
FAMA for Zoster Studies Memo - MenHibrix


 
 
MEMORANDUM

To: File
Through: Philip Krause, MD,
Keith Peden, Ph.D. 
Robin Levis, Ph.D. 
From: Shuang Tang, Ph.D. 
CC: Joseph Temenak 
Date: July 18, 2011 
Re: STN 125363 (Original BLA) Section 5.3.5.4.3 
Hib-MenCY-TT (Haemophilus influenzae type B and Neisseria meningitidis serogroups C and Y)

Information reviewed: Original BLA (STN 125363 Section 5.3.5.4.3 – Rec – 08/12/2009 – DATS#470646) and its amendment STN 125363/0.12.

Review MEMO

In this Original BLA, GlaxoSmithKline (GSK) Biologicals requests approval of a candidate vaccine “Hib-MenCY-TT (Haemophilus influenzae type B and Neisseria meningitidis serogroups C and Y)” for active immunization in infants and toddlers for prevention of invasive diseases caused by Haemophilus influenzae type b and Neisseria meningitidis serogroups C and Y. Section 5.3.5.4 Anti-Varicella (b)(4) of this Original BLA is under the Other Study Reports of the Clinical Study Reports Section. In this section (Section 5.3.5.4 Anti-Varicella (b)(4)), SOPs and a validation report for --------------------(b)(4)-------------------------------- for Antibody to Varicella Zoster Virus) were included. A response to previous CBER recommendations was also included.

The anti-Varicella (b)(4) is an --------------(b)(4)------------- antibody test of Varicella-Zoster virus (VZV). This assay is performed in ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- has historically been used as a seroconversion test for VZV vaccines and is supported by an extensive literature, mostly from the ---------------------(b)(4)--------------------. However, VARIVAX, a licensed Varicella vaccine (Merck), uses the validated gpELISA for the anti-VZV antibody assay, for which higher titers have been shown to correlate with protection from disease. The anti-Varicella ----------(b)(4)---------- lab was also recently used to support the concomitant administration study of another GSK vaccine, Havrix (Hepatitis A Vaccine, Inactivated) with Varicella vaccine. Thus, this review is related to a previous review for the anti-Varicella --(b)(4)-- in STN 103475 Section 5.3.5.4.3.

A through review for the GSK anti-Varicella (b)(4) SOP and validation was done by Dr. Philip Krause previously on the same SOP and validation of the assay. Questions and recommendations were made to the sponsor on Oct 30, 2007. In August 2008, sponsor submitted their response to these recommendations. The response from the sponsor provided additional information on the program parameters for the ----------------------------(b)(4)------------------------------, quality control within the run, positive and negative controls, VZV stocks, SOPs for equipment calibration, (b)(4) operator concerns and etc. The sponsor also provided additional evidence to change the -----------(b)(4)------------. It is likely that (b)(4) is the lower end of the linear range of the (b)(4). The seropositive definition is still set to (b)(4) as usually suggested in the academic field (though assay conditions may vary from lab to lab).

Although GSK has addressed several CBER questions and recommendations regarding to the anti-Varicella --(b)(4)--, I found there are still several questions remained unclear. Those concerns have been documented in my previous review for this submission. Therefore, we submitted our questions in the formal CR letter dated June 11, 2011. Our formal question related to the Varicella serology assay is listed as question 84 as below.


84. You have not demonstrated that the (b)(4) anti-varicella assay results are free of bias. Specifically, you have not provided information showing that the technicians who performed the assays for this study were capable of providing consistent (b)(4) readings, you have not shown that technicians who performed the assays were masked as to treatment group, and you have inconsistently applied a cutoff ((b)(4) in some places, (b)(4) in other places) for this assay. Moreover, this assay appears to possess high background (in Clinical Study 008, an unusually high number, more than 23% of varicella vaccine naïve subjects were varicella seropositive in the MenHibrix pre-booster groups), making results difficult to interpret. Until these deficiencies are addressed, it cannot be concluded that MenHibrix does not interfere with anti-varicella vaccine responses.
a.In your response to a previous FDA comment Item # 10 regarding (b)(4) validation study in a CBER letter dated 10/30/2007 ("Please describe the basis on which samples to compare the specificity of the various assays were selected. Was this study performed under a prospectively determined protocol? If so, please provide the protocol." Page 14 appended to the (b)(4) SOP), you did not provide the standard protocols or SOPs for the (b)(4), GSK's ---------------(b)(4)------------------. Please provide SOPs or protocols for the (b)(4), GSK’s -------------(b)(4)--------------- assay to support the results from these assays.
b.Please provide information regarding whether the clinical samples were handled in a blinded manner when using (b)(4) to detect anti-VZV antibody, and how many technicians were directly involved in the analysis of samples by (b)(4).
c.In Clinical Study 008, more than 23% (23.6% - 31.6%) of subjects were varicella seropositive in the Pre Booster groups (with anti-Varicella titers more than (b)(4) based on (b)(4)). This number is higher than previously published experience for children 1 to 1.5 years of age without previous varicella exposure or varicella vaccination, and suggests some level of assay artifact. Please explain.
d.The submission indicates that the Cut-Off for -(b)(4)- was changed from --(b)(4)--. However, in many parts of the submission, the Cut-Off is still labeled and used as (b)(4) . Please correct or clarify this apparent discrepancy or justify why two Cut-Offs are needed.

On June 23, 2010, GSK requested clarification related to Item 84 in an email through David Staten. CBER suggested in the reply that records showing that the technicians who were directly involved in the analysis of the clinical samples by --(b)(4)-- were successfully trained will also be helpful.

GSK submitted their response to Item 84 on April 15. In the response, GSK provided SOPs for Anti-Varicella (b)(4) and ----(b)(4)----, as well as the protocol for GSK’s ------------(b)(4)-------------. GSK indicated that all samples tested in the ---(b)(4)--- lab for anti-varicells --(b)(4)-- are blinded. Each tube is assigned a unique barcode and is labeled with the barcode identifier. The operator can not link the tubes and the treatment group. There are (b)(4) technicians performed the (b)(4) assay and their training records were provided. GSK suggests that the higher than normal percentage of subjects with varicella seropositive results in the Pre Booster group were based on (b)(4) cutoff values. GSK initially set up the cut-off value to (b)(4) and then modified it to (b)(4) based on CBER’s recommendation and new validation results. GSK provides a side-by-side comparision of using ---(b)(4)--- as cut-off values (Table 45 -53). According to the data in the Table 45, 46 and 47, the pre-dose seropositivity rates in all groups are dramatically reduced from approximately 23% to approximately 2 % when using (b)(4) as the cut-off. However, there is no difference between post-vaccination seropositivity rates in all groups, suggesting that post-vaccinination GMT are significantly higher. The non-inferiority hypothesis for anti-varicella titers in Hib_CY and Hib groups could be met if (b)(4) was used as the cut-off (Table 48, 49, 50. 51 and 52).

While certain aspects of the anti-Varicella ---(b)(4)--- validation appear to be less than optimal as documented in my previous review for this submission, if the study was performed in a blinded manner, any assay biases should have equally affected both groups. Moreover, the near superimposability of the anti-varicella reverse cumulative distribution (RCD) curves (Supplement 61 at Section 5.3.1.3 Study Report as shown below) strongly implies that even with different cutoffs, evidence of interference with anti-VZV immune response would not have been observed.

Conclusion 

Based on the data submitted in the supplement and its amendments, the submitted data support the conclusion that there is no interference in anti-varicella immune responses when Menhibrix and Varivax are administered concomitantly. I recommend approval of this supplement.
