Social difficulties and care burden of adult Duchenne muscular dystrophy in Japan: a questionnaire survey based on the Japanese Registry of Muscular Dystrophy (Remudy).

BACKGROUND: Little is known about the social difficulties and health care needs of adult Duchenne muscular dystrophy (DMD) patients in Japan, as well as the financial and physical stress experienced by their caregivers. This study aimed to clarify the social circumstances surrounding adult DMD patients and assess the degree of involvement of family members in their care and the associated economic burden of the disorder in Japan. METHODS: Adult DMD patients were identified through the Registry of Muscular Dystrophy (Remudy) in Japan and invited to complete a questionnaire together with a caregiver. Data on health care use, quality of life, work status, informal care, and household expenses were collected to estimate the costs associated with DMD from social and caregiver household perspectives. RESULTS: In total, 234 (63.7%) of 367 adult DMD patients (mean age, 27.4 ± 6.0; range, 20-48 years) completed the questionnaire. Of these, 38 (21%) had developmental disorders (mental retardation, autism, and learning disorders), 57 (33%) experienced bullying in school, and 44 (77%) indicated the reason for bullying to be their physical handicap. Employment histories were noted by 72 (31%), although 23 (10%) lost their jobs mainly due to physical difficulties. Of the 234 patients, 164 (74%) lived with their relatives, and 78% of care time was supplied by family members, in particular, their mothers. The mean rate of care work provided by family members was 81%. Household income of families with an adult DMD patient was lower, whereas the rate of living with parent(s) and grandparent(s) was higher, in comparison with the general Japanese population. CONCLUSIONS: Adult DMD patients in Japan experience many social difficulties from childhood up to adulthood. As adults, many DMD patients experience bullying and workplace difficulties. Families were found to provide most of the care and financial support for DMD patients. Our results suggest the need to improve public patient care systems, including financial support, to address the physical and economic burdens of care for adult DMD patients in Japan.

Spending on Targeted Therapies for Duchenne Muscular Dystrophy.

This study estimates public and private spending on genetically targeted treatments for Duchenne muscular dystrophy during years in which the drugs were marketed without completed confirmatory studies.

Characterizing demographics, comorbidities, and costs of care among populations with Duchenne muscular dystrophy with Medicaid and commercial coverage.

BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe X-linked progressive neurodegenerative disease characterized by loss of ambulation, cardiomyopathy, respiratory insufficiency, and early mortality. Few data are available that describe the direct medical costs among patients with DMD in the United States. OBJECTIVE: To characterize the demographics, comorbidity burden, and direct monthly costs of care among patients with DMD with Medicaid and with commercial insurance coverage. METHODS: IBM MarketScan Commercial and Multi-State Medicaid claims (2013-2018) were used to identify males aged 30 years or under with diagnostic codes for muscular dystrophy or DMD; additional exclusion criteria were applied to identify those with probable DMD. Baseline characteristics and comorbidities were tabulated. The frequency of health care resource use and median (interquartile range [IQR]) monthly costs (in 2018 USD) were estimated from those with at least 12 months of continuous follow-up. RESULTS: Median (IQR) baseline ages were similar between the Medicaid (14 [9-20] years; n = 2,007) and commercial (15 [9-21] years; n = 1,964) DMD cohorts. The frequency of comorbidities over the period was slightly higher with those on Medicaid. The median duration of follow-up was 3.1 years among members of the Medicaid DMD cohort and 1.7 years among the commercial DMD cohort. Median monthly resource use was generally higher among the Medicaid DMD cohort; nonetheless, median (IQR) monthly costs were similar at $1,735 ($367-$5,281) for the Medicaid DMD cohort vs $1,883 ($657-$6,796) for the commercial DMD cohort. CONCLUSIONS: The demographic characteristics and median direct medical costs were similar between patients with commercial vs Medicaid coverage, even though patients with Medicaid coverage had higher resource use. Despite challenges in definitively identifying DMD patients using claims data, these findings help characterize contemporary DMD populations in the United States and the related direct economic burden to the payer. DISCLOSURES: This study was funded by Sarepta Therapeutics, Inc. Klimchak and Gooch are employees of Sarepta Therapeutics Inc. Szabo, Qian, and Popoff are employees of Broadstreet HEOR, which received funds from Sarepta Therapeutics, Inc., for work on this study. Iannaccone has received research funding or consulting fees from Avexis, Biogen, Fibrogen, Mallinkrodt, Regeneron, Sarepta Therapeutics, Inc., Scholar Rock, PTC Therapeutics, Pfizer, MDA, CureSMA, NIH, Genentech-Roche, and BCBS. Publication of the study results was not contingent on the sponsor's approval or censorship of the manuscript. Information from this study was presented, in part, at the AMCP Virtual Annual Meeting, April 21-24, 2020.

