following 3 doses of DAPTACEL® in infants in doses of DAPTACEL® in infants in the Sweden I Efficacy Trial the Sweden I Efficacy Trial

Booster responses demonstratedBooster responses demonstrated

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Pivotal Trial – Td505 Pivotal Trial – Td505 Lot Consistency StudyLot Consistency Study

Phase 3, randomized, double-blind trial Phase 3, randomized, double-blind trial to assess the lot consistency of 3 to assess the lot consistency of 3 consecutively produced lots of Tdap, as consecutively produced lots of Tdap, as measured by safety and measured by safety and immunogenicity, when given as a immunogenicity, when given as a booster to 11-17 year oldsbooster to 11-17 year olds 99.9% had documented 5 previous 99.9% had documented 5 previous

doses of dip, tet and pertussis-doses of dip, tet and pertussis-containing vaccinecontaining vaccine

Received 0.5mL IM dose of one of 3 lots Received 0.5mL IM dose of one of 3 lots of Tdapof Tdap

Assessments for safety and Assessments for safety and immunogenicity were performed similar immunogenicity were performed similar to Td506 (except no 6 mo check)to Td506 (except no 6 mo check)

30

Td505: Endpoints – Td505: Endpoints – ImmunogenicityImmunogenicity

Immunogenicity - Consistency Immunogenicity - Consistency demonstrated (equivalence demonstrated (equivalence testing) if:testing) if: Dip and tet – 2-sided 95% CI of Dip and tet – 2-sided 95% CI of

difference in seroprotection rates difference in seroprotection rates and booster rates between any 2 and booster rates between any 2 lots were within interval (-10%, lots were within interval (-10%, 10%)10%)

Pertussis antigens – 2-sided 90% CI Pertussis antigens – 2-sided 90% CI for the ratio of GMCs for any 2 lots for the ratio of GMCs for any 2 lots within interval (0.67, 1.5)within interval (0.67, 1.5)

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Td505: ResultsTd505: Results

Enrolled N=1811 (~equal in each Enrolled N=1811 (~equal in each lot)lot) Demographic characteristics Demographic characteristics

similar for each lotsimilar for each lot Lot consistency demonstratedLot consistency demonstrated

Immunogenicity - similar Immunogenicity - similar results for each of the 3 lots for results for each of the 3 lots for dip, tet and pertussis responses; dip, tet and pertussis responses; similar to Td506 adolescentssimilar to Td506 adolescents

32

Td505: Safety Endpoints Td505: Safety Endpoints and Resultsand Results

SafetySafety Erythema, swelling, pain and fever Erythema, swelling, pain and fever

from Days 0-14 for “any” or from Days 0-14 for “any” or “moderate & severe”, equivalence “moderate & severe”, equivalence testingtesting

Safety evaluations Safety evaluations contributed to contributed to safety databasesafety database Results similar between lots and Results similar between lots and similar to adolescents in Td506 similar to adolescents in Td506

No anaphylaxis events No anaphylaxis events 4 SAEs, not vaccine related4 SAEs, not vaccine related

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Td505 SummaryTd505 Summary Consistency of manufacturing of Consistency of manufacturing of

3 production lots was 3 production lots was demonstrateddemonstrated

Contributed ~1800 adolescents Contributed ~1800 adolescents to the safety database of the BLAto the safety database of the BLA

Serum samples were assayed at Serum samples were assayed at the same time as Sweden I trial the same time as Sweden I trial samples (Serology Bridging samples (Serology Bridging Study)Study)

34

Td502 – Concomitant Study Td502 – Concomitant Study of ADACEL™ and Influenza of ADACEL™ and Influenza

VaccineVaccine Open-labeled, randomized, controlled trial of Open-labeled, randomized, controlled trial of

the safety and immunogenicity of Tdap and the safety and immunogenicity of Tdap and influenza vaccines when given concurrently influenza vaccines when given concurrently or separately in adults, 19-64 years of ageor separately in adults, 19-64 years of age Group A – Tdap and Flu concurrently (Tdap+flu)Group A – Tdap and Flu concurrently (Tdap+flu) Group B – Flu then Tdap 4-6 weeks later (flu, Group B – Flu then Tdap 4-6 weeks later (flu,

Tdap)Tdap) Assessments were performed similar to Assessments were performed similar to

Td506Td506 No active safety monitoring after flu vaccine aloneNo active safety monitoring after flu vaccine alone

35

Td502: Comparisons for Td502: Comparisons for Group A (Tdap + flu) vs. Group A (Tdap + flu) vs.

