Antihemophilic Factor (Recombinant BDD) Fc Fusion Protein (Eloctate): Treatment Cost Comparison and Budget Impact Analysis

Transcription

1 CADTH TECHNOLOGY REVIEW Antihemophilic Factor (Recombinant BDD) Fc Fusion Protein (): Treatment Cost Comparison and Budget Impact Analysis Product Line: Technology Review Version: 1.0 Issue Number: 2 Publication Date: November 2015 Report Length: 18

2 Authors: Doug Coyle, Karen M. Lee Disclaimer: CADTH would like to acknowledge various participants in the development of this report: Dr. Alan Tinmouth for providing clinical expertise and feedback on the approach to the economic model; William Sheffield, Peter Saunders from the Canadian Blood Services (CBS) for their input on the scope of the project, feedback on drafts, and review of final report; and Amanda Hodgson and Kelly Farrah (CADTH) for information services support. This report is prepared by the Canadian Agency for Drugs and Technologies in Health (CADTH). This report contains a comprehensive review of existing public literature, studies, materials, and other information and documentation available to CADTH at the time it was prepared. This report was produced, as part of a collaboration between CADTH and the Canadian Blood Services (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 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 the report to ensure that its contents are accurate, complete and up-to-date, CADTH does not make any guarantee to that effect. CADTH is not responsible for any errors or omissions or injury, loss, or damage arising from or as a result of the use (or misuse) of any information contained in or implied by the information in this report. CADTH takes sole responsibility for the final form and content of this report. The statements, conclusions and views expressed herein do not necessarily represent the view of Health Canada or any provincial or territorial government. Copyright CADTH This report may be reproduced for non-commercial purposes only provided it is not modified 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. About CADTH: CADTH is an independent, not-for-profit organization responsible for providing Canada s health care decision-makers with objective evidence to help make informed decisions about the optimal use of drugs, medical devices, diagnostics, and procedures in our health care system. Funding: CADTH receives funding from Canada s federal, provincial, and territorial governments, with the exception of Quebec. Views: CADTH takes sole responsibility for the final form and content of this report. The statements, conclusions and views expressed herein do not necessarily represent the view of Health Canada or any provincial or territorial government. Cite as: Antihemophilic factor (recombinant BDD) Fc fusion protein (): treatment cost comparison and budget impact analysis. Ottawa: CADTH; 2015 Nov. (CADTH technology review; no. 2) Contact requests@cadth.ca with inquiries about this notice or legal matters relating to CADTH services. ISSN:

3 Table of Contents ABBREVIATIONS... ii 1. BACKGROUND INFORMATION Current Treatment Options Coagulation Factor VIII Fc Fusion Protein () Comparative Efficacy and Safety Potential for Off-Label Use Policy and Ethical Issues OBJECTIVES TREATMENT COST COMPARISON Methods Cost Information Based on Manufacturer-Provided Information CADTH Analysis Base-case analysis Sensitivity analysis BUDGET IMPACT ANALYSIS Approach Methods Estimated Number of Treated Cases Manufacturer s Estimated Budget Impact Manufacturer s base-case analysis Manufacturer s sensitivity analysis CADTH Reanalysis CADTH base-case analysis CADTH sensitivity analysis SUMMARY REFERENCES Tables Table 1: Assumptions Used in Cost Comparison Analysis... 4 Table 2: Cost Comparison of Therapy With and Without Coverage of, Based on Manufacturer s Budget Impact Analysis Submission... 6 Table 3: Cost Comparison of Therapy With and Without Coverage of CADTH Reanalysis... 7 Table 4: Sensitivity Analysis Based on CADTH Reanalysis... 9 Table 5: Manufacturer s Estimate of Patient Numbers Table 6: Manufacturer s Estimate of Budget Impact Table 7: Manufacturer s Sensitivity Analyses Table 8: CADTH Estimate of Budget Impact Table 9: Sensitivity Analysis Based on CADTH Reanalysis CADTH TECHNOLOGY REVIEW i

4 ABBREVIATIONS BDD CBS IU rfviii B-domain deleted Canadian Blood Services international units recombinant factor VIII CADTH TECHNOLOGY REVIEW ii

