CADTH Technology Report

Canadian Agency for Drugs and Technologies in Health Agence canadienne des médicaments et des technologies de la santé CADTH Technology Report Issue 139 July 214 Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis Supporting Informed Decisions

Cite as: Blouin J, Boucher M, Lee KM. Factor XIII concentrate, human (Corifact): Treatment cost comparison and budget impact analysis [Internet]. Ottawa: Canadian Agency for Drugs and Technologies in Health (CADTH); 214 (Technology report; no.139). [cited YYYY-MM-DD]. Available from: http://cadth.ca/media/pdf/ob2_corifact_economic_report_e.pdf The Canadian Agency for Drugs and Technologies in Health (CADTH) would like to acknowledge various participants in the development of this report: Rick Trifunov, Cheryl Doncaster, and Kathryn Webert from the Canadian Blood Services (CBS) for their input on the scope of the project, feedback on drafts, and review of final report. This report is prepared by CADTH. The report contains a comprehensive review of the existing public literature, studies, materials, and other information and documentation (collectively the source documentation ) available to CADTH at the time of report preparation. This report was produced, as part of a collaboration between CADTH and the CBS, to provide an economic evaluation of a new plasma product to supplement a CBS clinical evidence report. The scope of the research questions in this CADTH report was discussed in collaboration with CBS and clinical experts. Based on the scope, the clinical data needs were determined, and any gaps in the data in the CBS clinical evidence report were addressed through a systematic review. CADTH used these data to inform this report. The information in this report is intended to be used by CBS, along with the CBS clinical evidence report, to make recommendations to the provincial and territorial ministries of health on whether to purchase and distribute the new plasma product. The information in this report should not be used as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process, nor is it intended to replace professional medical advice. While CADTH has taken care in the preparation of this document to ensure that its contents are accurate, complete, and up to date as of the date of publication, CADTH does not make any guarantee to that effect. CADTH is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in the source documentation. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or relating to the use (or misuse) of any information, statements, or conclusions contained in or implied by the information in this document or in any of the source documentation. This document and the information provided are prepared and intended for use in the context of the Canadian health care system. Other health care systems are different; the issues and information related to the subject matter of this document may be different in other jurisdictions and, if used outside of Canada, it is at the user s risk. This disclaimer and any questions or matters of any nature arising from or relating to the content or use (or misuse) of this document will be governed by and interpreted in accordance with the laws of the Province of Ontario and the laws of Canada applicable therein, and all proceedings shall be subject to the exclusive jurisdiction of the courts of the Province of Ontario, Canada. CADTH takes sole responsibility for the final form and content of this document, subject to the limitations noted above. The statements and conclusions in this document are those of CADTH and not of its advisory committees and reviewers. The statements, conclusions, and views expressed herein do not necessarily represent the views of Health Canada or any Canadian provincial or territorial government. Production of this document is made possible by financial contributions from Health Canada and the governments of Alberta, British Columbia, Manitoba, New Brunswick, Newfoundland and Labrador, Northwest Territories, Nova Scotia, Nunavut, Prince Edward Island, Saskatchewan, and Yukon.

Copyright CADTH 214. You are permitted to make copies of this document for non-commercial purposes provided it is not modified when reproduced and appropriate credit is given to CADTH. You may not otherwise copy, modify, translate, post on a website, store electronically, republish, or redistribute any material from the website in any form or by any means without the prior written permission of CADTH. Please contact CADTH s Vice-President of Corporate Services at corporateservices@cadth.ca with any inquiries about this notice or other legal matters relating to CADTH s services. ISSN: 1922-611X

TABLE OF CONTENTS ABBREVIATIONS... ii 1 BACKGROUND...1 1.1 Disease Overview... 1 1.2 Canadian Prevalence of Factor XIII Deficiency... 1 1.3 Current Treatment Options... 2 1.4 Plasma-Derived Factor XIII Concentrate (Corifact)... 3 1.5 Comparative Efficacy and Safety of Plasma-Derived Factor XIII Concentrate and Recombinant Factor XIII... 3 1.6 Potential for Off-Label Use... 4 1.7 Policy and Ethical Issues... 4 2 OBJECTIVES...5 3 TREATMENT COST COMPARISON...5 4 BUDGET IMPACT ANALYSIS (NATIONAL)...8 4.1 Approach... 8 4.2 Assumptions... 8 4.3 Estimated Number of Treated Cases Per Province in 212... 8 4.4 Proportion of Patients Treated... 9 4.5 Treatment Cost...1 4.6 Results...12 4.6.1 Base-case analysis... 12 4.6.2 Sensitivity analyses... 12 5 SUMMARY... 14 6 REFERENCES... 15 Tables Table 1: Prevalence of Congenital Factor XIII Deficiency in Canada, 213, By Age Category a..2 Table 2: Blood Products Available for the Prophylactic Treatment of Factor XIII Deficiency...3 Table 3: Cost Comparison of Agents Used for Routine Prophylaxis of Factor XIII Deficiency, Assuming a Body Weight of 41 kg (Pediatric Patient)...6 Table 4: Cost Comparison of Agents Used for Routine Prophylaxis of Factor XIII Deficiency, Assuming a Body Weight of 65 kg or 9 kg (Adult Patient)...7 Table 5: Estimated Number of Patients Having Plasma-Derived Factor XIII Concentrate Through SAP in 212, Stratified By Age and By Deficiency Severity...9 Table 6: Estimated National a Distribution of Patients... 1 Table 7: Average Annual Treatment Cost used for the Calculation of the Budget Impact Analysis... 11 Table 8: National a Budget Impact Analysis Results... 12 Table 9: National a Budget Impact Analysis Results Sensitivity Analysis 1... 12 Table 1: National a Budget Impact Analysis Results Sensitivity Analysis 2... 13 Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis i