Group B (flu, Tdap)Group B (flu, Tdap) Dip and TetDip and Tet

Endpoints similar to Td506Endpoints similar to Td506 Pertussis AntigensPertussis Antigens

GMC ratio A/B, if LL of 2-sided 90% CI > GMC ratio A/B, if LL of 2-sided 90% CI > 0.670.67

Influenza Strains (A/H3N2, A/H1N1, B)Influenza Strains (A/H3N2, A/H1N1, B) Seroprotection rates (defined as HAI* Seroprotection rates (defined as HAI* >>

1:40)1:40) Seroconverison (defined as Seroconverison (defined as >> 4-fold rise) 4-fold rise)

Non-inferior if UL of 2-sided 95% CI Non-inferior if UL of 2-sided 95% CI in in rates (B-A) < 10%rates (B-A) < 10%

*HAI = hemagglutination inhibition

36

Td502 Results: EnrollmentTd502 Results: Enrollment

Total =720Total =720 Group A = 359 and Group B = 361Group A = 359 and Group B = 361

Discontinued = 24Discontinued = 24 21 in Group B after flu but prior to 21 in Group B after flu but prior to

TdapTdap Demographics were similar for both Demographics were similar for both

groupsgroups 69% reported history of 5 previous 69% reported history of 5 previous

dip-tet-pertussis containing vaccines dip-tet-pertussis containing vaccines

37

Td502 Results: Immune Td502 Results: Immune ResponsesResponses

Dip, Tet and PertussisDip, Tet and PertussisImmuneResponse

Group ATdap +

FluN=354

Group B

Flu, Tdap

N=324

Seroprotection

> 0.1 IU/mL% % Diff %

Diphtheria

86.2 87 0.9 (-4.3, 6.0)

Tetanus 99.7 98.1 -1.6 (-3.1, 0.0)

Post-GMC GMC Ratio A/B (90% CI)

PT 186.4 234.5 0.79 (0.70, 0.90)

FHA 200.6 242.2 0.83 (0.75, 0.91)

FIM 925.8 1136.3 0.81 (0.68, 0.98)

PRN 191.7 260.3 0.74 (0.61, 0.88)

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Td502: Influenza Immune Td502: Influenza Immune ResponsesResponses

Group A

Tdap+flu

N=354

Group B

Flu, Tdap

N=324

B-A

Immune Response % % Diff %

95% CI

Seroprotection (HAI > 1:40)

A/Panama/2007/99 (H3N2)

86.5 88.8 2.3 -2.9, 7.4

A/New Caledonia/20/99 (H1N1)

54.0 46.9 -7.0 -14.8, 0.8

B/Yamanashi/166/98 80.6 80.3 -0.3 -6.5, 5.9

Seroconversion Rate (4-fold rise)

A/Panama/2007/99 (H3N2)

69.5 69.4 -0.1 -7.3, 7.1

A/New Caledonia/20/99 (H1N1)

68.3 67.7 -0.6 -7.9, 6.6

B/Yamanashi/166/98 62.8 65.1 2.3 -5.1, 9.8

39

Td502 Results: SafetyTd502 Results: Safety Non-inferiority of AE rates for concomitant Non-inferiority of AE rates for concomitant

vs. separate was demonstrated for vs. separate was demonstrated for erythema, swelling, and fever but erythema, swelling, and fever but notnot for for pain (‘any” and “moderate & severe” pain (‘any” and “moderate & severe” intensity) intensity) >> 1 local AEs were frequent (A=69% and 1 local AEs were frequent (A=69% and

B=64%)B=64%) Solicited systemic AE rates higher for Solicited systemic AE rates higher for

concomitant concomitant No anaphylaxis events No anaphylaxis events Two SAEs (one in each group) reported, Two SAEs (one in each group) reported,

not vaccine related; no deaths reportednot vaccine related; no deaths reported

40

Td502: Trial SummaryTd502: Trial Summary Not all endpoints were met:Not all endpoints were met: SafetySafety

Pain – more frequent with concomitant Pain – more frequent with concomitant Immunogenicity – for pertussisImmunogenicity – for pertussis

Non-inferiority of responses (GMCs) for Non-inferiority of responses (GMCs) for concomitant vs. separate was demonstrated concomitant vs. separate was demonstrated for PT, FHA and FIM, but not PRN for PT, FHA and FIM, but not PRN

Robust rises in antibodies for both groups, Robust rises in antibodies for both groups, though responses lower for concomitant though responses lower for concomitant administrationadministration

Clinical significance of failed endpoints not Clinical significance of failed endpoints not clear; should be considered in the context of clear; should be considered in the context of risks and benefits of concomitant risks and benefits of concomitant immunizationimmunization

