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

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Tetanus Toxoid, Reduced Diphtheria Toxoid and
Acellular Pertussis Vaccine, Adsorbed (BoostrixTM)
GlaxoSmithKline Biologicals
Vaccines and Related Biological Products Advisory
Committee Meeting March 15, 2005

• Ann T. Schwartz, MD
• CBER, FDA

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Outline

• Boostrix vs Infanrix
• Basis for Licensure
• Indication single dose, 10-18 years
• Immunogenicity
• Study Tdap/001
• Bridge to Pertussis Efficacy
• Safety
• Study Tdap/001
• Eleven non-IND studies
• Questions for the Committee

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Boostrix formulation per 0.5mL/dose comparison
with Infanrix
COMPONENT BOOSTRIX INFANRIX
Tetanus Toxoid Diphtheria Toxoid Pertussis Toxoid (PT) Filamentous Hemagglutinin (FHA) Pertactin (PRN) Aluminum Preservative 5.0 Lf 2.5 Lf 8.0 µg 8.0 µg 2.5 µg 0.3 mg (as AlOH3) None 10 Lf 25 Lf 25 µg 25 µg 8.0 µg lt 0.625 mg (as AlOH3) 2.5 mg 2-PE
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Basis for Licensure

• Indication 10-18 years, single dose booster
• Demonstration of safety
• Demonstration of non-inferiority of anti- tetanus
  and anti-diphtheria seroprotection and booster
  response vs. Td
• Demonstration of booster response to pertussis
  antigens
• Demonstration of serologic bridge to pertussis
  efficacy
• Demonstration of lot-to-lot consistency of
  Boostrix

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Pivotal Safety and Immunogenicity Study Tdap/001

• Safety, immunogenicity and lot consistency of
  Boostrix
• Comparator vaccine a U.S.-licensed Td vaccine
  (Massachusetts Public Health Biologic
  Laboratories)
•  

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Tdap/001 Primary Objectives

• To demonstrate
• non-inferiority of Boostrix vs. Td wrt anti-D
  and anti-T seroprotection rates
• non-inferiority of Boostrix vs. Td wrt anti-D
  and anti-T booster response rates
• anti-PT, anti-FHA and anti-PRN booster responses
  in vaccinees administered Boostrix
• non-inferiority of Boostrix vs. Td wrt Grade 3
  pain at the injection site

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Tdap/001 Study Design

• Prospective, randomized, observer-blinded,
  comparative multi-center study
• Adolescents 10-18 years of age
• Stratified by age before enrollment into two
  groups
• 10-14 years of age (N3000)
• 15-18 years of age (N1000)
• Randomized 1111 to four groups
• Boostrix lot 1 (N1000)
• Boostrix lot 2 (N1000)
• Boostrix lot 3 (N 1000)
• TdMPHBL (N1000)

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Tdap/001 Pertinent Inclusion / Exclusion
Criteria

• Completed routine childhood vaccinations against
  diphtheria, tetanus and pertussis diseases (4 or
  5 doses)
• DTwP doses 1-3
• DTwP or DTaP 4 and/or 5
• At least 5 years since the receipt of the
  pre-school dose of DTP
• Subjects who had received a Td booster within the
  previous 10 years were excluded

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Tdap/001 Study Vaccine Composition per 0.5mL
dose
Component Boostrix Td MPHBL
Tetanus toxoid Diphtheria toxoid Pertussis toxoid (PT) Filamentous hemagglutinin (FHA) Pertactin (PRN) Aluminum Preservative 5.0 Lf 2.5 Lf 8.0 µg 8.0 µg 2.5 µg 0.3 mg (as AlOH3) None 2.0 Lf 2.0 Lf -- -- -- 0.45 mg (as AlPO4) Thimerosal
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Tdap/001Safety surveillance and monitoring

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

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Tdap/001Overview of Study Procedures
Boostrix N 3000 TdMPHBL N 1000
10-18 years
Safety follow-up
Visit 1 Diary card Visit 2 Phone
call Bleed 1/ Vaccination Bleed 2 End
study Day 0 Day 14 Day 30 Month 6
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Tdap/001Populations for analysis

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

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• Results

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Tdap/001Demographics Total Vaccinated
Cohort(N 4114)

• 52.1 males and 47.9 females
• Ethnicity
• 85.7 Caucasian
• 5.6 African-Americans
• 5.7 Hispanics
• 0.8 Asians
• 2 Other
• Mean age 12.9 years
• 75.2 subjects 10-14 years of age
• 24.8 subjects 15-18 years

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Tdap/001

• IMMUNOGENICITY

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Tdap/001Immunogenicity

• Definitions, endpoints and results
• Diphtheria and Tetanus toxoids
• Seroprotection
• Pre-vaccination
• Booster response
• Results
• Pertussis antigens
• Booster response
• Results
• Serologic Bridge to Infanrix pertussis antigens