Rasch Analysis of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales Administered to Patients With Duchenne Muscular Dystrophy.

OBJECTIVES: The objective of this study was to examine the psychometric properties of the Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL 4.0 GCS) in Duchenne muscular dystrophy (DMD), a rare, severely debilitating, and ultimately fatal neuromuscular disease. METHODS: Patients with DMD were recruited from 20 centers across 9 countries as part of the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (NCT00468832). The psychometric properties of the PedsQL 4.0 GCS were examined using Rasch analysis. RESULTS: In total, 329 patients with DMD (mean age 9 years, range 3-18 years, 75% ambulatory) completed the PedsQL 4.0 GCS. The most difficult instrument items, expressing the greatest loss in health-related quality of life, were those associated with emotional well-being (eg, being teased by other children, feeling sad, and not making friends), as opposed to somatic disability (eg, lifting heavy objects, participating in sports, and running). The mean item and person fit residuals were estimated at 0.301 (SD: 1.385) and -0.255 (1.504), respectively. In total, 87% (20 of 23) of items displayed disordered thresholds, and many exhibited nontrivial dependency. The overall item-trait interaction χ2 value was 178 (115 degrees of freedom, P<.001). Our analysis also revealed significant issues with differential item functioning, and by investigating residual principal component loadings, the PedsQL 4.0 GCS total score was found to be multidimensional. CONCLUSIONS: The PedsQL 4.0 GCS records information clinically relevant to patients with DMD, but the total scale score may not be fit for purpose as a measure health-related quality of life in this disease population.

Quantifying the economic impact of caregiving for Duchenne muscular dystrophy (DMD) in Spain.

AIM: To establish the potential economic burden in caregivers to patients with DMD and the potential causative factors. METHOD: Caregivers to patients with DMD were recruited through the DMD patients Register and questioned about several economic aspects using "ad-hoc" questionnaires. RESULTS: All families, apart from one (97.2% n = 36), incurred in monthly medical costs (44% of the families more than 50 euros/month). 97.2% of the households considered looking after a patient of DMD as financially burdensome, and 80.5% of households declared to have suffered work changes, especially the mothers (job timetable-related mainly). The presence of obsessive-compulsive disorders (OCD) in patients was significantly associated with caregivers' high financial burden as these were six times more likely to have this perception OR = 6468 IC 95% (1056-39,601), p = 0.043. Also, when patients had learning difficulties, caregivers had up to six times more chances to incur in monthly expenditure for formal care OR = 6089 IC 95% (1112-33,342), p = 0.037. INTERPRETATION: Caregivers have relevant financial burden that might be conditioned by the clinical condition of the patient. WHAT THIS PAPER ADDS: Quantitative data about financial burden in DMD Spanish families providing informal care. Identification of the patient's main clinical issues associated with financial burden.

The Effectiveness and Value of Deflazacort and Exon-Skipping Therapies for the Management of Duchenne Muscular Dystrophy.

DISCLOSURES: Funding for this summary was contributed by Arnold Ventures, Commonwealth Fund, California Health Care Foundation, National Institute for Health Care Management (NIHCM), New England States Consortium Systems Organization, Blue Cross Blue Shield of Massachusetts, Harvard Pilgrim Health Care, Kaiser Foundation Health Plan, and Partners HealthCare to the Institute for Clinical and Economic Review (ICER), an independent organization that evaluates the evidence on the value of health care interventions. ICER's annual policy summit is supported by dues from Aetna, America's Health Insurance Plans, Anthem, Allergan, Alnylam, AstraZeneca, Biogen, Blue Shield of CA, Cambia Health Services, CVS, Editas, Express Scripts, Genentech/Roche, GlaxoSmithKline, Harvard Pilgrim, Health Care Service Corporation, Health Partners, Johnson & Johnson (Janssen), Kaiser Permanente, LEO Pharma, Mallinckrodt, Merck, Novartis, National Pharmaceutical Council, Premera, Prime Therapeutics, Regeneron, Sanofi, Spark Therapeutics, and United Healthcare. Agboola, Fluetsch, Rind, and Pearson are employed by ICER. Lin reports support from ICER during work on this economic model and grants from Mount Zion Health Fund, National Institutes of Health (National Cancer Institute and National Heart, Lung, and Blood Institute), and the Tobacco-Related Diseases Research Program, unrelated to this work. Walton reports support from ICER for work on this economic model and unrelated consulting fees from Baxter.