5 1. Background Information The current review focuses on the control and prevention of hemorrhagic bleeds and in patients with hemophilia A (classical hemophilia or factor VIII deficiency hemophilia). Factor VIII deficiency hemophilia is defined by a lack of factor VIII protein in the blood, which results in problems relating to clotting. 1 It is estimated that hemophilia A affects approximately one in 10,000 or about 2,500 Canadians. 1 Hemophilia may be classified by severity, based on the percentage of factor VIII circulating in the blood: severe (< 1% of normal), moderate (1% to 5% of normal), and mild (5% to 30% of normal). Those with severe hemophilia may experience hemorrhagic bleeds several times a month, with or without cause for bleed. Those with moderate hemophilia bleed less often and bleeding episodes are typically the results of minor trauma (e.g., sport/activity-based). Individuals with mild hemophilia have even fewer hemorrhagic events, which may only be problematic in cases such as surgery. 1 Current guidelines recommend routine prophylactic treatment for all patients with severe hemophilia A. However, not all patients with severe hemophilia A are currently on. Instead they follow on-demand therapy (i.e., factor VIII infusions restricted to treatment of bleeding events and/or prior to activities with risk bleeding). Some patients with moderate hemophilia may also use if they have had significant bleeding episodes in the past. More commonly, patients with moderate hemophilia use on-demand therapy for bleeding events or prior to surgeries or procedures with bleeding risks. 1.1 Current Treatment Options The primary current treatment options in Canada are recombinant antihemophilic factors. These include Advate, Kogenate FS, and Xyntha, which are currently available through Canadian Blood Services (CBS). Advate, a third-generation, full-length recombinant VIII product, is manufactured and provided by Baxter Healthcare Corporation. It is available in the form of a powder for intravenous injection in 250 IU, 500 IU, 1,000 IU, 1,500 IU, 2,000 IU, and 3,000 IU vials reconstituted in 5 ml of water for injection, and in 250 IU, 500 IU, 1,000 IU, and 1,500 IU vials reconstituted in 2 ml of water for injection. Kogenate FS, a second-generation, full-length recombinant factor VIII product, is manufactured and provided by Bayer. It is available in the form of lyophilized powder for injection in 250 IU, 500 IU, 1,000 IU, 2,000 IU, and 3,000 IU vials. Xyntha, a B-domain deleted third-generation recombinant factor VIII product, is manufactured and produced by Pfizer Canada. It is available as 250 IU, 500 IU, 1,000 IU, and 2,000 IU singleuse vials or as 250 IU, 500 IU, 1,000 IU, 2,000 IU, and 3,000 IU single-use, pre-filled, dualchamber syringes. For all three recombinant antihemophilic factors, the dose and the duration of treatment are dependent on the severity of the factor VIII deficiency, the location and extent of bleeding, and the clinical condition of the patient. For patients with severe hemophilia, typical doses for prophylactic treatment are 25 to 40 IU/kg three times per week or every two days; on-demand doses for treatment for bleeding of bleeding events vary from 20 to 30 IU/kg for joint bleeds to CADTH TECHNOLOGY REVIEW 1

6 50 IU/kg for life-threatening bleeding. The duration of treatment depends on the severity of bleeding, the location of the bleeding, and the response to treatment. Indications generally cover the control and prevention of hemorrhagic episodes. 1.2 Coagulation Factor VIII Fc Fusion Protein () is a coagulation factor VIII (recombinant [rfviii]) Fc fusion protein produced by Biogen Idec and distributed by Biogen Idec Canada Inc. More specifically, its factor VIII domain is B- domain deleted. The manufacturer/distributer received a Notice of Compliance for this drug from Health Canada on August 22, It is indicated in adults and children 12 years of age and older with hemophilia A (congenital factor VIII deficiency) for routine prophylactic treatment to prevent or reduce the frequency of bleeding episodes, and for control and prevention of bleeding episodes. 2 It is available in a number of single-use vial sizes: 250 IU, 500 IU, 750 IU, 1,000 IU, 2,000 IU, and 3,000 IU per vial. The submitted unit cost is $v.vv per IU. The dose and the duration of treatment are dependent on the severity of the factor VIII deficiency, the location and extent of bleeding, and the clinical condition of the patient. 1.3 Comparative Efficacy and Safety There are no clinical trials comparing with any of the alternate recombinant antihemophilic products (Advate, Kogenate FS, and/or Xyntha). Therefore, the comparative efficacy of these blood products is unknown. 3 The clinical experts feedback suggests that delivers equivalent benefit to hemophilia A patients with less frequent injections than other rfviii products, reducing the treatment burden. 3 The clinical experts felt that may increase compliance with prophylactic regimens known to provide greater patient benefit than episodic treatment in both the short and long term. Increased compliance could also deliver savings to the health care system by reducing the need for surgeries and the large attendant increased costs of rfviii drugs to provide patients with surgical coverage. However, no data are available to support this claim. 1.4 Potential for Off-Label Use Based on the clinical experts feedback, the potential for off-label use of is low. 1.5 Policy and Ethical Issues While the new technology provides possible benefits in terms of improved compliance, the major policy issue is the absence of direct evidence to support its impact on long-term health and its system impacts in terms of relative efficacy in controlling bleeding, compared with current products. Given the lack of evidence, consideration of a price premium based on incremental effectiveness is not possible and the focus on cost neutrality as per the manufacturer s submission 2 should be the focus of any policy decision. CADTH TECHNOLOGY REVIEW 2

