Cost Effectiveness of Adding Fenfluramine to Standard of Care for Patients with Dravet Syndrome in Sweden.

OBJECTIVE: This study evaluated, in a Swedish setting, the cost effectiveness of fenfluramine (FFA) as an add-on to standard of care (SoC) for reducing seizure frequency in Dravet syndrome, a severe developmental epileptic encephalopathy. METHODS: Cost effectiveness of FFA+SoC compared with SoC only was evaluated using a patient-level simulation model with a lifetime horizon. Patient characteristics and treatment effects, including convulsive seizures, seizure-free days and mortality, were derived from FFA clinical trials. Resource use and costs included cost of drug acquisition, routine care and monitoring, as well as ongoing and emergency resources. Quality of life (QoL) estimates for patients and their caregivers were derived from clinical trial data. Robustness was evaluated by one-way sensitivity analysis, probabilistic sensitivity analysis and scenario analyses. RESULTS: Lifetime cost of FFA+SoC was ~3 million SEK per patient compared with ~1.5 million SEK for SoC only. FFA+SoC generated 15% more QALYs than SoC only (21.2 vs 18.5 over a lifetime), resulting in an incremental cost-effectiveness ratio (ICER) of ~540,000 SEK. Moreover, FFA+SoC had a higher probability of being cost effective than SoC only from a willingness-to-pay threshold of 710,000 SEK. Results remained generally consistent across scenario analyses, with only few exceptions (exclusions of carer utility or FFA effect on sudden unexpected death in epilepsy). CONCLUSION: Due to better seizure control, FFA is a clinically meaningful add-on therapy and was estimated to be a cost-effective addition to current SoC for patients with this rare disease in Sweden at a willingness-to-pay threshold of 1,000,000 SEK.

The Direct Costs of Dravet's Syndrome before and after Diagnosis Assessment.

The objective of this study was to estimate the direct cost before and after diagnosis assessment in patients with Dravet's syndrome (DS). The basis of the economic study was to calculate the costs of health care before and after diagnosis of DS. We retrospectively evaluated all SCN1A positive patients with phenotype of DS treated in our hospital. Statistical analyses were performed by IBM SPSS Statistics 24.0 software. After the diagnosis of DS, there was a significant decline of health care costs (-85.6%) an average of €29.4 ± 26.1 monthly per patient. We estimated the monthly costs at €204.5 ± 167 (median: €193.9, range: €35.5-534.4) per patient before DS diagnosis. The major cost was for hospitalization in neurological department: €43.3 ± 52 (median: €21.9, range: €9.5-179.4) per patient. Minimal cost per patient per months before DS diagnosis was cost of psychological testing/care and complementary rehabilitation (0.13 and 0.6% of total cost). After DS diagnosis, the major cost was focused on nonhospitalization care of patients (64.8%), minimal (€0) for genetic testing and major for outpatient care (18%, mean: €5.3, median: €7). DS results in essential health care utilization and high financial burden before diagnosis elucidation caused by repeated hospitalization and extensive diagnostics tests of "epileptic encephalopathy of unknown etiology." The results of this study point out that early assessment of the diagnosis leads to significant decrease of the financial costs because of adequate therapeutic management and exclusion of redundant diagnostic testing after elucidation of correct diagnosis.

A multicenter, matched case-control analysis comparing burden-of-illness in Dravet syndrome to refractory epilepsy and seizure remission in patients and caregivers in Germany.