Evaluating a Stone of Hope: ICER's 2019 Review of Treatments for Duchenne Muscular Dystrophy.

DISCLOSURES: No funding contributed to the writing of this commentary. Brandsema reports consulting for Alexion, Audentes, AveXis, Biogen, Cytokinetics, PTC Therapeutics, Sarepta, and WaVe and has received research funding as a site investigator from Alexion, AveXis, Biogen, CSL Behring, Cytokinetics, Fibrogen, Pfizer, PTC Therapeutics, Sarepta, Summit, and WaVe.

Conservative gadolinium administration to patients with Duchenne muscular dystrophy: decreasing exposure, cost, and time, without change in medical management.

Cardiac MR (CMR) is increasingly used to assess for cardiac involvement in patients with Duchenne muscular dystrophy (DMD). The frequent use of gadolinium based contrast agents (GBCAs) has been called into question with reports of intracranial gadolinium deposition in patients receiving multiple administrations. We adopted a conservative GBCA administration policy, limiting the frequency of GBCA exposure in patients with previously documented late gadolinium enhancement. The aim of our study was to evaluate the clinical effects of this policy change. Data were retrospectively reviewed on 405 consecutive patients with DMD who underwent CMR evaluation. Patients were grouped into conservative GBCA administration or historical control. CMR reports were evaluated and clinical reports were reviewed to determine actionable changes. Ohio Medicaid reimbursements were used to estimate costs. A total of 187 patients comprised the conservative GBCA group and 218 patients the historical cohort. The conservative GBCA group had lower contrast administration rates (84% vs. 99%, p < 0.0001), shorter scan times (35.2 vs. 39.0 min, p < 0.0001), and lower estimated medical costs ($339 vs. $351/study). There was no change regarding the initial presence of first-time late gadolinium enhancement, and no difference in actionable change. Contrast administration substantially decreased 7 months post-policy change (65%) compared to the initial 7 months (96%, p < 0.0001). In the current era with unclear concern for intracranial gadolinium deposition, thoughtful GBCA administration is warranted in patients anticipated to undergo multiple CMRs. Our updated approach has resulted in fewer patients receiving contrast, shorter scan times, and less medical costs, without appreciable changes to patient management.

Unique Burdens of Pediatric Clinical Trials in Duchenne Muscular Dystrophy, April 20-21, 2017, Bethesda, Maryland, USA.

Recent increases in the number and breadth of clinical trials for patients with Duchenne muscular dystrophy (DMD) have engendered hope for a better future. Despite the overall enthusiasm by the DMD community for these trials, however, the burdens and pressures that they place on children with Duchenne muscular dystrophy and their families have become painfully apparent. In order to identify, and mediate, these challenges, Parent Project Muscular Dystrophy (PPMD) sponsored a meeting to examine some of these issues more closely in Bethesda, Maryland, on April 20-21, 2017. The meeting focused on key burdens for patients participating in clinical trials including technical (protocol complexity), financial, psychosocial and emotional issues, and informed consent. Participants recommended mitigation strategies falling into clinical, operations, regulatory, and ethical domains. The development of consensus action plans for short- and long-term enhancements in trials should facilitate discovery and development research for DMD patients.

Cost-Effectiveness of Ventricular Assist Device Destination Therapy for Advanced Heart Failure in Duchenne Muscular Dystrophy.

Destination ventricular assist device therapy (DT-VAD) is well accepted in select adults with medically refractory heart failure (HF) who are not transplant candidates; however, its use in younger patients with progressive diseases is unclear. We sought to evaluate the cost-effectiveness of DT-VAD in Duchenne muscular dystrophy (DMD) patients with advanced HF. We created a Markov-state transition model (5-year horizon) to compare survival, costs, and quality of life (QOL) between medical management and DT-VAD in DMD with advanced HF. Model input parameters were derived from the literature. We used sensitivity analyses to explore uncertainty around model assumptions. DT-VAD had higher costs ($435,602 vs. $125,696), survival (3.13 vs. 0.60 years), and quality-adjusted survival (1.99 vs. 0.26 years) than medical management. The incremental cost-effectiveness ratio (ICER) for DT-VAD was $179,086 per quality-adjusted life year (QALY). In sensitivity analyses that were widely varied to account for uncertainty in model assumptions, the DT-VAD strategy generally remained more costly and effective than medical management. Only when VAD implantation costs were <$113,142 did the DT-VAD strategy fall below the $100,000/QALY willingness-to-pay threshold commonly considered to be "cost-effective." In this exploratory analysis, DT-VAD for patients with DMD and advanced HF exceeded societal expectations for cost-effectiveness but had an ICER similar to the accepted practice of DT-VAD in adult HF patients. While more experience and research in this population is needed, our analysis suggests that DT-VAD for advanced HF in DMD should not be dismissed solely based on cost.

