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Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by skeletal muscle weakness and atrophy. Patients with SMA types 1 and 2 develop severe disabilities conferring substantial patient and caregiver burden. Caregiver treatment characteristic preferences are useful for informing treatment choices and improving adherence. We aimed to identify drivers of SMA treatment preference from the perspective of caregivers of patients with SMA types 1 or 2 in the United States. We quantified the relative importance of different treatment characteristics and compared preferences for hypothetical treatment scenarios. Treatment attributes and attribute levels elicited were based on a literature search and interviews with caregivers and health care professionals. The most important treatment characteristics from the perspective of health care professionals and caregivers were identified and used in a survey to quantify relative importance for caregivers. Caregivers completed surveys regarding their preferences using swing weighting methodology. These results were used to estimate the relative value of four hypothetical SMA treatment scenarios exploring different modes of treatment administration. The swing weighting survey, completed by 20 caregivers, demonstrated that the attributes driving treatment preference were reduction in permanent ventilation needs and risk of severe adverse events, followed by treatment access (including cost coverage and availability), increased ability to sit without support, and less treatment administration burden. The hypothetical SMA treatment scenarios with the highest relative value offered an easier mode of administration, lowest risk of severe adverse events, less need of permanent ventilation, and highest ability of patients to feed and sit without support. Our findings suggest that caregivers prefer a treatment with reduced clinical burden and risk in which the cost is covered and treatment is available in the short term. These results can provide important contextual information for decision-makers and help promote patient-centered care for patients with SMA., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: Anish Patel, Walter Toro, Sandra P. Reyna, and Omar Dabbous are employees of Novartis Gene Therapies, Inc., and own stock and options. Siobhan Bourke, Yemi Oluboyede, Sylvaine Barbier, and Natalyia Bogoeva are employees of Putnam Associates and were contracted by Novartis Gene Therapies, Inc., as part of this research and analysis. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2024 Patel et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

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., (© 2024. The Author(s).)

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., (© 2023. The Author(s).)

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., (© 2023. The Author(s).)

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., (© 2023. The Author(s).)

The purpose was to compare the effects of diet and exercise and laser interference and maneuver on anthropometric parameters and blood effects of object agents. The study was a randomized controlled longitudinal study. It included 45 adolescents from both sexes who were divided randomly into two groups: one group was treated with low calorie diet and exercise as group A and group B was treated with low calorie diet, exercise, and laser acupuncture. All parameters and blood samples were done before and after the interventions. Group A showed a highly significant reduction post intervention in anthropometric parameters: triceps skin fold thickness (SFT), biceps SFT, subscapular SFT, suprailiac SFT, abdominal SFT, mid-upper arm circumference (MUAC), waist C, and hip C, except for waste/hip (W/H) ratio which showed no significant difference, p > 0.05 and some lipid profiles (cholesterol, LDL) with p < 0.001 Whereas, a significant decrease in TG was observed (p < 0.05). On the other hand, a significant increase in HDL was observed (p < 0.05). Group B (LCD + exercise + LA) showed a highly significant reduction post intervention in anthropometric parameters: triceps SFT, biceps SFT, subscapular SFT, suprailiac SFT, abdominal SFT, MUAC, waist C, and Hip C, except for W/H ratio which showed no significant difference, p > 0.05 and lipid profile: cholesterol, LDL, and TG with (p < 0.001), whereas a highly significant increase in HDL was observed (p < 0.001). The current study revealed a significant difference between group A and group B regarding the percentage of change, where the highest values were found in group B compared to group A, in anthropometric parameters (weight, BMI, subscapular SFT, MUAC, waist circumference) and some lipid profiles (LDL and HDL) with p < 0.05. Laser acupuncture was a safe, easy, and more effective tool with extra effect in management of obesity when added to diet and exercise on anthropometric parameters and lipid profile., (© 2023. The Author(s).)

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., (Copyright © 2022. Published by Elsevier Inc.)

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., (© 2022. The Author(s).)

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., (© 2022. The Author(s).)

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.

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., (© 2021. The Author(s).)

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., (Copyright © 2021. Published by Elsevier B.V.)

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.

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.

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)., Competing Interests: Rebecca Dean, Ivar Jensen, Phil Cyr and Beckley Miller are employees of PRECISIONheor and PRECISIONheor received funding for the analysis from Novartis Gene Therapies. Benit Maru and Thomas Wiesner are employees of SSI Strategy, who were contracted to support Novartis Gene Therapies. Douglas M. Sproule, Douglas E. Feltner are former employees of Novartis Gene Therapies. Omar Dabbous, Matthias Bischof and Walter Toro are employees of Novartis Gene Therapies. Daniel C. Malone is a consultant to Novartis., (© The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

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., Competing Interests: Lisa Belter, Rosángel Cruz, and Jill Jarecki are employees of Cure SMA. Sierra Kulas and Omar Dabbous are employees of Novartis Gene Therapies, a Novartis Company, and own stock in Novartis. Emily McGinnis is a former employee of Novartis and owns stock in Novartis., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

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., Competing Interests: FUF reports personal fees and non-financial support from Novartis Gene Therapies (formerly AveXis, Inc.), outside the submitted work. DM reports personal fees from Novartis Gene Therapies (formerly AveXis, Inc.), outside the submitted work. OD is an employee of Novartis Gene Therapies (formerly AveXis, Inc.), a company which commercialises gene therapies. MP reports grants and personal fees from various pharmaceutical industries, all outside the submitted work. He holds stocks in Ingress Health and Pharmacoeconomics Advice Groningen (PAG Ltd) and is an advisor to Asc Academics, all pharmacoeconomic consultancy companies. SA, KT, CF, AM, and MT are employees of Creativ-Ceutical or were employed by Creativ-Ceutical at the time of the development of the guidelines. Creativ-Ceutical is a consulting company in the field of health economics. All other authors report no conflict of interest., (© 2020 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

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.

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.

