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Vaccines, Blood & Biologics

2/29/2008 Telecon - Rotarix


DATE: February 29, 2008

FROM: Laraine S. Henchal, Microbiologist Reviewer, DVRPA, CBER, Review Committee Chair, STN 125265/0

SUBJECT: Telecon to discuss the the potency release specifications for STN #125265/0, Rotarix®, Rotavirus Vaccine, Live, Oral from GlaxoSmithKline Biologicals

This meeting was held to discuss CBER's concern regarding the proposed release specification for potency for the final product as proposed in the BLA. The specification proposed by GSK is to release final product at a titer of -------- ---------------------------------. End-of expiry titer is then stated as not less than 106.0 CCID50. Requested dating period is -- months. CBER had sent an information request to GSK on 18 December 2007 regarding the proposed potency specification given that the pivotal clinical trials had been conducted with lots that had a mean potency of 106.5 CCID50. GSK responded to this question in an amendment received by CBER on February 13, 2008.

We don't consider the response to be satisfactory . It does not appear that GSK has considered the ------------- for the stability of vaccine products ---------------------------------------------------------------------------------------------------------------
-------------- in the computation for setting the release specification. In addition, it does not appear that proper consideration was given to the maximum titer determined for safety in the Phase 3 clinical trials. The level of potency tested in those trials was 106.5 , therefore this should be the maximum, and the release specifications should be calculated downward taking into account assay variability (---- logs) and loss of potency over time (stability calculation with the error accounted for). This may bring the release specification down to the ----------- range at end-of expiry (or even lower). What clinical data is there to support efficacy at this dose?

The efficacy of lower doses does fall off as seen in the 006 study to around 50% for any RV GE (in this study doses as low as 105.6 CCID50 were studied in Latin America). GSK pointed out that the confidence intervals overlap for the 5.6 and 6.6 doses in that study. CBER stated that does not necessarily mean that the doses are identical in effect.

GSK needs to address how the end-expiry of 106.0 is justified by the clinical data and what is known about the assay variability and the stability of the product. In addition the lower range of the release specification of ----- also needs to be justified. We also strongly recomment that a maximum release specification be chosen based on the cllinical data to support safety.

GSK agreed to reconsider their specifications and will submit an additional analysis of the data.

An additional question was raised by reviewers regarding the number of vials that are tested for final product release tests. What criteria are used to determine the number of vials used in the final product testing?

GSK will submit this information along with the above analysis of the potency specification.

CBER participants:

Laraine Henchal
Steve Rosenthal
Paul Kitsutani
Luba Vujcic
Phil Krause
Dino Feigelstock
Steve Feinstone
Rajesh Gupta
Bill McCormick
Loris McVittie

GSK participants:

Leonard Friedland
Donna Boyce
Benedicte Dupasquier
Norris Pyle
Serge Debrus
Corine Lecomte
Isabelle Ernest
Jean-Claude Mareschal
Michael Vanderwerf

Contact FDA

(800) 835-4709
(240) 402-8010
Consumer Affairs Branch (CBER)

Division of Communication and Consumer Affairs

Office of Communication, Outreach and Development

Food and Drug Administration

10903 New Hampshire Avenue

Building 71 Room 3103

Silver Spring, MD 20993-0002

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