Regulatory Decision Summary for Fibryga

Authorization of the indication related to acquired fibrinogen deficiency was based on data from two clinical studies in patients undergoing surgery. Due to the nature of these types of surgery such as their complexity and extent, they were considered appropriate models for investigating the efficacy of fibrinogen supplementation in acquired fibrinogen deficiency occurring through loss, consumption and haemodilution-induced reduction in concentration.

1. A prospective, single-center, randomized, controlled, open-label phase 2 study that assessed the hemostatic efficacy and safety of Fibryga compared with cryoprecipitate as sources of fibrinogen in 43 patients undergoing major abdominal surgery, specifically cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for the peritoneal malignancy pseudomyxoma peritonei who developed fibrinogen deficiency. For the Fibryga group, 21 patients received a total of 34 doses of 4 g each. For the Cryoprecipitate group, 22 patients received a total of 45 doses of 2 pools of 5 units each. The primary efficacy endpoint was the overall haemostatic efficacy rating as assessed by an Independent Data Monitoring & Endpoint Adjudication Committee (IDMEAC) based on a predefined algorithm. Hemostatic therapy based on fibrinogen supplementation was rated as successful by the IDMEAC in all patients in both groups. A median of 1 unit and 0.5 unit of RBC were administered intraoperatively to the patients treated with Fibryga and cryoprecipitate, respectively, with a median of 0 unit of RBC during the first 24 hours postoperatively in both groups. No fresh frozen plasma or platelet concentrates were transfused during the study.
2. A pragmatic, prospective, multicenter, randomized, controlled, single-blinded, phase 3 study conducted in adult cardiac surgical patients for whom fibrinogen supplementation, using Fibryga or cryoprecipitate was ordered in accordance with accepted clinical standards (significant hemorrhage and known or presumed fibrinogen deficiency). The primary efficacy endpoint was the comparison of the total number of units of allogeneic blood administered during the first 24 hours after termination of cardio-pulmonary bypass. Patients received a median of 4 g of fibrinogen concentrate and 10 units of cryoprecipitate. From a total of 735 patients who were included in the analysis, 372 were in the Fibryga group and 363 in the cryoprecipitate group. The mean increase in fibrinogen was of 0.850 ± 0.425 g/L in the Fibryga group and 0.692 ± 0.396 g/L in the cryoprecipitate group The mean ± standard deviation (SD) number of units of ABPs transfused in the Fibryga group during the first 24 hours after termination of cardio-pulmonary bypass was 16.3 ± 16.7 units (range 5.5-22.0 units). The mean ± SD number of units of ABPs transfused in the cryoprecipitate group was 17.0 ± 16.1 units (range 7.0-23.0 units).

The recommended initial dose of the drug is 4 g. Additional doses of 4 g are to be administered as needed. Please refer to the product monograph for details.

• Regarding congenital fibrinogen deficiency, the final results of the prospective, open label, uncontrolled, multicenter phase 3 study, conducted in patients who present this deficiency continues to support the efficacy of the product in the treatment of acute bleeding episodes and perioperative prophylaxis in adult and pediatric patients affected by this condition.
• The safety profile of the product was consistent with previous observations.

Overall benefit/risk conclusion

Fibryga (Fibrinogen Concentrate - Human ) is a sterile, freeze dried preparation of highly purified fibrinogen. It is considered to allow a precise dosing a predictable response, a fast administration in situations where fibrinogen is needed. The data regarding the efficacy of Fibryga was considered insufficient for granting the general indication of "treatment of bleeding in acquired fibrinogen deficiency" requested by the Sponsor given some statistical limitations identified in the data submitted; however the totality of the evidence submitted supports the following indication: "Fibryga may be used as complementary therapy during the management of uncontrolled severe bleeding in patients with acquired fibrinogen deficiency in the course of surgical interventions".

For the indication related to congenital fibrinogen deficiency, the benefit/risk profile of Fibryga continues to be favourable for the treatment of acute bleeding episodes and perioperative prophylaxis in adult and pediatric patients affected by this condition.