Hemophilia is a rare congenital disorder that affect predominantly males, and is caused by a mutation of clotting factor genes on the X chromosome (X-linked) that result in a deficiency of factor VIII (FVIII) or -IX (FIX) in hemophilia A or B, respectively.1 Globally, 173,711 patients with hemophilia A were identified in 2018, and 3,018 were from Canada.2 Bleeding is the main symptom of hemophilia and it occurs after trauma or surgery (including minor/trivial injury), with the severity correlated with the degree of clotting factor deficiency.1 Bleeding can occur in muscles, joints, or soft tissue, and in life-threatening cases in the neck, throat, chest, gastrointestinal system, or intracranially.1 The main treatment goal is to prevent or treat bleeding; treatment of bleeds is generally via on-demand administration of specific factor concentrate to compensate for the deficient clotting factor, and historically prevention has included prophylaxis regimens of these factor-replacement therapies,1 with non-replacement factors having more recently become available.3 Other treatment goals are to prevent joint and muscle damage, prevent inhibitor development, prevent transmission of infections from blood products, and improve health-related quality of life (HRQoL).1
Until recently, prophylactic and on-demand treatments have consisted of intravenous exogenous FVIII replacement therapy with recombinant FVIII products or plasma-derived FVIII concentrates.1 Historically hemophilia was primarily treated only when bleeding occurred (on-demand); over time the treatment paradigm shifted to prophylaxis with evidence that joint function is better preserved in patients with FVIII levels above 1% (> 1 IU dL− 1).1 Based on high quality evidence of the superiority of prophylactic treatment over on-demand treatment, it has become standard of care in Canada for patients with severe hemophilia.1 Exogenous FVIII has a short half-life and patients need multiple prophylactic infusions each week in order to maintain adequate trough levels.4, 5
Although exogenous FVIII concentrate is an effective treatment, one possible serious complication is the development of FVIII inhibitors.1 Inhibitors are immunoglobulin G antibodies that inactivate both exogenous and endogenous FVIII, making FVIII replacement treatment ineffective, at high titres.1, 5 Approximately 5–10% of patients with mild to moderate hemophilia A, and 20–30% of patients with severe hemophilia A, develop inhibitors.1 Inhibitors can be eradicated with immune tolerance induction (ITI), and bleeding controlled with bypassing agents in patients with inhibitors.6 ITI is not always effective and bleeding control with bypassing agents is often suboptimal compared to FVIII replacement therapy.1, 7, 8 Treatment with FVIII at much higher doses, or continuous infusions at “ultra-high doses”, may be needed in patients with high levels of inhibitors (≥ 5 Bethesda units) in order to induce immune tolerance.1 Therefore, treatments with a lower burden, increased efficacy, and resistance to the development of inhibitors are needed.4, 5
Emicizumab is a monoclonal antibody that restores the natural function of activated FVIII by bridging activated factor IX and factor X in hemophilia A patients to allow for effective hemostasis.4, 9, 10 Emicizumab, administered subcutaneously, has been shown to be effective in reducing bleeding events in patients with hemophilia A with inhibitors in the HAVEN 1 and 2 trials,11, 12 as well as in patients with hemophilia A without inhibitors in the HAVEN 3 and 4 trials.4, 13 Across the clinical trial program, clinical benefits of emicizumab have been observed for weekly, once every two weeks (Q2W), and once every four weeks (Q4W) dosing schedules (with Q4W dosing recommended only for adults and/or adolescents > 40 kg [in the Canadian label]).14
The HRQoL of patients with hemophilia is negatively affected by both the disease and treatment.15 Recurrent bleeding and resulting complications such as joint and muscle damage, and pain and disability, can significantly affect patients' HRQoL.15 Treatment-related factors include the need for frequent infusions due to the half-life of available therapies, and specific infusion-related problems such as difficulty with accessing veins, the time required to administer treatment, and development of inhibitors - all of which can have a negative effect on treatment adherence, lifestyle, and HRQoL.16 Quality-adjusted life years (QALYs), a measure of health that quantifies both quality and length of life, are used to assess the effectiveness of health technologies. Quality of life is quantified in utility values, on a scale where 0 is equivalent to death and 1 represents perfect health, where states worse than