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  • The VRBPAC committee did not comment on specific immunogenicity criteria to use in comparative analyses.

Overview Presentation Transcript

  • 1. Primary Immunogenicity Endpoints for New Infant Pneumococcal Conjugate Vaccines Vaccines and Related Biological Products Advisory Committee Meeting Lucia H. Lee, M.D. CBER, FDA November 18, 2009 Prevnar 13 Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein]
  • 2. Overview
    • Background
      • Prevnar clinical efficacy trial: invasive pneumococcal disease (IPD)
    • VRBPAC 2001
      • Comparative immunogenicity studies in U.S. children
    • WHO Technical Report Series (TRS) No.927
      • Pneumococcal IgG antibody concentration: 0.35 µg/mL
      • Opsonophagocytic antibody (OPA): important supportive data
      • Post-marketing effectiveness studies
    • PCV13 pivotal U.S. immunogenicity trial design
      • Immunogenicity assessment to support licensure
  • 3. 7-valent pneumococcal conjugate vaccine (Prevnar, PCV7)
    • Prevnar efficacy trial: NCKP 1
      • Primary clinical outcome: prevention of vaccine serotype IPD
      • Aggregate vaccine clinical efficacy: 97% (95%CI 85,100)
    • Vaccine effectiveness for each serotype shown post-licensure 2
    • U.S. Licensure in February 2000
      • Routine infant immunization schedule
    • New Multivalent Pneumococcal Conjugate (PnC) Vaccines
      • Late stage clinical development
      • Placebo controlled trial not ethically feasible in the U.S.
    1 Black PIDJ 2000 Mar;19(3):187 2 Whitney Lancet 2006; 348: 1737
  • 4. VRBPAC Meeting March 8, 2001
    • Acceptable licensure approach
    • Comparative immunogenicity studies in U.S. children
      • Control group: U.S. licensed PnC
      • Applicable to all serotypes contained in the a candidate PnC
    • Endpoints
      • Primary endpoint: non-inferiority of serotype-specific IgG antibody response
      • Secondary endpoint: OPA seropositive rate, GMT/GMC, (reverse cumulative distribution (RCD) curve
    http://www.fda.gov/ohrms/dockets/ac/01/transcripts/3733t1.htm . Accessed 09-Nov-2009.
  • 5. Overview
    • Background
      • Prevnar clinical efficacy trial: invasive pneumococcal disease (IPD)
    • VRBPAC 2001
      • Comparative immunogenicity studies in U.S. children
    • WHO Technical Report Series (TRS) No.927
      • Pneumococcal IgG antibody concentration: 0.35 µg/mL
      • Opsonophagocytic antibody (OPA): important supportive data
      • Post-marketing effectiveness studies
    • PCV13 pivotal U.S. immunogenicity trial design
      • Immunogenicity assessment to support licensure
  • 6. WHO consultation meetings 2003-03
    • WHO TRS No. 927 : published in 2005
    • WHO recommendations to assure the quality, safety and efficacy of pneumococcal conjugate vaccines
    • IgG antibody concentration: 0.35 µg/mL
      • Reference point: Immunogenicity of a candidate pneumococcal conjugate vaccine to a U.S. licensed vaccine. Prevention of vaccine serotype IPD.
      • Not a correlate of protection
    • OPA
      • Assay limitations
      • Important supportive data
    • Post-licensure safety and effectiveness
  • 7. Immunological Bridging of Two ELISA Assay Methods
    • New ELISA assay method (22F pre-adsorption)
      • Increased assay specificity after a 2 step pre-adsorption
    • WHO reference ELISA ( no 22F pre-adsorption)
      • 0.35 µg/mL IgG antibody reference value
    • Bridging of two ELISA assay methods
      • Equivalent IgG antibody concentration = 0.32ug/mL
      • 0.35ug/mL retained as the reference value
  • 8. Overview
    • Background
      • Prevnar clinical efficacy trial: IPD
    • VRBPAC 2001
      • Comparative immunogenicity studies in US children
    • WHO Technical Report Series (TRS) No.927
      • Pneumococcal IgG antibody concentration: 0.35 µg/mL
      • Opsonophagocytic antibody (OPA): important supportive data
      • Post-marketing effectiveness studies
    • PCV13 pivotal U.S. immunogenicity trial design
      • Immunogenicity assessment to support licensure
  • 9. Study-004 U.S. Pivotal Immunogenicity trial Immunogenicity Evaluation
    • Primary endpoints
      • Post-dose 3: seroresponse rates > 0.35 µg/mL
      • Post-dose 4: 2-fold differences in GMC ratio
      • OPA not a primary endpoint: no established
      • non-inferiority criteria
    • Non-inferiority criteria: 6 new serotypes
      • Comparison to the lowest antibody response elicited by
      • a PCV7 serotype
      • Comparison not to an average seroresponse rate
    • Other immunological parameters
      • OPA seropositive rate, GMT/GMC,
      • RCD curves (descriptive comparison),
      • Seroresponse rate at alternative IgG antibody levels
  • 10. Summary
    • VRBPAC 2001: Comparative immunogenicity studies in U.S. children is an acceptable licensure approach for prevention of IPD in infants.
    • A pneumococcal IgG antibody concentration of 0.35 µg/mL is a reference point for immunogenicity comparisons of a candidate pneumococcal conjugate vaccine to a U.S. licensed vaccine. Not an correlate of protection.
    • Pivotal U.S. immunogenicity trial design
      • Post-dose 4 primary endpoints
      • 6 new serotypes: comparison to the lowest antibody response elicited by a PCV7 serotype
      • OPA: important supportive data
      • Immunogenicity assessment to support licensure: IgG, OPA, GMT/GMC, RDC curves, seroresponse rate at alternative levels