Food and Drug Administration
Center for Biologics Evaluation and Research
Date: March 10, 2008
To: Jay Epstein, M.D.
Director, Office of Blood Research and Review
From: Basil Golding, M.D.,
Director, Division of Hematology
Subject: Request to waive STN 125266 from referral to Blood Products Advisory Committee
CC: Robert Yetter, Ph.D., Associate Director for Review Management, CBER
Diane Maloney, J.D., Associate Director for Policy, CBER
STN 125266 is an original biologics license application (BLA) submitted by Baxter Healthcare Corporation, Baxter Bioscience, Inc. (Baxter) for Fibrin Sealant (Human) VH S/D 4, under the trade name ARTISSTM. Baxter holds a Biologics License for a similar product, TISSEEL, which only differs in the concentration of the thrombin component. The proposed indication is for skin graft adhesion in both adult and pediatric burn patients. The lower concentration of thrombin in ARTISSTM allows manipulation of the graft on the wound area. The Fibrin Sealant replaces sutures or staples to hold the graft in place.
Reasons for Waiving Referral to BPAC
The Division of Hematology in the Office of Blood Research and Review reviewed information from this application and determined that referral to the Blood Products Advisory Committee (BPAC) prior to approval was not needed for the following reasons (FDAAA [HR 3580-138 SEC. 918: REFERRAL TO ADVISORY COMMITTEE]):
Baxter's manufacture of ARTISSTM is ------------------------------------------------------------------------------------------------- the final concentration of the thrombin is 4 U/ml compared to 500 U/ml in TISEEL, to allow for slower clot formation. The fibrinogen and thrombin are human plasma-derived and undergo vapor heat treatment and solvent/detergent treatment to inactivate viruses. Aprotinin, included as a fibrinolysis inhibitor, is synthesized using an organic chemical process.
Omrix Biopharmaceuticals, Ltd. also manufactures a similar fibrin sealant product, which was licensed in the U.S. in March 2003.
The mechanisms of action of fibrinogen and thrombin and their role in blood coagulation are well understood.
From a historical perspective, fibrin sealants were originally developed during World War II to stop bleeding from battle injuries. They have been marketed in Western Europe and Japan since the 1980's and in the United States since 1998.
Today, fibrin sealants are widely used in surgical settings to control bleeding, seal off hollow body organs and to provide slow release delivery of medications.
ARTISSTM was investigated for fixation of split thickness sheet skin grafts in burn patients in a prospective, randomized, controlled, multicenter clinical study. In each of the 138 patients, two comparable test sites were identified. In one test site, the skin graft was fixed with ARTISSTM; in the other test site, the graft was fixed with staples (control). ARTISSTM proved to be non-inferior to staples with respect to the primary efficacy endpoint, complete wound closure at Day 28 using a one-sided 97.5% confidence interval on the difference in the proportion of test sites successfully treated.
The most frequent adverse events noted were hematoma and seroma formation, which are common events in skin grafting procedures. There were no statistically significant differences between the stapled group and the ARTISSTM treated group with respect to hematoma and seroma formations. In the clinical trial, there were a few incidences of non-adherence of the skin grafts and pruritus, which may have been associated with ARTISSTM. However, these adverse events were also noted in the control (stapled) group and are not uncommon in skin grafting procedures.
The results of the pivotal safety and efficacy study did not raise any concern related to safety and efficacy.
Review of information submitted in the BLA for ARTISSTM did not raise any controversial issues or pose unanswered scientific questions which would have benefited from advisory committee discussion and recommendation.
There are no current concerns regarding the risk/benefit ratio.
Letter ready comments that summarize this memo to be included in the approval letter:
We did not refer your application to the Blood Products Advisory Committee because the active ingredients in Fibrin Sealant (Human) VH S/D 4 [ARTISSTM] are similar to those in your licensed product, Fibrin Sealant VH S/D 500 s-apr [TISSEEL®]. The mechanisms of action of fibrinogen and thrombin and their role in blood coagulation are well understood. Our review of information submitted in your BLA, including the clinical study design and trial results, did not raise concerns or controversial issues which would have benefited from an advisory committee discussion.