Tetanus Toxoid, Reduced Diphtheria Toxoid and Acellular Pertussis Vaccine, Adsorbed Tdap, ADACEL Ave

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Tetanus Toxoid, Reduced Diphtheria Toxoid and
Acellular Pertussis Vaccine, Adsorbed(Tdap,
ADACEL)Aventis Pasteur, Ltd.

• VRBPAC March 15, 2005
• ChrisAnna M. Mink, M.D.
• FDA/OVRR/DVRPA

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Composition of Study Vaccines
1DTaP licensed in U.S. for first 4 doses of
primary series evaluated in Sweden I 2Td
manufactured by Aventis Pasteur Inc, U.S.
(API) 3Aluminum as AlPO4
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Indication Sought

• ADACEL is indicated for the active immunization
  for the prevention of diphtheria, tetanus and
  pertussis in adolescents and adults aged 11
  through 64 years as a booster.
• The dosing schedule is one dose administered
  intramuscularly (IM).

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Tdap Trials Submitted to the BLA

• Pivotal
• Td506 Comparative study
• Serology Bridge for Efficacy (lab study)
• Td505 Lot consistency
• Non-Pivotal (Concomitant immunizations)
• Td502 Tdap with influenza vaccine
• Td501 Tdap with hepatitis B vaccine
• Historical Trials 3 abbreviated reports
• Safety Database 6803 Tdap recipients

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Pivotal Trial Td506

• Phase 3, randomized, observer-blinded, controlled
  trial comparing Tdap (ADACEL) with Td in
  adolescents and adults 11-64 years of age
• No diphtheria-tetanus-pertussis containing
  vaccines in previous 5 years
• Stratified within age groups
• Tdap Td 32 for 11-17yr
• 31 for 18-64yr
• One 0.5 mL IM dose of Tdap or Td

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Pivotal Trial Td506

• Monitoring
• Immunogenicity
• Randomly selected subset in each age strata
• Serum - pre-vac and post-vac (35 7 days)
• Safety
• Immediate adverse events (AEs) 30 min
• Solicited AEs diary card x 14 days
• SAEs, new onset medical conditions 6 mo

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Td506 - Objectives

• Tdap vs. Td
• To compare safety
• To assess the immune responses to diphtheria
  (dip) and tetanus (tet)
• Tdap vs. DTaP (DAPTACEL)
• To compare the immune response to pertussis
  antigens
• Separate assessments for adolescents
• (11-17 yrs) and adults (18-64 yrs)

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Td506 Results Enrollment
19 were not vaccinated
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Td506 Results Populations

• Demographic characteristics
• Similar for Tdap and Td groups
• Populations for analysis
• Intent-to-treat, safety (ITTS) all randomized
  and received study vaccine (Tdap or Td)
• ITT, Immunogenicity (ITTI) randomized,
  vaccinated and bled
• Per-Protocol Immunogenicity (PPI) ITTI subset
  with no major protocol violations

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Td506 Endpoints - Dip and Tet Immune Responses

• Tdap vs. Td, of subjects achieving response
  non-inferior if lower limit (LL) of 2-sided 95
  CI of the difference (?) in rates is gt -10
• Seroprotective levels
• Defined gt 0.1 IU/mL
• Booster responses
• Defined as 4-fold rise if pre-vac level below
  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)

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Td506 Results Dip and TetSeroprotective Levels
in Adolescents
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Td506 Results Dip and TetSeroprotective Levels
in Adults
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Td506 Results Dip and TetBooster Response Rates
Defined as 4-fold rise if pre-vac level below
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)
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Td506 Endpoints - Pertussis Immune Responses for
Efficacy Bridge

• Tdap vs. DTaP (DAPTACEL)
• DTaP 85 efficacy against B. pertussis infection
  with 21 days of paroxysmal cough in Sweden I
  Efficacy Trial
• Geometric mean concentrations (GMCs) for each
  antigen (PT, FHA, PRN and FIM), non-inferior if
• LL of 2-sided 95 CI ratio of GMC (Tdap/DTaP) gt
  0.67