death (less than 0) may exist.17 Alternately, visual analogue scale (VAS) measures of HRQoL are obtained by asking participants where they would rate their overall health on a ‘scale’ of 0-100, with 0 being equivalent to death and 100 perfect health. Based on values from the 2013–2014 Canadian Community Health Survey, the mean and median self-reported utility scores for Canadians were estimated using the Health Utilities Index Mark 3 (HUI3) at 0.86 and 0.93, respectively.18 A cross-sectional study of 101 Canadian patients with hemophilia found that they have increased morbidity compared to the general population [(HUI3 of 0.71 ± 0.29 for those with hemophilia vs. 0.91 for the general population), and that the burden of morbidity was correlated with disease severity [mean HUI3 of 0.79 ± 0.30 for mild hemophilia vs. 0.71 ± 0.23 for severe hemophilia vs. 0.57 ± 0.32 for severe hemophilia with human immunodeficiency virus (HIV)].19 In addition to hemophilia patients, having a family member with hemophilia inevitably increases the burden on the caregivers and the family, especially when a child is affected.20, 21 The emotional and practical aspects of caregiver burden are especially high when the patient requires frequent infusions of hemophilia treatment. Worse social, physical, emotional, financial, and lifestyle impact were associated with more infusions per week in a large study of hemophilia caregivers.22
A study from six countries, including Canada, reported that Canadian patients with severe hemophilia (n = 40) had the second highest EuroQuol-5D (EQ-5D) utility scores (0.791).23 In comparison, the mean the EQ-5D (using an European value set) was 0.925 for the general population in Alberta, Canada.24 In another study, Canadian adults with hemophilia report better Standard Gamble utilities than the general population (0.94 to 0.90).15 One possible reason for this discrepancy is the “disability paradox” where patients have adapted to their specific situation to such an extent that they report similar or higher HRQoL utilities than the general population.25, 26 Another explanation may be the instrument that was used. Of the primary techniques, the Standard Gamble generates the highest utility values,25 and may overestimate utility scores while underestimating the impact of worse health states.6 These and other issues present challenges for economic evaluations of treatments.
Within an economic evaluation, health state utilities can be informed by either patient-reported values, or by HRQoL measures evaluated by members of the general population to reflect community values.6, 27 In the United States and United Kingdom there is a preference for using utilities derived from the general population/societal perspective rather than utilities from patients to assign a value to a specific health state.6 To date, cost utility analysis (CUA)s that compare on-demand treatment with prophylactic treatment for hemophilia have reported inconsistent results, with uncertainty in health state utilities being an important source of variability.28
Factors that positively influenced willingness to pay from a patient-perspective include increased effectiveness of treatments, reduced adverse events, and reduced dosing frequency.29 Patients generally prefer prophylactic to on-demand treatment, likely due to improved clinical outcomes with prophylactic treatment.29 However, the impact of frequent intravenous infusions and the type of treatment on HRQoL has not been explored adequately.6 Recently, subcutaneous treatments have become available for hemophilia A, and while currently emicizumab is the only available subcutaneous therapy, other pipeline therapies are likely to become available in the future. There are challenges with understanding health state utilities for subcutaneous treatments because the impact of subcutaneous administration compared to intravenous administration has not been previously explored in hemophilia patients. However, there are studies in patients with other chronic conditions that found a preference for subcutaneous administration compared to intravenous administration.30–32 Current intravenous hemophilia treatments can be time-consuming, challenging, complex, and painful to administer, and can lead to difficulty in coordinating schedules (including work schedules) and maintaining a routine, cause anxiety, trauma, exhaustion, social stigma, and impact personal relationships and career opportunities.15 Participants in a Canadian survey study reported that delivery via an alternate route of administration (subcutaneous or oral), and treatments with longer-lasting effects in order to reduce the frequency of administration, would be substantial improvements over the current standard of care.33