Real-world evidence for coverage determination of treatments for rare diseases.

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

A practical approach for adoption of a hub and spoke model for cell and gene therapies in low- and middle-income countries: framework and case studies.

In the rapidly evolving landscape of biotechnologies, cell and gene therapies are being developed and adopted at an unprecedented pace. However, their access and adoption remain limited, particularly in low- and middle-income countries (LMICs). This study aims to address this critical gap by exploring the potential of applying a hub and spoke model for cell and gene therapy delivery in LMICs. We establish the identity and roles of relevant stakeholders, propose a hub and spoke model for cell and gene therapy delivery, and simulate its application in Brazil and the Middle East and North Africa. The development and simulation of this model were informed by a comprehensive review of academic articles, grey literature, relevant websites, and publicly available data sets. The proposed hub and spoke model is expected to expand availability of and access to cell and gene therapy in LMICs and presents a comprehensive framework for the roles of core stakeholders, laying the groundwork for more equitable access to these lifesaving therapies. More research is needed to explore the practical adoption and implications of this model.

Patient and Caregiver Outcomes After Onasemnogene Abeparvovec Treatment: Findings from the Cure SMA 2021 Membership Survey.

INTRODUCTION: Onasemnogene abeparvovec (OA) is the only gene replacement therapy currently approved for spinal muscular atrophy (SMA) treatment. We sought to assess real-world patient and caregiver outcomes after OA treatment for SMA. METHODS: Patients who received OA were identified from the 2021 Cure SMA Membership Survey. Those treated at 6-23 months of age were matched to non-patients treated with OA on the basis of age at the time of survey and survival motor neuron 2 gene copy number. Patient characteristics, motor milestones, and resource and supportive care use, as well as caregiver proxy-reported health-related quality of life (HRQOL), were described. Caregiver unmet needs and HRQOL were also assessed. RESULTS: Of the 614 patients in the survey, 64 received OA, and 17 were matched with 28 non-OA-treated patients. In general, a greater percentage of OA-treated patients achieved various motor milestones, including 100% sitting without support and 58.8% walking with assistance. OA-treated patients also had numerically lower rates of hospitalization and surgery. None required tracheostomy with a ventilator. The rate of using oxygen or a breathing machine for more than 16 h was also lower for OA-treated patients. OA-treated patients had less frequent trouble swallowing. HRQOL was reported to be similar to non-OA-treated patients. Caregivers of OA-treated patients reported better patient mobility scores and less work impairment. CONCLUSIONS: The study suggests that treatment with OA is associated with greater rates of motor milestone achievements and less resource and supportive care use for patients with SMA treated at 6-23 months of age in the real world. For caregivers, it may also potentially reduce unmet needs, improve HRQOL, and reduce work impairment.

Health Care Resource Utilization and Costs for Patients with Spinal Muscular Atrophy: Findings from a Retrospective US Claims Database Analysis.

INTRODUCTION: Spinal muscular atrophy (SMA) is a neurogenic disorder associated with progressive loss of muscle function, respiratory failure, and premature mortality. This study aimed to describe and compare real-world health care resource utilization (HCRU) and costs for US patients with SMA treated with disease-modifying treatments, including onasemnogene abeparvovec, nusinersen, and/or risdiplam. METHODS: This study used claims and structured electronic medical record data from the HealthVerity claims database (January 1, 2017-March 31, 2021). Eligible patients were aged ≤ 2 years at index (treatment initiation or switch), diagnosed with SMA, had ≥ 1 pharmacy/medical claim for onasemnogene abeparvovec, nusinersen, and/or risdiplam, and continuous enrollment ≥ 1 month pre- and ≥ 2 months post-index. SMA-related HCRU and costs during the study period (> 12 months post-index) were compared between treatment groups before and after propensity score weighting. Costs were adjusted to 2021 USD. RESULTS: Of 74 included patients, 62 (83.8%) received nusinersen and 12 (16.2%) received onasemnogene abeparvovec (monotherapy, n = 9; onasemnogene abeparvovec after nusinersen [switching], n = 3). After weighting, nusinersen-treated patients had greater annual numbers of inpatient (mean 5.3 nusinersen vs. 1.8 onasemnogene abeparvovec) and emergency department (mean 3.0 nusinersen vs. 1.5 onasemnogene abeparvovec; p < 0.05) visits, and greater annual SMA-related medical costs (mean $78,446 nusinersen vs. $29,438 onasemnogene abeparvovec; mean difference $49,007, p < 0.05) than onasemnogene abeparvovec-treated patients. Onasemnogene abeparvovec-treated patients incurred greater SMA-treatment pharmacy costs than nusinersen-treated patients (mean $2,241,875 onasemnogene abeparvovec vs. $693,191 nusinersen; mean difference $1,548,684, p < 0.05). CONCLUSIONS: SMA is associated with substantial economic burden. Patients treated with onasemnogene abeparvovec had greater SMA treatment-related pharmacy costs but lower SMA-related HCRU and medical costs compared with patients receiving nusinersen monotherapy.

