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. 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. 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.htmhttp://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. 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