Optimizing the management of inherited blood disorders in a changing market: Findings from the AMCP Market Insights Program.

In this market insights program, AMCP brought together a panel of experts representing various stakeholders: national and regional health plans, integrated health care systems, employer benefits groups, clinical experts, the Centers for Disease Control and Prevention, and patient advocacy organizations. The objectives were to gain insights into the current and evolving treatments in hemophilia, sickle cell disease, and ß-thalassemia; measure the effects of recently approved therapies on clinicians, payers, and patients; recognize emerging trends within the stop-loss market; address potential issues and obstacles related to monitoring and reporting outcomes; and identify concerns associated with both existing and emerging contracting and reimbursement models. This article aims to summarize expert perspectives on health care system challenges and strategies concerning the management of inherited blood disorders and to advance managed care professionals' understanding of their role in supporting care for these patients. The experts emphasized that when shaping coverage policies, a patient-centered approach is crucial, focusing on preserving organ function to maintain eligibility for future gene therapies among individuals with inherited blood disorders. These strategies, including benefit design modifications, specialized provider networks, and centralized mechanisms like registries, are vital for evaluating effectiveness, facilitating decision-making, and managing costs and risks associated with new and emerging treatment options for inherited blood disorders.

Diagnosis and treatment challenges in lower resource countries: State-of-the-art.

The 2022 World Federation of Haemophilia Annual Global Survey (AGS) reports that 454,690 patients with inherited bleeding disorders (IBD) have been identified globally. While this represents noteworthy progress, haemophilia epidemiology data indicate that 75% of people with inherited bleeding disorders living in low-income and low-to-middle-income countries have yet to be diagnosed. The AGS also revealed that 11 billion clotting factor units are available to treat haemophilia A and B globally. Due to a lack of finance, these treatments are unavailable to haemophilia in low-income countries with a consequence lack of access equity for haemophilia treatment in these communities. This sobering reality is not limited to haemophilia but applies to von Willebrand Disease (VWD). While VWD is the most prevalent IBD, only 103,844 people living with this condition have been diagnosed globally. Of the diagnosed patients, only a fraction live in low- or middle-income countries. Moreover, the majority of VWD patients are still treated sub-optimally without replacement therapies or prophylaxis, both of which are now accepted as global standards of care. In this state-of-the-art review, the authors reflect on three issues. First, the minimum elements required to diagnose haemophilia in a resource-constrained setting are identified. Second, this review points to the critical stakeholders and outlines their roles in removing access to haemophilia treatment barriers. Finally, the authors examine von Willebrand disease's ongoing diagnostic and treatment challenges and compare these to haemophilia. With the rapidly evolving novel therapies, the therapeutic landscape of all IBD will likely change for the better.

Multicenter assessment and longitudinal study of the prevalence of antibodies and related adaptive immune responses to AAV in adult males with hemophilia.

Adeno-associated virus (AAV) based gene therapy has demonstrated effective disease control in hemophilia. However, pre-existing immunity from wild-type AAV exposure impacts gene therapy eligibility. The aim of this multicenter epidemiologic study was to determine the prevalence and persistence of preexisting immunity against AAV2, AAV5, and AAV8, in adult participants with hemophilia A or B. Blood samples were collected at baseline and annually for ≤3 years at trial sites in Austria, France, Germany, Italy, Spain, and the United States. At baseline, AAV8, AAV2, and AAV5 neutralizing antibodies (NAbs) were present in 46.9%, 53.1%, and 53.4% of participants, respectively; these values remained stable at Years 1 and 2. Co-prevalence of NAbs to at least two serotypes and all three serotypes was present at baseline for ~40% and 38.2% of participants, respectively. For each serotype, ~10% of participants who tested negative for NAbs at baseline were seropositive at Year 1. At baseline, 38.3% of participants had detectable cell mediated immunity by ELISpot, although no correlations were observed with the humoral response. In conclusion, participants with hemophilia may have significant preexisting immunity to AAV capsids. Insights from this study may assist in understanding capsid-based immunity trends in participants considering AAV vector-based gene therapy.