ABBREVIATIONS BMI CADTH CBS IU NOC SAP body mass index Canadian Agency for Drugs and Technologies in Health Canadian Blood Services international units Notice of Compliance Special Access Programme (Health Canada) Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis ii

1 BACKGROUND 1.1 Disease Overview Congenital factor XIII deficiency is a rare, potentially life-threatening, inherited coagulation disorder. The prevalence of severe factor XIII deficiency is estimated to be one case in 3 to 5 million people. 1 Congenital factor XIII deficiency can be due to defects in either factor XIII-A gene (A-subunit deficiency) or factor XIII-B gene (B-subunit deficiency). A-subunit deficiency is the most common form of factor XIII deficiency. B-subunit deficiency occurs in less than 5% of reported factor XIII deficiency cases. 2 The diagnosis of severe factor XIII deficiency is often made in early life. 2 Bleeding from the umbilical stump in the newborn is a typical early clinical manifestation of the condition, and is reported in as many as 8% of cases of factor XIII deficiency. 3 Other common clinical manifestations include subcutaneous bleeding, intramuscular bleeding, and intracranial hemorrhage. 4 Intracranial hemorrhage is the main cause of death or disability in patients with congenital factor XIII deficiency. 2,5 Factor XIII deficiency has also been associated with poor wound healing and recurrent pregnancy loss. The rate of miscarriage in females with severe factor XIII deficiency has been reported to be as high as 8%. 6 Coagulation factor deficiencies are classified according to severity, as follows: 7 Severe (factor activity level less than or equal to 1%) Moderate (factor activity level between 1 and 5%) Mild (factor activity level greater than 5%). Factor XIII deficiency can also be acquired, although most cases of acquired deficiency usually do not require prophylactic treatment. 8 1.2 Canadian Prevalence of Factor XIII Deficiency The number of Canadian patients with congenital factor XIII deficiency reported in the Canadian Hemophilia Registry and Rare Inherited Bleeding Disorders Registry, as of May 213, 7 is reported in Table 1. Of note, there was only one reported case of severe acquired factor XIII deficiency (in a male aged 85+). Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 1

Table 1: Prevalence of Congenital Factor XIII Deficiency in Canada, 213, By Age Category a Severity b Gender Count Age Category - 4 5-9 1-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 85 + Severe F 17 1 3 4 1 4 2 1 1 M 14 1 2 1 4 1 4 1 Total severe 31 2 5 5 5 5 2 5 2 Moderate F 4 1 1 1 1 M 2 1 1 Total 6 1 1 2 1 1 moderate Mild F M 6 5 1 1 1 4 1 1 2 Total mild 11 1 1 1 4 1 1 2 Total number of patients 48 1 3 6 1 7 8 5 6 2 a Includes data on all individuals registered with Canadian hemophilia clinics (also includes patients from Quebec). b There were five reported cases of factor XIII deficiency for which the severity was unknown or not reported. 1.3 Current Treatment Options Lifelong prophylaxis is recommended in all patients with severe congenital factor XIII deficiency in order to prevent spontaneous hemorrhage, especially intracranial bleeding. In patients with moderate factor XIII deficiency, routine prophylaxis will be considered on a caseby-case basis, depending on the individual patient s bleeding history. Patients with mild deficiency typically only require periprocedural factor replacement. 9 Evidence suggests that increasing the factor XIII activity level to anywhere from 3% to 1% of the normal population mean is sufficient to prevent spontaneous bleeds. 5,9 In the past, whole blood, fresh-frozen plasma, and cryoprecipitate have been used in the treatment of factor XIII deficiency. However, these agents carry a risk for allergic reaction and potential risk of disease transmission among other adverse reactions. Patients with severe factor XIII deficiency in Canada currently receive either recombinant coagulation factor XIII, A- subunit (catridecacog, Tretten), or an unlicensed plasma-derived factor XIII concentrate (Fibrogammin P) available through Health Canada s Special Access Programme (SAP). Prior to the licensure of catridecacog in 212, plasma-derived factor XIII concentrate was the only treatment available for Canadian patients with factor XIII deficiency. It has been used in several countries for many years. Plasma-derived factor XIII concentrate is effective for deficiencies of both subunits A and B, which is an advantage over catridecacog, which is only indicated for A-subunit deficiencies. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 2