7 2. Objectives This report aims to: Assess the comparative cost of coagulation factor VIII (recombinant) Fc fusion protein () with recombinant antihemophilic factors (Kogenate FS, Xyntha, and Advate) in both control and prevention of bleeding episodes. Assess, from the Canadian health ministry perspective, the budgetary impact of reimbursing, over a three-year period, for both control of bleeding episodes and for prophylactic treatment of patients with hemophilia A who require to prevent or reduce the frequency of bleeding. Neither perioperative management of bleeding nor use in children aged 12 or under was considered in this analysis. 3. Treatment Cost Comparison 3.1 Methods As part of the review process, the methods and assumptions of the manufacturer s economic analysis were assessed, and where possible validated, and any further assessment of uncertainty considered in reanalyses. In this case, the manufacturer did not provide an economic evaluation. As such, reviewers obtained cost information from the manufacturer s budget impact analysis (as part of its submission to CBS) 2 to inform a cost comparison for coagulation factor VIII Fc fusion protein and recombinant antihemophilic factors, based on the assumption of similar clinical effects and harms. All other health care costs (such as physician visits and monitoring) would be identical between the two drugs, given the sole focus on the budget impact as part of the manufacturer s submission. This information was extracted from the budget impact analysis to better understand the assumptions used, which are further explored in section 4 of this report. Analysis was restricted to patients with severe factor deficiency. Two patient groups were considered: Patients currently taking antihemophilic factors on an on-demand basis. It is assumed that a proportion of these patients will switch to on-demand and a proportion will convert to. Patients currently taking antihemophilic factors on a basis. It is assumed that a proportion of these patients will convert to. Patients under 12 years of age were excluded from the analysis. Based on comments from CBS clinical experts within the briefing note, 3 Kogenate FS, Xyntha, and Advate are considered appropriate comparators to. CADTH TECHNOLOGY REVIEW 3

8 The average cost per dose depends on the patient s weight. Blood products are available either as single-dose vials, powder for reconstitution, or single-use, pre-filled, dual-chamber syringes. All products are available in a variety of sizes, thus wastage should not be a significant issue. Table 1 details the assumptions made within the manufacturer s budget impact analysis and any revised assumptions used for the CADTH reanalysis, as well as any alternate estimates used in sensitivity analysis. Table 1: Assumptions Used in Cost Comparison Analysis Manufacturer Base-Case Assumption (as Provided in its Budget Impact Analysis) Analysis restricted to patients with severe hemophilia A Revised Assumption for CADTH Reanalysis No change Additional Sensitivity Analysis None, within budget impact analysis (section 4), the impact of including moderate patients will be explored Average hemophilia A patient weight of vv.v Asked for mean value 65 kg and 90 kg kg a 82% of current hemophilia A patients receiving recombinant factor VIII are being treated prophylactically the rest are treated on-demand No change None Market shares of comparator products (Advate: 38.5%; Xyntha: 3.0%; Kogenate FS: 58.5%) 83% of patients receiving will receive individualized and 17% weekly 12.5% of on-demand patients will convert to in year 1, 22% in year 2, 25% in year 3 1% of short-acting on-demand patients will convert to prophylactic in year 1, 2% in year 2, and 3% in year 3 No change No change No change Assumed that 10% will convert based on manufacturer s sensitivity analysis on-demand treatment requires Assumed 40 treatments 1,039.2 IU/kg per annum a required for severe patients and either 10 or 4 for moderate IU/kg per bleed gives 1,240 (175.6) IU/kg for severe, 310 (124) IU/kg for moderate An additional analysis is based on revised market shares of vv%, vv%, and vv% f None Analysis assumes no use of in on-demand patients Analysis will adopt both a conversion rate of 3% as per year 3 of manufacturer base analysis and a conversion rate of 20% as suggested by clinical expert Assume 30 treatments required for severe patients The annual dose based on the once-weekly Dosage based on last three None regimen is 3,804.7 IU/kg; for the individualized interval prophylactic dose: 4,211.7 IU/kg a months more reasonable; for once a week: 3,406 IU/kg; and for individualized: 4,042 IU/kg d The unit cost for is $v.vv per IU No change Analysis will identify price that reflects cost neutrality The unit costs of Advate, Kogenate FS, and Xyntha are assumed to be equal at $v.vv per IU b No change An additional analysis is based on revised costs of Advate $v.vv, Kogenate FS $v.vv and Xyntha $v.vv CADTH TECHNOLOGY REVIEW 4