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Serologic Bridge to Efficacy

• DTaP (DAPTACEL) Samples from Sweden I
• 80 of original 181 paired samples available (not
  randomized)
• Samples obtained pre- and 1 mo post-3rd dose from
  infants immunized at 2, 4 and 6 mo of age
• Laboratory
• Assayed concurrently with Tdap samples from
  adolescents in Td505 using ELISA in 2002 at APL
• Antibody values for comparisons with adolescents
  and adults in Td506 (primary comparisons for
  efficacy bridge)

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Tdap and DTaP Pertussis Post-Vaccination GMC
GMC geometric mean concentration (ELISA
Units/mL) 1 month after 3 doses (2, 4 and 6 mo)
in Sweden I Efficacy Trial
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Efficacy Bridge Tdap vs. DTaP Post-Vaccination
GMC Ratios
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 Pertussis Booster Responses

• Tdap vs. Historical limits for Tdap
• Booster Responses - of subjects achieving
  booster response compared to acceptable rate for
  each antigen determined in historical studies,
  non-inferior if the LL 95 CI gt acceptable rate
  (80)

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Td506 Results Pertussis Booster Responses
Rates in historical trials used to define rate
for each antigen Non-inferiority demonstrated,
LL of 95 CIs gt acceptable rate for each antigen
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Td506 Endpoints - Safety

• Tdap vs. Td Safety
• Safety comparisons for erythema, swelling, pain
  and fever from Days 0-14
• Rates of events, non-inferior if upper limit (UL)
  of 2-sided 95 CI ? lt 10

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Td506 Safety EndpointComparisons in Adolescents
Non-inferiority was demonstrated for all
comparisons, except pain
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Td506 Safety EndpointComparisons in Adults
Non-inferiority was demonstrated for all
comparisons
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Td506 Results Safety Overview
1 Local AE pain, swelling, erythema axillary
node swelling 2 Systemic fever, chills,
headache, nausea, vomiting, bodyache,
lethargy, rash, sore/swollen joints
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Td506 Results Safety

• Immediate AEs no anaphylaxis events
• Solicited systemic AE rates similar in Tdap and
  Td groups
• Sore/swollen joints reported by 11.5 Tdap and
  Td adolescent groups 9.1 in Tdap and 7 in Td
  adult groups
• Unsolicited AEs (Days 0-28) no pattern
• Trend for higher rate of local AEs in Tdap and Td
  vaccinees in young adolescents (11-14 yrs)

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Td506 Results Safety

• SAEs
• 83 events in 63 participants
• Rate of 1.5 in both Tdap and Td groups
• No deaths reported
• 2 neuropathic events in adults
• 1 day post-Tdap, 26yo female hospitalized for
  migraine and unilateral facial paralysis ?BP
  (160/100) at time of vaccination
• 12 days post-Tdap, 49yo female hospitalized for
  dysasthesia in neck and left arm evaluated for
  myocardial infarction and diagnosed as nerve
  compression

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Td506 Trial Summary

• Safety and immunogenicity endpoints were met for
  both adolescents and adults
• Safety
• Non-inferiority was demonstrated for AE rates
  after ADACEL as compared to AE rates after Td
  (except any pain in adolescents)

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Td506 Trial Summary, cont.

• Immunogenicity for dip and tet
• Non-inferiority was demonstrated for dip and tet
  following ADACEL as compared to Td for
• Seroprotective rates
• Booster responses

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Td506 Trial Summary, cont.