1.4 Plasma-Derived Factor XIII Concentrate (Corifact) Plasma-derived factor XIII concentrate (Corifact) received a Notice of Compliance (NOC) from Health Canada on December 24, 213. The manufacturing process and composition of Corifact are identical to Fibrogammin P except that, based on the Canadian regulations and requirements, Corifact will be produced only from United States-sourced plasma (according to the manufacturer s submission). Plasma-derived factor XIII concentrate is indicated for routine prophylactic treatment and perioperative management of surgical bleeding in patients with congenital factor XIII deficiency. 1 Corifact dosing regimen should be individualized based on body weight, laboratory values, and the patient s clinical condition. The recommended starting dose for routine prophylaxis is 4 international units (IU) per kg of body weight. Dosing is to be guided by the most recent trough factor XIII activity level, with dosing every 28 days (4 weeks) to maintain a trough factor XIII activity level of approximately 5% to 2%. 1 The recommended dose for prophylaxis prior to surgery will depend on the timing of the surgery versus the patient s last routine prophylactic dose. Adjustments to dosing are to be individualized based on factor XIII activity levels and the patient s clinical condition. 1 Table 2: Blood Products Available for the Prophylactic Treatment of Factor XIII Deficiency Generic Name Trade Name Regulatory Status in Canada Efficacy for Subunit Deficiency Catridecacog Tretten Licensed B recombinant coagulation factor XIII Factor XIII concentrate, human Fibrogammin P Unlicensed available through SAP A and B Factor XIII concentrate, human Corifact Licensed A and B SAP = Special Access Programme (Health Canada). 1.5 Comparative Efficacy and Safety of Plasma-Derived Factor XIII Concentrate and Recombinant Factor XIII There are no clinical trials comparing plasma-derived factor XIII concentrate products with catridecacog. Therefore, the comparative efficacy of these blood products is unknown. However, both blood products showed efficacy in reducing the risk of spontaneous bleeding episodes in patients with factor XIII deficiency (Canadian Blood Services [CBS] Therapeutic Drug Product Review of Corifact). From a safety perspective, catridecacog offers a potential advantage over plasma- derived factor XIII concentrate products, as there is no human or mammalian plasma used in its manufacturing process. However, the manufacturer notes that all plasma used in the manufacturing of plasma- Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 3

derived factor XIII concentrate products goes through several safety and purification processes to ensure a high degree of assurance that the production process results in a very low risk of transmission of infectious agents such as prions, bacteria, and viruses. 1 1.6 Potential for Off-Label Use Based on the clinical experts feedback, the potential for off-label use of plasma- derived factor XIII concentrate products is low. Experts indicated that it could be used for patients presenting with severe acquired factor XIII deficiency, although, as of May 213, there was only one reported case in the Canadian Hemophilia Registry and Rare Inherited Bleeding Disorders Registry. 7 1.7 Policy and Ethical Issues Plasma-derived factor XIII concentrate has been available in Canada through the SAP program for several years. Currently, based on information received by CBS, the majority of patients receiving routine prophylaxis for severe factor XIII deficiency receive plasma-derived factor XIII concentrate and there have been no reports of adverse events associated with its use. Corifact received a NOC from Health Canada on December 24, 213. Thus, it is expected that Fibrogammin P may only be available for a short period of time in Canada through SAP. If plasma-derived factor XIII concentrate was not made available, only catridecacog would be available. Such a situation would generate the following issues that must be considered: Patients with B-subunit deficiency would no longer have access to an effective therapy. For patients in whom the factor XIII mutation is unknown or is known to be in the B-subunit, catridecacog should not be used. Routinely used laboratory testing does not differentiate between A- and B-subunit deficiencies. The clinical experts consulted for this review noted that there is limited access and delays for the testing for A- or B-subunit deficiency differentiation. All patients currently receiving plasma-derived factor XIII concentrate would need to be switched to catridecacog. Based on consultation with two clinical experts, both patients and physicians are hesitant to discontinue a therapy that has been effective in treating the patients disease. There are also concerns about the risk of developing inhibitory antibodies against factor XIII, which may result in inadequate response to therapy. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 4

2 OBJECTIVES This report aims to: Perform a cost comparison of plasma-derived factor XIII concentrate and catridecacog for the routine prophylactic treatment of patients with congenital factor XIII deficiency. From the Canadian health ministry perspective, assess the budgetary impact resulting from the reimbursement of plasma-derived factor XIII concentrate, over a three-year period, for routine prophylactic treatment of patients with congenital factor XIII deficiency. Perioperative management of surgical bleeding was not considered in this analysis, because dosing is to be individualized based on factor XIII activity levels and the patient s clinical condition. 1 3 TREATMENT COST COMPARISON Based on clinical experts consulted for this review, catridecacog was considered to be the most appropriate comparator to plasma-derived factor XIII concentrate. The average cost per dose depends on the patient s weight. Both blood products are available in single-dose vials; therefore, wastage is an important consideration if patients doses require only a fraction of a vial. Plasma-derived factor XIII concentrate is available in 25 IU or 1,25 IU vials, which reduces wastage, whereas catridecacog is only available in a 2,5 IU vial. Plasma-derived factor XIII concentrate is indicated for both children and adults. As of May 213, there were ten reported cases of severe factor XIII deficiency in Canada in patients younger than 18 years old, most of them (five out of ten) being in the 1 to 14 age group. 7 There were no reported cases of moderate deficiency in patients under 18 years of age. 7 Two price scenarios were considered: one in pediatric patients (Table 3), and one in adult patients (Table 4). The following approach was taken to estimate the average weight of pediatric patients: Most of the reported cases in patients under 18 years of age are in the 1 to 14 age group. 7 Based on the World Health Organization s growth charts adapted for Canada, the median body mass index (BMI) and height in girls aged 12 years are 18 kg/m 2 and 15 cm, respectively; in boys aged 12 years, the median BMI and height are 17.5 kg/m 2 and 15 cm, respectively. 11,12 A BMI of 18 kg/m 2 and a height of 15 cm correspond to a body weight of 41 kg. 13 For adult patients, a body weight ranging from 65 kg to 9 kg was assessed. Only the blood product cost was considered. Other costs related to the blood product administration were not considered, as it was assumed that these costs would be similar for the two products. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 5

Table 3: Cost Comparison of Agents Used for Routine Prophylaxis of Factor XIII Deficiency, Assuming a Body Weight of 41 kg (Pediatric Patient) Product Strength Dosage Form Factor XIII Concentrate, Human (Corifact) Catridecacog recombinant coagulation factor XIII (Tretten) 25 IU and 1,25 IU Singleuse vial 2,5 IU Singleuse vial Price ($) $vvvv/iu c $vvv per 25 IU vial $vvvvv per 1,25 IU vial $vvvvv/iu d $vvvvvv per 2,5 IU vial Recommended Dose 4 IU/kg (1,64 IU ) every 28 days (4 weeks) 35 IU/kg (1,435 IU) approximately once monthly Average Cost per dose($) a $vvvvv (2 vials of 25 IU and 1 vial of 1,25 IU) $vvvvvv (1 vial of 2,5 IU) Average Annual Drug Cost ($) b $vvvvvv $vvvvvvv a Wastage included in the cost. b Assuming 12 doses per year. c The proposed pricing of product from the manufacturer s submission, Appendix I, is US$vvvv /IU. Exchange rate from the Bank of Canada, Dec 18 213, US$1= CAN$1.689. d Current Canadian Blood Services (CBS) cost (Corifact CBS medical review). As shown in Table 3, in a pediatric population (assuming a body weight of 41 kg), plasmaderived factor XIII concentrate was 1.5 times less expensive than catridecacog, yielding to an average cost saving of $293,7 per patient, per year. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 6