9 Manufacturer Base-Case Assumption (as Provided in its Budget Impact Analysis) It is assumed that Advate, Kogenate FS, and Xyntha have the same dosing. On-demand treatment using any of these three short-acting products requires 2,152.2 IU/kg. Standard prophylactic treatment requires 5,768.2 IU/kg. Individualized interval treatment requires 5,197 IU/kg. c Revised Assumption for CADTH Reanalysis Adopt 4,030 IU/kg for prophylactic treatment. Based on number of bleeds. e On-demand dosage is 1,960 IU/kg for severe patients and 439 IU/kg for moderate. Additional Sensitivity Analysis None IU = international units. a Based on the median weight in the A-LONG study. b Based on CBC management analysis. c Based on Valentino study of Advate. d Based on last three months of data from A-LONG study. e Based on manufacturer s sensitivity analysis based on real-world clinical settings. f CBS (June 2015). The cost per patient for treatment with was compared with treatment with antihemophilic factor VIII (no ). Patients were stratified by whether they were currently treated by antihemophilic factor VIII on a basis and an on-demand basis. Figures were derived based on the manufacturer s base-case assumptions used in its budget impact analysis. In addition, a weighted cost for both antihemophilic factor VIII and for was calculated, based on the manufacturer s assumptions that 82% of current users are treated prophylactically. This would allow identification of the price point for, which would lead to no cost increase with its introduction. Analysis was first conducted based on costs and market shares within the manufacturer s submission. Further analysis was based on revised estimates from CBS. 3.2 Cost Information Based on Manufacturer-Provided Information Based on the manufacturer s assumptions, is less costly than current treatments for those who were previously treated on-demand and those treated prophylactically. For patients previously treated with antihemophilic factor VIII on-demand, treatment with is less costly per patient ($vvv,vvv versus $vvv,vvv savings of $27,123 per patient annually). Similarly, for patients previously treated with antihemophilic factor VIII, is less costly per patient ($vvv,vvv versus $vvv,vvv savings of $4,360 per patient annually). Overall treatment with would lead to cost savings of $8,457 per patient. CADTH TECHNOLOGY REVIEW 5

10 Table 2: Cost Comparison of Therapy With and Without Coverage of, Based on Manufacturer s Budget Impact Analysis Submission Patient Group Comparator Products Price per IU ($) Patients who would previously be treated with antihemophilic factor VIII on-demand Patients who would previously be treated with antihemophilic factor VIII No Annual Dose per kg Annual Drug Cost ($) c Average Annual Cost ($) Cost (Savings), $ Advate $v.vv 2,152.2 $vvv,vvv $vvv,vvv ($27,123) (38.5%) a Xyntha (3%) a $v.vv 2,152.2 $vvv,vvv Kogenate FS $v.vv 2,152.2 $vvv,vvv (58.5%) a $v.vv 1, $vv,vvv $vvv,vvv on-demand (92.6%) b fixed $v.vv 3,804.7 $vvv,vvv (1.3%) b individualized (6.1%) b $v.vv 4, $vvv,vvv No Advate $v.vv 5,768.2 $vvv,vvv $vvv,vvv ($4,360) standard (19.25%) a Advate $v.vv 5,197.8 $vvv,vvv individualized (19.25%) a Xyntha (3%) a $v.vv 5,768.2 $vvv,vvv Kogenate FS $v.vv 5,768.2 $vvv,vvv (58.5%) a fixed $v.vv 3,804.7 $vvv,vvv $vvv,vvv (17%) b individualized (83%) b $v.vv 4, $vvv,vvv Weighted $309,560 ($8,457) Sum a No $301,103 Source: Manufacturer s Economic Submission. 2 a Based on distribution of current usage. b Based on manufacturer s assumptions on use of in first year after coverage. c Assuming patient weight of vv.v kg. 3.3 CADTH Analysis Base-case analysis CADTH reanalysis incorporated alternate assumptions listed in Table 1. As a result, coverage of would be more costly for patients who would previously be treated with antihemophilic factor VIII on-demand ($202,431 versus $120,689 increased cost of $81,742 per patient annually) and for patients who would previously be treated with antihemophilic factor VIII ($326,732 versus $248,151 increased cost of $78,581 per patient annually) (Table 3). Overall, coverage of will cost an additional $79,150 per patient annually. CADTH TECHNOLOGY REVIEW 6

