Immunogenicity of Pentacel

1
Immunogenicity of Pentacel

• Theresa Finn, Ph.D.
• OVRR, CBER

2
Overview of presentation

• Clinical Studies
• Immunogenicity
• Endpoints
• Diphtheria toxoid
• Tetanus toxoid
• Polioviruses
• Hib
• Pertussis
• Serology bridge to DAPTACEL in Sweden I
• Comparison to DAPTACEL in US-children
• Concurrent Prevnar
• (Concomitant Vaccines)
• Summary

3
Controlled Studies

• 494-01 (U.S.)
• Pentacel compared to HCPDT (DTaP) POLIOVAX
  ActHIB (doses 1-4)
  
• P3T06 (U.S.)
• Pentacel compared to DAPTACEL IPOL ActHIB
  (doses 1-3)
  
• Pentacel compared to DAPTACEL ActHIB (dose 4)

4
Pentacel Studies which did not include a group
receiving control vaccines

• 494-03 (U.S.) dose 1-4
• 5A9908 (Canada) dose 4
• M5A07 (U.S.)

5
Immunogenicity Population Pentacel Studies

• Population for primary immunogenicity analyses
  Per Protocol for Immunogenicity (PPI)
  Population
  
• Eligible subjects, blood draws and vaccines
  within protocol specified windows, and serology
  result for at least one antigen post-dose 3 or 4
  

6
Statistical considerations

• Non-inferiority analyses
• Previously, CBER used 90 CI for difference in
  sero-protection/seroconversion rates and for
  ratio of GMCs
  
• Currently, CBER recommends 95 CI for difference
  in rates and for ratio of GMCs

7
Immunogenicity of Diphtheria, Tetanus, Polio and
Hib components
8
Immune response to Diphtheria and Tetanus Toxoids
9
Study P3T06 Diphtheria and Tetanus
seroprotection rates post dose 3
10
Immune response to Poliovirus types 1, 2 and 3
11
P3T06 Polio seroprotection rates post dose 3
12
Immune response to PRP-T
13
Study 494-01 PRP antibody levels post-dose 3
1Non-inferiority UL 90 CI difference 2Non-inferiority UL 90 CI ratio 14
Study P3T06 PRP antibody levels post-dose 3
1Non-inferiority UL 90 CI difference 2Non-inferiority criteria not specified in the
protocol
15
Study 494-01 and Study P3T06 Exploratory
analysis PRP antibody levels pre-dose 4
Study P3T06 Group 1 (DAPTACEL ActHIB)
16
Immune response to PT, FHA, Fimbriae 23 and
Pertactin
17
Efficacy of Pertussis Component

• Serology bridge
• Pentacel Study 494-01 compared to DAPTACEL Sweden
  I
  
• Comparison to DAPTACEL in US children
• Study P3T06
• Endpoints
• 4-fold rise relative to pre-dose 1 antibody
  levels
  
• GMC

18
Sweden I Efficacy Trial

• Sweden I Efficacy Trial
• March 1992-January 1995
• 2500 infants administered DAPTACEL at 2, 4 and
  6 months of age
  
• Compared to DT control vaccine efficacy of three
  doses of DAPTACEL against WHO defined pertussis
  ( 21 days cough with culture/serologic
  confirmation/epi link 84.9 (95 CI 80.1, 88.6)

