Burden of illness of aromatic L-amino acid decarboxylase deficiency: a survey of physicians in Southern Europe.

BACKGROUND: Aromatic L-amino acid decarboxylase deficiency (AADCd) is an ultra-rare genetic neurometabolic disorder caused by mutations in the DDC gene. OBJECTIVE: This retrospective, noninterventional study was designed to describe the burden of AADCd including the associated healthcare resource utilization in Southern Europe. METHODS: Eleven clinicians completed a patient case study survey for patients with AADCd currently or previously under their care, followed by an interview with each clinician to assess healthcare resource utilization, patient characteristics, and symptoms. RESULTS: Clinicians provided data for 20 patients with AADCd, of whom 60% were male. All patients experienced movement disorders, 90% exhibited developmental delay, 85% reported sleeping problems, and 80% experienced gastrointestinal problems. The symptoms varied with disease severity. Patients with AADCd received care from more than 16 different specialists including both medical and paramedical healthcare professionals. Hospitalizations and visits to accident and emergency departments were also frequent. CONCLUSION: In terms of symptoms and healthcare resource utilization, the burden of illness of AADCd is substantial. This study provides insights into several aspects of the disease that are difficult to ascertain from published case reports.

A Discrete Choice Experiment to Derive Health Utilities for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency in France.

PURPOSE: Cost-effectiveness evaluations of interventions require health utility data. However, in medical conditions, such as aromatic L-amino acid decarboxylase (AADC) deficiency, this presents problems due to the rarity of the disease. The study aim therefore was to employ a discrete choice experiment (DCE) to generate health utilities for AADC deficiency. METHODS: A previous literature review, clinician and parent interviews had identified six key AADC deficiency attributes: mobility, muscle weakness, oculogyric crises (OCG), feeding ability, cognitive impairment and screaming. A representative sample of the French general population was recruited. Participants rated 5 health state vignettes describing AADC deficiency using time-trade-off (TTO) and standard gamble (SG). Additionally, participants rated the worst health state using the Health Utility Index version 3 (HUI3). Subsequently, participants completed DCE 11 choice sets. Indirect DCE part-worth utilities were converted to health utilities using the anchors from the TTO, SG and HUI3. RESULTS: The DCE was completed online by 1001 participants (50.9% female; mean age 45.7 years). Most participants (596, 59.5%) provided consistent responses to the repeated choice task. Five models were evaluated, and one preference reversal ("head control"/"sitting unaided") was identified in all models. The rescaled utilities ranged from 0.3891 to 0.5577 (difference of 0.17 utilities) for TTO anchors corresponding to the worst (633233) and best (111111) health states. Health utilities ranged from 0.5534 to 0.7093 for the SG anchors. The disutility associated with a transition from "no problems walking" to "bedridden" was -0.0533, whereas disutility of moving from "constant screaming" relative to "no screaming" was -0.0248. The disutility associated with daily OCG was -0.0167. Disutilities for the other attributes were small although there were exceptions. CONCLUSION: A DCE was used to derive health utilities for AADC deficiency. These health utilities will subsequently be used in an economic model evaluating an AADC deficiency intervention.

Eliciting Health State Utilities for Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency: A Vignette Study in France.

PURPOSE: Health-related quality of life (HRQoL) is difficult to measure in rare diseases, especially in paediatric populations, yet capturing HRQoL is critical to evaluating treatment, including the cost-effectiveness of treatments. Given the ultra-rare nature of AADC deficiency indirect elicitation of HRQoL data through proxy caregiver/parent ratings is not feasible. In these circumstances, HRQoL data may be derived through vignette studies using the general population. The aim of the study was to generate health utility values specific for France for AADC deficiency using vignettes. METHODS: The study was completed online by panel participants from a French representative sample. Five health state vignettes, reflecting key milestones in the eladocagene exuparvovec clinical trials and economic model, were presented to the participants: "bedridden", "head control", "sitting unsupported", "standing with assistance" and "walking with assistance". The vignettes had been previously developed with input from parents of patients with AADC deficiency, patients and expert opinion. Participants also completed the Health Utilities Index-3 for the "bedridden" health state. RESULTS: A total of 1001 participants (51% females; mean age 46 years) completed the vignettes. Utilities increased linearly as the health state improved for both the time trade-off (TTO): 0.47 (standard deviation, SD 0.36) to 0.54 (SD 0.36) and standard gamble (SG): 0.61 (SD 0.29) to 0.67 (SD 0.27). A significant minority had incongruent responses (high utilities for the bedridden compared to walking health states) for the vignette (27%). When these were removed, the TTO health utilities (N=729) ranged from 0.39 (SD 0.36) to 0.56 (SD 0.38) and 0.61 (SD 0.30) to 0.69 (SD 0.27) for the SG. CONCLUSION: Health utilities were derived for AADC deficiency which will be used for a cost-effectiveness model of an AADC deficiency treatment.

Cost-Effectiveness of Treatments for Relapsing Remitting Multiple Sclerosis: A French Societal Perspective.

OBJECTIVES: The paper aimed to estimate the incremental cost-effectiveness ratio (ICER) at the public published price for delayed-release dimethyl fumarate versus relevant Multiple Sclerosis disease-modifying therapies available in France in June 2015. METHODS: The economic model was adapted to the French setting in accordance with the Haute Autorité de Santé guidelines using a model previously developed for NICE. A cohort of Relapsing Remitting Multiple Sclerosis patients was simulated over a 30-year time horizon. Twenty one health states were taken into account: Kurtzke Expanded Disability Status Scale (EDSS) 0-9 for Relapsing Remitting Multiple Sclerosis patients, EDSS 0-9 for Secondary Progressive Multiple Sclerosis patients, and death. Estimates of relative treatment efficacy were determined using a mixed-treatment comparison. Probabilities of events were derived from the dimethyl fumarate pivotal clinical trials and the London Ontario Dataset. Costs and utilities were extracted from the published literature from both the payer and societal perspectives. Univariate and probabilistic sensitivity analyses were performed to assess the robustness of the model results. RESULTS: From both perspectives, dimethyl fumarate and interferon beta-1a (IFN beta-1a) 44 mcg were the two optimal treatments, as the other treatments (IFN beta-1a 30 mcg, IFN beta-1b 250 mcg, teriflunomide, glatiramer acetate, fingolimod) were dominated on the efficiency frontier. From the societal perspective, dimethyl fumarate versus IFN beta-1a 44 mcg incurred an incremental cost of €3,684 and an incremental quality-adjusted life year (QALY) of 0.281, corresponding to an ICER of €13,110/QALY. CONCLUSIONS: Despite no reference threshold for France, dimethyl fumarate can be considered as a cost-effective option as it is on the efficiency frontier.

Critical appraisal of network meta-analyses evaluating the efficacy and safety of new oral anticoagulants in atrial fibrillation stroke prevention trials.

OBJECTIVES: To critically appraise published network meta-analyses (NMAs) evaluating the efficacy or safety of the new oral anticogulants (NOACs) dabigatran, rivaroxaban, and apixaban for the prevention of stroke in patients with nonvalvular atrial fibrillation (AF). METHODS: A systematic literature review was performed to identify the relevant NMAs using MEDLINE, EMBASE, