
Validation Report and Standard Operating Procedure (SOP) for Measurement of Total IgG Antibody to Streptococcus pneumoniae Polysaccharides (PS) in Human Serum - Rotarix

 
 
MEMORANDUM

DATE: March 11, 2008

TO: File, STN: BL 125265/0
GlaxoSmithKline (GSK), Inc.
Biologics License Application (BLA) for Rotarix® Live Attenuated Human Retrovirus (HRV) Vaccine, Oral, US License No. 1617
Laraine Henchal, MAS, Committee Chair

FROM: Christian D. Lynch

SUBJECT: Validation Report and Standard Operating Procedure (SOP) for Measurement of Total IgG Antibody to Streptococcus pneumoniae Polysaccharides (PS) in Human Serum (By ELISA, One Dilution Format, Protocol 22F)
Final Review Memo

THROUGH: Milan Blake, Ph.D., Deputy Director, DBPAP
Willie Vann, Ph.D., Chief, LBP

Summary

GSK submitted a BLA for Live Attenuated HRV, Oral, (Rotarix®) on 1 June 2007. Rotarix® is supplied as a vial of lyophilized vaccine that is subsequently reconstituted with liquid diluent provided in a prefilled oral applicator. Following reconstitution, each 1 mL dose contains at least 106.0 median cell culture infective dose (CCID50) of live, attenuated HRV. Rotarix® is intended for the prevention of rotavirus gastroenteritis caused by G1 and non G-1 types (including G2, G3, G4, and G9) when administered as a 2-dose series to infants 2 to 24 weeks of age.

In support of the BLA, GSK submitted the SOPs and validation reports for the Tetanus, Diphtheria, Pertussis, Pneumococcal, Meningococcal, Haemophilus influenzae type b, and Hepatitis B ELISAs, the serum bactericidal assay (SBA) for Neisseria meningitidis serogroup C (MenC), and the poliovirus -------------- assay. These assays were used in several clinical trials to demonstrate that co-administration of routine infant vaccines with Rotarix® did not impair the immune response to any of the preceding vaccine antigens. Specifically, in the phase II trial (Rota-005), Infanrix, Prevnar, OmniHiB, and IPOL were co-administered with Rotarix®. The phase IIb trials (Rota-006 and Rota-007) were conducted with concomitant administration of DTPw-HepB, Hib, and OPV and DTPa-IPV, Hib and HepB respectively. Prevnar and Hib serological analyses for these trials were performed at ---------------------------------. In the phase IIIb clinical trial (Rota-036), Infanrex Hexa, Infanrix Polio, Hib, Prevnar, and Meningitec were concomitantly administered in 6 European Union countries. A second phase III trial (Rota-060) was conducted in the US to evaluate the co-administration of Pediarix, Prevnar, and ActHiB with Rotarix®. The serological analyses of both phase III trials were performed at GSK's Biological facilities in Rixensart, Belgium.

Reference is made to CBER comment #3a (BLA filing letter dated 6 August 2007) regarding the supportive studies and serological analyses conducted at ------------------------. GSK's response (eBLA amendment 008 dated 9 November 2007) indicated that data from studies Rota-005, Rota-006, and Rota-007 are not considered pivotal for licensure. Moreover, based on recent guidance from CBER regarding the supportive data performed at ---------------- for GSK's ------------------------, GSK proposed that CBER not consider the validations performed at ---------------- for licensure. The firm also noted that results from the Rota-060 co-administration study are considered pivotal for US licensure of Rotarix®.

This memo focuses specifically on the SOP and validation report for the pneumococcal ELISA used in the phase III clinical trials (Rota-036 and Rota-060). The SOP and validation report were previously reviewed for GSK's -----------------------------------------. CBER queries regarding these documents were submitted to STN --------------- and cross-referenced to STN 125265. GSK's responses were also submitted to STN ----------- and cross-referenced to STN 125265.

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Information Requests

Review of the preceding serology package indicates that additional information is required to ensure that the PS ELISA is sufficiently validated to provide meaningful data for co-administration of Prevnar with Havrix in healthy children 15 months of age. Specifically, the validation report for the ------------ format did not address any of the methodology changes that distinguish it from the ---------- prototype. The -------------------- has ----------------------------- of controls and samples, and a working range --------------- based on parameters --------------------- ----------------. In contrast, the --------------- format has ------------, -------------- dilutions of controls and samples, and a working range ------------- based on parameter ------------------ ------------- and parameter -------------------------. The current submission also contains validation results for ------------------------------------ (---- and -----) that were not evaluated in the ---------- report.

The report also failed to provide information regarding the evaluation or monitoring of the -- value for the --------- curve. Additionally, no procedure was submitted for monitoring non-specific binding of enzyme-conjugated anti-human IgG. These parameters are outlined in the ------------------------------ and are critical for monitoring assay variability and performance2. Moreover, no acceptance criteria were included for any of the evaluated parameters; results were simply summarized and listed. Acceptance criteria should be clearly specified in the validation report, with the subsequent criteria for assay performance based on the data generated in the validation. Quality control rules for assay validity are outlined in the report and SOP RD-CIB-035 (the SOP also contains validity criteria for results based on a "valid" assay), however, it is unclear if these criteria are based on actual validation data.

In summary, the format changes dictate that a full validation be conducted ------------------- --------------------- format. CBER's requests regarding re-validation of the pneumococcal ELISA were submitted to ------------------------ on 23 May 2007 and are listed below in bold. GSK's response was submitted to --------------- on 10 October 2007 and cross-referenced to STN 125265 on 9 November 2007.

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This response is satisfactory.

Recommendation

Based on the information provided, the ELISA for measurement of total IgG antibody to Streptococcus pneumoniae polysaccharides (-----, -----, PS4, -----, PS6B, ------, PS9V, PS14, PS18C, PS19F, and PS23F) in human serum (in a ------------ format) appears to be adequately validated. The results of the validation demonstrate that the pneumococcal ELISA is precise, accurate, linear, specific, and stable. The assay appears to be capable of assessing the immunogenicity of pediatric vaccines given concomitantly with Rotarix® in phase III clinical trials (Rota-036 and Rota-060).

References
1.Concepcion, N., and C. Frasch. 1998. Evaluation of previously assigned antibody concentration in pneumococcal polysaccharide reference serum 89SF by the method of cross-standardization. Clin. Diagn. Lab. Immunol. 5(2):199-204.

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