A checklist for clinical trials in rare disease: obstacles and anticipatory actions-lessons learned from the FOR-DMD trial.

BACKGROUND: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. METHOD: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. RESULTS: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. CONCLUSION: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate.

The Direct Cost of Managing a Rare Disease: Assessing Medical and Pharmacy Costs Associated with Duchenne Muscular Dystrophy in the United States.

BACKGROUND: A Duchenne muscular dystrophy (DMD) cohort was identified using a claims-based algorithm to estimate health care utilization and costs for commercially insured DMD patients in the United States. Previous analyses have used broad diagnosis codes that include a range of muscular dystrophy types as a proxy to estimate the burden of DMD. OBJECTIVE: To estimate DMD-associated resource utilization and costs in a sample of patients identified via a claims-based algorithm using diagnosis codes, pharmacy prescriptions, and procedure codes unique to DMD management based on DMD clinical milestones. METHODS: DMD patients were selected from a commercially insured claims database (2000-2009). Patients with claims suggestive of a non-DMD diagnosis or who were aged 30 years or older were excluded. Each DMD patient was matched by age, gender, and region to controls without DMD in a 1:10 ratio (DMD patients n = 75; controls n = 750). All-cause health care resource utilization, including emergency department, inpatient, outpatient, and physician office visits, and all-cause health care costs were examined over a minimum 1-year period. Costs were computed as total health-plan and patient-paid amounts of adjudicated medical claims (in annualized U.S. dollars). RESULTS: The average age of the DMD cohort was 13 years. Patients in the DMD cohort had a 10-fold increase in health care costs compared with controls ($23,005 vs. $2,277, P < 0.001). Health care costs were significantly higher for the DMD cohort across age strata and, in particular, for DMD patients aged 14-29 years ($40,132 vs. $2,746, P < 0.001). CONCLUSIONS: In the United States, resource use and medical costs of DMD are substantial and increase with age. DISCLOSURES: Funding for this study (GHO-10-4441) was provided by GlaxoSmithKline (GSK). Optum was contracted by GSK to conduct the study. Thayer was an employee of Optum Health Economics and Outcomes Research at the time of this study and was not compensated for her participation as an author of this manuscript. Bell is an employee and shareholder of GSK. McDonald has been a consultant for GSK, Sarepta, PTC Therapeutics, Biomarin, and Catabasis on clinical trials regarding Duchenne muscular dystrophy clinical trial design, endpoint selection, and data analysis; Mitobridge for drug development; and Eli Lilly as part of a steering committee for clinical trials. Study concept and design were contributed primarily by Bell, along with Thayer and McDonald. Thayer collected the data, and data interpretation was performed by Thayer and Bell, along with McDonald. The manuscript was written by Thayer and Bell, along with McDonald, and revised by all the authors.

Variations in Duchenne muscular dystrophy course in a multi-ethnic UK population: potential influence of socio-economic factors.

AIM: To explore variation in clinical course and steroid treatment in Duchenne muscular dystrophy (DMD) by ethnic origin and socio-economic status. METHOD: In this longitudinal cohort study, clinical outcome was defined as age at loss of ambulation (LOA). Ages are presented as months for accurate calculation. Steroid use was reviewed against national guidelines. Kaplan-Meier survival analysis was used to determine probabilities over time of LOA. Log-rank test was used to evaluate comparisons between ethnic and socio-economic groups. RESULTS: From 2005 to 2014, 71 children were newly diagnosed with DMD. Complete data were available on 69, including 33 of white British heritage and 23 of South Asian heritage. Mean age at diagnosis (without known family history) was 45.7 months; white British ethnicity 42.1 months (range 14-86mo), South Asian ethnicity 50.2 months (range 5-98mo). Twenty-four males lost ambulation. Those of South Asian heritage lost ambulation earlier (mean LOA 105.8mo [8y 10mo]) than those of white British heritage (mean LOA 117.8mo [9y 10mo]): log-rank test score 0.012 (p<0.05). Those most deprived did worse: mean age at LOA 130.0 months (10y 10mo) for the top 20 per cent and 102.5 months (8y 6mo) in the lower 20 per cent: log-rank test score 0.035 (p<0.05). The most socially deprived were diagnosed earlier and started steroids earlier. Of those of South Asian heritage, 18 per cent declined steroids, compared with 9 per cent of white British heritage. Also, 44 per cent of those of South Asian heritage stopped steroids compared with 17 per cent of those of white British heritage. INTERPRETATION: Patients from South Asian and deprived backgrounds had earlier LOA. Genetic disease modifiers are likely to be implicated, but social and cultural factors influence access to treatment.