Spinal muscular atrophy (SMA) is a crippling neurodegenerative disease with symptoms of respiratory failure, muscle weakness and loss of function, and premature death. This study describes and compares real-world health care resource utilization (HCRU) and costs for US patients with SMA receiving current treatments (e.g., onasemnogene abeparvovec, nusinersen, risdiplam) using claims and electronic medical record data from a US claims database. Patients included (n = 74) in the study were ≤ 2 years old at treatment initiation/switching of treatments (index), had been diagnosed with SMA and had one or more pharmacy or medical claim for onasemnogene abeparvovec, nusinersen, or risdiplam, and were continuously enrolled for ≥ 1 month before and ≥ 2 months after index. SMA-related HCRU and costs during the study period (up to 12 months post-index) were compared between treatment groups before and after propensity score weighting, with costs adjusted to 2021 USD. Propensity score weighting allows better comparison between patients in treatment and comparison groups by assigning patients different "weights." This weighting allows investigators to be certain that differences in outcomes between patient groups are a result of a particular treatment. After weighting, nusinersen-treated patients had a greater number of inpatient and emergency department visits and greater SMA-related medical costs annually, whereas patients who received onasemnogene abeparvovec had greater pharmacy costs. Our study indicates the greater medical costs among patients receiving nusinersen were largely driven by invasive procedures, such as tracheostomy and gastrostomy, that required hospitalization, but the exact mechanism of greater HCRU/costs associated with nusinersen needs to be further assessed.

Recommendations for economic evaluations of cell and gene therapies: a systematic literature review with critical appraisal.

OBJECTIVE: No consensus exists on the ideal methodology to evaluate the economic impact and value of new, potentially curative gene therapies. We aimed to identify and describe published methodologic recommendations for the economic evaluation of gene therapies and assess whether these recommendations have been applied in published evaluations. METHODS: This study was conducted in three stages: a systematic literature review of methodologic recommendations for economic evaluation of gene therapies; an assessment of the appropriateness of recommendations; and a review to assess the degree to which the recommendations were applied in published evaluations. RESULTS: A total of 2,888 references were screened, 83 articles were reviewed to assess eligibility, and 20 papers were included. Fifty recommendations were identified, and 21 reached consensus thresholds. Most evaluations were based on naive treatment comparisons and did not apply consensus recommendations. Innovative payment mechanisms for gene therapies were rarely considered. The only widely applied recommendations related to modeling choices and methods. CONCLUSIONS: Methodological recommendations for economic evaluations of gene therapies are generally not being followed. Assessing the applicability and impact of the recommendations from this study may facilitate the implementation of consensus recommendations in future evaluations.

Valuation of Treatments for Rare Diseases: A Systematic Literature Review of Societal Preference Studies.