• Immunogenicity for pertussis antigens
• Non-inferiority was demonstrated for the immune
  responses to the pertussis antigens following
  ADACEL as compared to the immune responses
  following 3 doses of DAPTACEL in infants in the
  Sweden I Efficacy Trial
• Booster responses demonstrated

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Pivotal Trial Td505 Lot Consistency Study

• Phase 3, randomized, double-blind trial to assess
  the lot consistency of 3 consecutively produced
  lots of Tdap, as measured by safety and
  immunogenicity, when given as a booster to 11-17
  year olds
• 99.9 had documented 5 previous doses of dip, tet
  and pertussis-containing vaccine
• Received 0.5mL IM dose of one of 3 lots of Tdap
• Assessments for safety and immunogenicity were
  performed similar to Td506 (except no 6 mo check)

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Td505 Endpoints Immunogenicity

• Immunogenicity - Consistency demonstrated
  (equivalence testing) if
• Dip and tet 2-sided 95 CI of difference in
  seroprotection rates and booster rates between
  any 2 lots were within interval (-10, 10)
• Pertussis antigens 2-sided 90 CI for the ratio
  of GMCs for any 2 lots within interval (0.67, 1.5)

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Td505 Results

• Enrolled N1811 (equal in each lot)
• Demographic characteristics similar for each lot
• Lot consistency demonstrated
• Immunogenicity - similar results for each of the
  3 lots for dip, tet and pertussis responses
  similar to Td506 adolescents

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Td505 Safety Endpoints and Results

• Safety
• Erythema, swelling, pain and fever from Days 0-14
  for any or moderate severe, equivalence
  testing
• Safety evaluations ? contributed to safety
  database
• Results similar between lots and similar to
  adolescents in Td506
• No anaphylaxis events
• 4 SAEs, not vaccine related

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Td505 Summary

• Consistency of manufacturing of 3 production lots
  was demonstrated
• Contributed 1800 adolescents to the safety
  database of the BLA
• Serum samples were assayed at the same time as
  Sweden I trial samples (Serology Bridging Study)

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Td502 Concomitant Study of ADACEL and
Influenza Vaccine

• Open-labeled, randomized, controlled trial of the
  safety and immunogenicity of Tdap and influenza
  vaccines when given concurrently or separately in
  adults, 19-64 years of age
• Group A Tdap and Flu concurrently (Tdapflu)
• Group B Flu then Tdap 4-6 weeks later (flu,
  Tdap)
• Assessments were performed similar to Td506
• No active safety monitoring after flu vaccine
  alone

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Td502 Comparisons for Group A (Tdap flu) vs.
Group B (flu, Tdap)

• Dip and Tet
• Endpoints similar to Td506
• Pertussis Antigens
• GMC ratio A/B, if LL of 2-sided 90 CI gt 0.67
• Influenza Strains (A/H3N2, A/H1N1, B)
• Seroprotection rates (defined as HAI gt 140)
• Seroconverison (defined as gt 4-fold rise)
• Non-inferior if UL of 2-sided 95 CI ? in
• rates (B-A) lt 10

HAI hemagglutination inhibition
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Td502 Results Enrollment

• Total 720
• Group A 359 and Group B 361
• Discontinued 24
• 21 in Group B after flu but prior to Tdap
• Demographics were similar for both groups
• 69 reported history of 5 previous
  dip-tet-pertussis containing vaccines

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Td502 Results Immune ResponsesDip, Tet and
Pertussis
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Td502 Influenza Immune Responses
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Td502 Results Safety

• Non-inferiority of AE rates for concomitant vs.
  separate was demonstrated for erythema, swelling,
  and fever but not for pain (any and moderate
  severe intensity)
• gt 1 local AEs were frequent (A69 and B64)
• Solicited systemic AE rates higher for
  concomitant
• No anaphylaxis events
• Two SAEs (one in each group) reported, not
  vaccine related no deaths reported

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Td502 Trial Summary

• Not all endpoints were met
• Safety
• Pain more frequent with concomitant
• Immunogenicity for pertussis
• Non-inferiority of responses (GMCs) for
  concomitant vs. separate was demonstrated for PT,
  FHA and FIM, but not PRN
• Robust rises in antibodies for both groups,
  though responses lower for concomitant
  administration
• Clinical significance of failed endpoints not
  clear should be considered in the context of
  risks and benefits of concomitant immunization

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Trial Td501 Concomitant Study of ADACEL and
Hepatitis B Vaccine