11 The price reduction required to achieve cost neutrality to cover would be such that it be priced equally to antihemophilic factor VIII (a reduction of $v.vvv per IU or 26%). Reanalysis based on the revised market share and costs from Canadian Blood Services found the incremental cost per patient annually was $125,344 with a required price reduction for cost neutrality of $v.vvv (i.e., a reduction of 41.2%). Table 3: Cost Comparison of Therapy With and Without Coverage of CADTH Reanalysis Patient Group Comparator Products Price per IU ($) Original Market Share and Unit Costs Patients who would previously be treated with antihemophilic factor VIII on-demand Patients who would previously be treated with antihemophilic factor VIII Annual Dose per kg Annual Drug Cost ($) c Average Annual Cost ($) Cost (Savings), $ No Advate (38.5%) a $v.vv 1,960 $vvv,vvv $vvv,vvv $81,742 Xyntha (3%) a $v.vv 1,960 $vvv,vvv Kogenate FS (58.5%) a $v.vv 1,960 $vvv,vvv $v.vv 1,240 $vvv,vvv $vvv,vvv on-demand (55.6%) b fixed $v.vv 3,406 $vvv,vvv (7.6%) b individualized (36.9%) b $v.vv 4,042 $vvv,vvv No Advate $v.vv 4,030 $vvv,vvv $vvv,vvv $78,581 standard (19.25%) a Advate $v.vv 4,030 $vvv,vvv individualized (19.25%) a Xyntha (3%) a $v.vv 4,030 $vvv,vvv Kogenate FS (58.5%) a $v.vv 4,030 $vvv,vvv fixed $v.vv 3,406 $vvv,vvv $vvv,vvv (17%) b $v.vv 4,042 $vvv,vvv individualized (83%) b Weighted $225,208 $79,150 Sum a No $304,358 Revised Market Share and Unit Costs Patients who would previously be treated with antihemophilic factor VIII on-demand No Advate $v.vv 1,960 $vv,vvv $95,934 $106,497 (vv.v%) a Xyntha (v%) a $v.vv 1,960 $vvv,vvv Kogenate FS (vv%) a $v.vv 1,960 $vvv,vvv ondemand $v.vv 1,240 $vvv,vvv $202,431 CADTH TECHNOLOGY REVIEW 7

12 Patient Group Comparator Products Price per IU ($) (55.6%) b fixed (7.6%) b Patients who would previously be treated with antihemophilic factor VIII individualized (36.9%) b No Advate standard (vv%) Advate individualized (vv%) a Annual Dose per kg Annual Drug Cost ($) c $v.vv 3,406 $vvv,vvv $v.vv 4,042 $vvv,vvv Average Annual Cost ($) Cost (Savings), $ $v.vv 4,030 $vvv,vvv $197,251 $129,481 $v.vv 4,030 $vvv,vvv Xyntha (v%) a $v.vv 4,030 $vvv,vvv Kogenate FS (vv%) a $v.vv 4,030 $vvv,vvv fixed $v.vv 3,406 $vvv,vvv $326, (17%) b $v.vv 4,042 $vvv,vvv individualized (83%) b Weighted $179,014 $125,344 Sum a No $304,358 IU = international unit. a Based on distribution of current usage. b Based on assumption of 10% conversion rate for on-demand to. c Assuming patient weight of vv.v kg Sensitivity analysis Based on CADTH sensitivity analysis, the price reductions required for coverage of to be cost-neutral, using the CADTH base case, ranged from 23% to 28% (Table 4). Analysis based on the revised data relating to market share and unit costs suggests a price reduction between 39% and 43% is required. CADTH TECHNOLOGY REVIEW 8