INTRODUCTION: We sought to synthesize published empirical studies that elicited and characterized societal valuations of orphan drugs and the attributes that may drive different valuations for orphan drugs versus other treatments. METHODS: We conducted a systematic literature review (SLR) in MEDLINE and EMBASE databases up to November 2, 2020. Search terms covered societal preferences and attributes of orphan drugs (e.g., disease prevalence, severity, burden, unmet needs, and benefits). RESULTS: We identified 38 eligible publications: 33 societal preference studies and 5 reviews discussing societal valuations and attributes of orphan drugs. Most publications suggested that a majority of respondents favored allocating funds to more prevalent diseases. However, trade-off studies and discrete-choice experiments found that survey participants chose to allocate resources to orphan drugs even when the cost per unit of health benefit was greater than for therapies for more prevalent diseases. Overall, 19 of 27 studies assessing severity in treatment valuation revealed that respondents prioritized patients with severe diseases over those with milder ones for equal health benefits. Members of the general public tended to prefer treatments for diseases with no alternative or when existing alternatives had limited efficacy over diseases with clear therapeutic alternatives. There was evidence that individuals preferred sharing resources, so no patient was left without treatment. CONCLUSIONS: Our SLR indicates the general public typically attaches greater value to orphan drugs than to other treatments for common diseases. This is not because of rarity per se, but primarily because of disease severity and lack of therapeutic alternatives typically associated with rare diseases.

Orphan drugs are drugs serving a substantial public health need by treating life-threatening or chronically debilitating medical conditions affecting a small number of people with very high unmet needs. We reviewed 38 published studies looking at drug characteristics that may cause people to value orphan drugs differently versus treatments for common conditions. Most people surveyed in these publications favored health care funds going to more prevalent diseases. However, some people preferred funding orphan drugs even when the cost versus health benefit was higher compared with treatments for more common diseases. The majority of studies that investigated the impact of disease severity on the valuation of treatments found that people prioritized patients with severe disease over those with milder disease, for the same extent of health benefit. People also preferred funding treatments for diseases that have no alternative treatments, or treatments with limited benefits, over treatments for diseases with many treatments or more effective treatments. We also found evidence of a societal preference for shared resources, meaning that no patient would be left without treatment, including those who receive limited benefits from health care resources, even if this does not lead to the maximization of health benefits across society. In conclusion, our literature review indicated that the general public attaches greater value to orphan drugs versus treatments for more common diseases, not because of rarity per se, but largely because the rare diseases treated by orphan drugs are often severe and have no or few treatment options.

Value-Based Pricing for Patent-Protected Medicines Over the Product Life Cycle: Pricing Anomalies in the "Age of Cures" and Their Implications for Dynamic Efficiency.

OBJECTIVES: Conventional cost-effectiveness analysis (CEA) for the value-based pricing of new medicines largely ignores the implications of limited market exclusivity (ie, patent-protection periods plus any exclusivity granted by regulators). This paper explores the implications of this methodological shortcoming, which produces several pricing anomalies with potentially unintended effects on research and development (R&D) incentives. METHODS: We illustrate these implications by comparing 4 stylized examples of increasing complexity, from short-term cures for acute conditions to long-term cures for rare, health-catastrophic conditions. RESULTS: (1) Conventional-CEA will project a different result than an adjusted CEA that considers generic or biosimilar entry; (2) free and flexible pricing of long-term treatments (eg, statins for hypercholesterolemia) or repeated-dose cures (eg, insulin for type 1 diabetes) for chronic conditions will likely result in predictable price increases at the end of the exclusivity period that may be perceived as unjustified or unsupported; and (3) one-time administration "cures" (eg, gene therapy for spinal muscular atrophy) have the potential to allocate a large share of the social surplus to the manufacturer over the product lifetime, which may or may not be dynamically efficient per se, but may also inadvertently disadvantage the development of valuable long-term treatments or repeated-dose cures for chronic conditions. CONCLUSIONS: We highlight the need for additional research on long-term solutions to these issues that would aim to promote dynamically efficient global R&D. More work is needed on the following: (1) relationships between social surplus allocation and the amount and composition of global R&D, as we may be as likely to be encouraging excessive R&D in some areas as to be undersupplying it in others; and (2) relating the size of the surplus reward to R&D cost and, thus, the return on investment.

International reference pricing of pharmaceuticals in the United States: Implications for potentially curative treatments.