OBJECTIVE: To compare direct and indirect costs and quality of life (QoL) of pediatric and adult patients with Dravet syndrome (DS), with drug-resistant epilepsy (DRE) and in seizure remission (SR), and their caregivers, in Germany. METHODS: Questionnaire responses from 93 DS patients and their caregivers were matched by age and gender with responses from 93 DRE and 93 SR patients collected in independent studies, and were compared across main components of QoL, direct costs (patient visits, medication use, care level, medical equipment, and ancillary treatments), and indirect costs (quitting job, reduced working hours, missed days). RESULTS: Mean total direct costs were highest for DS patients (€4864 [median €3564] vs €3049 [median €1506] for DRE [excluding outliers], P = 0.01; and €1007 [median €311], P < 0.001 for SR). Total lost productivity over 3 months was highest among caregivers of pediatric DS (€4757, median €2841), compared with those of DRE (€1541, P < 0.001; median €0) and SR patients (€891, P < 0.001; median €0). The proportions of caregivers in employment were similar across groups (62% DS, 63% DRE, and 63% SR) but DS caregivers were more likely to experience changes to their working situation, such as quitting their job (40% DS vs 16% DRE and 9% SR, P < 0.001 in both comparisons). KINDL scores were significantly lower for DS patients (62 vs 74 and 72, P < 0.001 in both comparisons), and lower than for the average German population (77). Pediatric caregiver EQ-5D scores across all cohorts were comparable with population norms, but more DS caregivers experienced moderate to severe depressive symptoms (24% vs 11% and 5%). Mean Beck Depression Inventory (BDI-II) score was significantly higher in DS caregivers than either of the other groups (P < 0.001). SIGNIFICANCE: This first comparative study of Dravet syndrome to difficult-to-treat epilepsy and to epilepsy patients in seizure remission emphasizes the excess burden of DS in components of QoL and direct costs. The caregivers of DS patients have a greater impairment of their working lives (indirect costs) and increased depression symptoms.

Burden-of-illness and cost-driving factors in Dravet syndrome patients and carers: A prospective, multicenter study from Germany.

INTRODUCTION: Dravet syndrome (DS) is a rare developmental and epileptic encephalopathy. This study estimated cost, cost-driving factors and quality of life (QoL) in patients with Dravet syndrome and their caregivers in a prospective, multicenter study in Germany. METHODS: A validated 3-12-month retrospective questionnaire and a prospective 3-month diary assessing clinical characteristics, QoL, and direct, indirect and out-of-pocket (OOP) costs were administered to caregivers of patients with DS throughout Germany. RESULTS: Caregivers of 93 patients (mean age 10.1 years, ±7.1, range 15 months-33.7 years) submitted questionnaires and 77 prospective diaries. The majority of patients (95%) experienced at least one seizure during the previous 12 months and 77% a status epilepticus (SE) at least once in their lives. Over 70% of patients had behavioural problems and delayed speech development and over 80% attention deficit symptoms and disturbance of motor skills and movement coordination. Patient QoL was lower than in the general population and 45% of caregivers had some form of depressive symptoms. Direct health care costs per three months were a mean of €6,043 ± €5,825 (median €4054, CI €4935-€7350) per patient. Inpatient costs formed the single most important cost category (28%, €1,702 ± €4,315), followed by care grade benefits (19%, €1,130 ± €805), anti-epileptic drug (AED) costs (15%, €892 ± €1,017) and ancillary treatments (9%, €559 ± €503). Total indirect costs were €4,399 ±€ 4,989 (median €0, CI €3466-€5551) in mothers and €391 ± €1,352 (median €0, CI €195-€841) in fathers. In univariate analysis seizure frequency, experience of SE, nursing care level and severe additional symptoms were found to be associated with total direct healthcare costs. Severe additional symptoms was the single independently significant explanatory factor in a multivariate analysis. CONCLUSIONS: This study over a period up to 15 months revealed substantial direct and indirect healthcare costs of DS in Germany and highlights the relatively low patient and caregiver QoL compared with the general population.

Caregiver impact and health service use in high and low severity Dravet syndrome: A multinational cohort study.

