Submission Type: BLA Submission ID: 125363/0 Office: OVRR Product:
Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine
Telecon Date/Time: 09-Feb-2010 10:00 AM Initiated by FDA? Yes
Telephone Number: ----b(4)-------
1. Information Request
Author: JASON HUMBERT
Telecon Summary: Discussion regarding Men-Y assays
Milan Blake Mustafa Akkoyunlu Tina Roecklein
Clare Kahn, VP, North American Regulatory Affairs, Vaccines
Jacqueline M Miller, Director, GCDC, Philadelphia
Katalin G Abraham, Director, North American Regulatory Affairs, Vaccines
Pascal R Lestrate, Project Manager, R&D
Jody A Gould, Director, North American Regulatory Affairs, Vaccines
CBER requested this teleconference to discuss the hSBA-Men-Y assay, particularly with the data in the BLA which shows a –b(4)---- in titers in sera from the Men-Y assay in Study 101858 (Hib-MenCY-TT-005), a phase II, single-blinded, randomized, controlled, multicenter primary and booster vaccination study to evaluate the immunogenicity, reactogenicity and safety of GSK Biologicals’ Haemophilus influenzae type b and Neisseria meningitides serogroups C and Y-tetanus toxoid conjugate vaccine combined
(Hib-MenCY-TT) compared to ActHIB, each co-administered with Pediarix and Prevnar, in healthy infants at 2, 4, and 6 months of age and in healthy toddlers at 12 to 15 months of age (booster dose).
CBER provided an overview of the questions raised during review to be discussed during this teleconference, including:
• Whether the Y strain used in the assay for study -005 was used for any other purpose,
• Where the –b(4)---- from for the Men-Y assay used in study -005 came from
• Whether GSK has performed any characterization of the Y strain used in these assays, and if GSK has made any progress on providing a scientific rationale for the –b(4)- in titers for the Men-Y assay from study -005
GSK stated that after investigating the –b(4)- in titers further, they were not able to determine a root cause. They noted that the age of the sera in study -005 was older, but they could not explain why this would result in a –b(4)- in Y titers but not C titers. They stated, however, that they would provide additional data for CBER to consider. More recent data has shown that the Y strain (which came from the CDC) is ---b(4)------------------------------------------------------------------------------------- In addition, GSK stated that the strain –b(4)-- used in Men-Y hSBA expressed increased amounts of factor H binding protein (fHbp). However, they were not able to determine whether there was a change in fHbp content because the original –b(4)- was not assessed for fHbp content. GSK also stated that they have identified the LOS typing of the strain as –b(4)-GSK has no further characterization data.
CBER asked if GSK had developed a scientific rationale that explains the performance of the assays, in particular the –b(4)- in Y titers in the bactericidal assay seen over time from sera aliquots that is not seen with C titers. The –b(4)- is particularly evident in Study -005 but was also seen to some degree in study -008. CBER also asked if the firm still had the Y –b(4)-------- strain used in the assay in -005 or any sera left from this study. CBER asked what characterization of the strain had been performed upon receipt of the strain from CDC, and if GSK has observed any changes in characterization over time. GSK stated that they had not seen any characterization changes over time; however it was unclear whether GSK had conducted any initial characterization of the strain. GSK is going to review what, if any, characterization was done when the strain was received from CDC.
GSK indicated that they are using a different complement in the Y assay as opposed to the C assay. The complement is comprised of a donor pool, which has changed over time. Therefore different complement has been used through the history of the assay. However, GSK stated that they have not observed any changes in the assay controls. GSK stated that a –b(4)------ test was performed over a year ago on the ---b(4)---------- from study-005. This test determined that the capsule was present on all –b(4)------------ strains. GSK will check to see if the strain for Men-Y in -005 was used in other production. GSK also offered to provide a document listing all characterization of the strain(s) and any noted changes, including the amount of –b(4)--, amount of –b(4)------, and the genealogy of the strain (including the number and where it came from).
CBER reiterated the need for scientific rationale to explain the significant -b(4)- in Men-Y titers. GSK noted that for study -009, the pivotal study, all of the Men-Y objectives were met and that in study -005, the failures were in statistical endpoints. CBER stated that because licensure is based on serology assays only, the firm must prove scientifically with firm supporting data that their assay is working reliably and consistently. Currently, there is not assurance that data from the Y assay is reliable. The –b(4)- in titer in particular for study -005 are indicative of a problem with the assay that must be addressed. GSK asked what impact these questions will have on the status of the BLA. CBER stated that this cannot be determined at this time. GSK needs to submit the information that CBER has requested for review first. Once the information from GSK has been received and reviewed, further discussions may be necessary to resolve outstanding issues. GSK stated that they understood what information CBER needed, will work on compiling the information, and will let us know an approximate date when the requested information can be submitted to CBER.
As an additional item, CBER asked that the raw data from the serology results reported for study -008 be provided to CBER, as the tendency for a –b(4)- in titers has also been observed in this study. GSK noted this request and will provide this with the other requested information.
No other items were discussed and the call concluded.