Recent federal drug price control proposals have included mechanisms to benchmark US prices to international prices. These international price referencing (IRP) proposals recommend that the US government develop an index based on prices paid by a group of higher-income countries and restrict US prices to a narrow range of the index. IRP is a policy tool used across the globe to control drug costs, particularly in markets in which health care resources are limited. If IRP is implemented in the United States, where the drug industry derives roughly 50% of global pharmaceutical sales, what impact might it have on innovation and access? In this brief commentary, we explore this question in the context of cell and gene therapies (CGTs) (evolving therapeutics that have high clinical potential as well as uncertainty and risk). Many CGTs are in development, and the world faces a challenge in providing access. Pressure to provide access to patients who would benefit may create greater global concerns about health equity and access. We conclude that an IRP policy in the United States might exacerbate access problems to promising CGTs and impact innovation and population health. Disclosures: Funding for this project was provided by Novartis Gene Therapies, Inc. Sean D Sullivan has received research support from and served as a consultant to Novartis Gene Therapies, Inc. Omar Dabbous is an employee of Novartis Gene Therapies, Inc., and owns stock and other equities. Louis P Garrison has received consulting fees from BioMarin, Inc., and Novartis Gene Therapies, Inc. Kiera D Sullivan has no conflicts to report. The opinions expressed in this commentary are solely those of the authors and not necessarily their institutions.

Systematic Literature Review of Clinical and Economic Evidence for Spinal Muscular Atrophy.

INTRODUCTION: The recent advent of disease-modifying therapies (DMTs) has dramatically changed the treatment landscape of spinal muscular atrophy (SMA), and the multifaceted impact of this advancement has not been assessed thoroughly in the growing body of literature. We sought to summarize the literature on the natural history of SMA and the impact of SMA DMTs, including health-related quality of life (HRQOL) and utilities, clinical efficacy and safety, and economic impact. METHODS: Systematic literature reviews were conducted following PRISMA guidelines with no inclusive dates. Relevant studies were identified by searching full-text databases on November 12-13, 2020, including MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and EconLit, conference proceedings, health technology assessment databases, and clinical trial registries. All searches used a combination of MeSH and key terms. Studies were screened according to criteria based upon population, intervention, outcomes, and study design structure. RESULTS: Findings from 17, 23, 32, and 42 studies were included for the evaluation of natural history of SMA, HRQOL and utilities, clinical efficacy and safety, and economic impact of DMTs, respectively. Currently available data indicate that untreated SMA is associated with considerable humanistic and economic burden, with estimates of costs varying by treatment. While a variety of interventions have been evaluated in SMA clinical trials, quantitative synthesis of safety and efficacy findings was not feasible because of inconsistencies in reported outcomes. Data assessing impacts of DMTs on HRQOL were also lacking. CONCLUSIONS: Overall, this systematic literature review highlights a clear need for up-to-date and methodologically rigorous clinical, HRQOL, and economic data to support unbiased assessments of the relative clinical and economic effectiveness of SMA treatments. More research is required to extend our understanding of the burden of SMA on HRQOL utility assessments and the impact of new DMTs on HRQOL and utilities for patients with SMA.

Variation in market access decisions for cell and gene therapies across the United States, Canada, and Europe.

Transformative cell and gene therapies have now launched worldwide, and many potentially curative cell and gene therapies are in development, offering the prospect of significant health gains for patients. Access to these therapies depend on decisions made by health technology assessment (HTA) and payer organizations. We sought to describe the emerging cell and gene therapies market access landscape by analyzing 17 US commercial payer medical policies, and HTA reports from five European countries and Canada. We found that some US health plans applied coverage restrictions more often than others (four plans applied restrictions in all decisions, while four plans applied restrictions in <30% of decisions). The European and Canadian HTA bodies recommend access to fewer therapies than US health plans, reflecting a more stringent approach in the context of limited evidence and high scientific uncertainty that is commonly associated with these treatments. Our findings suggest that patient access to approved cell and gene therapies is restricted in all regions studied, though the nature of these restrictions differs between US health plans and the European/Canada HTA recommendations. Payers, HTA groups, pharmaceutical companies, and other stakeholders should collaborate to more clearly define the "uncertainties" and develop market access policies that balance benefits of early access with ongoing data collection to close evidence gaps over time.

Nusinersen for Spinal Muscular Atrophy in the United States: Findings From a Retrospective Claims Database Analysis.