Table 4: Cost Comparison of Agents Used for Routine Prophylaxis of Factor XIII Deficiency, Assuming a Body Weight of 65 kg or 9 kg (Adult Patient) Product Strength Dosage Form Factor XIII Concentrate, Human (Corifact) Catridecacog recombinant coagulation factor XIII (Tretten) 25 IU and 1,25 IU Single-use vial 2,5 IU Single-use vial Price ($) $vvvv/iu c $vvv per 25 IU vial $vvvvv per 1,25 IU vial $vvvvv/iu d $vvvvvv per 2,5 IU vial Recommended Dose 4 IU/kg every 28 days (4 weeks) 65 kg: 2,6 IU 9 kg: 3,6 IU 35 IU/kg approximately once monthly 65 kg: 2,275 IU 9 kg: 3,15 IU Average Cost per dose($) a 65 kg: $vvvvv (2 vials of 1,25 IU and 1 vial of 25 IU) 9 kg: $vvvvv (3 vials of 1,25 IU) 65 kg: $vvvvvv (1 vial of 2,5 IU) 9 kg: $vvvvvv (2 vials of 2,5 IU) Average Annual Drug Cost ($) b $vvvvvv (65 kg) $vvvvvv (9 kg) $vvvvvvv (65 kg) $vvvvvvv (9 kg) a Wastage included in the cost. b Assuming 12 doses per year. c The proposed pricing of product from the manufacturer s submission, Appendix I, is US$vvvv /IU exchange rate from Bank of Canada, Dec. 18 213, US$1= CAN$1.689. d Current Canadian Blood Services (CBS) cost (Corifact CBS medical review). As shown in Table 4, in an adult population (assuming a body weight ranging from 65 to 9 kg), plasma-derived factor XIII concentrate was 6.6 to 9.6 times less expensive than catridecacog, yielding to an average cost saving of $275,4 and $581,7 per patient, per year, respectively. Of note, the treatment cost comparison was based on Health Canada s recommended starting doses for plasma-derived factor XIII concentrate (4 IU/kg) and catridecacog (35 IU/kg) for routine prophylaxis. Dosing of factor XIII is to be individualized, to maintain a trough factor XIII activity level of approximately 5% to 2%. 1 The recommended starting dose of plasmaderived factor XIII concentrate in Canada is higher than that of other countries and other clinical guidelines, which recommend a dose of 1-15 IU/kg administered at intervals of 4 weeks. 9 For patients already receiving plasma-derived factor XIII concentrate through SAP, it is possible that physicians would maintain their current dose, basing that approach on the 1-15 IU/kg dosing recommendation, especially if patients are stable. Even for patients initiating treatment, physicians might use the 1-15 IU/kg dosing regimen because they are experienced with it. These scenarios would yield to greater savings compared with catridecacog. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 7

4 BUDGET IMPACT ANALYSIS (NATIONAL) 4.1 Approach This analysis used a prevalence-based approach. The time horizon for the analysis was three years: Reference Year: 213; Year 1: 214; Year 2: 215; Year 3: 216. A national perspective was applied; however, Quebec was excluded from the analysis. Only the use of plasma-derived factor XIII concentrate for the routine prophylactic treatment of patients with factor XIII deficiency was considered. Perioperative management of surgical bleeding was not included in this analysis because dosing is to be individualized based on factor XIII activity levels and the patient s clinical condition. 1 4.2 Assumptions Key assumptions used to generate the budget impact analysis are as follows: Corifact received a NOC from Health Canada on December 24, 213. Thus, it was assumed that for Year 1 (214) and beyond, Fibrogammin P would no longer be available through SAP. Only patients with severe, and some of the patients with moderate, deficiency would receive prophylactic treatment. The proportion of treated patients with moderate versus severe deficiency was assumed to be 16% (6 patients out of 37), based on the Canadian Hemophilia Registry and Rare Inherited Bleeding Disorders Registry, as of May 213. 7 It was assumed that there were no pediatric patients with moderate deficiency for Years 1 and 2 (and that there would be one new case in Year 3). In patients with severe deficiency, the proportion of patients under 18 years was 32% (1 patients out of 31), based on the Canadian Hemophilia Registry and Rare Inherited Bleeding Disorders Registry, as of May 213. 7 4.3 Estimated Number of Treated Cases Per Province in 212 The number of patients per province who received Fibrogammin P through SAP in 212 (excluding Quebec) was obtained from CBS and was used as the basis for the treated patients in 212. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 8

Table 5: Estimated Number of Patients Having Plasma-Derived Factor XIII Concentrate Through SAP in 212, Stratified By Age and By Deficiency Severity BC AB SK MB ON NB NS NL Total a Number of patients having received 1 4 15 1 3 9 33 Fibrogammin P in 212 b Patients with moderate deficiency (all 1 2 1 4 18 years old) Patients with severe deficiency 1 3 13 1 3 8 29 Patients < 18 years old 1 4 1 2 9 Patients 18 years old 1 2 9 1 2 6 2 a Excluding Quebec b Data provided by Canadian Blood Services. AB = Alberta; BC = British Columbia; MB = Manitoba; NB = New Brunswick; NL = Newfoundland and Labrador; NS = Nova Scotia; ON = Ontario; SAP = Special Access Programme (Health Canada); SK = Saskatchewan. 4.4 Proportion of Patients Treated Based on data provided by CBS, at the end of 213, approximately 15% of total factor XIII usage in hospitals was for catridecacog and 85% was for plasma-derived factor XIII concentrate. In the base-case analysis, CADTH assumed that 15% of patients with moderate deficiency, 2% of pediatric patients with severe deficiency, and 1% of adult patients with severe deficiency were switched to the recombinant product in 213. Considering patients and physicians concern in switching therapies because of the risk of developing inhibitors, and their hesitation to discontinue a therapy that has been shown to be effective, for Year 1 (214), it was assumed that, upon reimbursement of plasma-derived factor XIII concentrate, all patients currently on Fibrogammin P would receive Corifact. However, patients receiving catridecacog would remain on it (would not change treatments). As factor XIII deficiency is a rare disease, the incidence of new cases is low. For the base-case analysis, over the three-year period of the analysis, it was assumed that there would be one new treated case of moderate deficiency, and one new treated case of severe deficiency (all in patients under the 18 years of age, as diagnosis is usually made in early life). It was assumed that one new case would be treated with plasma-derived factor XIII concentrate, and the other new case would be treated with recombinant factor XIII. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 9