[Translated article] Consensus recommendations for the improvement of inter- and intra-centre care coordination in the management of hemophilia.

OBJECTIVE: Define consensus recommendations to improve care coordination between Hospital Pharmacy, Hematology and Nursing, inter- and intra-center, in the care of hemophilia patients. METHOD: Recommendations for the improvement of care coordination in the management of hemophilia patients were identified and assessed by a multidisciplinary panel of professionals with experience in this field (Hospital Pharmacy, Hematology and Nursing) and supported by scientific evidence. The identified recommendations were assessed by Rand/UCLA consensus methodology (Delphi-adapted) based on their appropriateness and, subsequently, on their necessity. In both cases, it was used ordinal Likert scale. Data were statistically analyzed through different metrics. RESULTS: Fifty-three recommendations for the improvement of care coordination between Hospital Pharmacy, Hematology and Nursing in the management of hemophilia patients were identified, grouped into eight areas of action: i) Hemophilia units, reference centers and multidisciplinary care; ii) Role of Hematology, Hospital Pharmacy and Nursing in the patient journey of hemophilia patients; iii) Telepharmacy and telemedicine; iv) Pharmacokinetic monitoring; v) Transition to adult patient regimen; vi) Patient health education; vii) Surgery, emergency room and hospital admission; and viii) Outcome evaluation. All recommendations were assessed as appropriate and necessary by the external expert panel. CONCLUSIONS: Hemophilia patient journey is complex and depends on different variables. It also requires the involvement of different healthcare professionals who must act in a coordinated and integrated manner at all stages of the patient's life, adapted to their individual needs. On this matter, the identified and agreed recommendations may improve continuity and quality of care, as they facilitate the integration and coordination of the professionals involved in the management of this pathology, especially Hospital Pharmacy, Hematology and Nursing.

The effectiveness and value of gene therapy for hemophilia: A Summary from the Institute for Clinical and Economic Review's California Technology Assessment Forum.

DISCLOSURES: Dr Tice and Mr Sarker received ICER grants during the conduct of the study. Dr Moradi, Ms Herce-Hagiwara, Dr Faghim, Dr Agboola, Dr Rind, and Dr Pearson reports grants from Arnold Ventures, grants from Blue Cross Blue Shield of MA, grants from California Healthcare Foundation, grants from The Commonwealth Fund, grants from The Peterson Center on Healthcare, during the conduct of the study; other from Aetna, other from America's Health Insurance Plans, other from Anthem, other from AbbVie, other from Alnylam, other from AstraZeneca, other from Biogen, other from Blue Shield of CA, other from Cambia Health Services, other from CVS, other from Editas, other from Express Scripts, other from Genentech/Roche, other from GlaxoSmithKline, other from Harvard Pilgrim, other from Health Care Service Corporation, other from Health Partners, other from Johnson & Johnson (Janssen), other from Kaiser Permanente, other from LEO Pharma, other from Mallinckrodt, other from Merck, other from Novartis, other from National Pharmaceutical Council, other from Premera, other from Prime Therapeutics, other from Regeneron, other from Sanofi, other from Spark Therapeutics, other from United Healthcare, other from HealthFirst, other from Pfizer, other from Boehringer-Ingelheim, other from uniQure, other from Evolve Pharmacy Solutions, other from Humana, other from Sun Life, outside the submitted work.

Cost-effectiveness of recombinant factor VIII Fc versus emicizumab for prophylaxis in adults and adolescents with haemophilia A without inhibitors in the UK.