INTRODUCTION: Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disorder caused by deletion/mutation of the survival motor neuron 1 gene, characterized by progressive loss of motor neurons, resulting in increasing muscular weakness, deteriorating motor function, and, in its most severe form, death before 2 years. Nusinersen, an antisense oligonucleotide that increases expression of the functional SMN protein, was approved for SMA by US and European regulatory agencies in 2016 and 2017, respectively. The indicated regimen requires intrathecal injections every 4 months, following the first four injections during the loading phase. Adherence is integral to treatment success. Adherence to nusinersen may pose particular challenges as most patients with SMA are young children who require complex multidisciplinary care (including ongoing intrathecal treatment administration and potential specialized anesthetic and surgical procedures) at specialized centers. However, real-world data on adherence to nusinersen are limited. METHODS: We conducted a retrospective claims database analysis from December 23, 2016, to November 20, 2019, to study nusinersen adherence and discontinuation/persistence in US patients with SMA types 1-3 who completed the loading phase, and to determine the impact of non-adherence or treatment discontinuation on SMA-related comorbidities, health care resource utilization (HCRU), and costs. RESULTS: We identified 23 patients with SMA type 1, 41 patients with SMA type 2, and 260 patients with SMA type 3 who had completed the loading phase. Deviations from the indicated nusinersen treatment schedule were frequent in real-world usage, with most patients receiving ≥1 dose outside the scheduled interval. Across SMA types, non-adherent patients were more likely to have had SMA-related comorbidities (e.g., feeding difficulties, dyspnea and respiratory anomalies, and muscle weakness) and greater HCRU. Persistence rates 12 months after treatment initiation for patients with SMA types 1, 2, and 3 were 55.2%, 42.4%, and 54.6%, respectively. Patients who discontinued nusinersen and those who did not had generally similar comorbidity profiles. Discontinuation was associated with greater health care costs across SMA types. CONCLUSION: Our analysis of claims data indicated that discontinuation and non-adherence to nusinersen treatment were prevalent, and associated with greater frequency of comorbidities, greater HCRU, and increased costs for patients.

Matching-adjusted indirect treatment comparison of onasemnogene abeparvovec and nusinersen for the treatment of symptomatic patients with spinal muscular atrophy type 1.

OBJECTIVE: Onasemnogene abeparvovec, a one-time intravenous gene replacement therapy, and nusinersen, an antisense oligonucleotide that requires ongoing intrathecal administration, have been evaluated as treatments for spinal muscular atrophy (SMA) type 1 in separate Phase III trials, but no head-to-head comparison studies have been conducted. Onasemnogene abeparvovec was compared with nusinersen using a matching-adjusted indirect comparison (MAIC) to estimate the treatment effect of onasemnogene abeparvovec relative to nusinersen for the treatment of symptomatic patients with SMA type 1 for up to 24 months of follow-up. METHODS: In the absence of studies for both onasemnogene abeparvovec and nusinersen with a common comparator, a Bayesian naïve indirect treatment comparison (ITC) and MAIC between onasemnogene abeparvovec and nusinersen were conducted to compare efficacy and safety of onasemnogene abeparvovec with nusinersen. Outcomes of interest were event-free survival (EFS), overall survival (OS), and motor milestone achievements (independent sitting and independent walking). Relative treatment effects were expressed as relative risk (RR) and risk difference. RESULTS: Pooled and weighted patient-level data illustrated a favorable effect toward onasemnogene abeparvovec, suggesting longer EFS for patients compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.19 [95% CI: 0.07-0.54; 99% CI: 0.05-0.74]). At 24 months of follow-up, patients receiving onasemnogene abeparvovec were statistically significantly more likely to achieve the motor milestone of sitting independently compared with patients treated with nusinersen. Although statistically significant differences were not observed at 6 to 18 months between treatment options, the likelihood of sitting independently at 12 and 18 months numerically favored onasemnogene abeparvovec. A numerically greater likelihood of walking by 18 and 24 months was also observed for patients treated with onasemnogene abeparvovec compared with nusinersen. Onasemnogene abeparvovec therapy was also associated with a favorable (but statistically nonsignificant) outcome for OS and may be associated with prolonged survival compared with nusinersen (HR of onasemnogene abeparvovec vs. nusinersen: 0.35 [95% CI: 0.09-1.32; 99% CI: 0.06-2.01]). Bayesian naïve ITC results were similar to the MAIC analysis for EFS, OS, and motor milestone achievements. Small sample size limited covariate matching to baseline CHOP INTEND and nutritional support requirement, leading to wider CIs and statistically inconclusive outcomes for some of the results. CONCLUSIONS: Despite limitations of the current MAIC analysis (mainly a small sample size for statistical testing, even for the pooled onasemnogene abeparvovec trials, and potential differences in prognostic and predictive factors between studies), the relative treatment effects in EFS, OS, and motor milestone achievement indicate that onasemnogene abeparvovec may offer continued benefit compared with nusinersen through 24 months of follow-up.