• Open-labeled, randomized, controlled trial of
  safety and immune responses of Tdap and hepatitis
  B vaccines in adolescents 11-14 years of age
• Study Groups
• 1 dose of Tdap and 2 dose regimen (1.0 mL per
  dose) of Hep B vaccine given 4 months apart
• Group A Tdap and Hep B 1 concurrently
• (Tdap Hep B)
• Group B Tdap then Hep B dose 1, 4-6 weeks
  later (Tdap, Hep B)

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

• Dip, Tet and Pertussis Comparisons
• Similar to Td502
• Hepatitis B
• Seroprotection rates (gt 10 mIU/mL, Abbott RIA
  Kit), non-inferior if UL of 2-sided 95 CI ? in
  rates (B-A) lt 10
• Safety (monitoring after Tdap similar to other
  trials)
• Erythema, swelling, pain and fever, non-inferior
  if rates of events A vs. B, if UL of 95 CI ?
  (A-B) lt 10

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Td501 Results Enrollment

• Total 410
• Group A (Tdap Hep B) 206
• Group B (Tdap, Hep B) 204
• Demographics comparable for 2 groups
• 89 with 5 previous dip-tet-pertussis vaccines

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Td501 Results Immune Responses to Diphtheria,
Tetanus and Pertussis
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Td501 Results Hepatitis B Post-VaccinationSerop
rotection Levels
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Td501 Results Safety

• Safety endpoints were met for fever and any
  pain but not for any erythema , and any and
  moderate severe swelling
• Local AEs were common in both groups (concomitant
  88 and separate 86.6)

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Td501 Results Safety

• Solicited systemic AEs after Tdap generally
  higher for concomitant group
• Sore and/or swollen joints - frequent in both
  concomitant (22.5) and separate (18) higher
  rates than other trials
• No anaphylaxis events
• Two SAEs, one in each group, reported - not
  vaccine related no deaths reported

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Td501 Trial Summary

• All of the immunogenicity, but not all of the
  safety endpoints (local AEs) were met
• The clinical significance of the failed safety
  endpoints not clear should be considered in the
  context of risks and benefits of concomitant
  immunization

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Safety Events of InterestAcross Trials

• Whole limb swelling
• No occurrences reported in 4 main trials
• Seizures
• 3 seizure events
• 15 yo male 135 days post-Tdap (known Sz)
• 17 yo male 133 days post-Td (known Sz)
• 51 yo female 22 days post-Tdap (substance abuse)

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Safety Events of InterestAcross Trials

• Diabetes and Autoimmune Disorders
• 1 new-onset insulin-dependent diabetes mellitus
  (IDDM) in 11yo 23 days post-Tdap (sibling with
  IDDM)
• 1 non-IDDM in 56yo 13 days post-Tdap with
  suprasellar mass and trauma
• 1 IDDM in 11yo 105 days post-Td
• No other autoimmune disorders identified

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Safety Events of Interest

• Pregnancy (Td506, 6 month follow-up)
• 30 women with 31 pregnancies, data for 29
• 19 of 29 healthy full-term infants
• 5 spontaneous abortions (Tdap4, Td1)
• 1 therapeutic abortion
• 4 premature infants, otherwise healthy
• No congenital abnormalities

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Safety Events Exploratory Analyses of Local AEs

• Age at Immunization
• Trend for higher rates of local AEs for younger
  adolescents (11 - 13 yrs) compared to older
  adolescents (14 - 17 yrs)
• Gender
• Trend for higher rates of local AEs in females
  than in males (in adolescents and adults)

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ADACEL BLA Summary

• Data submitted support
• Similar safety profile of ADACEL as compared to
  a U.S. licensed Td
• Non-inferiority of the immune responses to dip
  and tet as compared to a U.S. licensed Td

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ADACEL BLA Summary

• Data submitted support
• Non-inferiority of the immune responses to the
  pertussis antigens following ADACEL as compared
  to those observed after three doses of DAPTACEL
  in infants in Sweden I Efficacy Trial
• A booster response to all of the vaccine antigens
• Consistency of manufacture of ADACEL
• Additionally, data to assess concomitant use of
  Tdap with influenza and hepatitis B vaccines were
  provided

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