The concept of a reference case, first proposed by the US Panel on Cost-Effectiveness in Health and Medicine, has been used to specify the required methodological features of economic evaluations of healthcare interventions. In the case of gene therapy, there is a difference of opinion on whether a specific methodological reference case is required. The aim of this article was to provide a more detailed analysis of the characteristics of gene therapy and the extent to which these characteristics warrant modifications to the methods suggested in general reference cases for economic evaluation. We argue that a completely new reference case is not required, but propose a tailored checklist that can be used by analysts and decision makers to determine which aspects of economic evaluation should be considered further, given the unique nature of gene therapy., (Copyright © 2019 ISPOR–The Professional Society for Health Economics and Outcomes Research. Published by Elsevier Inc. All rights reserved.)

Background : Spinal muscular atrophy type 1 (SMA1) is a devastating genetic disease for which gene-replacement therapy may bring substantial survival and quality of life benefits. Objective : This study investigated the cost-effectiveness of onasemnogene abeparvovec (AVXS-101) gene-replacement therapy for SMA1. Study design : A Markov model was used to estimate the incremental cost-effectiveness ratio (ICER), expressed as cost/quality-adjusted life year ($/QALY), of AVXS-101 versus nusinersen over a lifetime. Survival, healthcare costs and QALYs were estimated using natural history data for SMA patients who achieved motor milestones (sitting/walking). Health utility weights were obtained from the CHERISH trial. Setting : USA; commercial payer perspective Participants : SMA1 infants Interventions : AVXS-101 was compared to nusinersen. Main outcome measure : The primary outcome was the ICER. Results : Expected survival (undiscounted) over a lifetime predicted by the model was 37.20 life years for AVXS-101 and 9.68 for nusinersen (discounted QALYs, 15.65 and 5.29, respectively). Using a potential AVXS-101 price range ($2.5-5.0M/treatment), the average lifetime cost/patient was $4.2-6.6M for AVXS-101 and $6.3M for nusinersen. The ICER range was (-$203,072) to $31,379 per QALY gained for AVXS-101 versus nusinersen, indicating that AVXS-101 was cost-effective with prices of ≤$5M. Conclusion : Single-dose AVXS-101 was cost-effective compared to chronic nusinersen for SMA1 patients.

Introduction: Infants with spinal muscular atrophy (SMA) type 1 typically face a decline in motor function and a severely shortened life expectancy. Clinical trials for SMA type 1 therapies, onasemnogene abeparvovec (AVXS-101) and nusinersen, demonstrated meaningful improvements in efficacy (e.g., overall survival) but there were no head-to-head clinical trials assessing comparative efficacy. This study estimated the treatment effects of AVXS-101 relative to nusinersen for the treatment of SMA type 1., Methods: Overall survival, event-free survival (no death or need to use permanent assisted ventilation), improvement in motor function [increase of ≥ 4 points in Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) score from baseline], and motor milestone achievements (head control, rolling over, and sitting unassisted) reported in the onasemnogene abeparvovec (AVXS-101-CL-101; NCT02122952) and nusinersen (ENDEAR; NCT02193074) clinical trials were indirectly compared using frequentist and Bayesian approaches., Results: Among symptomatic infants with SMA type 1, the number needed to treat (NNT) to prevent one more death with AVXS-101 instead of nusinersen was 6.2 [95% confidence intervals (CI) = 4.1-12.2], and the probability of preventing death was 20% higher for patients treated with AVXS-101 than nusinersen [risk ratio (RR) = 1.2, 95% CI 1.1-1.3]. For event-free survival, the NNT to prevent one more event was 2.6 (95% CI 2.0-3.6) and RR was 1.6 (95% CI 1.4-1.9). For improvement in motor function, NNT was 3.5 (95% CI 2.6-5.3) and RR was 1.4 (95% CI 1.2-1.6). For milestone achievements, the NNTs were 1.4 (95% CI 1.1-1.9), 1.5 (95% CI 1.1-2.5), and 1.2 (95% CI 1.0-1.5); RRs 4.2 (95% CI 2.6-6.7), 7.8 (95% CI 3.6-17.0), and 11.2 (95% CI 5.1-24.5) for head control, rolling over, and sitting unassisted, respectively. Results were similar using the Bayesian approach., Conclusion: This indirect comparison (AVXS-101-CL-101 vs. ENDEAR) among symptomatic SMA type 1 infants suggests that AVXS-101 may have an efficacy advantage relative to nusinersen for overall survival, independence from permanent assisted ventilation, motor function, and motor milestones., Funding: AveXis.

Background: Spinal Muscular Atrophy type 1 (SMA1) is a rare genetic neuromuscular disease where 75% of SMA1 patients die/require permanent-ventilation by 13.6 months. This study assessed the health outcomes of SMA1 infants treated with AVXS-101 gene replacement therapy., Methods: Twelve genetically confirmed SMA1 infants with homozygous deletions of the SMN1 gene and two SMN2 gene copies received a one-time intravenous proposed therapeutic dose of AVXS-101 in an open label study conducted between December 2014 and 2017. Patients were followed for 2-years post-treatment for outcomes including (1) pulmonary interventions; (2) nutritional interventions; (3) swallow function; (4) hospitalization rates; and (5) motor function., Results: All 12 patients completed the study. Seven infants did not require noninvasive ventilation (NIV) by study completion. Eleven patients had stable or improved swallow function, demonstrated by the ability to feed orally; 11 patients were able to speak. The mean proportion of time hospitalized was 4.4%; the mean unadjusted annualized hospitalization rate was 2.1 (range = 0, 7.6), with a mean length of stay/hospitalization of 6.7 (range = 3, 12.1) days. Eleven patients achieved full head control and sitting unassisted and two patients were walking independently., Conclusions: AVXS-101 treatment in SMA1 was associated with reduced pulmonary and nutritional support requirements, improved motor function, and decreased hospitalization rate over the follow-up period. This contrasts with the natural history of progressive respiratory failure and reduced survival. The reduced healthcare utilization could potentially alleviate patient and caregiver burden, suggesting an overall improved quality of life following gene replacement therapy., Trial Registration: ClinicalTrials.gov number, NCT02122952., (© 2018 The Authors. Pediatric Pulmonology Published by Wiley Periodicals, Inc.)