Table 6: Estimated National a Distribution of Patients Reference b Year 1 c Year 2 d 213 214 215 Patients with moderate deficiency f 4 4 4 5 Patients < 18 years old 1 Plasma-derived factor XIII concentrate Year 3 e 216 (Fibrogammin P/ Corifact) Catridecacog (Tretten) 1 Patients 18 years old 4 4 4 4 Plasma-derived factor XIII concentrate 3 3 3 3 (Fibrogammin P/ Corifact) Catridecacog (Tretten) 1 1 1 1 Patients with severe deficiency f 29 29 3 3 Patients < 18 years old 8 8 8 8 Plasma-derived factor XIII concentrate 6 6 6 6 (Fibrogammin P/ Corifact) Catridecacog (Tretten) 2 2 2 2 Patients 18 years old 21 21 22 22 Plasma-derived factor XIII concentrate (Fibrogammin P/ Corifact) 19 19 2 2 Catridecacog (Tretten) 2 2 2 2 Total number of patients treated f 33 33 34 35 Plasma-derived factor XIII concentrate 28 29 29 28 (85%) (Fibrogammin P/ Corifact) (85%) (85%) (83%) Catridecacog (Tretten) 5 (15%) 5 (15%) 5 (15%) 6 (17%) a Excluding Quebec. b It was assumed that, compared with 212, 15% of patients with moderate deficiency, 2% of pediatric patients with severe deficiency, and 1% of adult patients with severe deficiency were switched to catridecacog. It was assumed that one patient with severe deficiency turned 18 years old, and there was no new reported case of moderate or severe factor XIII deficiency. c No switch, no new reported case of moderate or severe factor XIII deficiency. d No switch, 1 new reported case of severe deficiency in a patient <18 years old (assumed to be treated with plasma-derived factor XIII concentrate), and 1 patient with severe deficiency turned 18 years old. e One new case of moderate deficiency in patient <18 years old (assumed to be treated with catridecacog). f These numbers were derived from the total number of patients having received Fibrogammin P through SAP in 212 (Table 5). 4.5 Treatment Cost For the calculation of the annual treatment cost, it was assumed that for patients under 18 years of age, the average weight was 41 kg, and for patients greater than or equal to 18 years of age, the average weight was 75 kg. The average annual treatment cost for each product, based on patient s weight, is presented in Table 7. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 1

Table 7: Average Annual Treatment Cost used for the Calculation of the Budget Impact Analysis Product Strength Dosage Form Factor XIII concentrate, human (Corifact) Catridecacog recombinant coagulation factor XIII (Tretten) 25 IU and 1,25 IU Singleuse vial 2,5 IU Singleuse vial Price ($) $vvvv/iu c $vvv per 25 IU vial $vvvvv per 1,25 IU vial $vvvvv/iu f $vvvvvv per 2,5 IU vial Recommended Dose 4 IU/kg every 28 days (4 weeks) < 18: 1,64 IU d 18: 3, IU e 35 IU/kg approximately once monthly < 18: 1,435 IU d 18: 2,625 IU e Average Cost Per Dose($) a < 18: $vvvv (1 vial of 1,25 IU and 2 vials of 25 IU) 18: $vvvvv (2 vials of 1,25 IU and 2 vials of 25 IU) < 18: $vvvvvv (1 vial of 2,5 IU) 18: $vvvvvv (2 vials of 2,5 IU) Average Annual Drug Cost ($) b < 18: $vvvvvv 18: $vvvvvv < 18: $vvvvvvv 18: $vvvvvvv a Wastage included in the cost. b Assuming 12 doses per year. c The proposed pricing of product from the manufacturer s submission, Appendix I, is US$vvvv /IU exchange rate from the Bank of Canada, Dec. 18 213, US$1= CAD$1.689. d Assuming a body weight of 41 kg for patients < 18 years old. e Assuming a body weight of 75 kg for patients 18 years old. f Current Canadian Blood Services (CBS) cost (Corifact CBS medical review). The total annual treatment cost was then calculated, as follows: Total annual treatment cost = (Average annual cost per patient < 18 years old x number of patients < 18 years old) + (Average annual cost per patient 18 years old x number of patients 18 years old) Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 11