Gene therapy may not be as expensive as people think: challenges in assessing the value of single and short-term therapies.

At an upfront price of $2.125 million, the one-time gene therapy onasemnogene abeparvovec for spinal muscular atrophy, a rare neuromuscular disorder that is usually fatal by 2 years of age if untreated, has been called the "most expensive drug ever." This flawed characterization raises important methodological and policy issues regarding valuation of high-cost treatments. We reviewed several other high-cost therapies-with a particular focus on hemophilia A treatment-studied by the nonprofit Institute for Clinical and Economic Review (ICER). In ICER's summary report of 2 treatments for managing hemophilia A, published in this month's JMCP issue, the estimated $15-$18 million lifetime cost of factor VIII is characterized as "far too high," representing "a failure of competition [that] … builds a platform for pricing of treatments … that will only exacerbate these problems." Current literature indicates several factors underlying high factor VIII treatment cost (eg, historical pattern of innovation and lack of market competition) that may also drive the pricing dynamics of advanced therapies for other rare diseases. When a treatment's price is driven high (or "distorted"), an economic principle known as "theory of the second best" suggests that market price becomes a poor estimate of social opportunity cost, and adjustments should be made for such distortions. In any case, a high-cost standard of care creates an opportunity for new technology to generate cost savings, providing an inducement for market entry. Recognizing that this potentially creates a tendency to produce price distortions for new treatments, ICER has attempted to apply some ad hoc adjustments. However, challenges remain in creating a "level playing field" across different disease-modifying or potentially curative innovations (eg, one-time therapy vs ongoing or lifelong treatment with repeated doses). While additional policy work is needed to address this dilemma, it would clearly be misleading to assume that gene therapies are inherently expensive. Rigorous economic evaluation of novel therapies requires careful comparison of lifetime cost and benefits vs standard of care, including adjustments for pricing distortions. Fortunately, economic theory suggests that we could adjust to this circumstance by using the social opportunity costs of interventions based on an appropriate variable cost-effectiveness threshold that would be higher for rare severe diseases. DISCLOSURES: The research reported in this Viewpoints article was funded by Novartis Gene Therapies, Inc. Garrison and Jiao were paid by Novartis Gene Therapies, Inc., to conduct this research. Garrison has also received consulting fees from BioMarin, Inc, and UniQure. Dabbous is a full-time employee of Novartis Gene Therapies, Inc., and holds Novartis stock and stock options.

An updated cost-utility model for onasemnogene abeparvovec (Zolgensma®) in spinal muscular atrophy type 1 patients and comparison with evaluation by the Institute for Clinical and Effectiveness Review (ICER).