Background: Drug development for disease modifying agents in Alzheimer's disease (AD) is focused increasingly on targeting underlying pathology in very early stages of AD or in cognitively normal patients at elevated risk of developing dementia due to Alzheimer's. Very early interventional studies of this type have many uncertainties, including whether they can provide the clinical results that payers, providers, and patients will wish to see for decisions. This paper describes an initiative to create greater transparency for researchers to anticipate these decision needs., Objective: To create multi-stakeholder-vetted recommendations for the design of studies in later phases of drug development to evaluate the ability of disease modifying agents to delay or prevent the onset of dementia due to Alzheimer's disease (AD)., Design: A multi-stakeholder expert workgroup and overseeing steering group were convened to discuss current advances in early interventional clinical trial design and the evidence needs of patients, providers, and payers. Eight teleconferences and one in-person all-day meeting were held. Meetings were recorded and summary notes prepared between sessions. Final conclusions were consolidated by the project team with the workgroup Chair based on these discussions and were reviewed by group members., Setting: The in-person meeting was held in Baltimore, MD., Participants: In total, 36 stakeholders representing life sciences industry, payers or health technology assessors, patient advocates and research advocacy organizations, regulators, clinical experts and academic or NIH researchers., Intervention: N/A., Measurements: N/A., Results: Certain aspects of clinical trial design were deemed important to address stakeholder decision needs for future Alzheimer's prevention drugs even as the field rapidly progresses. These include the need for more robust behavioral and psychological outcome data in early symptomatic disease and the need to update activities of daily living measures to include "digital independence.", Conclusions: Amyloid, tau, and biomarkers of neurodegeneration should be included in trials and studied in relation to other early measures of change meaningful to individuals with AD, their families, and health plans. These measures include early sensitive changes in behavioral and psychological measures and ability to navigate the contemporary digital landscape. Additional work is needed to generate more robust behavioral and psychological outcome data in early symptomatic disease, and to generate multi-stakeholder consensus on early measures of change and magnitudes of change that will be meaningful to patients, providers, and payers., Competing Interests: All potential conflicts of interest have been reported in the disclosures above.

Background: Advanced therapy medicinal products (ATMPs) are innovative therapies likely associated with high prices. Payers need guidance to create a balance between ensuring patient access to breakthrough therapies and maintaining the financial sustainability of the healthcare system., Objective: The aims of this study were to identify, define, classify and compare the approaches to funding high-cost medicines proposed in the literature, to analyze their appropriateness for ATMP funding and to suggest an optimal funding model for ATMPs., Results: Forty-eight articles suggesting new funding models for innovative high-cost therapies were identified. The models were classified into 3 groups: financial agreement, health outcomes-based agreement and healthcoin. Financial agreement encompassed: discounts, rebates, price and volume caps, price-volume agreements, loans, cost-plus price, intellectual-based payment and fund-based payment. Health outcomes-based agreements were defined as agreements between manufacturers and payers based on drug performance, and were divided into performance-based payment and coverage with evidence development. Healthcoin described a new suggested tradeable currency used to assign monetary value to incremental outcomes., Conclusion: With a large number of ATMPs in development, it is time for stakeholders to start thinking about new pathways and funding strategies for these innovative high-cost therapies. An "ATMP-specific fund" may constitute a reasonable solution to ensure rapid patient access to innovation without threatening the sustainability of the health care system., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objective: To examine the burden of depression on work productivity., Methods: Full-time employees with diagnosed depression were surveyed using the Patient Health Questionnaire for depression severity, and the Health and Work Performance Questionnaire and Work Productivity and Activity Impairment (WPAI) questionnaire for absenteeism and presenteeism., Results: Of the 1051 employees with depression, 40.3% had no depressive symptoms at the time of the survey, 30.4% had mild depression, 15.8% had moderate depression, 7.8% had moderately severe depression, and 5.8% had severe depression. All levels of depression were associated with decreased work productivity. Presenteeism was positively associated with severity of depression (Health and Work Performance Questionnaire, P < 0.0001; WPAI, P < 0.0001). Absenteeism was significantly positively associated with severity of depression using the WPAI., Conclusions: Decreased overall productivity was seen at all levels of depression, and as severity increased, presenteeism and absenteeism worsened.

Objective: To assess the relationship between self-perceived deficits in cognition and severity of depression reported by individuals in full-time employment., Method: Individuals ≥ 18 years of age employed full-time with diagnosed depression excluding bipolar disorder (participants had to be told by a doctor that they had depression based on DSM-IV criteria) completed a 25-minute Web-based survey in February 2010 (study population identified by Harris Interactive, Rochester, New York). The survey used the Perceived Deficits Questionnaire (PDQ) to assess self-perceived cognitive impairment and the 9-item Patient Health Questionnaire (PHQ-9) to assess depression severity. The 20-question PDQ was used to assess self-perceived cognitive difficulties within the domains of prospective memory, retrospective memory, attention/concentration, and planning/organization (range, 0-20: higher scores indicate greater impairment). Subjects answered how often they experienced such difficulties during the previous 4 weeks (0 = never, 1 = rarely, 2 = sometimes, 3 = often, 4 = almost always). The scale ranges from 0-20 for each of the 4 subscales, with higher scores indicating greater cognitive impairment. The impact of depression on PDQ scores was assessed using a trend test based on an analysis of covariance controlling for potential confounders., Results: Subjects (N = 1,051) (58% women) had a mean ± SD age of 47 ± 12 years; 38% held professional employment. PHQ-9 scores indicated that 423 employees (40.3%) had no depressive symptoms at the time of the survey, 319 (30.4%) had mild depression, 166 (15.8%) had moderate depression, 82 (7.8%) had moderately severe depression, and 61 (5.8%) had severe depression. Perceived cognitive functioning worsened with increasing severity of depression symptoms (P < .0001) on the basis of PDQ scores. On the basis of responses to the PDQ, in the current study, most impairment was seen in the attention/concentration and planning/organization subscales in severely depressed subjects (12.2 for both) compared with those with no depressive symptoms (4.4 and 3.5, respectively), indicating more cognitive impairment in the severely depressed subjects compared to the subjects with no depression., Conclusions: In currently employed individuals, self-perceived cognitive dysfunction worsened with increasing severity of depressive symptoms. This association was independent of antidepressant use. The greatest impairment in self-perceived cognition was observed in the planning/organization and attention/concentration subscales.