The burden, epidemiology, costs and treatment for Duchenne muscular dystrophy: an evidence review.

BACKGROUND: Duchenne Muscular Dystrophy (DMD) is a rapidly progressive, lethal neuromuscular disorder, present from birth, which occurs almost exclusively in males. We have reviewed contemporary evidence of burden, epidemiology, illness costs and treatment patterns of DMD. This systematic review adhered to published methods with information also sought from the web and contacting registries. Searches were carried out from 2005 to June 2015. The population of interest was individuals with clearly defined DMD or their carers. RESULTS: Nine thousand eight hundred fifty titles were retrieved from searches. Fifty-eight studies were reviewed with three assessed as high, 33 as medium and 22 as low quality. We found two studies reporting birth and four reporting point prevalence, three reporting mortality, 41 reporting severity and/or progression, 18 reporting treatment patterns, 12 reporting quality of life, two reporting utility measures, three reporting costs of illness and three treatment guidelines. Birth prevalence ranged from 15.9 to 19.5 per 100,000 live births. Point prevalence per 100,000 males was for France, USA, UK and Canada, 10.9, 1.9, 2.2 and 6.1 respectively. A study of adult DMD patients at a centre in France found median survival for those born between 1970 and 1994 was 40.95 years compared to 25.77 years for those born between 1955 and 1969. Loss of ambulation occurred at a median age of 12 and ventilation starts at about 20 years. There was international variation in use of corticosteroids, scoliosis surgery, ventilation and physiotherapy. The economic cost of DMD climbs dramatically with disease progression - rising as much as 5.7 fold from the early ambulatory phase to the non-ambulatory phase in Germany. CONCLUSIONS: This is the first systematic review of treatment, progression, severity and quality of life in DMD. It also provides the most recent description of the burden, epidemiology, illness costs and treatment patterns in DMD. There are evidence gaps, particularly in prevalence and mortality. People with DMD seem to be living longer, possibly due to corticosteroid use, cardiac medical management and ventilation. Future research should incorporate registry data to improve comparability across time and between countries and to investigate the quality of life impact as the condition progresses.

Economic Evaluation in Duchenne Muscular Dystrophy: Model Frameworks for Cost-Effectiveness Analysis.

BACKGROUND: Several treatments are on the horizon for Duchenne muscular dystrophy (DMD), a terminal orphan disease. In many jurisdictions, decisions regarding pricing and reimbursement of these health technologies comprise evidence of value for money. OBJECTIVE: The objective of this study was to develop a cost-effectiveness model based on the Duchenne muscular dystrophy Functional Ability Self-Assessment Tool (DMDSAT), a new rating scale created specifically to measure disease progression in clinical practice and trials and model DMD in economic evaluations, and compare it with two alternative model structures. METHODS: We constructed three Markov cohort state-transition models to evaluate the cost-effectiveness of a hypothetical intervention for DMD versus standard of care in a UK setting. Model I was based on the DMDSAT, model II on stages of disease as defined in the DMD clinical care guidelines and model III on patients' ventilation status. The conceptual model structures were formulated in collaboration with three DMD experts. RESULTS: All three models were judged to have good validity with regards to the appropriateness of the choice of modelling technique, conceptual representation of the disease, model input data and model outcomes. Across frameworks, lifetime direct medical costs with standard of care ranged between £217,510 and £284,640, total costs between £624,240 and £713,840, and total number of quality-adjusted life-years between 5.96 and 7.17. CONCLUSIONS: We present a first version of a model for the economic evaluation of treatments for DMD based on the DMDSAT, as well as two alternative frameworks encompassing conventional staging of disease progression. Our findings should be helpful to inform health technology assessments and health economic programmes of future treatments for DMD.