INTRODUCTION: The economic and clinical burden of haemophilia A is high. Primary prophylaxis with factor VIII replacement therapy is the recognised standard of care, but the emergence of non-factor therapies, such as emicizumab, is extending treatment options for people with haemophilia A. AIM: There are currently no direct comparisons of efficacy or cost between recombinant factor FVIII Fc-fusion protein efmoroctocog alfa (a recombinant factor FVIII Fc-fusion protein referred to herein as rFVIIIFc) and emicizumab; therefore, a cost-effectiveness model was developed to compare prophylactic treatment with rFVIIIFc versus emicizumab in patients with haemophilia A without inhibitors in the UK. METHODS: The cost-effectiveness model was based on a matching-adjusted indirect comparison and included male patients, aged ≥12 years, with haemophilia A without inhibitors. The model was designed as a Markov process with a flexible lifelong time horizon, and cost-effectiveness was presented as an incremental cost-effectiveness ratio. Base-case analysis and sensitivity analyses (including scenario analyses, one-way deterministic sensitivity analysis [DSA] and probability sensitivity analysis [PSA]) were performed using the following treatment strategies: individualised prophylaxis with rFVIIIFc and prophylaxis with emicizumab administered once weekly (scenario analyses used regimens of once every 2 weeks or once every 4 weeks). RESULTS: Base-case analysis, DSA and PSA indicated that, compared with emicizumab administered once weekly, rFVIIIFc individualised prophylaxis was the dominant treatment strategy, with lower costs, a greater number of quality-adjusted life years, and a lower number of bleeds. CONCLUSIONS: rFVIIIFc has proven efficacy and is cost-effective compared with emicizumab, providing clinicians with a viable treatment option to improve the health outcomes for adults and adolescents with haemophilia A in the UK.

Multiple criteria decision analysis for therapeutic innovations in a hemophilia care center: A pilot study of the organizational impact of innovation in hemophilia care management.

BACKGROUND: Several innovative drugs liable to lead to changes in healthcare organization are or soon will be available for the management of hemophilia. Analyzing their implementation can shed further light on healthcare decision-making, to anticipate changes and risk of breakdown in the patient's care pathway. METHODS: Multiple criteria decision analysis (MCDA), based on ISPOR recommendations, was used to assess the organizational impact of innovation in hemophilia care management. The MCDA process designed for this specific context involved ten French experts in hemophilia care management (physicians, nurses, pharmacist, physiotherapist and psychologist) in the hemophilia care center of Chambéry, in the Rhône-Alpes Region of France. This pilot study involved seven steps: (i) defining the decision problem; (ii) selecting and structuring criteria; (iii) assessing the relative weight of each criterion with software-assisted simulation based on pairwise comparisons of different organizational change scenarios; (iv) measuring the performance of the selected innovations; (v) scoring alternatives; (vi) calculating aggregate scores; (vii) discussion. The endpoint was to determine the expected overall organizational impact on a 0-100 scale. RESULTS: Seven organizational criteria were selected. "Acceptability for patient/caregiver/association" was the most heavily weighted. Factor VIII by subcutaneous route obtained the highest aggregate score: i.e., low impact on care organization (88.8 out of 100). The innovation with strongest organizational impact was gene therapy (27.3 out of 100). CONCLUSION: This approach provided a useful support for discussion, integrating organizational aspects in the treatment decision-making process, at healthcare team level. The study needs repeating in a few years' time and in other hemophilia centers.

The important impact of dental care on haemostatic treatment burden in patients with mild haemophilia.

BACKGROUND: Mild haemophilia (MH) is mainly characterized by haemorrhages secondary to surgery/invasive procedures or trauma. Haemostatic treatment in MH ranges from on demand to short prophylaxis according to the type of bleeding events and the basal clotting factor level. Oral surgery and dental extractions can represent a frequent haemostatic challenge in MH requiring appropriate treatment. However, only few studies on limited numbers of patients are available in the literature regarding the implications of dental management in patients with MH. OBJECTIVES: The purpose of the study was to evaluate the impact of dental care on the burden of haemostatic treatment in patients affected by MH. METHODS: We conducted a retrospective multicentre study evaluating adult patients with MH regularly examined at the Haemophilia Treatment Centres (HTCs) of the Saint-Luc University Hospital, Brussels (Belgium) and of Paolo Giaccone Hospital, Palermo (Italy). The population consisted of 107 male patients with MH, with a mean age of 39 years (range 18-81 years). RESULTS: The majority of patients (86/107, 79%) needed at least one treatment within the study period, and 44% (38/86) of them received haemostatic therapy for dental care. Haemostatic therapy in our study varied from antifibrinolytic therapy alone and perioperative factor replacement to the absence of treatment at all. The great majority of oral interventions (27/42, 64%) were managed with clotting factor concentrate. CONCLUSION: This study demonstrates that dental care currently represents a major reason for haemostatic treatments in patients with MH. Maintaining good oral health appears as a priority to minimize avoidable replacement therapy and optimize resources.