41

Trial Trial Td501 – Concomitant Td501 – Concomitant Study Study

of ADACEL™ and Hepatitis B of ADACEL™ and Hepatitis B VaccineVaccine Open-labeled, randomized, controlled trial of Open-labeled, randomized, controlled trial of

safety and immune responses of Tdap and safety and immune responses of Tdap and hepatitis B vaccines in adolescents 11-14 years hepatitis B vaccines in adolescents 11-14 years of ageof age

Study Groups: Study Groups: 1 dose of Tdap and 2 dose regimen (1.0 mL 1 dose of Tdap and 2 dose regimen (1.0 mL

per dose) of Hep B vaccine given ~ 4 months per dose) of Hep B vaccine given ~ 4 months apart:apart: Group A – Tdap and Hep B #1 concurrently Group A – Tdap and Hep B #1 concurrently (Tdap + Hep B)(Tdap + Hep B) Group B – Tdap then Hep B dose #1, 4-6 Group B – Tdap then Hep B dose #1, 4-6

weeks later (Tdap, Hep B)weeks later (Tdap, Hep B)

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Td501: Comparisons for Group Td501: Comparisons for Group A (Tdap + Hep B) vs. Group B A (Tdap + Hep B) vs. Group B

(Tdap, Hep B)(Tdap, Hep B) Dip, Tet and Pertussis ComparisonsDip, Tet and Pertussis Comparisons

Similar to Td502Similar to Td502 Hepatitis BHepatitis B

Seroprotection rates (Seroprotection rates (>> 10 mIU/mL, Abbott 10 mIU/mL, Abbott RIA Kit), non-inferior if UL of 2-sided 95% CI RIA Kit), non-inferior if UL of 2-sided 95% CI in rates (B-A) < 10% in rates (B-A) < 10%

Safety (monitoring after Tdap similar to other Safety (monitoring after Tdap similar to other trials)trials) Erythema, swelling, pain and fever, non-Erythema, swelling, pain and fever, non-

inferior if rates of events A vs. B, if UL of inferior if rates of events A vs. B, if UL of 95% CI 95% CI (A-B) < 10% (A-B) < 10%

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Td501 Results: Td501 Results: EnrollmentEnrollment

Total = 410Total = 410 Group A (Tdap + Hep B) = 206Group A (Tdap + Hep B) = 206 Group B (Tdap, Hep B) = 204Group B (Tdap, Hep B) = 204

Demographics comparable for 2 Demographics comparable for 2 groupsgroups 89% with 5 previous dip-tet-89% with 5 previous dip-tet-

pertussis vaccines pertussis vaccines

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Td501 Results: Immune Td501 Results: Immune Responses to Diphtheria, Responses to Diphtheria,

Tetanus and PertussisTetanus and PertussisImmune Responses

Group ATdap + Hep BN=161

Group BTdap, Hep

BN=151

Seroprotection > 0.1 IU/mL

% % Diff %

Diphtheria

100 99.3 -0.7 (-1.9, 0.6)

Tetanus 100 100 0.0 (0.0, 0.0)

Post-GMC GMC Ratio A/B (90% CI)

PT 303.5 321.6 0.94 (0.8, 1.1)

FHA 301.5 305.4 0.99 (0.8, 1.2)

FIM 1906.4 1926.7 0.99 (0.8, 1.2)

PRN 292.9 284.6 1.03 (0.8, 1.3)

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Td501 Results: Td501 Results: Hepatitis B Post-Hepatitis B Post-

VaccinationVaccinationSeroprotection LevelsSeroprotection Levels

Seroprotection > 10 mIU/mL

Group ATdap + Hep BN=161

%

Group BTdap, Hep

BN=151

%

Diff %(95% CI)

Hepatitis B

96.3 97.3 1.0 (-2.8, 4.9)

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Td501 Results: SafetyTd501 Results: Safety

Safety endpoints were met for Safety endpoints were met for fever and “any” pain but fever and “any” pain but notnot for for “any” erythema , and “any” and “any” erythema , and “any” and “moderate & severe” swelling “moderate & severe” swelling Local AEs were common in Local AEs were common in

both groups (concomitant = both groups (concomitant = 88% and separate = 86.6%)88% and separate = 86.6%)

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Td501 Results: SafetyTd501 Results: Safety

Solicited systemic AEs after Tdap Solicited systemic AEs after Tdap generally higher for concomitant generally higher for concomitant groupgroup

Sore and/or swollen joints - frequent in Sore and/or swollen joints - frequent in both concomitant (22.5%) and separate both concomitant (22.5%) and separate (18%); higher rates than other trials(18%); higher rates than other trials