4.6 Results 4.6.1 Base-case analysis As presented in Table 8, the results of base-case budget impact analysis show that reimbursing plasma-derived factor XIII concentrate and catridecacog (instead of catridecacog only) would generate national savings of $ 14,166,8 in Year 1, $ 14,73,1 in Year 2, and $ 14,713,9 in Year 3. Table 8: National a Budget Impact Analysis Results Year 1 214 Year 2 215 Year 3 216 Total cost if plasma-derived factor XIII b concentrate not reimbursed $ vvvvvvvvvv $ vvvvvvvvvv $ vvvvvvvvvv Total cost if plasma-derived factor XIII c concentrate reimbursed $ vvvvvvvvv $ vvvvvvvvv $ vvvvvvvvv Budget impact (savings) of reimbursing plasma-derived factor XIII $(14,166,8) $ (14,73,1) $(14,713,9) a Excluding Quebec. b This assumes that all patients would be treated with Tretten, except patients with subunit B deficiency (5% of patients), who would be left without treatment. There are ethical issues with this option. c Using patient shares from Table 6 and treatment costs from section 4.5. 4.6.2 Sensitivity analyses Sensitivity analyses were conducted to determine the effect of varying individual parameter estimates from those used in the base-case analysis. a) Sensitivity analysis 1: For this analysis, it was assumed that: All new cases would be treated with catridecacog. For Year 1 (214), 25% of adult patients with moderate deficiency, 5% of pediatric patients with severe deficiency, and 25% of adult patients with severe deficiency would be switched to catridecacog. There would be no further switches in Year 2 and Year 3. Table 9: National a Budget Impact Analysis Results Sensitivity Analysis 1 Year 1 214 Year 2 215 Year 3 216 Total cost if plasma-derived factor XIII b concentrate not reimbursed $ vvvvvvvvvv $ vvvvvvvvvv $ vvvvvvvvvv Total cost if plasma-derived factor XIII concentrate reimbursed $vvvvvvvvv $ vvvvvvvvv $ vvvvvvvvv Budget impact (savings) of reimbursing plasma-derived factor XIII $(11,44,7) $(11,521,2) $(11,55,) a Excluding Quebec. b This assumes that all patients would be treated with catridecacog, except patients with subunit B deficiency (5% of patients), who would be left without treatment. There are ethical issues with this option. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 12

This sensitivity analysis shows that, should the proportion of patients having switched to catridecacog in 213 be greater than what was assumed in the base-case analysis, savings associated with the distribution of plasma-derived factor XIII would be smaller than what was observed in the base-case analysis. b) Sensitivity analysis 2: For this analysis, it was assumed that: All new cases would be treated with plasma-derived factor XIII concentrate. 5% of patients who had been switched to catridecacog in 213 would return to plasmaderived factor XIII in Year 1 (214). There would be no further switches in Year 2 and Year 3. Table 1: National a Budget Impact Analysis Results Sensitivity Analysis 2 Year 1 b 214 Year 2 215 Year 3 216 Total cost if plasma-derived factor XIII b concentrate not reimbursed $ vvvvvvvvvv $ vvvvvvvvvv $ vvvvvvvvvv Total cost if plasma-derived factor XIII concentrate reimbursed $ vvvvvvvvv $ vvvvvvvvv $ vvvvvvvvv Budget impact (savings) of reimbursing plasma-derived factor XIII $ (15,413,8) $ (15,977,1) $ (16,254,6) a Excluding Quebec. b This assumes that all patients would be treated with catridecacog, except patients with subunit B deficiency (5% of patients), who would be left without treatment. There are ethical issues with this option. This sensitivity analysis shows that, should the proportion of patients having switched to catridecacog in 213 return to their original treatment, or should new patients be initiated on plasma-derived factor XIII instead of catridecacog, savings associated with the reimbursement of plasma-derived factor XIII concentrate would be greater than what was observed in the base-case analysis. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 13