Health care utilization and expenditures of parents of children with and without hemophilia A.

BACKGROUND: Caring for children with hemophilia A (HA) impacts many aspects of parents' lives. How this translates to caregivers' utilization of health services is unknown, and its elicitation can inform future evaluations of interventions that address caregiver burden for HA. OBJECTIVE: To understand the impact of caring for children with HA on parents' utilization of nonmental and mental health services by comparing 1-year costs and number of claims with parents of children without HA. METHODS: Retrospective matched cohort study using MarketScan commercial medical and pharmacy claims from 2011 to 2019. Children with HA were male sex, aged younger than 18 years, dependent policyholders, and had at least 1 HA-related medical claim from 2011 to 2018 and either an HA-related procedure or drug claim. Parents of children with HA (PCH) were primary or secondary policyholders, shared the same family ID as children with HA, and were continuously enrolled for 1-year post-index. PCH were matched (1:2) with parents of children without HA on age, sex, beneficiary type, child's age, number of children, index month and year, health plan type, employment status, and region. Primary outcomes were nonmental and mental health care costs (2020 US dollars). Secondary outcomes were number of nonmental health outpatient claims and utilization of mental health outpatient or drug claim. Subgroup analyses excluding parents with HA were also conducted. Productivity loss was also explored. Outcomes were compared using 2-sided, paired t-tests, and McNemar test. RESULTS: 1,068 PCH met inclusion criteria and were matched to 2,122 control parents. Mean 1-year cost for PCH was higher for nonmental health (mean difference $1,826 [95% CI = -1,000 to 4,652; P = 0.20]) and similar for mental health services (mean difference $14 [95% CI = -77 to 105; P = 0.76]). When parents with HA were excluded in the subgroup analyses, mental health cost was significantly higher for PCH (mean difference $676 [95% CI = 399 to 953; P < 0.001]). PCH had more nonmental health outpatient claims compared with parents of children without HA (mean difference 1.9 [95% CI = -1.1 to 4.9; P = 0.21]) and were 1.2 times (95% CI = 0.99 to 1.45; P = 0.07) more likely to have a mental health outpatient or drug claim. CONCLUSIONS: PCH had moderately higher health care costs and utilization compared with parents of children without HA; however, these results were not statistically significant. Future studies to better characterize HA disease severity and assess its impact on caregiver burden or to expand caregivers to spouses of adult patients with HA may be warranted. Limitations include inability to ascertain severity of HA in children and the use of claims data to capture complex effects on health care utilization. DISCLOSURES: Dr. Kim's postdoctoral fellowship is supported by Genentech, Inc. Dr. Raimundo is an employee of Genentech, Inc.

Association of factor expression levels with health-related quality of life and direct medical costs for people with haemophilia B.

