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U.S. Department of Health and Human Services

Vaccines, Blood & Biologics

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Deficiencies Filiing Memorandum - EVARREST

To: File (STN 125392/0 Original BLA EvarrestTM)

From: La’Nissa A. Brown-Baker, Ph.D., Pharmacologist, Division of Hematology (DH)/OBRR

Through: Iftekhar Mahmood, Ph.D., Team Lead, DH/OBRR

For: Information Requests for Original BLA STN 125392/0- Omrix’s Fibrin Pad Evarrest



This memorandum is a summary of the deficiencies identified in the pre-clinical program based on the preliminary non-clinical review of the original biological license application (BLA) for EvarrestTM, Fibrin Sealant Pad. Evarrest is indicated as adjunct to hemostasis for mild to moderate bleeding for soft tissue during retroperitoneal, intra-abdominal, pelvic and (non-cardiac) thoracic surgery when standard surgical methods of hemostasis are ineffective or impractical. There were pre-clinical deficiencies identified in STN 125392 BLA for Omrix’s Fibrin pad, EvarrestTM, based on review of the pharmacological and toxicological data presented.

The following pre-clinical information requests should be addressed by the sponsor within three weeks of notification:

  1. There are numerous studies and data submitted for EVARREST fibrin pad’s pre-clinical program. Many of these studies do not appear relevant for the current licensure indication of this product. Therefore:
     
  • Please list in tabular format (summary) only those pre-clinical studies which are relevant for the current BLA indication for EVARREST.
  • In addition, please ensure that these relevant pre-clinical studies are submitted as complete finalized study reports. Please submit in aforementioned table summary the fibrin pad identifiers to correlate selected relevant pre-clinical studies to batches of fibrin pad that can readily be accessed. The identifiers should include the manufacturer, biologic component(s) concentrations, treatment of pad (-------------- –b(4)-----), and any other pertinent information on fibrin pads to clarify pre-clinical studies.

    2. It is noted that there are discrepancies for the final endpoint (day) on complete absorption of the fibrin pad in pre-clinical reports ranging from 56 days up to 119 days (Study Reports 05-0636, 06-0658, 08-0146 and 08-0220); and these variations extend to animal models (nude mice, rats, and swine) tested. You claim that the complete absorption/degradation is 56 days for clinical trial observation period. Please submit the actual number of days for complete absorption of EVARREST under “normal” conditions and “worst case scenario” conditions as determined in pre-clinical studies or based on clinical experience (clinical observations) following EVARREST use (final clinical grade product). Please provide an explanation for differences noted in absorption rates in animals tested; and note identifiers for the product tested in each study (batch, production site/ manufacturer, fibrin pad composition). Additionally, please provide justification to establish 56 days as an accurate endpoint estimate for complete fibrin pad absorption in clinical trials.