Regulatory Decision Summary for Bivalirudin Injection

One pivotal in vitro study was provided in this submission. It compared the pharmacodynamic effects of the proposed ready to use (liquid) formulation of bivalirudin (MAIA Bivalirudin Injection 5 milligrams (mg)/milliliter (mL)) with the United States Food and Drug Administration (FDA) approved powered formulation (Angiomax for Injection, 250 mg/vial).

This pivotal in vitro study was designed to determine if the anticoagulant effect of the test product is equivalent to that of the reference product, the United States FDA approved Angiomax (bivalirudin for injection, 250 mg/vial).

This study employed an appropriate design to assess the equivalence of the liquid versus (vs.) powdered forms of bivalirudin in human plasma. The design was similar to an open controlled 2-way replicated crossover study that is traditionally used for the assessment of bioequivalence between a Test Drug and a Reference Drug. Blank (plasma only) and vehicle (0.9% sodium chloride) controls were also included.

Three common clotting parameters were used to evaluate anticoagulant efficacy: Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT) and Thrombin Time (TT). Each of these three parameters were evaluated over the therapeutic concentration range in male and female plasma samples (e.g., PT at the 5.0, 10.0, 15.0, and 20.0 micrograms (µg)/mL concentration levels, aPTT at the 1.0, 2.5, 5.0, 10.0, and 20.0 µg/mL levels, and TT at the 0.5, 0.75, and 1.0 µg/mL concentration levels).

The plasma from fifty subjects (25 male and 25 female) were included in the study. All data points (ranging between 98.9 and 103.5%) for the evaluable samples fell well within the predefined criteria for equivalence (90.0% to 111.0%). The results from the all-samples analysis were similar to the evaluable sample results (all data points fell within the range of 98.9 and 103.4% for all samples), thereby demonstrating the robustness of the study results. The results of the pivotal in vitro study demonstrated the equivalency of MAIA Bivalirudin Injection, 5 mg/mL vs. Angiomax (bivalirudin for injection in terms of the three clotting parameters: PT, aPTT and TT).

The use of United States FDA approved Angiomax for Injection was considered to be acceptable, provided it was demonstrated that there were no significant differences in the formulations, instructions for use, and physicochemical properties between the United States Angiomax for Injection and Health Canada approved Angiomax for Injection (both products are supplied as lyophilized powders). The Sponsor has demonstrated that there are no significant differences between the Canadian and United States Angiomax lyophilized powders from a quality perspective, including the formulations, packaging, instructions for use and physicochemical properties; thus, supporting the use of the United States FDA Angiomax for Injection as a reference product.

The overall benefit-risk-uncertainty profile of Bivalirudin Injection is favorable.