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Vaccines, Blood & Biologics

Mid-Cycle Post Resubmission Meeting Summary - Berinert, July 1, 2009

Date:               July 1, 2009                 Time:  10:30 AM – 11:30 AM           

From:              Nannette Cagungun, CBER/OBRR/DBA, HFM-380

To:                  STN 125287/0

Subject:         Mid-cycle Meeting post resubmission for CSLB’s C1 Esterase Inhibitor BLA


CBER Participants:

Paul Buehler- absent

Felice D’Agnillo

Dave Doleski – on the phone

Marion Michaelis – on the phone

Mahmood Farshid

Ross Pierce

Jean Makie- on the phone

Bhanu Kannan – absent

Xue (Mary) Lin

Craig Zinderman - absent

Faith Barash

Aileen Buckler

Joe Quander-on the phone

Nannette Cagungun



The review team provided a status update on their review of the BLA resubmission.  Felice D’Agnillo stated that CSLB’s response to the viral validation item is acceptable and that the addition of ---b(4)-------- can be a postmarketing commitment.  It was noted that this PMC recommendation could in theory be overruled and changed to a PMR by the Safety Working group. Felice D’Agnillo also indicated that CMC CR letter items 3 and 4 were satisfactorily addressed in CSLB’s responses.

Dave Doleski stated that some inspectional issues still need to be resolved.  Specifically, he said CSLB’s proposed approach for the handling of out of specification results obtained during validation needs further consideration, and might not be acceptable at the present time. However, Dave Doleski also stated that he would likely speak to the firm and it is likely that we can come to resolution on this issue in the near future.

Also Marion Michaelis noted that in their response to several (#8 and #14) 483 Observations, CSLB indicated that final validation data will not be available until later in 2009 and early in 2010. The preliminary data supplied to date looks good and we would be able to approve the file if necessary based on the data received for those observations.

With regard to the product labeling, Ross Pierce stated that the package insert cannot be finalized until FDA completes statistical analyses, which may in turn depend on receiving answers to the 29 May 2009 fax information request, which included a re-request for a combined clinical dataset to facilitate verification of primary endpoint analyses.  Dr. D’Agnillo asked if the draft labeling needs to be submitted to the PLR review committee.    

Nisha Jain responded that the draft PI does not need to be reviewed by the PLR committee because of the availability of the Cinryze PI as a model.  Since there are placeholders in the revised draft Berinert PI that FDA sent the firm on 5 November 2008, the applicant should be contacted to again urge them to submit a revised PI so the review of the PI could move forward.

Iftekhar Mahmood stated that the PK section of the PI will be changed as CSLB’s calculation of the PK data is incorrect. 

Nannette Cagungun stated that CSLB should submit the draft labeling in an SPL format as well.  The UNII Code for the product will also need to be determined.

Jean Makie stated that the carton and container labeling should be submitted with the artwork.

Joe Quander said he has not yet received the lot release samples and protocol from the applicant.  Felice D’Agnillo said will contact the company to request that the samples be expedited.  He also noted that the Lot Release Testing Plan was finalized but was awaiting sign off by DMPQ. Lots will be reviewed by paper release only.

Felice D’Agnillo relayed his discussions with Paul Buehler who indicated that the Pharmtox section of the PI was missing and must be added in the revised label submission.

Faith Barash recommended that CSLB consider the use of a patient registry for all or a subset of HAE patients treated with the product who experience thromboembolic events or viral seroconversion.  Ross Pierce agreed and said the patient registry should be a made a postmarketing requirement. 

Faith Barash also recommended that all thromboembolic events should be reported as expedited 15-day reports as part of the pharmacovigilance plan for the product.

Nisha Jain will bring the PMC and possible PMR recommendations for this BLA to the FDAA Safety Working Group. 

The draft press release was emailed to Ross Pierce for review (June 29, 2009).  Once CRB provides comments, it will then be sent to APLB to verify for possible promotional content.  The review committee agreed that the press release should be sent back to APLB after its review by OCAD.

Ross Pierce then provided an update on the status of the clinical review.  He said that CSLB had notified CBER that they cannot respond to the 29 May 2009 information request until the end of July 2009.  CBER had requested a response to the information request by June 9, 2009.  He said it is very important to determine as soon as possible what should go into the PI.  The magnitude of the missing source data is still unclear.  CSLB needs to clarify the concomitant medication data (as per the 29 May 2009 fax information request).  The sponsor was also asked on 29 May 2009 to provide an interim report of routine biochemical, CBC, and urinalysis data before and following exposure to the product.  These data were requested both in a telecon early on during the initial review cycle, as well as in the CR letter.  The sponsor was slow in amending their open label extension study to provide for collection of these data.

Because CBER’s internal timelines might not be met unless CSL submits their response soon, it is quite possible that CBER will not be able to take action on the BLA at the due date.  For this reason, CBER will contact CSLB today to emphasize that their response to the information request should be submitted right away so that the review of the BLA can move forward.

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