The objective of this study was to assess the utility of hyperuricemia as a marker for diabetes and prediabetes (impaired fasting glucose) and insulin resistance in young adults. Using Cox proportional hazards regression models, the authors analyzed 15-year follow-up data on 5,012 persons in 4 US cities who were aged 18-30 years and diabetes-free at the time of enrollment. At baseline (1986), 88% of participants had a body mass index (weight (kg)/height (m)(2)) less than 30. During the follow-up period (through 2001), the incidence rates of diabetes and prediabetes (insulin resistance and impaired fasting glucose) were higher among persons with greater serum urate concentrations. In multivariable Cox regression analyses that adjusted for age, gender, race, body mass index, family history of diabetes, diastolic blood pressure, total cholesterol, smoking, and alcohol use, the hazard ratios for diabetes, insulin resistance, and prediabetes among persons with hyperuricemia (serum urate level >7 mg/dL vs. ≤7.0 mg/dL) were 1.87 (95% confidence interval (CI): 1.33, 2.62), 1.36 (95% CI: 1.23, 1.51), and 1.25 (95% CI: 1.04, 1.52), respectively. This observation was generally consistent across subgroups. The authors conclude that hyperuricemia in the midtwenties is an independent marker for predicting diabetes and prediabetes among young adults in the subsequent 15 years.

Few studies have investigated the association between hyperuricemia and subclinical myocardial dysfunction. The authors analyzed the relationship between serum uric acid and subclinical markers of heart failure in participants in the Framingham Offspring Cohort (N=2169, mean age 57.3 years, 55.4% women). Cardiac dysfunction was assessed through echocardiographic measurements of left ventricular (LV) mass and thickness, end-diastolic LV thickness, and LV fractional shortening at the sixth visit, approximately 24 years after study onset. Participants in the highest serum uric acid quartile (≥ 6.2 mg/dL serum uric acid) had a significantly greater frequency of echocardiographic abnormalities compared with those in the lowest quartile (<4.3 mg/dL). Those in the highest quartile had multivariable-adjusted odds ratios of 9.013 (95% confidence interval, 2.051-39.604) for abnormal LV ejection fraction and 4.584 (95% confidence interval, 1.951-10.768) for LV systolic dysfunction compared with those in the lowest quartile. Hyperuricemia in young adults can be a marker for subsequent heart failure., (© 2011 Wiley Periodicals, Inc.)

Introduction: Patients with a history of myocardial infarction (MI) are often at risk for complications, including subsequent MI and death. Use of prognostic markers may aid in preventing these poor outcomes. Hyperuricemia is associated with increased risk for coronary heart disease (CHD) and/or mortality; however, it is unknown if serum urate (sUA) levels predict outcomes in patients with previous MI. The purpose of this study was to assess hyperuricemia as a biomarker of CHD outcomes in such patients., Methods: These were post hoc analyses of datasets from the Aspirin Myocardial Infarction Study, a 1:1 randomized, double-blind clinical trial, conducted from 1975 to 1979, that examined mortality rates following daily aspirin administration over three years in individuals with documented MI. The primary outcome measures were all-cause death, CHD mortality, coronary incidence, and stroke by quartile of baseline sUA. A sub-analysis of all outcome measures in the presence or absence of gouty arthritis was also performed., Results: Of 4,524 enrolled participants, data on 4,352 were analyzed here. All outcomes were greatest for patients in the fourth sUA quartile. In multivariate regression models, the hazard ratios (HR) for patients in the highest quartile were 1.88 for all-cause mortality (95% confidence interval (CI), 1.45 to 2.46), 1.99 for CHD mortality (95% CI, 1.49 to 2.66), and 1.36 for coronary incidence (95% CI, 1.08 to 1.70). Participants with untreated gout had an adjusted hazard ratio ranging from 1.5 to 2.0 (all P < 0.01) for these outcomes. Participants with gout who were receiving treatment did not exhibit this additional risk., Conclusions: sUA and untreated gout may be independent prognostic markers for poor all-cause and CHD mortality in patients with recent acute MI.

Background: There has been limited research addressing the effects of constipation on work productivity and healthcare resource use., Aims: To assess the effect of chronic constipation on health outcomes and healthcare resource use., Methods: Using data from the 2007 National Health and Wellness Survey (NHWS), chronic constipation patients (n = 1,430) were propensity score-matched to controls (n = 1,430) on demographic and clinical characteristics. Differences between groups in health-related quality of life (SF-12v2), work productivity and activity impairment, and resource use in the last 6 months were examined. Mediation analyses were conducted in order to determine whether the relationship between constipation and resource use was caused by a reduction in health status., Results: Chronic constipation patients reported significantly lower levels of health-related quality of life (physical component summary score: 39.57 vs. 43.73; mental component summary score: 43.19 vs. 47.86, all P-values < 0.01) and significantly higher levels of loss of work productivity and activity impairment (absenteeism: 9.08% vs. 5.20%; presenteeism: 29.52% vs. 19.09%; overall work impairment: 33.65% vs. 21.56%; activity impairment: 46.58% vs. 33.90%, all P-values < 0.01) compared to the matched controls. Chronic constipation patients also reported significantly more provider (7.73 vs. 5.63) and emergency room visits (0.52 vs. 0.30) in the past 6 months (all P-values < 0.01). Mediation analyses suggested that increased resource use among chronic constipation patients were partially a result of reduced health status., Conclusions: Compared to matched controls, chronic constipation patients reported greater economic and humanistic burden. Alleviating the humanistic burden associated with constipation may have economic benefits.