13 Table 4: Sensitivity Analysis Based on CADTH Reanalysis Scenario Original Market Share and Unit Costs Revised Market Share and Unit Costs Increased Annual Cost From Coverage per Patient Receiving % Price Reduction Required for Cost Neutrality (Revised $ per IU) Increased Annual Cost From Coverage per Patient Receiving % Price Reduction Required for Cost Neutrality (Revised $ per IU) Base case $vv,vvv 26% (v.vvv) $vvv,vvv 41% (v.vvv) Weight = 65 kg $vv,vvv 26% (v.vvv) $vvv,vvv 41% (v.vvv) Weight = 90 kg $vv,vvv 26% (v.vvv) $vvv,vvv 41% (v.vvv) On-demand $vv,vvv 27% (v.vvv) $vvv,vvv 42% (v.vvv) patients require 30 treatments per annum 3% on-demand $vv,vvv 23% (v.vvv) $vvv,vvv 39% (v.vvv) patients convert to 20% on-demand $vv,vvv 28% (v.vvv) $vvv,vvv 43% (v.vvv) patients convert to No use of in patients currently treated on-demand $vv,vvv 24% (v.vvv) $vvv,vvv 40% (v.vvv) IU = international unit. 4. Budget Impact Analysis 4.1 Approach The manufacturer provided a budget impact analysis to assess the national budgetary implications of reimbursing in Canada. 4 A prevalence-based approach was taken using a three-year analysis time frame: reference year: 2014; year 1: 2015; year 2: 2016; year 3: A national perspective was applied; however, Quebec was excluded from the analysis. As part of the review, the methods and assumptions of the manufacturer s budget impact analysis were assessed, and where possible validated, and any further assessment of uncertainty considered in reanalyses. 4.2 Methods In addition to the assumptions adopted by the manufacturer, detailed in section 3.1 of this report, the following assumptions are required to estimate the budget impact analysis over the three-year period: The total number of hemophilia A patients in Canada will increase by 4.1% per annum. 6% of patients will convert to in year 1, 10.8% in year 2, and 12.2% in year 3. CADTH TECHNOLOGY REVIEW 9

14 The manufacturer presented the results in terms of the estimated costs with and without within the base case and within a range of sensitivity analyses. Scenarios considered were: 10% of on-demand patients will switch to. 20% of on-demand patients will switch to. market share is increased 25% over the base-case estimate. market share is decreased 25% over the base-case estimate. Utilization will differ from the trial setting, specifically: o 50% of patients on will follow the once-weekly regimen. o Comparator annual dose will be 4,030 IU/kg. o annual dose will be 4,042 IU/kg and 3,406 IU/kg for the two dosing regimens. o Moderate hemophilia A patients will be eligible for treatment with. o 29% of moderate hemophilia A patients receive and 71% are treated ondemand. o 12.5%, 22.0%, and 25.0% of on-demand moderate patients will switch to on-demand in years 1, 2, and 3, respectively. o 1.0%, 2.0%, and 3.0% of on-demand moderate patients will switch to prophylactic in years 1, 2, and 3, respectively. o 6.0%, 10.8%, and 12.2% of prophylactic moderate patients will switch to prophylactic in years 1, 2, and 3, respectively. The CADTH reanalysis will be based on the alternative assumptions used in the cost comparison analysis. The same scenarios will be considered within sensitivity analysis along with an additional scenario assuming a 25% increase in market share. 4.3 Estimated Number of Treated Cases Table 5 details the estimated number of patients treated with short-acting factor VIII and from 2014 to 2017, where is and is not covered. Table 5: Manufacturer s Estimate of Patient Numbers Without On-demand Advate Xyntha Kogenate FS Prophylaxis Advate standard Advate individualized Xyntha Kogenate FS TOTAL With On-demand Advate Xyntha Kogenate FS Prophylaxis CADTH TECHNOLOGY REVIEW 10