5 SUMMARY In Canada, patients with factor XIII are currently managed with prophylactic treatment with either plasma-derived factor XIII concentrate (Fibrogammin P) through SAP, or catridecacog. Plasma-derived factor XIII concentrate (Corifact) received a NOC from Health Canada on December 24, 213. Thus, it is expected that Fibrogammin P may only be available for a short period of time in Canada. If plasma-derived factor XIII concentrate was not made available, a situation where only catridecacog is available would generate some issues such as unavailability of treatment for patients with subunit B deficiency, and would force all patients currently receiving plasma-derived factor XIII concentrate to be switched to catridecacog. Based on consultation with two clinical experts, both patients and physicians are hesitant to discontinue a therapy that has been effective in treating the patients disease. There are also concerns about the risk of developing inhibitory antibodies against factor XIII, which may result in inadequate response to therapy. The comparative efficacy of plasma-derived factor XIII concentrate with catridecacog is unknown. However, both blood products reduce the risk of spontaneous bleeding episodes in patients with factor XIII deficiency (CBS medical review). Catridecacog offers a theoretical safety advantage over factor XIII concentrate, as there is no human plasma used in its manufacturing process. Plasma-derived factor XIII concentrate (proposed price $vvvv /IU) is less expensive than recombinant factor XIII (current CBS price $vvvvv /IU). Plasma-derived factor XIII concentrate provides more flexible dosing options because of the additional vial sizes, which reduces wastage. The pricing scenarios performed by CADTH showed that depending on patient s body weight, the use of plasma-derived factor XIII concentrate instead of catridecacog for the routine prophylactic treatment of patients with congenital factor XIII deficiency could generate savings ranging from $275,4 to $581,7 per patient, per year. Considering that the Product Monograph s recommended dose for routine prophylaxis (4 IU/kg) is greater than that from other countries and other clinical guidelines, 9 physicians might continue to use a lower starting dose in new patients. As well, patients already receiving (and stable on) lower doses of plasmaderived factor XIII concentrate through SAP might remain on their current dose, which would yield to greater savings. The budget impact analysis performed by CADTH suggests that, at the national level, the reimbursement of plasma-derived factor XIII for the routine prophylactic treatment of patients with factor XIII deficiency would generate savings ranging from $11.4M to $15.4M in Year 1 (214), $11.5M to $16M in Year 2 (215), and $11.5M to $16.3M in Year 3 (216) in Canada. Of note, the reference scenario used in the budget impact analysis assumes that, should plasmaderived factor XIII concentrate not be reimbursed, and not be available through SAP, all patients would be treated with catridecacog, except patients with subunit B deficiency (assumed to affect 5% of patients), who would be left without treatment. Perioperative management of surgical bleeding was not included in this analysis because dosing is to be individualized based on factor XIII activity levels and the patient s clinical condition. Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 14

6 REFERENCES 1. Board PG, Losowsky MS, Miloszewski KJ. Factor XIII: inherited and acquired deficiency. Blood Rev. 1993 Dec;7(4):229-42. 2. Hsieh L, Nugent D. Factor XIII deficiency. Haemophilia. 28 Nov;14(6):119-2. 3. Anwar R, Miloszewski KJ. Factor XIII deficiency. Br J Haematol. 1999 Dec;17(3):468-84. 4. Ivaskevicius V, Seitz R, Kohler HP, Schroeder V, Muszbek L, Ariens RA, et al. International registry on factor XIII deficiency: a basis formed mostly on European data. Thromb Haemost. 27 Jun;97(6):914-21. 5. Fadoo Z, Merchant Q, Rehman KA. New developments in the management of congenital factor XIII deficiency. Journal of Blood Medicine [Internet]. 213 [cited 214 Jan 14];4:65-73. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/pmc367414 6. Asahina T, Kobayashi T, Takeuchi K, Kanayama N. Congenital blood coagulation factor XIII deficiency and successful deliveries: a review of the literature. Obstet Gynecol Surv. 27 Apr;62(4):255-6. 7. Canadian Hemophilia Registry. Rare coagulation disorders. Stats Canada - age groups [Internet]. Ottawa: Statistics Canada; 213 May 17. [cited 213 Dec 2]. Available from: http://fhs.mcmaster.ca/chr/pdf/13/chrrarecoag13517.pdf 8. Karimi M, Bereczky Z, Cohan N, Muszbek L. Factor XIII deficiency. Semin Thromb Hemost. 29 Jun;35(4):426-38. 9. Bolton-Maggs PH, Perry DJ, Chalmers EA, Parapia LA, Wilde JT, Williams MD, et al. The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation. Haemophilia. 24 Sep;1(5):593-628. 1. Corifact 25/Corifact 125 factor XIII concentrate, human. Lyophilized powder and solvent for solution for injection [product monograph]. Ottawa: CSL Behring Canada, Inc.; 213 Dec 24. 11. WHO growth charts for Canada. 2 to 19 years: girls [Internet]. Toronto: Dietitians of Canada; 21. [cited 214 Jan 17]. Available from: http://www.dietitians.ca/downloadable-content/public/bmi_2-19_girls_en.aspx Based on the World Health Organization (WHO) child growth standards (26) and WHO reference (27). 12. WHO growth charts for Canada. 2 to 19 years: boys [Internet]. Toronto: Dietitians of Canada; 21. [cited 214 Jan 17]. Available from: http://www.dietitians.ca/downloadable-content/public/bmi_2-19_boys_en.aspx Based on the World Health Organization (WHO) child growth standards (26) and WHO reference (27). 13. Body mass index table - to calculate from centimetres and kilograms [Internet]. Toronto: Dietitians of Canada; 21. [cited 214 Jan 17]. Available from: http://www.dietitians.ca/downloadable- Content/Public/911-189-BMI_Metric.aspx Factor XIII Concentrate, Human (Corifact): Treatment Cost Comparison and Budget Impact Analysis 15