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

• Seroprotection gt 0.1 IU/mL
• Booster response
• Pre lt 0.1 IU/mL Post gt 0.4 IU/mL
• Pre gt 0.1 IU/mL Post Four-fold rise

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Tdap/001 Pre-vaccination anti-toxoid
levels(ATP cohort for immunogenicity)
Antigen Boostrix N2466-2471 TdMPHBL N814-817
Antigen (95 CI) (95 CI)
Diphtheria ? 0.1 IU/mL 85.8 (84.3, 87.1) 84.8 (82.1, 87.2)
? 1.0 IU/mL 17.1 (15.6, 18.6) 19.5 (16.9, 22.4)
Tetanus ? 0.1 IU/mL 97.7 (97.1, 98.3) 96.8 (95.4, 97.9)
? 1.0 IU/mL 36.8 (34.9, 38.7) 39.9 (36.5, 43.4)
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Tdap/001 Primary Immunogenicity Endpoints and
Non-inferiority Criteria (Boostrix vs TdMPHBL)
Antigen Endpoint Td -Boostrix
anti-diphtheria ? 0.1 IU/mL UL 95 CI ? ?10
anti-diphtheria booster UL 95 CI ? ?10
anti-tetanus ? 0.1 IU/mL UL 95 CI ? ?10
anti-tetanus booster UL 95 CI ? ?10
2-sided 95 CI
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Tdap/001 Differences in anti-diphtheria
response rates between Boostrix and TdMPHBL
one month post vaccination (ATP cohort for
immunogenicity)
Endpoint Boostrix TdMPHBL Td - Boostrix ? (95 CI)
() ()
? 0.1 IU/mL 99.9 99.9 0.0 (-0.6, 0.3)
Booster response 90.6 95.9 5.3 (3.4, 7.0)
? 1.0 IU/mL 97.3 99.3 2.0 (1.0, 2.8)
Boostrix N 2463-2516, Td N814-834
Non-inferiority criterion met Non-inferiority
criteria were not pre-specified
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Tdap/001 Differences in anti-tetanus response
rates between Boostrix and TdMPHBL one month
post vaccination (ATP cohort for immunogenicity)
Endpoint Boostrix TdMPHBL Td - Boostrix ? (95 CI)
() ()
? 0.1 IU/mL 100 100 0.0 (-0.4, 0.2)
Booster response 89.7 92.5 2.9 (0.6, 4.9)
? 1.0 IU/mL 99.5 99.8 0.3 (-0.4, 0.7)

• Boostrix N 2463-2516, Td N814-834
• Non-inferiority criterion met
• Non-inferiority criteria were not pre-specified

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

• Booster response to PT, FHA, PRN
• Pre lt 5 EU/mL Post gt 20 EU/mL
• Pre gt 5 EU/mLlt 20 EU/mL Post 4-fold rise
• Pre gt 20 EU/mL Post gt 2-fold rise

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Tdap/001 Primary Immunogenicity Endpoints
(Boostrixpertussis antigens)
Antigens Endpoint Evaluation criteria LL of 2-sided 95 CI
anti-PT booster ?80
anti-FHA booster ?80
anti-PRN booster ?80
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Tdap/001 Booster response (BR) to pertussis
antigens one month post-Boostrix in 10-18 years
old (ATP cohort for immunogenicity)
Antigen BR Rate () 95 CI
PT 84.5 (83.0, 85.8)
FHA 95.1 (94.2, 95.9)
PRN 95.4 (94.5, 96.1)

• Boostrix N 2677 2752
• Primary endpoint met

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Serologic bridge to pertussis efficacy study
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Serologic bridge to clinical efficacy
StudyTdap/001 and APV/039, APV/050

• Non-inferiority to Infanrix, administered as a
  3-dose primary series
• GMCs one month post Boostrix compared to GMCs
  one month after completing infant series with
  Infanrix

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Serologic bridge APV-039 and APV-050

• Study APV-039
• Safety, immunogenicity and lot consistency study
  of Infanrix
• 3-dose series at 3, 4, and 5 months of age
• Pop. for household contact study APV-050
• Study APV-050
• Efficacy 89 (95 CI 77- 95) against
  WHO-defined pertussis
• gt 21 days of paroxysmal cough with positive
  culture and/or serologic testing

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Serologic bridge Testing of study samples

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

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Endpoints for serologic bridge
Pertussis antigens Endpoint (EU/mL) Ratio Infanrix/Boostrix
anti-PT GMC UL 95 CI lt 1.5
anti-FHA GMC UL 95 CI lt 1.5
anti-PRN GMC UL 95 CI lt 1.5
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Ratios of GMCs between Boostrix and Infanrix
one month post-vaccination (TVC)
Antigen Infanrix Infanrix Boostrix Boostrix Infanrix/ Boostrix
Antigen N GMC N GMC Ratio (95 CI)
anti-PT 2884 45.7 2941 86.9 0.53 (0.50,0.55)
anti-FHA 685 83.6 2979 614.8 0.14 (0.13,0.15)
anti-PRN 631 112.3 2978 470.7 0.24 (0.21,0.27)
ELISA units / mL pre-specified
non-inferiority criteria met
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• Safety

