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Vaccines, Blood & Biologics

Zoster Studies Memorandum - MenHibrix

To:                   File
Through:          Philip Krause, MD, Robin Levis, Ph.D.
From:               Shuang Tang, Ph.D.
CC:                  Joseph Temenak
Date:               May 14, 2010
Re:                   STN 125363 (Original BLA) Section
Hib-MenCY-TT (Haemophilus influenzae type B and Neisseria meningitidis serogroups C and Y)
Information reviewed: Original BLA (STN 125363  Section – Rec – 08/12/2009 – DATS#470646)

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 Anti-Varicella (b)(4) of this Original BLA is under the Other Study Reports of the Clinical Study Reports Section. In this section (Section 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. 

After reading through the SOP Immunoserology -21.04, I found that several key control procedures were not described clearly. For example, in Section V Step (b)(4) (page 4),     -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------.

Regarding validation of (b)(4), I also found some issues related to the analytical parameters, repeatability, reproducibility, robustness and linearity.  For example, there is no evidence to support the proposed analytical range: --------(b)(4)--------.  The majority of higher fold dilutions seem drifted. There is only (b)(4) operator for the repeatability and reproducibility studies. There is no validation data on the effect of several key factors including the --------------------------------------------------------------------(b)(4)---------------------------------------------- and etc to support the robustness of the assay.

A through review was done by Dr. Philip Krause previously on the same SOP and validation of the assay. Similar questions and recommendations were made to the sponsor on Oct 30, 2007.  In August 2008, the 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).  

While certain aspects of the assay validation appear to be less than optimal, if the study was performed in a blinded manner, any assay biases should have equally affected both groups.  Moreover, while there may still be some residual questions about the assay cutoff and the assay linearity, the near superimposability of the --------------------------------(b)(4)---------------------------- (Supplement 61 at Section Study Report as shown below) demonstrates that even with different cutoffs, evidence of interference with anti-VZV immune response would not have been observed.




As a summary of the above, I would request the following information from the sponsor:

  1. Please provide training records for the technicians who participated in this study, demonstrating that they are able to provide consistent (b)(4) readings. 
  2. Regarding Item 10, please provide SOPs or protocols for (b)(4), GSK’s          ------------(b)(4)----------- assay to support the results from these assays.    
  3. Please provide information about 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 (b)(4) with the clinical samples.
  4. More than -----------(b)(4)------------ (Clinical study 008) of subjects were varicella seropositive in the Pre Booster groups (with anti-Varicella titers more than ---------(b)(4)-----------. This number is higher than previously published experience for 1 to 1.5 years old children without previous varicella exposure or varicella vaccination, and suggests some level of assay artifact.  Please explain.
  5.  The submission indicates that the Cut-Off for (b)(4) was changed from (b)(4) to (b)(4).  However, in many parts of the submission, the Cut-Off is still labeled and used as (b)(4), which is confusing. Please justify why two Cut-Offs are needed.   

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