PURPOSE: To estimate costs associated with the current management of Dravet syndrome (DS), explore psychosocial aspects of the disease in caregivers and siblings, and identify patient characteristics associated with higher costs in a large, predominantly European survey cohort of patients and their caregivers conducted in 2016. METHODS: Health and social care resource use, productivity and quality of life (QoL) data were summarised. Costs for European five (EU5) countries (France, Germany, Italy, Spain and UK) were calculated and patients with high and low current seizure burden compared. Direct healthcare costs and out-of-pocket costs were calculated using literature reported health service costs and participant reported costs, respectively. RESULTS: Direct annual costs of management of non-seizure-related symptoms ($7929) contributed to approximately 50% of all costs (including medication). Excluding medication, non-seizure-related costs dominated costs of care. Cost for patients with high seizure burden were higher for seizure-related healthcare use and physiotherapy, but lower for other therapies. Most (80%) caregivers reported an influence on their career choices and 28% of those in work had missed over three working days in the past four weeks for emergency or routine needs of their child. Caregivers had little free time, relied on family members for support and respite, and experienced emotional stress and uncertainty about their child's future healthcare needs. CONCLUSION: Families caring for a DS patient manage considerable social and financial impacts. Total direct costs of DS patients (excluding drugs) are driven by non-seizure-related healthcare use and high seizure burden is associated with higher healthcare costs.

Economic Evaluation of Stiripentol for Dravet Syndrome: A Cost-Utility Analysis.

BACKGROUND: Dravet syndrome is a catastrophic form of pediatric treatment-resistant epilepsy with few effective treatment options. Stiripentol is approved for use in Canada for treatment of Dravet syndrome, but the associated long-term costs and benefits have not been well-studied and its cost effectiveness is unclear. OBJECTIVE: The aim of this study was to evaluate the cost effectiveness of stiripentol as an adjunctive treatment to clobazam and valproate for treatment of Dravet syndrome from the perspective of the Canadian public healthcare payer. METHODS: A cost-utility analysis was performed to estimate the costs and quality-adjusted life-years (QALYs) associated with adjunctive stiripentol treatment compared with clobazam and valproate alone in children with Dravet syndrome. Transition probabilities, drug efficacy, utility weights, and costs were obtained from a review of the literature. Probabilistic analyses were conducted using a Markov model with health states related to seizure frequency. A 10-year horizon was used. The incremental cost per QALY gained (incremental cost-effectiveness ratio [ICER]) for adjunctive use of stiripentol was calculated, and assumptions were explored in scenario analyses. All costs are expressed in 2017 Canadian dollars ($Can). RESULTS: Compared with clobazam and valproate alone, the adjunctive use of stiripentol is associated with an ICER of $Can151,310. At a willingness-to-pay threshold of $Can50,000, the probability that stiripentol was the optimal treatment was 5.2%. The cost of stiripentol would need to be reduced by 61.4% for stiripentol to be cost effective. CONCLUSION: From the perspective of the Canadian public healthcare payer, stiripentol is not cost effective at its current price at a willingness-to-pay threshold of $Can50,000. Funding stiripentol will be associated with important opportunity costs that bear consideration.

The direct and indirect costs of Dravet Syndrome.

OBJECTIVE: The objective of this study was to estimate the annual direct and indirect costs associated with Dravet Syndrome (DS). METHODS: A survey was electronically administered to the caregivers of patients with DS treated at Children's Hospital Colorado. Survey domains included healthcare utilization of the patient with DS and DS caregiver work productivity and activity impairment. Patient healthcare utilization was measured using modified questions from the National Health Interview Survey; caregiver work productivity and activity impairment were measured using modified questions from the Work Productivity and Activity Impairment questionnaire. Direct costs were calculated by multiplying the caregiver-reported healthcare utilization rates by the mean unit cost for each healthcare utilization category. Indirect costs included lost productivity, income loss, and lost leisure time. The indirect costs were a function of caregiver-reported hours spent caregiving and an hourly unit cost. RESULTS: The survey was emailed to 60 DS caregivers, of which 34 (57% response rate) responded. Direct costs on average were $27,276 (95% interval: $15,757, $41,904) per patient with DS. Hospitalizations ($11,565 a year) and in-home medical care visits ($9894 a year) were substantial cost drivers. Additionally, caregivers reported extensive time spent providing care to an individual with DS. This caregiver time resulted in average annual indirect costs of $81,582 (95% interval: $57,253, $110,151), resulting in an average total annual financial burden of $106,378 (95% interval: $78,894, $137,906). CONCLUSION: Dravet Syndrome results in substantial healthcare utilization, financial burden, and time commitment. Establishing evidence on the financial burden of DS is essential to understanding the overall impact of DS, identifying potential areas for support needs, and assessing the impact of novel treatments as they become available. Based on the study findings, in-home visits, hospitalizations, and lost productivity and leisure time of caregivers are key domains for DS economic evaluations. Future research should extend these estimates to include the potential additional healthcare utilization of the DS caregiver.