Background: To study the prevalence of chronic kidney disease (CKD) and its impact on allopurinol dosing and uric acid control among patients with gout., Methods: This was a retrospective study using data from a large US health plan. Claims and laboratory data were analyzed for enrollees from the health plan database from January 2002 through December 2005. Patients with gout were identified from pharmacy and medical claims data based on the presence of codes for gout medication or gout diagnosis. Severity of CKD was determined using the estimated glomerular filtration rate (eGFR). Allopurinol titration was defined as a change in average daily dose from first prescription to last prescription of ≥ 50 mg., Results: A total of 3,929 patients were identified for inclusion in this study, 39% of whom had CKD (based on having an eGFR < 90 mL/min/1.73 m2). Subjects with CKD were older (p < 0.01) and more likely to be women (p < 0.01), had a greater number of comorbid conditions (p < 0.01), and were more likely to be prescribed allopurinol (p < 0.01) compared to those with no CKD. The average starting dose of allopurinol was lower among those with CKD, and it decreased with worsening kidney function. Among the 3,122 gout patients who used allopurinol, only 25.6% without CKD and 22.2% with CKD achieved a serum uric acid concentration of < 6.0 mg/dL (p = 0.0409). Also, only 15% of allopurinol users had an upward dose titration (by ≥50 mg), but the average increase in dose did not differ significantly between those with and without CKD., Conclusions: About two out of every five patients with gout in this population had CKD. Allopurinol doses were not adjusted in the majority of CKD patients. Serum uric acid control in gout was poor among patients without CKD and even worse among those with CKD.

Objective: To summarize the endorsement of measures of patient-reported outcome (PRO) domains in chronic gout at the 2010 Outcome Measures in Rheumatology Meeting (OMERACT 10)., Methods: During the OMERACT 10 gout workshop, validation data were presented for key PRO domains including pain [pain by visual analog scale (VAS)], patient global (patient global VAS), activity limitation [Health Assessment Questionnaire-Disability Index (HAQ-DI)], and a disease-specific measure, the Gout Assessment Questionnaire version 2.0 (GAQ v2.0). Data were presented on all 3 aspects of the OMERACT filters of truth, discrimination, and feasibility. One PRO, health-related quality of life measurement with the Medical Outcomes Study Short-form 36 (SF-36), was previously endorsed at OMERACT 9., Results: One measure for each of the 3 PRO of pain, patient global, and activity limitation was endorsed by > 70% of the OMERACT delegates to have appropriate validation data. Specifically, pain measurement by VAS was endorsed by 85%, patient global assessment by VAS by 73%, and activity limitation by HAQ-DI by 71%. GAQ v2.0 received 30% vote and was not endorsed due to several concerns including low internal consistency and lack of familiarity with the measure. More validation studies are needed for this measure., Conclusion: With the endorsement of one measure each for pain, patient global, SF-36, and activity limitation, all 4 PRO for chronic gout have been endorsed. Future validation studies are needed for the disease-specific measure, GAQ v2.0. Validation for PRO for acute gout will be the focus of the next validation exercise for the OMERACT gout group.

Objectives: The Pediatric Gastroesophageal Reflux Disease Symptom and Quality of Life Questionnaire (PGSQ) represents 2 related age-stratified tools developed to assess pediatric gastroesophageal reflux disease (GERD). These include the PGSQ-Cp (for children ages 2 to 8 years, parent/caregiver report) and the PGSQ-A (for adolescents ages 9-17 years). The objective of the present study was to develop and evaluate PGSQ measurement properties., Materials and Methods: The PGSQ items were generated based on information from focus groups, expert clinician review, and cognitive debriefing interviews. The symptoms of pediatric GERD and the effect of these symptoms were addressed. The tools were evaluated in a 3-week psychometric evaluation with participants from 11 clinical sites in the United States. The study included other measures such as the Pediatric Quality of Life questionnaire (PedsQL) and clinician-rated GERD severity. After item reduction, internal consistency, reproducibility, construct validity, known-group validity, and responsiveness were assessed., Results: The 231 participants included 75 parents of children ages 2 to 8 years and 75 children ages 9 to 17 years with GERD and 41 parents of children and 40 children ages 9 to 17 years without GERD. Exploratory factor analysis demonstrated 4 symptom subscales for the PGSQ-Cp and 3 symptom subscales for the PGSQ-A. Both had subscales for total impact and school impact. High to moderate internal consistency was observed, ranging from 0.76 to 0.96 for the PGSQ-Cp and from 0.67 to 0.94 for the PGSQ-A. The PGSQ significantly differentiated between patients with GERD and controls (P < 0.0001, PGSQ-Cp; P < 0.0022-0.0001, PGSQ-A) and demonstrated responsiveness., Conclusions: These results support the reliability, validity, and responsiveness of both versions of the PGSQ. The instruments should be useful for clinical studies.