AIMS: Gene therapy trials aim to provide a functional cure for patients with haemophilia B (HB), and treatment impact is analyzed by factor IX expression levels (FELs). We investigated the relationship of FELs with health-related quality of life (HRQoL) and costs. MATERIALS AND METHODS: This was a retrospective cross-sectional analysis of the European (CHESS I-II) and US (CHESS-US) CHESS population studies. Physicians recruited consecutive patients and extracted information from the medical records; patients completed questionnaires between 2014 and 2015 (CHESS-I), 2018-2019 (CHESS-II) and 2019 (CHESS US). Patients with inhibitors were excluded. HRQoL was assessed using the EQ-5D-5L. Twelve-month haemophilia-related direct medical costs included office visits and hospitalizations based on country-level unit costs. A Tobit model was used to analyze FELs and HRQoL and generalized linear models for direct medical costs. RESULTS: A total of 191 men with HB completed the EQ-5D questionnaire; the mean age was 36.8 years, with a mean FEL of 10.1 IU/dL (median, 4.0). Mean EQ-5D was 0.77 (SD, 0.23). The Tobit model adjusting for age, body mass index and blood-borne viruses showed every 1% increase in FEL was associated with +0.006 points in the mean EQ-5D score (p = .003). Mean haemophilia-related direct medical costs excluding factor replacement therapy were €2,028/year (median, €919) in CHESS I-II (EU, n = 226), and $7,171/year (median, $586) in CHESS US (n = 181). Adjusted EU and US models showed every 1% increase in FEL was associated with a decrease in haemophilia-related direct medical costs of €108/year and $529/year, respectively. LIMITATIONS: Direct medical costs were based on physician extraction of encounters from medical records, potentially underestimating costs of care. The voluntary nature of participation may have introduced selection biases. CONCLUSIONS: We observed a significant association of increases in FEL with increased HRQoL and decreased costs in Europe and the United States among men with HB and no inhibitors.

Is the world ready for gene therapy?

KEY POINTS OF CONSIDERATION: To prepare for the introduction of gene therapies in haemophilia care, healthcare frameworks for evaluation and valuation will need to evolve to address the unique requirements of current and future innovations for treating this rare disease. The papers in this supplement provide an insightful and comprehensive state-of-the-art assessment of these requirements and challenges. In terms of evaluation, the definition of a patient-defined value framework that captures multi-dimensional, patient-centered outcomes is an important first step for determining the full benefit of gene therapy for persons with haemophilia. In terms of valuation and rewards for innovation, health systems will need to develop alternative payment models for risk-sharing that will allow payers and society to address uncertainties about the ultimate clinical and economic value of these innovations. And health technology assessment authorities will need to exercise greater flexibility in evidence requirements given the unique features of data collection for a potentially curative therapy for a rare disease with long-term uncertainties about durability of impact. Collaboration among stakeholders will be essential for developing the critical evidence requirements and providing the incentives needed to achieve sustainable budgets and broad access for persons with haemophilia worldwide.

Alternative payment models for durable and potentially curative therapies: The case of gene therapy for haemophilia A.

INTRODUCTION: The emergence of durable and potentially curative cell and gene therapies (also known as advanced therapy medicinal products) with high price tags is challenging conventional health care payment systems. Among these are gene therapies in various phases of development for haemophilia A and B. The emergence of these therapies comes with clinical and economic uncertainties for payers, providers, patients, and manufacturers. These include uncertainties about expression of the intended physiological response, patient outcomes, and duration of treatment effect, along with potentially high upfront costs, variable additional costs, and uncertainties about uptake of the therapy among indicated patient populations. These clinical and economic uncertainties raise interest among payers, providers, and manufacturers in risk-sharing arrangements, including alternative payment models (APMs). SUMMARY: APMs differ from traditional fee-for-service payment for health care. For example, some APMs are designed to reward clinicians and provider organizations for delivering high-quality and cost-effective care. The APMs described here, outcomes-based models (or value- or performance-based models) and finance-based models, are designed to mitigate or otherwise manage financial risks associated with health care payment, including instances in which patient outcomes for costly therapies are uncertain. We examine how such APMs may be applicable in the context of emerging gene therapies for haemophilia A, including considerations in determining whether any particular APM may be most suitable. KEY POINTS OF CONSIDERATION: Gene therapies for haemophilia are among the emerging durable and potentially curative cell and gene therapies with high price tags that are challenging conventional payment systems. These therapies present clinical and economic uncertainties for payers, providers, patients, and manufacturers, including regarding expression of the intended physiological response, duration of treatment effect, patient outcomes, potentially high upfront costs and variable additional costs, and uptake among potentially indicated, diverse patient subgroups. These uncertainties raise interest among payers, manufacturers, and providers in risk-sharing arrangements, including alternative payment models (APMs) such as various outcomes-based and finance-based models. This paper describes a taxonomy of APMs. Then, for the particular context of gene therapy for haemophilia A, we present a set of factors to be considered when determining whether an APM risk-sharing arrangement may be appropriate for a given gene therapy, and, if so, which APM may be most suitable. [Correction added on 21 February 2022, after first online publication: the 'Key Points of Consideration' have been added in this version.].

