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]

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

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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.

1Black PIDJ 2000 Mar;19(3):187 2Whitney Lancet 2006; 348: 1737

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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.

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

WHO consultation meetings2003-03

WHO TRS No. 927: published in 2005WHO 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

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

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

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

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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