Background: Recent cost-utility analysis (CUA) models for onasemnogene abeparvovec (Zolgensma®, formerly AVXS-101) in spinal muscular atrophy type 1 (SMA1) differ on key assumptions and results. Objective: To compare the manufacturer's proprietary CUA model to the model published by the Institute for Clinical and Economic Review (ICER), and to update the manufacturer's model with long-term follow-up data and some key ICER assumptions. Study design: We updated a recent CUA evaluating value for money in cost per incremental Quality-adjusted Life Year (QALY) of onasemnogene abeparvovec versus nusinersen (Spinraza®) or best supportive care (BSC) in symptomatic SMA1 patients, and compared it to the ICER model. Setting/Perspective: USA/Commercial payer Participants: Children aged <2 years with SMA1. Interventions: Onasemnogene abeparvovec, a single-dose gene replacement therapy, versus nusinersen, an antisense oligonucleotide, versus BSC. Main outcome measure: Incremental-cost effectiveness ratio and value-based price using traditional thresholds for general medicines in the US. Results: Updated survival (undiscounted) predicted by the model was 37.60 years for onasemnogene abeparvovec compared to 12.10 years for nusinersen and 7.27 years for BSC. Updated quality-adjusted survival using ICER's utility scores and discounted at 3% were 13.33, 2.85, and 1.15 discounted QALYs for onasemnogene abeparvovec, nusinersen, and BSC, respectively. Using estimated net prices, the discounted lifetime cost/patient was $3.93 M for onasemnogene abeparvovec, $4.60 M for nusinersen, and $1.96 M for BSC. The incremental cost per QALY gained for onasemnogene abeparvovec was dominant against nusinersen and $161,648 against BSC. These results broadly align with the results of the ICER model, which predicted a cost per QALY gained of $139,000 compared with nusinersen, and $243,000 compared with BSC (assuming a placeholder price of $2 M for onasemnogene abeparvovec), differences in methodology notwithstanding. Exploratory analyses in presymptomatic patients were similar. Conclusion: This updated CUA model is similar to ICER analyses comparing onasemnogene abeparvovec with nusinersen in the symptomatic and presymptomatic SMA populations. At a list price of $2.125 M, onasemnogene abeparvovec is cost-effective compared to nusinersen for SMA1 patients treated before age 2 years. When compared to BSC, cost per QALY of onasemnogene abeparvovec is higher than commonly used thresholds for therapies in the USA ($150,000 per QALY).

Health economic evaluation of gene replacement therapies: methodological issues and recommendations.

Objective: To provide recommendations for addressing previously identified key challenges in health economic evaluations of Gene Replacement Therapies (GRTs), including: 1) the assessment of clinical effectiveness; 2) the valuation of health outcomes; 3) the time horizon and extrapolation of effects beyond trial duration; 4) the estimation of costs; 5) the selection of appropriate discount rates; 6) the incorporation of broader elements of value; and 7) affordability. Methods: A literature review on economic evaluations of GRT was performed. Interviews were conducted with 8 European and US health economic experts with experience in evaluations of GRT. Targeted literature reviews were conducted to investigate further potential solutions to specific challenges. Recommendations: Experts agreed on factors to be considered to ensure the acceptability of historical cohorts by HTA bodies. Existing prospective registries or, if not available, retrospective registries, may be used to analyse different disease trajectories and inform extrapolations. The importance of expert opinion due to limited data was acknowledged. Expert opinion should be obtained using structured elicitation techniques. Broader elements of value, beyond health gains directly related to treatment, can be considered through the application of a factor to inflate the quality-adjusted life years (QALYs) or a higher cost-effectiveness threshold. Additionally, the use of cost-benefit analysis and saved young life equivalents (SAVE) were proposed as alternatives to QALYs for the valuations of outcomes of GRT as they can incorporate broader elements of value and avoid problems of eliciting utilities for paediatric diseases. Conclusions: While some of the limitations of economic evaluations of GRT are inherent to limited clinical data and lack of experience with these treatments, others may be addressed by methodological research to be conducted by health economists.

Economic burden of spinal muscular atrophy: an analysis of claims data.

Background: Spinal muscular atrophy (SMA) is a rare genetic neuromuscular disease. Objective: Characterize direct costs associated with SMA management. Data source: Truven Health Analytics MarketScan claims data (2012-2016). Patients: Eligible patients had ≥2 SMA-related medical claims ≥30 days apart. Patients were matched (1:1) to controls by birth year, gender, and geographic region. Patients were categorized as having infantile, child, or juvenile SMA based on diagnosis at age <1, 1-3, or 3-18 years, respectively. Main outcome measures: Annual inpatient and outpatient insurance claims and costs (2019 USD) for cases versus controls. Results: Fifty-eight, 56, and 279 cases and controls comprised the infantile, child, and juvenile cohorts, respectively. Cases had more inpatient claims than controls (infantile: 60.3% vs 1.7%; child: 35.7% vs 3.6%; juvenile: 47.0% vs 4.3%; all P ≤ 0.002). Mean net payments for inpatient admissions were higher for cases versus controls (infantile: $118,609.00 vs $58.79; child: $26,940.01 vs $143.56; juvenile: $39,389.91 vs $701.21; all P ≤ 0.01), as were mean net payments for outpatient services (infantile: $55,537.83 vs $2,047.20; child: $73,093.66 vs $1,307.56; juvenile: $49,067.83 vs $1,134.69; all P ≤ 0.0002). Conclusions: Direct costs of SMA are tremendous, often >50-fold higher compared with matched controls. Efforts are needed to reduce costs through improved standards of care.