Introduction: Our purpose was to test the hypothesis that hyperuricemia is associated with coronary artery calcification (CAC) among a relatively healthy population, and that the extent of calcification is directly proportional to the serum uric acid (sUA) concentration., Methods: Data from 2,498 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were analyzed using logistic regression models. Subjects were free of clinical heart disease, diabetes, and renal impairment. The main measure was the presence of any CAC by computerized tomography (Agatston score >0)., Results: Forty-eight percent of the study participants were male and 45% were African-American. Mean (± SD) age was 40 ± 4 years, body mass index 28 ± 6 kg/m2, Framingham risk score -0.7 ± 5%, blood pressure 113 ± 14/75 ± 11 mmHg, alcohol consumption 12 ± 27 ml/day, and sUA 297 ± 89 μmol/L (5.0 ± 1.5 mg/dL). Prevalence of CAC increased with sUA concentration among both men and women. Adjusted for age, gender, race, lipoproteins, triglycerides, smoking, blood pressure, presence of metabolic syndrome, C-reactive protein, waist circumference, alcohol use, creatinine, and serum albumin, the highest quartile of sUA (>393 μmol/L [6.6 mg/dL] for men and >274 μmol/L [4.6 mg/dL] for women) was associated with an odds ratio of 1.87 (1.19-2.93) compared to the lowest quartile (<291 μmol/L [4.9 mg/dL] for men and <196 μmol/L [3.3 mg/dL] for women). Among those with any CAC, each unit increase in sUA was associated with a 22% increase in Agatston score (P = 0.008) after adjusting for the above covariates., Conclusions: Hyperuricemia is an independent risk factor for subclinical atherosclerosis in young adults.

Objective: Allopurinol is used to lower serum uric acid (sUA) levels in gout patients. The objective of this study was to investigate the influence of physician specialty on allopurinol treatment patterns and sUA control., Design and Methods: This was a retrospective study using claims from a managed care database of US health plan enrollees. Gout patients at least 18 years of age who received allopurinol were identified from the database between January 1, 2002 and April 30, 2007. The index date was defined as the date of the earliest allopurinol claim, and patients were required to have health plan enrollment for at least 365 days prior to and following the index date for inclusion. Physician specialty was determined using the index allopurinol claim. Dosage of allopurinol prescription(s) and number of gout flares were determined from claims data. sUA measurements were used to assess goal attainment over a period of at least one year following the index allopurinol prescription., Results: There were 3363 patients with gout of whom 69.9% received an index allopurinol prescription from a generalist/internist, 5.7% from a rheumatologist, 2.6% from a nephrologist, and 21.8% from a physician with other specialty. Of patients receiving their index prescription from a nephrologist, 38.7% reached the sUA goal of <6 mg/dL (357 μmol/L), as compared to patients prescribed by a rheumatologist, generalist/internist, or other physician (35.4%, 31.4%, and 39.4%, respectively; P = 0.015). When controlling for patient characteristics, multivariate analysis did not reveal statistically significant different odds of sUA goal attainment based on prescribing physician specialty, though separate analyses indicated that patients prescribed by a nephrologist had fewer gout flares. Change in allopurinol dosage from initial to final dose was more frequent among patients prescribed by rheumatologists and nephrologists., Conclusion: There is significant heterogeneity in the specialists' management of sUA levels in patients with gout, possibly reflecting differences in case mix and treatment approaches. Limitations related to the use of claims data, such as inability to observe medications filled over-the-counter, should be considered when interpreting study results.

Background: Current questionnaires for assessing gastro-oesophageal reflux disease (GERD) symptoms are limited in their ability to capture nocturnal symptoms., Aim: To develop and validate an instrument, the Nocturnal Gastro-oesophageal Reflux Disease Symptom Severity and Impact Questionnaire (N-GSSIQ), to assess severity and impact of nocturnal GERD symptoms., Methods: Two focus groups and 16 cognitive debriefing interviews were conducted among GERD patients to identify key issues about nocturnal symptoms. A draft instrument was tested in 196 patients at 11 clinics in the US to evaluate psychometric properties. Exploratory factor and item response theory analyses were conducted to finalize items and subscales. Internal consistency reliability, reproducibility and construct validity were examined., Results: Mean age was 45 (s.d. = 13.8) years; 76% were female and 68% were Caucasian. Patient-rated severity was mild-moderate for 69% of participants; 48% reported symptoms on two to three nights the past week. The final questionnaire includes 20 items and three subscales: Nocturnal GERD Symptoms, Morning Impact of Nocturnal GERD and Concern about Nocturnal GERD. The subscales demonstrated internal consistency reliability (Cronbach's alpha 0.84-0.94) and were significantly correlated with similar measures and disease severity (0.41-0.81; P < 0.0001)., Conclusion: The results support the reliability and validity of the N-GSSIQ as a measure of severity, morning impact and concern about nocturnal GERD.

Purpose: Patient flow between primary care physicians and gastroenterologists in the continuum of gastroesophageal reflux disease (GERD) care is poorly understood. Using administrative claims data from a large US health plan linked with data abstracted from medical records, we examined: health care resource utilization for GERD subjects treated by primary care physicians (PCPs) and gastroenterologists (GEs), determinants of GERD subject transfer between these physician types, and reasons for GERD therapy change., Results: Within a sample of 169,884 patients, 211,043 PCP-based episodes of care and 40,304 GE-based episodes of care were developed. In unadjusted comparisons, GE episodes were characterized by more endoscopic procedures, on average (50.5/100 episodes), compared with PCP episodes (6.3/100, P < 0.001). Multivariate analysis showed that patients with esophagitis had 57.3% higher odds (P < 0.01) of transfer from PCP to GE compared with patients without esophagitis; patients with esophageal stricture had 98.6% higher odds (P < 0.01) of PCP-GE transfer. Patients with endoscopy during a first GE episode had 32.2% higher odds of transfer to a PCP (P < 0.01). The principal reasons for change in GERD therapy were no change or worsening of symptoms (51.7% of PCP charts; 9.5% of GE charts) and lack of response to therapy (51.7% of PCP charts, 26.2% of GE charts)., Conclusion: Resource utilization varies greatly based on the physician's specialty. We infer that timely transfer of GERD patients to gastroenterologists when empiric treatment is insufficient may lead to more efficient clinical management.

