Filing Meet Minutes - EVARREST, January 3, 2011

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

Subject: Filing 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 
 Statistics: John Scott
 BiMO: Dennis Cato 
 APLB: Loan Nguyen
 OBE: Faith Barash
 CDRH: Roxolana Horbowyj 


Meeting minutes

The purpose and the outcome of this meeting are presented below:
•Each member of the review committee is expected to discuss the relevant content of the submission and present an overview that includes:
•A summary of the submitted material.
•A description of any required material that may have been omitted from the submission.
•Any substantive deficiencies or issues that potentially have significant impact on the ability to complete the review or approve the application. 

Natalya gave an overview of the sections she reviewed.

Human Fibrinogen and Thrombin used with the Fibrin Pad are manufactured using ---------------------------------------------------------------(b)(4)---------------------------------------------------------------------------------. Both Fibrinogen and Thrombin are manufactured at ------------------------(b)(4)---------------------------------------------------------. The Matrix is composed of an oxidized, regenerated cellulose (ORC) backing layer under a layer of polyglactin 910 (PG910). Both ORC and PG910 are used in the manufacture of other products currently marketed by ETHICON (for details, please refer to the Filing CMC Memorandum). There were changes in the --------------------------------------(b)(4)---------------------------------------------------------. Currently, the Matrix is manufactured at -------------------(b)(4)------------------------.

The Fibrin Pad is manufactured at Omrix Biopharmaceuticals Ltd., Fibrin Pad Production Facility in Israel. --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------(b)(4)--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------. The changes in the manufacturing process and product comparability will need in-depth review.

The submission contains general categories of information to permit review and meets the requirements for filing.

Randa summarized the sections pertinent to the DMPQ review. 

 OMRIX has (b)(4) facilities listed which are used for the manufacture of Fibrin Pad; (b)(4) are currently registered with the FDA. The (b)(4), the Fibrin Pad Production Facility, is not registered with the FDA.

DMPQ (Randa and Nancy) has no objection to the filing of the application. Of note, the application is missing a justification for the categorical exclusion of an environmental assessment.

John summarized the statistical sections.

OMRIX performed an appropriate analysis of the primary end-points in their pivotal clinical study. Analysis of the secondary end-points needs to be completed accordingly and this will be discussed during the review process.

The application meets the CBER requirements for filing.

Dennis summarized the BIMO (Bio-Research Monitoring) sections.

All data that would be included in an assignment for BIMO review are available, therefore the application is filable.

Faith (OBE) confirmed that the OMRIX’s submission includes a pharmacovigilance plan. In the OBE’s opinion, the application is filable.
•To assess whether the application is subjected to BPAC (Blood Products Advisory Committee) review

The present members noted that the Fibrin Pad does not represent a historically novel product class as fibrin sealants have been on the market for extended time. On the other hand, the adverse events noted in clinical trials and the novel use of (b)(4) in the matrix may warrant a BPAC review.

A final decision on the eligibility of the application for the BPAC review will be made during the follow-up Filing Meeting on January 11, 2011 with the input from the entire review team.
•To asses whether PREA(Pediatric Review Equity Act) studies are needed

In the Filing Memo, dated December 20, 2010, Kimberly Lindsey, Clinical Reviewer, stated that this application does trigger PREA and that a deferral has been requested.
•To identify if PNR (Proprietary Name Review) has been triggered

A PNR “EVARREST” was approved late in the IND phase of this product (IND # 13563; Agency approval date: October 26, 2010). Omrix submitted a new request for proprietary name review in conjunction with this BLA. The APLB reviewer will issue a letter of approval in the next couple of weeks that will serve as the initial PNR under this BLA. The PNR will be continued.
•To identify if facility and BIMO inspections are needed

Considering that the Fibrin Pad Production Facility is not registered with FDA, facility inspection(s) will be necessary and are planned for the period around the Mid-Cycle (April 2011). An internal DMPQ discussion will take place to determine which sites will be included in the inspection.

BIMO plans to select three sites for inspection according to the number of adverse events reported in clinical studies. So far, the sites 11 and 14 have been selected for inspection. Dennis asked that the reviewers e-mail him any concerns (safety, efficacy, facility) that should be included in the inspection plan. It was noted that BIMO inspections are performed by the Field Office, and specific times for inspections are not available to CBER at this time.
•ACTION ITEMS:
•All review team members will email Sonday that the application is filable that will serve as a record/filing memo in the EDR.
•A follow-up Filing Meeting will be held on January 11, 2011 to: ?Hear the filing comments from the Clinical and Pharmacology/Toxicology reviewers.
?Decide on BPAC review eligibility of this BLA.
?Determine if PLR (Physician Labeling Rules) apply.


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