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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Vaccines

Additional Comments to CMC Review - Agriflu, October 6, 2009

Department of Health and Human Services

Food and Drug Administration/Center for Biologics Evaluation and Research

Memorandum

Date: October 6, 2009

From: Jerry P. Weir, Ph.D., Director, Division of Viral Products

To: License Application File 125297

Subject: STN# BL125297

License Application from Novartis Vaccines for Agrippal/Agriflu (Influenza Virus Vaccine, Inactivated).  Additional comments to the CMC review.          

The purpose of this memorandum is to provide additional information and clarification for the CMC review of license application 125297.  The CMC review of that license application, submitted August 14, 2009 by Dr. Ira Berkower, Division of Viral Products/OVRR/CBER recommended approval but noted some product-related concerns.

Specifically, the CMC review notes a concern that the ---b(4)---------------------------- used for inactivation may damage “key antigenic determinants” of the vaccine (p. 35-36).  Proposals were suggested for analyzing key antigenic determinants after treatment at --b(4)------------ and testing immunogenicity of such vaccines in human trials or animal studies.  The rationale provided was that the current -b(4)- assay used for potency might not detect such changes.

Although manufacturing steps such as inactivation might have the potential for altering vaccine antigenic determinants, this should not be viewed as a concern for this product.  In this situation, the manufacturer uses an accepted -b(4)-  potency assay ----b(4)----------------------------------------------------------------------------  The manufacturer has validated this assay.  The --b(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------  The manufacturer has demonstrated that the new inactivation condition at -b(4)- has no significant effect on HA yield as measured by a hemagglutination assay, nor on potency of the product as measured by -b(4)-, so we can be confident that the final product has a potency that will provide the expected clinical benefit.  Any suggestion that the current potency assay would not detect meaningful changes in the protective immunogenicity of the vaccine is speculative and not supported by data.  As already stated, potency as determined by -b(4)-, has been shown to correlate with --b(4)---------.  There is no other existing assay that can make that claim.  In addition, the suggestions to perform clinical trials to detect changes in vaccine immunogenicity are neither feasible nor advisable.  Hemagglutination inhibition (HI) titers measured following vaccination to measure immunogenicity would have far more variability than the -b(4)- potency assay and would not be sensitive enough to even distinguish small differences in vaccine potency that can be measured by -b(4)-.

In summary, the manufacturer has a validated potency assay that is the accepted standard for quality control of inactivated influenza vaccines.  I do not agree with the assessment of the CMC reviewer that they antigenic determinants in the vaccine can be lost without being detected by the manufacturer’s current quality control procedures, and therefore I have no concerns regarding the potency and efficacy of their vaccine.  Based on the data submitted, I also recommend approval of the license application for Agrifl