M E M O R A N D U M
Department of Health and Human Services
Public Health Service
United States Food and Drug Administration
Center for Biologics Evaluation and Research
To:   Basil Golding, MD, Division Director, Division of Hematology Research and Review (DHRR)/OBRR/CBER
        Paul D. Mintz, MD, Division Director, Division of Hematology Clinical Review (DHCR)/OBRR/CBER
From:   Natalya Ananyeva, PhD, Laboratory of Hemostasis (LH)/DHRR/OBRR 
             Lisa Faulcon, MD, Clinical Review Branch (CRB)/DHCR/OBRR
Through:   Nisha Jain, MD, Chief, CRB/DHCR/OBRR 
                 Tim Lee, PhD, Acting Chief, LH/DHRR/OBRR
Subject:   Rationale for waiving Baxter’s BLA for Antihemophilic Factor (Recombinant), Porcine Sequence [OBIZUR], STN 125512/0, from referral to the Blood Products Advisory Committee
BACKGROUND
STN 125512/0 is an original biologics license application (BLA) submitted by Baxter Healthcare Corporation (Baxter) for Antihemophilic Factor (Recombinant), Porcine Sequence, with the proprietary name OBIZUR. OBIZUR is a B domain-deleted recombinant analog of porcine Factor VIII (FVIII) produced in baby hamster kidney cells by recombinant DNA technology. OBIZUR is supplied as a sterile, non-pyrogenic, lyophilized powder in single-use vials containing nominally 500 units per vial.
OBIZUR is indicated for the treatment of bleeding episodes in adults with acquired hemophilia A.
REASONS FOR WAIVING REFERRAL TO BPAC
The Division of Hematology Research and Review and Division of Hematology Clinical Review in the Office of Blood Research and Review reviewed the information in 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]):
1. New molecular entity provision (NME) does not apply to OBIZUR as it does not represent a novel product class. Recombinant FVIII products have been licensed in the U.S. since 1992 and have been used to control and prevent bleeding in patients with hemophilia A. The first product in this class, RECOMBINATE, was approved by the FDA in 1992, and currently there are several full-length (KOGENATE FS, ADVATE) and B-domain-deleted (XYNTHA, Novoeight and ELOCTATE) FVIII products licensed in the U.S. 
 
2. The mechanism of action of FVIII and its function in blood coagulation is well studied and understood. Upon activation by thrombin, FVIIIa acts as a cofactor for activated Factor IX triggering a chain of biochemical reactions – activation of Factor X, which converts prothrombin into thrombin, and subsequent interaction of thrombin with fibrinogen results in the formation of a fibrin clot that stops bleeding. When administered into a patient with hemophilia A, FVIII products temporarily replace the missing or inhibited endogenous FVIII. 
 
3. OBIZUR shares approximately (b)(4) pair-wise homology with the B-domain deleted human FVIII. The amino acid composition of OBIZUR is consistent with that predicted from the cDNA sequence of the expression construct. The functional characteristics and hemostatic activity of OBIZUR are consistent with those of human FVIII products and enable the formation of a fibrin clot via the intrinsic coagulation pathway. 
 
4. The manufacturing process for OBIZUR includes two viral clearance steps – solvent/detergent treatment for virus inactivation and nanofiltration for virus removal – that meet the current requirements for assuring product safety with regard to adventitious viruses. 
 
5. The proposed indication for OBIZUR is similar to that of other U.S. licensed recombinant FVIII products for patients with hemophilia A, but focuses on the patient population with acquired hemophilia A. 
 
6. The design of the pivotal clinical studies to evaluate the safety and efficacy of OBIZUR was adequate and the results of the studies did not raise any concerns. Evaluation of the safety data for OBIZUR (43 subjects) did not reveal any concerns. 
 
7. Review of information submitted in the BLA for OBIZUR did not raise any controversial issues or pose unanswered scientific questions which would have benefited from Advisory Committee discussion and recommendations.
