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Primary Immunogenicity Endpoints for New Infant Pneumococcal Conjugate Vaccines

Primary Immunogenicity Endpoints for New Infant Pneumococcal Conjugate Vaccines. Vaccines and Related Biological Products Advisory Committee Meeting. Prevnar 13 Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein]. Lucia H. Lee, M.D. CBER, FDA November 18, 2009. Overview.

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Primary Immunogenicity Endpoints for New Infant Pneumococcal Conjugate Vaccines

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  1. Primary Immunogenicity Endpoints for New Infant Pneumococcal Conjugate Vaccines Vaccines and Related Biological Products Advisory Committee Meeting Prevnar 13 Pneumococcal 13-valent Conjugate Vaccine [Diphtheria CRM197 Protein] Lucia H. Lee, M.D. CBER, FDA November 18, 2009

  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: NCKP1 Primary clinical outcome: prevention of vaccine serotype IPD Aggregate vaccine clinical efficacy: 97% (95%CI 85,100) Vaccine effectiveness for each serotype shown post-licensure2 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. 3 1Black PIDJ 2000 Mar;19(3):187 2Whitney Lancet 2006; 348: 1737

  4. VRBPAC MeetingMarch 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 meetings2003-03 • 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 trialImmunogenicity 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

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