First Committee Meeting MInutes - EVARREST, December 7, 2010

To: STN 125392/0 File 

Meeting Date: December 7, 2010 

From: Sonday Kelly, Regulatory Project Manager CBER/ OBRR/ DBA/ RPMB 

Subject: First Committee Meeting Minutes 

Applicant: OMRIX Biopharmaceuticals, Ltd 

Product: Fibrin Pad 

Meeting Attendees: RPM: Sonday Kelly 
 RPM: Mark Shields 
 CMC/Chairperson: Natalya Ananyeva
 DMPQ: Nancy Waites
 DMPQ: Randa Melhem 
 Pre-Clinical: La’Nissa Brown
 Clinical: Kimberly Lindsey
 Statistics: John Scott
 BIMO: Dennis Cato 
 APLB: Loan Nguyen


Meeting minutes

CMC reviewer gave an introduction to the original BLA submission and the product.

Fibrin Pad is a sterile bio-absorbable combination product made from a flexible composite Matrix (device component) coated with Human Fibrinogen and Human Thrombin plasma-derived proteins (biological drug substances). Both Fibrinogen and Thrombin are manufactured at -----------------------------------(b)(4)---------------------------------------------------. The Matrix is composed of a knitted, oxidized, regenerated cellulose backing layer under a layer of polyglactin 910 non-woven fibers. Matrix is manufactured at -----------------(b)(4)------------------. The Fibrin Pad is manufactured at Omrix Biopharmaceuticals Ltd., Fibrin Pad Production Facility in Israel. Proposed proprietary name: EVARREST.

Clinical reviewer gave an overview of the pre-BLA clinical development program for OMRIX’s Fibrin Pad. The clinical review memo for this meeting is attached.

Pharmacology-Toxicology reviewer gave an overview of the pre-BLA non-clinical studies with OMRIX’s Fibrin Pad. Some concerns are noted below under “the review findings to date”.

The purpose and the outcome of this meeting are presented below:
•To ensure the submission is complete

The submission contains general categories of information required for submission of Biologics License Applications according to CBER guidance.
•To ensure a reviewer is assigned to review each section of the BLA

Reviewers from each discipline have been assigned.
•To identify if consult reviewers are needed in the review process


The following Consult reviewers need to be included in the Review Committee:
?OBE: Pharmacovigilance
?CDRH: to assess the composition of Matrix (device component) and its manufacturing process development
?CDRH: to assess the safety aspects of Matrix in Fibrin Pad from clinical Case Reports; to comment on Protocol design for the soft tissue study 400-07-002


•Assess whether inspections (Establishment and/or BIMO) are required


Manufacture of Fibrin Pad involves multiple sites and the manufacturing process underwent a number of changes. In clinical studies related to this BLA, adverse events were noted. Both the Facility Inspection and BIMO inspections will be necessary; foreign inspections require a 60-day notice.
•To share the review findings to date and advice if there are any actions required at this time. 


Non-clinical concerns:
•Incomplete pre-clinical study reports.
•Incomplete ADME (absorption, distribution, metabolism, elimination) studies for the Fibrin Pad (the entire pad, not the individual components of the pad) to assess the safety of EVARREST for clinical use.
•Insufficient toxicology risk assessment.


Clinical concerns:
•The proposed indication for use does not specify the grade of bleeding when Fibrin Pad can be used.
•Safety data intended to support the BLA are derived from Clinical Phase II Study. Regarding Clinical Phase III studies, the BLA at the time of original submission contains the information from the first interim safety review of an ongoing Phase III study outside the US.
•There are safety concerns with this Fibrin Pad product, as indicated by adverse events in clinical studies (thrombotic events and recurrent bleeding). During the pre-BLA meetings, additional studies were recommended by FDA to expand the safety profile of the product.
•To identify follow up activities to be completed before the Filing Meeting


The following activities should be initiated before the Filing Meeting scheduled for 03 January 2011:
•All reviewers: perform a cursory review of the submission for completeness to determine its filability, and to identify any issues;
•Notify the upper management of the current concerns with the application.
•To determine if application is eligible for BPAC or PREA Review

The need for BPAC and PREA review will be discussed after the filability of the application is determined.

END