RESTORE: A Prospective Multinational Registry of Patients with Genetically Confirmed Spinal Muscular Atrophy - Rationale and Study Design.

BACKGROUND: Dramatic improvements in spinal muscular atrophy (SMA) treatment have changed the prognosis for patients with this disease, leading to important new questions. Gathering representative, real-world data about the long-term efficacy and safety of emerging SMA interventions is essential to document their impact on patients and caregivers. OBJECTIVES: This registry will assess outcomes in patients with genetically confirmed SMA and provide information on the effectiveness and long-term safety of approved and emerging treatments. DESIGN AND METHODS: RESTORE is a prospective, multicenter, multinational observational registry. Patients will be managed according to usual clinical practice. Both newly recruitedSMAtreatment centers and sites involved in existing SMA registries, including iSMAC, Treat-NMD, French SMA Assistance Publique- Hôpitaux de Paris (AP-HP), Cure-SMA, SMArtCARE, will be eligible to participate; de novo; sites already participating in another registry may be included via consortium agreements. Data from patients enrolled in partnering registries will be shared with the RESTORE Registry and data for newly diagnosed patients will be added upon enrollment. Patients will be enrolled over a 5-year period and followed for 15 years or until death. Assessments will include SMA history and treatment, pulmonary, nutritional, and motor milestones, healthcare resource utilization, work productivity, activity impairment, adverse events, quality of life, caregiver burden, and survival.Status:Recruitment started in September 2018. As of January 3, 2020, 64 patients were enrolled at 25 participating sites. CONCLUSIONS: The RESTORE Registry has begun recruiting recently diagnosed patients with genetically confirmed SMA, enabling assessment of both short- and long-term patient outcomes.

Economic burden of spinal muscular atrophy in the United States: a contemporary assessment.

Aims: To estimate healthcare resource utilization (HRU) and costs among patients with spinal muscular atrophy (SMA) type 1 (SMA1) in real-world practice, overall and among patients treated with nusinersen. As a secondary objective, HRU and costs were estimated among patients with other SMA types (i.e. 2, 3, or 4 combined), overall and among patients treated with nusinersen.Materials and methods: Patients with SMA were identified from the Symphony Health's Integrated Dataverse (IDV) open claims database (September 1, 2016-August 31, 2018) and were classified into four cohorts based on SMA type and nusinersen treatment (i.e. SMA1, SMA1 nusinersen, other SMA, and other SMA nusinersen cohorts). The index date was the date of the first SMA diagnosis after December 23, 2016 or, for nusinersen cohorts, the date of nusinersen initiation. The study period spanned from the index date to the earlier among the end of clinical activity or data availability.Results: Patients in the SMA1 (n = 349) and SMA1 nusinersen (n = 45) cohorts experienced an average of 59.4 and 56.6 days with medical visits per-patient-per-year (PPPY), respectively, including 14.1 and 4.6 inpatient days. Excluding nusinersen-related costs, total mean healthcare costs were $137,627 and $92,618 PPPY in the SMA1 and SMA1 nusinersen cohorts, respectively. Mean nusinersen-related costs were $191,909 per-patient-per-month (PPPM) for the first 3 months post-initiation (i.e. loading phase) and $36,882 PPPM thereafter (i.e. maintenance phase). HRU and costs were also substantial among patients in the other SMA (n = 5,728) and other SMA nusinersen (n = 404) cohorts, with an average of 44.5 and 63.7 days with medical visits PPPY and total mean healthcare costs (excluding nusinersen-related costs) of $49,175 and $76,371 PPPY, respectively.Limitations: The database may contain inaccuracies or omissions in diagnoses, procedures, or costs, and does not capture medical services outside of the IDV network.Conclusions: HRU and healthcare costs were substantial in patients with SMA, including in nusinersen-treated patients.