15 Advate standard Advate individualized Xyntha Kogenate FS once weekly individualized TOTAL Source: Manufacturer s Economic Submission Manufacturer s Estimated Budget Impact Manufacturer s base-case analysis The manufacturer estimated that the budget will decrease by $385,043 in year 1, $685,908 in year 2, and $728,966 in year 3 (Table 6). Table 6: Manufacturer s Estimate of Budget Impact Year Total Total costs with $vvv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv Total costs without $vvv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv Incremental costs $385,043 $685,908 $728,966 $1,799,918 Source: Manufacturer s Economic Submission Manufacturer s sensitivity analysis Sensitivity analysis found the three-year budget impact ranging from savings of $2.5 million to a cost increase of $8.4 million (Table 7). Table 7: Manufacturer s Sensitivity Analyses Incremental Budget Impact Year Total Manufacturer's base case $vvv,vvv $vvv,vvv $vvv,vvv $1,799,918 10% of on-demand patients will switch to $v,vvv,vvv $vvv,vvv $vvv,vvv $2,627,840 20% of on-demand patients will switch to $v,vvv,vvv $v,vvv,vvv $v,vvv,vvv $8,359,307 market share is increased 25% over the $vvv,vvv $vvv,vvv $vvv,vvv $2,520,229 base-case estimate market share is decreased 25% over the $vvv,vvv $vvv,vvv $vvv,vvv $1,018,586 base-case estimate Utilization will differ from the trial setting $vvv,vvv $v,vvv,vvv $v,vvv,vvv $4,228,242 Source: Manufacturer s Economic Submission CADTH Reanalysis CADTH base-case analysis For the CADTH reanalysis, the same revised assumptions adopted in the cost comparison were adopted (Table 1). Based on revised assumptions and the original market share and unit costs, coverage of resulted in an incremental cost of $14,192,480 over three years. For the coverage of CADTH TECHNOLOGY REVIEW 11

16 to be cost-neutral over the three-year period, the price of would need to be reduced by 27% (a price of $v.vvv vvv IU/kg) (Table 8). Based on the revised market share and unit costs, coverage of resulted in an incremental cost of $21,510,509 over three years. For the coverage of to be costneutral over the three-year period, the price of would need to be reduced by 42% (a price of $v.vvv per IU/kg). Table 8: CADTH Estimate of Budget Impact Year Total Original Market Share and Unit Costs Total costs with $vvv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv Total costs without $vvv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv Incremental costs $3,481,714 $5,035,528 $5,675,238 $14,192,480 Revised Market Share and Unit Costs Total costs with $vv,vvv,vvv $vv,vvv,vvv $vvv,vvv,vvv $vvv,vvv,vvv Total costs without $vv,vvv,vvv $vv,vvv,vvv $vv,vvv,vvv $vvv,vvv,vvv Incremental costs $5,145,704 $7,964,305 $9,095,509 $22,205, CADTH sensitivity analysis Sensitivity analysis was conducted adopting the same alternate assumptions used in the cost comparison analysis (section 3.3.2). In addition, sensitivity analyses were conducted to assess the impact of assuming that moderate patients may be covered under the CADTH base-case analysis and assuming a 25% increase in market share of. The results of the sensitivity analysis with the original market share and unit costs show that if the rate of conversion from on-demand to is lower (3%), the price reduction required for to be cost-neutral over the three-year period would be lower (22%, or a price of $v.vvv per IU). If, however, the rate of conversion from on-demand to is higher (20%), the price reduction required for to be cost-neutral over the three-year period would be lower (32%, or a price of $v.vvv per IU). Based on other analyses, similar results to the base case were found, with required price reductions ranging from 25% to 29%. The results of the sensitivity analysis with the revised market share and unit costs show that if the rate of conversion from on-demand to is lower (3%), the price reduction required for to be cost-neutral over the three-year period would be lower 38%, or a price of $v.vvv per IU. At a 20% rate of conversion the price reduction required would be 46% i.e., a price of $v.vvv per IU. Based on other analyses, similar results to the base case were found, with required price reductions ranging from 40% to 44%. CADTH TECHNOLOGY REVIEW 12