19
Basis for DAPTACEL efficacy in U.S.

• Serology bridge post-dose 3 DAPTACEL in US
  children to post-dose 3 Sweden I
  
• pertactin seroconversion rates and GMCs
  significantly lower in US infants
  
• response to PT, FHA and FIM similar in US and
  Swedish infants
  
• Serology bridge post-dose 4 DAPTACEL in Canada to
  post-dose 3 Sweden I
  
• post-dose 4 GMCs were at least as high as those
  of Swedish infants

20
Serology bridge Non-inferiority of GMCs
1Non-inferiority UL 90 CI ratio 21
Serology bridge Non-inferiority of
seroconversion rates
1Post dose 3/pre-dose 1, 2Post dose 4/pre-dose 1
,
3Non-inferiority UL 95 CI 22
Serology bridge CBER Exploratory Analyses -
Seroconversion rates post-dose 3
CBER generated 95 CI (STAT EXACT)
Subjects in Study 494-01 had 3 concurrently
administered doses of Prevnar with Pentacel
23
Serology bridge CBER Exploratory Analysis - GMCs
post-dose 3
CBER generated 90 CI (STAT EXACT)
Subjects in Study 494-01 had 3 concurrently
administered doses of Prevnar with Pentacel
24
Comparison to DAPTACEL in Study P3T06
25
Comparison to DAPTACEL, Study P3T06
Non-inferiority of seroconversion rates post
dose 3
1Post-dose3/pre-dose1 2Non-inferiority UL 90 CI
difference 26
Comparison to DAPTACEL, Study P3T06
Non-inferiority of GMCs post-dose 3
1Non-inferiority is demonstrated when UL 90 CI
ratio 27
Comparison to DAPTACEL, Study P3T06
Non-inferiority of seroconversion rates
post-dose 4
1Post-dose4/pre-dose1 2Non-inferiority is demonst
rated when UL 90 CI difference 28
Comparison to DAPTACEL, Study P3T06
Non-inferiority of GMCs post-dose 4
1Non-inferiority is demonstrated when UL 90 CI
ratio 29
Effect of Prevnar

• Study 494-01 exploratory analyses
• Post-dose 4 across pivotal studies

30
Effect of Prevnar Pertussis GMCs following four
doses of Pentacel in pivotal studies
31
Effect of Prevnar

• Study M5A07
• Pentacel Prevnar at 2, 4, 6, 15 months of age
• Pentacel at 2, 4, 6 and 15 months of age, Prevnar
  at 3, 5, 7 and 12 months of age
  
• Summary post-dose 3 data in BLA

32
Effect of Prevnar, Study M5A07 Non-inferiority
of seroconversion rates post-dose 3
1The fold rise Post-Dose 3/Pre-Dose 1 antibody
level (EU/mL).
²Non-inferiority UL 95 CI 33
Effect of Prevnar, Study M5A07Non-inferiority
of GMCs post-dose 3
1Non-inferiority UL 90 CI ratio is 34
Response to concomitantly administered vaccines

• Hepatitis B
• 10mIU/mL and GMC similar when given with
  Pentacel or Control vaccines
  
• Prevnar
• Post dose 3 0.15 ug/mL, 0.5ug/mL and GMC
  similar when given with Pentacel or Control
  vaccines
  
• Post-dose 4 Non-inferiority demonstrated (
  0.15 ug/mL, 0.5 ug/mL and GMC) when given with
  Pentacel or MMR Varivax (Study 494-03)
  
• MMR
• Varicella

Non-inferiority demonstrated for
seroresponse rates
35
Summary Pentacel immunogenicity concerns PRP-T

• PRP-T component
• Study 494-01
• diminished 1.0 ug/mL vs. ActHIB
• diminished GMC vs. ActHIB
• Study P3T06
• similar 1.0 ug/mL vs. ActHIB
• similar GMC vs. ActHIB

36
Summary Pentacel immunogenicity concerns
Pertussis antigens

• Post dose 3
• Serology bridge to Sweden I (exploratory)
• diminished anti-FIM (GMC),
• diminished anti-pertactin (4x rise and GMC)
• Post dose 4
• Serology bridge to Sweden I
• diminished anti-pertactin (4x rise)
• Study P3T06
• diminished anti-pertactin (GMC)

37
Questions and Discussion Items

• Are the available data adequate to support the
  safety of four doses of Pentacel administered at
  2, 4, 6 and 15-18 months of age?
  
• (Voting Item)
• If the available data are not adequate, what
  additional data are needed?
  

38
Questions and Discussion Items contd.

• Please discuss whether the available data are
  adequate to support the efficacy of
  
• a) The diphtheria, tetanus and polio components
  of Pentacel,
  
• b) The Hib (PRP-T) component of Pentacel, and
• c) The pertussis component of Pentacel.
• Are the available data adequate to support the
  efficacy of Pentacel?
  
• (Voting Item)
• If the available data are not adequate, what
  additional data are needed?
  

39
Questions and Discussion Items contd.

• 3. If Pentacel is licensed, please identify any
  issues which should be addressed in
  post-licensure studies.