No anaphylaxis events No anaphylaxis events Two SAEs, one in each group, reported Two SAEs, one in each group, reported

- not vaccine related; no deaths - not vaccine related; no deaths reportedreported

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Td501: Trial SummaryTd501: Trial Summary

All of the immunogenicity, but All of the immunogenicity, but not all of the safety endpoints not all of the safety endpoints (local AEs) were met(local AEs) were met

The clinical significance of the The clinical significance of the failed safety endpoints not failed safety endpoints not clear; should be considered in clear; should be considered in the context of risks and benefits the context of risks and benefits of concomitant immunizationof concomitant immunization

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Safety Events of InterestSafety Events of InterestAcross TrialsAcross Trials

Whole limb swellingWhole limb swelling No occurrences reported in 4 main No occurrences reported in 4 main

trialstrials SeizuresSeizures

3 seizure events 3 seizure events 15 yo male 135 days post-Tdap (known 15 yo male 135 days post-Tdap (known Sz) Sz)

17 yo male 133 days post-Td (known Sz) 17 yo male 133 days post-Td (known Sz) 51 yo female 22 days post-Tdap 51 yo female 22 days post-Tdap (substance abuse)(substance abuse)

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Safety Events of InterestSafety Events of InterestAcross TrialsAcross Trials

Diabetes and Autoimmune DisordersDiabetes and Autoimmune Disorders 1 new-onset insulin-dependent diabetes 1 new-onset insulin-dependent diabetes

mellitus (IDDM) in 11yo 23 days post-mellitus (IDDM) in 11yo 23 days post-Tdap (sibling with IDDM)Tdap (sibling with IDDM)

1 non-IDDM in 56yo 13 days post-Tdap 1 non-IDDM in 56yo 13 days post-Tdap with suprasellar mass and trauma with suprasellar mass and trauma

1 IDDM in 11yo 105 days post-Td1 IDDM in 11yo 105 days post-Td No other autoimmune disorders No other autoimmune disorders

identifiedidentified

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Safety Events of Interest Safety Events of Interest

Pregnancy (Td506, 6 month follow-up)Pregnancy (Td506, 6 month follow-up) 30 women with 31 pregnancies, data 30 women with 31 pregnancies, data

for 29:for 29: 19 of 29 healthy full-term infants19 of 29 healthy full-term infants 5 spontaneous abortions (Tdap=4, Td=1)5 spontaneous abortions (Tdap=4, Td=1) 1 therapeutic abortion1 therapeutic abortion 4 premature infants, otherwise healthy4 premature infants, otherwise healthy No congenital abnormalitiesNo congenital abnormalities

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Safety Events Safety Events Exploratory Analyses of Exploratory Analyses of

Local AEsLocal AEs Age at ImmunizationAge at Immunization

Trend for higher rates of local AEs for Trend for higher rates of local AEs for younger adolescents (11 - 13 yrs) younger adolescents (11 - 13 yrs) compared to older adolescents (14 - compared to older adolescents (14 - 17 yrs) 17 yrs)

GenderGender Trend for higher rates of local AEs in Trend for higher rates of local AEs in

females than in males (in adolescents females than in males (in adolescents and adults) and adults)

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ADACEL™ BLA SummaryADACEL™ BLA Summary

Data submitted support:Data submitted support: Similar safety profile of Similar safety profile of

ADACEL™ as compared to a ADACEL™ as compared to a U.S. licensed Td U.S. licensed Td

Non-inferiority of the immune Non-inferiority of the immune responses to dip and tet as responses to dip and tet as compared to a U.S. licensed Td compared to a U.S. licensed Td

54

ADACEL™ BLA SummaryADACEL™ BLA Summary Data submitted support:Data submitted support:

Non-inferiority of the immune responses Non-inferiority of the immune responses to the pertussis antigens following to the pertussis antigens following ADACEL™ as compared to those observed ADACEL™ as compared to those observed after three doses of DAPTACEL ® in after three doses of DAPTACEL ® in infants in Sweden I Efficacy Trialinfants in Sweden I Efficacy Trial

A booster response to all of the vaccine A booster response to all of the vaccine antigensantigens

Consistency of manufacture of ADACEL™ Consistency of manufacture of ADACEL™ Additionally, data to assess Additionally, data to assess

concomitant use of Tdap with concomitant use of Tdap with influenza and hepatitis B vaccines influenza and hepatitis B vaccines were provided were provided

55

Douglas Pratt, M.D.Ms. Martha MonserBruce Meade, Ph.D.Henry Hsu, Ph.D.DVRPA