Objective: This study was designed to investigate the incidence, prevalence, treatment patterns, disease severity, and direct costs associated with ulcerative colitis (UC) for claimants in health plans offered by a large self-insured employer in the United States., Methods: Retrospective analysis of medical claims with and without UC identified from a population of approximately 500,000 employees, retirees, and dependents., Results: Costs for UC claimants were more than twice those for the comparator group ($14,486 vs $6158; P < 0.005). Total health care costs for the severe disease cohort were double those of the mild or moderate cohorts ($26,875 vs $12,154 and $12,731), as were inpatient costs ($13,516 vs $3235 and $2244). The annual incremental cost of treating severe disease was $6812 (P < 0.005) compared with mild UC., Conclusion: UC is a significant predictor of increased medical costs with severe disease, driven mainly by inpatient costs.

Background: Ulcerative colitis (UC) is a chronic inflammatory disease with peak incidence in the third decade of life and a second peak in the sixth or seventh decade. While drug therapy can be used to control the inflammation and reduce symptoms, patients with UC may be treated surgically. There is little information in the published literature evaluating the all-cause health care costs of patients with UC according to age., Objective: To assess from administrative claims the direct all-cause (not disease-related) costs of care and resource utilization for patients with UC compared with members without UC by 3 age categories., Methods: A retrospective analysis was conducted using the PharMetrics database of patients with a diagnosis of UC (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 556.x) from January 1, 2000, through June 30, 2005. This database contains enrollment data and pharmacy and medical claims from more than 85 different managed care organizations and more than 55 million patients in the United States. Patients had to be continuously enrolled for 6 months before and 12 months after the initial UC diagnosis and have at least 2 distinct claims with a diagnosis code for UC. The mean per-patient health care resource utilization and costs were calculated for patients in the year following their initial UC diagnosis and compared with the same measures for a group of age- and gender-matched members (without UC claims) at a ratio of 4:1. Three age groups were analyzed: pediatric-adolescent (aged < 18 years), adults (aged 18 to 64 years), and older adults (aged e 65 years). Differences in the measures of all-cause health care resource utilization (claims and costs) between the UC and non-UC groups were tested for statistical significance using the Wilcoxon signed-rank test, a non-parametric alternative to the paired t test. Differences between the 3 age cohorts were tested using the Mann-Whitney U test., Results: Data were collected for 15,105 patients with UC and for 59,159 members in the comparator cohort without UC matched by age and gender. The average age for both cohorts was 44 years, and 54% were female. Mean ([SD], median) annual all-cause total health care costs in 2005 dollars for patients with UC were $13,233 ([$40,715], $5,190) versus $3,214 ([$12,741], $753) for the comparator group (P < 0.001). For all UC patients, all-cause inpatient hospitalization costs constituted the largest component ($5,771, 43.6%) of the mean annual total costs, followed by prescription medications ($2,423, 18.3%); miscellaneous services, such as hospice, psychiatric facility, and nursing home care ($2,092, 15.8%); outpatient hospital visits ($1,310, 9.9%); physician office visits ($899, 6.8%); laboratory procedures ($470, 3.6%); and emergency department visits ($268, 2.0%). Resource utilization (e.g., physician visits, laboratory claims, pharmacy claims) was highest for older adults aged e 65 years, followed by pediatricadolescent patients and adults aged 18 to 64 years (all comparisons P < 0.01). The mean ([SD], median) all-cause total health care costs were highest for pediatric-adolescent patients with UC (n = 589, 3.9%) at $23,113 ([$70,999], $6,214), followed by older adults (n = 650, 4.3%) at $15,811 ([$23,882], $6,886, P < 0.001), while adults aged 18 to 64 years (n = 13,866, 91.8%) incurred the lowest cost at $12,693 ([$39,505], $5,108, P < 0.001)., Conclusion: Patients with UC identified from medical claims incurred significantly higher all-cause health care costs for all 3 age categories than did the comparator group of health plan members without diagnosis for UC.

Background: Natural disasters, war, and terrorist attacks, have been linked to cardiac mortality. We sought to investigate whether a major financial crisis may impact on the medical management and outcomes of acute coronary syndromes., Methods: We analyzed the Argentine cohort of the international multicenter Global Registry of Acute Coronary Events (GRACE). The primary objective was to estimate if there was an association between the financial crisis period (April 1999 to December 2002) and in- hospital cardiovascular mortality, with the post-crisis period (January 2003 to September 2004) as the referent. Each period was defined according to the evolution of the Gross Domestic Product. We investigated the demographic characteristics, diagnostic and therapeutic procedures, morbidity and mortality., Results: We analyzed data from 3220 patients, 2246 (69.8%) patients in the crisis period and 974 (30.2%) in the post-crisis frame. The distribution of demographic and clinical baseline characteristics were not significantly different between both periods. During the crisis period the incidence of in-hospital myocardial infarction was higher (6.9% Vs 2.9%; p value < 0.0001), as well as congestive heart failure (16% Vs 11%; p value < 0.0001). Time to intervention with angioplasty was longer during the crisis, especially among public sites (median 190 min Vs 27 min). The incidence proportion of mortality during hospitalization was 6.2% Vs 5.1% after crisis. The crude OR for mortality was 1.2 (95% C.I. 0.87, 1.7). The odds for mortality were higher among private institutions {1.9 (95% C.I. 0.9, 3.8)} than for public centers {1.2 (95% C.I. 0.83, 1.79)}. We did not observe a significant interaction between type of hospital and crisis., Conclusion: Our findings suggest that the financial crisis may have had a negative impact on cardiovascular mortality during hospitalization, and higher incidence of medical complications.