The humanistic and economic burden of Dravet syndrome on caregivers and families: Implications for future research.

We reviewed the current literature with respect to the humanistic and financial burdens of Dravet Syndrome (DS) on the caregivers of children with DS, in order to (1) identify key unanswered questions or gaps in knowledge that need to be addressed and then, based on these knowledge gaps, (2) propose a research agenda for the scientific community to address in the coming decade. The findings support the conclusion that caring for a child with DS is associated with significant humanistic burden and direct costs. However, due in part to the paucity of studies, as well as the lack of measures of specific burden domains, there remains much that is not known regarding the burden of caregiving for children with DS. To address the significant knowledge gaps in this area, research is needed that will: (1) identify the specific domains of caregivers' lives that are impacted by caring for a child with DS; (2) identify or, if needed, develop measures of caregiving impact in this area; (3) identify the factors that influence DS caregiving burden; (4) develop and evaluate the efficacy of treatments for reducing the negative impact of DS and its comorbidities on DS caregivers; (5) quantify the direct medical costs associated with DS and DS comorbidities and identify the factors that influence these costs; and (6) quantify and fully explore the indirect costs of DS. Research that addresses these goals will provide the empirical foundation needed for improving the quality of life of children with DS and their families.

Evaluation of health-care utilization in patients with Dravet syndrome and on adjunctive treatment with stiripentol and clobazam.

Dravet syndrome (DS) is a rare, severe childhood epilepsy syndrome that imposes a substantial burden on patients and their caregivers. This study evaluated health-care utilization over a 2-year period in patients with DS at an outpatient clinic of a German epilepsy center. Data on the course of epilepsy, anticonvulsant treatment, and direct costs were recorded using the electronic seizure diary Epivista and patients' files. We enrolled 13 patients with DS (6 females, mean age: 12.3±7.5 years) between 2007 and 2010 and evaluated them during a 1-year baseline. All patients had drug-resistant epilepsy and their seizures failed to improve with a mean number of 6.7±3.4 anticonvulsants. They had an overall mean seizure frequency of 102.1 seizures per year (median: 31, range: 3-538) with 43.2 GTCSs per year (median: 14, range: 0-228). We estimated the annual total direct costs at €6506±3974 (range: €1174-11,783) per patient with hospitalization (68.9% of total direct costs) as the major cost factor ahead of costs for anticonvulsants (24.0%). For the 1-year follow-up period, less severely affected patients were continued on conventional anticonvulsants (n=4) or switched to adjunctive treatment with stiripentol and clobazam (n=9). In the latter group, six patients (67%) were long-term responders, with between 25% and 100% seizure reduction with respect to either GTCSs or the overall seizure frequency. This reduction in seizure frequency was associated with a shift in the distribution of cost components towards higher medication costs and decreased hospitalization costs. The total direct costs increased by 42.7%, mainly due to the newly introduced stiripentol, with an annual cost of €6610. This study showed that direct costs of patients with DS were above the average European costs of drug-resistant epilepsy in children. Treatment with new anticonvulsants resulted in reduction of seizures and inpatient admissions.