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Overall Safety Database

• 3289 subjects, age 10-18 years, received a single
  dose of Boostrix (Studies Tdap/001 and Tdap/029)
• 2163 additional subjects, 4-78 years of age,
  analyzed for safety after receipt of a single
  dose of Tdap (0.5 mg Al) in eleven non-IND studies

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Tdap/001Safety

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

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Tdap/001 Primary Safety Endpoint and
Non-inferiority criterion
Event Endpoint Boostrix - Td
Grade 3 pain UL 95 CI ? ? 4
Grade 3 pain spontaneously painful and/or
prevented normal activity
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Tdap/001 Incidence of Pain within 15 days
post-vaccination in subjects 10-18 years of age
(TVC)
Intensity Boostrix TdMPHBL Boostrix Td ? (95 CI)
Any 75.3 71.7 3.66 (0.55,6.89)
Grade gt2 51.2 42.5 8.67 (5.13,12.17)
Grade 3 4.6 4.0 0.54 (-1.01, 1.87)
Any pain painful on touch Grade 2 pain
painful when limb moved Grade 3 pain
spontaneously painful and/or prevented normal
activity non-inferiority criterion met (upper
limit 95 CI on the difference ?4)  
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Tdap/001 Incidence of local symptoms in
subjects 10-18 years within 72 hours of
vaccination (TVC)
Event Intensity Boostrix () Td MPHBL ()
Redness Any 21.9 19.5
Redness gt 20 mm 4.0 3.8
Redness gt 50 mm 1.6 1.5
Swelling Any 20.2 19.8
Swelling gt 20 mm 5.0 4.8
Swelling gt 50 mm 2.4 3.2
Increased arm circumference gt5 mm 21.4 23.2
Increased arm circumference gt 20 mm 1.6 1.5
Increased arm circumference gt 40 mm 0.3 0.3
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Tdap/001 Incidence of solicited systemic
symptoms within 15 days following administration
of Boostrix or TdMPHBL (TVC)
Event Intensity Boostrix () N 3030 Td MPHBL () N 1013
Fever (oral/axillary) gt 37.5C 13.4 13.1
Fever (oral/axillary) gt 38C 5.0 4.7
Fever (oral/axillary) gt 39C 1.4 1.0
Headache Any 43.1 41.5
Headache Grade ?2 15.7 12.7
Headache Grade 3 3.7 2.7
Fatigue Any 37.0 36.7
Fatigue Grade ?2 14.4 12.9
Fatigue Grade 3 3.7 3.2
GI Symptoms Any 26.0 25.8
GI Symptoms Grade ?2 9.8 9.7
GI Symptoms Grade 3 3.0 3.2
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Tdap/001 Occurrence of Serious Adverse events

• Serious adverse events occurring during the 6
  month post vaccination
• 0.5 (15) events in the Boostrix group
• 0.2 (2) events in the TdMPHBL group
• No SAEs reported during days 0-30
  post-vaccination

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

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

• Wounds/fractures (4)
• Overdose/drug abuse(3)
• Depression/ADHD (2)
• Cholecystitis (1)
• Headache (1)
• Spontaneous AB (1)
• Menorrhagia (1)

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Tdap/001 Percentage of subjects (10-18 years
old) reporting AEs during the 5 month follow-up
period by type (TVC)
AE Type Boostrix () N 3005 Boostrix () N 3005 TdMPHBL () N 1003 TdMPHBL () N 1003
AE Type n () n ()
Chronic illness 22 0.7 9 0.9
ER visit 101 3.4 25 2.5
Non-routine medical visit 52 1.7 16 1.6
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Occurrence of Serious adverse events in eleven
additional studies post-vaccination
Vaccine N 2372 Age/Gender Event Onset (days)
Boostrix 14 / F Alcohol intoxication 21
Non-US formulation Boostrix 13 / M Syncope 28
Non-US formulation Boostrix 11 / F Diabetic hypoglycemia / seizure 37
Non-US formulation Boostrix 11 / F Diabetes 20
Non-US formulation Boostrix 10 / F Appendicitis 23
Non-US formulation Boostrix 12 / F LOC immediate
Non-US formulation Boostrix 49 / F Uveitis 7
Non-US formulation Boostrix 6 / F Polypectomy 29
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Summary

• Primary immunogenicity endpoints all met
• Primary safety endpoint met
• No unexpected adverse events or serious safety
  concerns
• Serologic Bridge Non-inferiority criteria met

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Questions and discussion items for the committee

• 1. Are the available data adequate to support
  the efficacy of Boostrix in
  individuals 10-18 years of age?
• VOTE
• 2. Are the available data adequate to support
  the safety of Boostrix when administered to
  individuals 10-18 years of age?
• VOTE
• 3. Please identify any issues which should be
  addressed, including post-licensure studies.
• Discussion