DEPARTMENT OF HEALTH AND HUMAN SERVICES
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation and Research
Date: March 15, 2010
From: Drusilla Burns, Ph.D.
Through: Milan Blake, Ph.D., Director, DBPAP
Subject: Review of STN: 125363: MenHibrix® (Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine)
FOCUS OF REVIEW
GlaxoSmithKline (GSK) Biologics submitted a Biologics License Application (BLA) for MenHibrix, a vaccine that contains Neisseria meningitides serogroup C capsular polysaccharide, Neisseria meningitides serogroup Y capsular polysaccharide, and Haemophilus influenze type b capsular polysaccharide. The proposed indication of this vaccine is for active immunization of infants and toddlers 6 weeks through 15 months of age for the prevention of invasive diseases caused by Neisseria meningitides serogroups C and Y and Haemophilus influenzae type b. The focus of this review is the pertussis assays used to measure pertussis antigen immunogenicity in studies to assess the effect of concomitant immunization of MenHibrix with a pertussis-containing vaccine (Pediarix). Specifically, I reviewed the assays to determine whether the assays were adequately validated when considered in the context of the pertussis immunogenicity endpoints used in the pivotal concomitant vaccination trials.
SUMMARY OF THE REVIEWER’S CONCLUSIONS
Based on my review, I consider the pertussis –b(4)--- performed at the GSK Biologicals’ Laboratory in Rixensart, Belgium to be validated for their intended purpose in regards to this BLA supplement.
REVIEW OF 125363 IN REGARDS TO PERTUSSIS SEROLOGICAL ASSAYS
Portions of BLA reviewed were:
126.96.36.199.anti-pertussis, containing SOP and validation report for anti-PT –b(4)-
188.8.131.52.anti-fha, containing SOP and validation report for anti-FHA –b(4)--
184.108.40.206.anti-prn, containing SOP and validation report for anti-pertactin –b(4)--
In addition, I examined pertinent portions of the study reports for clinical studies Hib-MenCY-TT-005 and Hib-MenCY-TT-009 to assess the performance of the pertussis serological assays in regards to the specific clinical endpoints used in the pivotal studies evaluating concomitant vaccination with pertussis vaccines.
Information was included in the BLA concerning the performance of the pertussis serological assays including limit of detection, limit of quantitation, repeatability, intermediate precision, accuracy including spiking and recovery information, specificity, linearity, range and some information concerning robustness of the assays. Much of this information has been reviewed previously in the context of use of these assays for other clinical trials. In regards to evaluation of the assays for the purpose for which they were used in the clinical trials presented in this BLA, the specific clinical trial immunogenicity endpoints must be considered.
The immune response to Pediarix, a pertussis-containing vaccine, when given concomitantly with MenHibrix was evaluated in two clinical trials, Hib-MenCY-TT-005 and -009. In study -005, Pediarix was co-administered with Menhibrix or ActHIB at 2, 4, and 6 months of age. Pertussis antibody responses were assessed one month after the third dose. The non-inferiority of the immune responses to the three pertussis antigens was evaluated as a primary objective. Non-inferiority was assessed based on the ratios of the GMCs for each of the pertussis antigens. The criteria for non-inferiority were met if the lower limts of the two-sided 95% CI (Menhibrix over ActHIB) were ï‚³ 0.67 for each antigen. In study -009, immunogenicity of the pertussis antigens in Pediarix were evaluated following a three dose primary series. Differences between groups were evaluated as powered secondary objectives. For anti-PT, anti-FHA, and anti-PRN, non-inferiority was assessed based on GMC ratios; non-inferiority was met if the lower limit of the 95% CI of the GMC ratio was ï‚³ 0.67 for each antigen. In my opinion, the information contained in this BLA indicates that the performance of the pertussis –b(4)-- is appropriate for purposes of these analyses.
For both -005 and -009, additional analyses were conducted to determine the differences in percentages of subjects with anti-PT, anti-FHA, and anti-PRN ï‚³ 5 ELU/ml. While I do not have assay issues in regards to these endpoints, I am concerned that the endpoints lack sensitivity to determine differences between vaccine groups since 1) a significant number of individuals have titers that meet this level pre-vaccination and 2) when the reverse cumulative distributions curves obtained in -005 and -009 are examined, a response of 5 ELU/ml is observed to be on the upper asymptote of the response curve for each of the antigens and therefore is in a region that is relatively insensitive to differences between groups. Thus, I view these additional analyses as relatively uninformative. I conveyed these concerns to the clinical reviewer for this BLA.
After reviewing information concerning the performance of the pertussis serological assays, I believe that the pertussis serological assays are sufficiently validated for the purposes used. I have no remaining issues.