Relatively limited data are available, particularly from the perspective of a multinational registry, about the post-discharge outcomes and management practices of patients with an acute coronary syndrome (ACS). The objectives of this longitudinal study were to examine 6-month outcomes in a large multinational sample of patients hospitalized with an ACS. A total of 5,476 patients with ST-segment elevation acute myocardial infarction (STEAMI), 5,209 patients with non-ST-segment elevation acute myocardial infarction (NSTEAMI), and 6,149 patients with unstable angina pectoris discharged from 90 hospitals in 14 countries comprised the study population. The study sample was recruited from 18 cluster sites in 14 countries that are currently collaborating in the Global Registry of Acute Coronary Events (GRACE) study. The 6-month post-discharge death rates were 4.8% in patients with STEAMI, 6.2% in patients with NSTEAMI, and 3.6% in patients with unstable angina pectoris. Approximately 1 in 5 of each of our comparison groups were rehospitalized for heart disease during the 6-month follow-up, and approximately 15% of each of the respective study cohorts underwent coronary revascularization during follow-up. Demographic and clinical characteristics of post-discharge decedents were identified according to type of ACS. Our results suggest that a considerable proportion of patients who were discharged from the hospital after an ACS, with some differences noted according to type of ACS, remain at increased risk for adverse outcomes during the relatively brief post-discharge period. These data suggest the need for better long-term medical management and more intense follow-up of patients with an ACS to improve their long-term outlook.

Background: Management of acute coronary syndromes (ACS) should be guided by an estimate of patient risk., Objective: To develop a simple model to assess the risk for in-hospital mortality for the entire spectrum of ACS treated in general clinical practice., Methods: A multivariable logistic regression model was developed using 11 389 patients (including 509 in-hospital deaths) with ACS with and without ST-segment elevation enrolled in the Global Registry of Acute Coronary Events (GRACE) from April 1, 1999, through March 31, 2001. Validation data sets included a subsequent cohort of 3972 patients enrolled in GRACE and 12 142 in the Global Use of Strategies to Open Occluded Coronary Arteries IIb (GUSTO-IIb) trial., Results: The following 8 independent risk factors accounted for 89.9% of the prognostic information: age (odds ratio [OR], 1.7 per 10 years), Killip class (OR, 2.0 per class), systolic blood pressure (OR, 1.4 per 20-mm Hg decrease), ST-segment deviation (OR, 2.4), cardiac arrest during presentation (OR, 4.3), serum creatinine level (OR, 1.2 per 1-mg/dL [88.4- micro mol/L] increase), positive initial cardiac enzyme findings (OR, 1.6), and heart rate (OR, 1.3 per 30-beat/min increase). The discrimination ability of the simplified model was excellent with c statistics of 0.83 in the derived database, 0.84 in the confirmation GRACE data set, and 0.79 in the GUSTO-IIb database., Conclusions: Across the entire spectrum of ACS and in general clinical practice, this model provides excellent ability to assess the risk for death and can be used as a simple nomogram to estimate risk in individual patients.

Objectives: This study was designed to evaluate the ability of microvolt-level T-wave alternans (MTWA) to identify prospectively patients with idiopathic dilated cardiomyopathy (DCM) at risk of ventricular tachyarrhythmic events and to compare its predictive accuracy with that of conventional risk stratifiers., Background: Patients with DCM are at increased risk of sudden death from ventricular tachyarrhythmias. At present, there are no established methods of assessing this risk., Methods: A total of 137 patients with DCM underwent risk stratification through assessment of MTWA, left ventricular ejection fraction, baroreflex sensitivity (BRS), heart rate variability, presence of nonsustained ventricular tachycardia (VT), signal-averaged electrocardiogram, and presence of intraventricular conduction defect. The study end point was either sudden death, resuscitated ventricular fibrillation, or documented hemodynamically unstable VT., Results: During an average follow-up of 14 +/- 6 months, MTWA and BRS were significant univariate predictors of ventricular tachyarrhythmic events (p < 0.035 and p < 0.015, respectively). Multivariate Cox regression analysis revealed that only MTWA was a significant predictor., Conclusions: Microvolt-level T-wave alternans is a powerful independent predictor of ventricular tachyarrhythmic events in patients with DCM.

Aims: Despite advances in the treatment of acute coronary syndromes based on randomized trial data and published guidelines, the extent to which such treatments are applied in practice remains uncertain. Data from clinical trials derive from selected geographical areas and in highly selected populations of patients, and hence may not reflect the overall population. The aim of the study was to investigate variations in hospital management and outcome using unselected data collected in the prospective Global Registry of Acute Coronary Events (GRACE)., Methods and Results: The 95 hospitals in GRACE were organized into 18 population-based clusters in 14 countries. Information was recorded about patient management and outcome during hospitalization and after discharge. Data on treatments administered were analysed by baseline condition, hospital type, by the presence or absence of a catheterization laboratory, and by geographical region. Of 11543 patients, 44% had an admission diagnosis of unstable angina, 36% presented with myocardial infarction, 9% were admitted to rule out a myocardial infarction, 7% had chest pain and 4% were hospitalized for 'other cardiac' and 'non-cardiac' diagnoses. Of the total GRACE population 38% had a final diagnosis of unstable angina, 30% ST-segment elevation myocardial infarction, 25% non-ST-segment elevation myocardial infarction, and 7% of 'other cardiac' and 'non-cardiac' final diagnoses. The event rates for hospital death or reinfarction were six and 2% for non-ST-segment elevation myocardial infarction, seven and 3% for ST-segment elevation myocardial infarction, and 3% hospital death for unstable angina. The use of aspirin was similar across all hospital types and geographical regions. In contrast, the use of percutaneous coronary intervention and glycoprotein IIb/IIIa inhibitors was higher (P<0.0001) in teaching hospitals and hospitals with catheterization laboratories and was also higher in the United States. At discharge a higher percentage (P<0.0001) of patients received angiotensin-converting enzyme inhibitors in hospitals without catheterization laboratories. The use of statins was lower in non-teaching hospitals and in centres without a catheterization laboratory., Conclusions: The GRACE study reveals substantial differences in the management of patients based on hospital type and geographical location. Further analyses will determine whether such variations translate into differences in longer term outcomes. GRACE provides a multinational reference for the implementation of therapies of proven efficacy., (Copyright 2002 The European Society of Cardiology. Published by Elsevier Science Ltd. All rights reserved.)