17 Table 9: Sensitivity Analysis Based on CADTH Reanalysis Scenario Original Market Share and Unit Costs Revised Market Share and Unit Costs Incremental Budget Impact (Years 1 to 3) Incremental Budget Impact (Years 1 to 3) Percentage Price Reduction Required for Cost Neutrality (Revised Cost ($) per IU) Base case $vv,vvv,vvv 27% (v.vvv) $vv,vvv,vvv 42% (v.vvv) Weight = 65 kg $vv,vvv,vvv 27% (v.vvv) $vv,vvv,vvv 42% (v.vvv) Weight = 90 kg $vv,vvv,vvv 27% (v.vvv) $vv,vvv,vvv 42% (v.vvv) On-demand $vv,vvv,vvv 29% (v.vvv) $vv,vvv,vvv 44% (v.vvv) patients require 30 treatments per annum 3% on-demand $vv,vvv,vvv 22% (v.vvv) $vv,vvv,vvv 38% (v.vvv) patients convert to 20% on-demand $vv,vvv,vvv 32% (v.vvv) $vv,vvv,vvv 46% ((v.vvv) patients convert to Moderate patients $vv,vvv,vvv 28% (v.vvv) $vv,vvv,vvv 43% (v.vvv) will receive with 10 bleeds per annum Moderate patients $vv,vvv,vvv 29% (v.vvv) $vv,vvv,vvv 44% (v.vvv) will receive with 4 bleeds per annum 25% increase in $vv,vvv,vvv 25% (v.vvv) $vv,vvv,vvv 42% (v.vvv) market share of No use of in patients currently treated on-demand $v,vvv,vvv 24% (v.vvv) $vv,vvv,vvv 40% (v.vvv) IU = international unit. Percentage Price Reduction Required for Cost Neutrality (Revised Cost ($) per IU) CADTH TECHNOLOGY REVIEW 13

18 5. Summary In Canada, patients with hemophilia A factor VIII deficiency at high risk of bleeding are currently managed with either on-demand therapy or prophylactic treatment with Advate, Kogenate FS, or Xyntha. belongs to a new category of longer-acting recombinant factor VIII products. The comparative efficacy of, Advate, Kogenate FS, and Xyntha is unknown. The major advantage of is a longer half-life potentially leading to fewer infusions, though the clinical benefit to patients is unclear. In the manufacturer s submission, Advate, Kogenate FS, and Xyntha are priced at $v.vv per IU, while is priced at $v.vv per IU. CBS provided alternative costs: Advate $v.vv per IU, Kogenate FS $v.vv per IU, and Xyntha $v.vv per IU. Based on the manufacturer s figures for unit costs and market shares, CADTH analysis suggests when assessing uncertain parameters, the funding of may be cost-neutral if a price reduction of 27% or $v.vv per IU (cost of other comparators) can be negotiated. However, CADTH analysis based on the revised unit costs and current market shares obtained from CBS suggests that the required price reduction is 42%. These findings differ from the manufacturer s submission. The difference in findings is primarily due to differences in assumptions relating to the dosing of Advate, Kogenate FS, and Xyntha. The CADTH analysis used estimates for treatment considered by the manufacturer in sensitivity analyses and adopted consistent number of treatments for on-demand use. This conclusion is qualified by the uncertainty around key assumptions relating to the adoption of in practice. Little information is known about patient preference for over current therapeutic options. Analysis assumes that is of equal clinical efficacy to current therapies. The results of the CADTH sensitivity analyses were robust to changes to input parameters, with the price reduction for based on the revised unit costs and market shares ranging from 40% to 44% to achieve cost neutrality over the three-year period considered within the analysis. The above analysis assumes that there are no clinical benefits from the use of. The approach adopted is based on the manufacturer s submission of a budget impact analysis to assess the economic implications of funding for. If the extended half-life for leads to better compliance, this will lead to a larger cost increase than forecasted in the analysis. However, in such an instance, focus solely on the cost impact of funding of would provide only a partial analysis. To adequately address any clinical benefits, the manufacturer would have needed to submit a formal economic evaluation allowing assessment of the incremental costs per benefit obtained. CADTH TECHNOLOGY REVIEW 14

19 References 1. Canadian Hemophilia Society [Internet]. Montreal: The Society; What is hemophilia; 2015 [cited 2015 May 5]. Available from: 2. Canadian Blood Services submission: ELOCTATE, Antihemophilic Factor (Recombinant BDD), Fc fusion protein. Company: Biogen Idec Canada Inc. [CONFIDENTIAL manufacturer's submission]. Mississauga (ON): Biogen Idec Canada Inc.; 2014 Sep. 3. Canadian Blood Services. Briefing note for the Product Innovation Operating Committee: New Product Selection Process (NPSP) regarding ELOCTATE (Biogen Idec). Ottawa: Canadian Blood Services; Budget impact analysis. In: Canadian Blood Services submission: ELOCTATE, Antihemophilic Factor (Recombinant BDD), Fc fusion protein. Company: Biogen Idec Canada Inc. [CONFIDENTIAL manufacturer's submission]. Mississauga (ON): Biogen Idec Canada Inc.; 2014 Sep. CADTH TECHNOLOGY REVIEW 15