Health technology assessment for gene therapies in haemophilia.

INTRODUCTION: Gene therapies are poised to become a new therapeutic option for persons with haemophilia (PwH), having begun to show durable efficacy and safety in clinical trials to date. However, value assessment of gene therapies faces challenges from small populations that preclude randomized clinical trials (RCT), ethical considerations when treating a serious genetic disorder with lifelong consequences, and appropriate endpoint selection that captures the full scope of the disorder and its lifelong complications. SUMMARY: Health technology assessment (HTA) for new haemophilia therapies may require greater flexibility in evidence requirements and recognition of factors that vary across patient populations and health systems, including current standard-of-care, gains in survival and health-related quality-of-life (HRQoL), and reduced replacement factor utilization. It will be important for HTAs to consider limitations of RCTs for gene therapy and to consider intra-patient data as evidence of clinical effectiveness. Despite long-term clinical trials with up to 8 years of follow-up, ongoing uncertainties about durability of effect may be informed by extrapolating clinical data out ∼10 years, using different projections of durability. Beyond objective endpoints, such as Petersson scores or annualized bleed rates, health utilities that accompany gene therapy (e.g., mental health, freedom of choice, peace of mind) should be considered in HTA evaluations, particularly for comparisons with low dose or no prophylaxis. CONCLUSION: HTAs of gene therapies in haemophilia are encouraged to rise to the challenge of filling evidence gaps and conducting assessments. KEY POINTS OF CONSIDERATION: It is important for HTA bodies to consider the limitations to conduct randomized controlled trials for gene therapy and to consider intrapatient data as evidence of comparative effectiveness. Given the uncertainties around the long-term gene therapy use, clinical trial data should be extrapolated ∼10 years, using scenarios that consider different durations of effect. The major value drivers in a model, in addition to drug pricing itself, will be based on assumptions about duration of effect and savings/cost offsets from reduced use of replacement therapy. Assessment methodologies and modelling configurations need to evolve to fully capture the value of gene therapy, including patient meaningful outcomes, in a validated and quantitative fashion. Regardless of payment system archetype, the intersection between NGOs, the clinical community's voice, HTA willingness to collaborate, and alignment with regulatory acceptance of benefit is critical. [Correction added on 21 February 2022, after first online publication: the 'Key Points of Consideration' have been added in this version.].

Improving assessment and management of pain in hemophilia: an Italian Delphi consensus statement.

Comprehensive evidence-based guidelines and well-validated assessment scales for pain in people with hemophilia (PwH) are needed. Here, we report 28 statements covering five topics on pain assessment and management in pediatric and adult PwH that were developed by 60 Italian hemophilia specialists during a Delphi consensus process. Overall, a clear consensus was achieved for 19 of the 28 statements. Consensus was reached on all statements on the topic of pain assessment and quality of life (QoL), including the need for regular pain assessment on a quantitative scale, the importance of distinguishing between different pain types, and the need to evaluate the impact of pain on patient QoL. The other four topics concerned acute and chronic pain management in adults and in children. Consensus was reached on statements regarding non-pharmacologic treatment and the use of first-line paracetamol (acetaminophen). There was a lack of consensus regarding the use of non-steroidal anti-inflammatory drugs, cyclooxygenase-2 inhibitors, or opioids.

The experiences and beliefs of people with severe haemophilia and healthcare professionals on pain management, and their views of using exercise as an aspect of intervention: a qualitative study.

PURPOSE: To explore the experiences, views and beliefs of people with severe haemophilia and healthcare professionals (HCPs) on approaches for pain management, as well as their views on exercise being used as an aspect of management. METHODS: Taking a qualitative inquiry approach using focus groups and semi-structured interviews, participants included people with severe haemophilia living with chronic pain and haemophilia HCPs. Data were analysed using reflexive thematic analysis. RESULTS: Fourteen men with haemophilia with a median age of 47 (range 23-73) and six haemophilia HCPs agreed to participate. Of the people with haemophilia, 11 attended two focus groups and three were interviewed over telephone. Healthcare professionals were interviewed face-to-face. Two themes were conceptualised from the data: (i) haemophilia management and pain management is discordant (imbalance between good haemophilia care but poor pain management, historical medico-social influences on pain management, the need for trust); (ii) uncertain about exercise but clear on what matters (conflicting views on exercise, the need for proof of safety, personalised care). CONCLUSIONS: Options for effective pain management remain limited and what is used is heavily influenced by beliefs and experience. Exercise as a treatment option in pain management is conceptually acceptable for people with haemophilia. Effective pain management requires understanding of individual beliefs and fears, and a personalised approach supported by knowledgeable, trusted clinicians.Implications for rehabilitationMusculoskeletal joint pain and its relationship with bleeding in people with haemophilia continues to be a management challenge.Current pain management strategies are of limited effectiveness with little evidence of an approach that reflects the multi-modal pain experience.Whilst exercise and rehabilitation approaches are conceptually possible for people with severe haemophilia, barriers remain regarding perception of overall safety and effectiveness.People with severe haemophilia may consider exercise as part of a pain management strategy if it is individualised, and they are supported to do it by clinicians who understand them and their haemophilia.

Hemophilia Gene Therapy Value Assessment: Methodological Challenges and Recommendations.

Gene therapy for hemophilia is designed to produce health gains for patients over many years. Rewarding that value creation on the basis of a one-time treatment implies a large upfront cost. This cost can only be justified by long-term health benefits and being cost-effective compared with conventional treatments. Yet, uncertainties about the long-term benefits make it challenging to assess clinical and economic value of gene therapies at launch. We identify and discuss key methodological challenges in assessing the value of gene therapy for hemophilia, including the immaturity of evidence on the durability of benefits, lack of definition and valuation of cure for chronic diseases, absence of randomized controlled trials, limitations of traditional quality of life measures in hemophilia, approach for qualifying cost-savings compared with current treatments, and choice of perspective. The Institute for Clinical and Economic Review has developed a framework for assessing single or short-term therapies (ICER-SST) and has applied it in hemophilia. After reviewing this framework and its application, we recommend the following when assessing the value of hemophilia gene therapies: (1) leveraging expert clinical opinion to justify assumptions on the durability of benefits; (2) using external synthetic controls and lead-in, self-controlled trials to assess comparative effectiveness; (3) addressing limitations of traditional quality of life measures through the use of modified utility collection approaches; (4) adjusting cost offsets from gene therapies with caution; (5) considering outcome-based contracting to address uncertainties about prices and long-term outcomes; and (6) presenting societal and healthcare system perspectives in parallel.

Real-world treatment, clinical outcomes and healthcare resource utilization among persons with hemophilia A by age.

Aim: Examine real-world characteristics, treatment patterns, and outcomes among treated persons with hemophilia A (PwHA) stratified by age. Patients & methods: This study utilized US claims data from 1 January 2007-31 July 2018 from the Humana Research Database. Unadjusted comparisons were conducted across PwHA (<18, 18-55, 56-89 years) enrolled in commercial or Medicare Advantage Prescription Drug plans. Results: A total of 294 PwHA were identified; 21.1% experienced ≥1 bleeding event, and 41.2 and 53.1% had evidence of arthropathy or related disorders, and pain, respectively. Along with all-cause and hemophilia-related healthcare resource utilization (HCRU), these were highest among PwHA aged 56-89 years. Conclusion: Insights into treatment, outcomes and HCRU may identify opportunities for enhanced disease management, particularly in older PwHA.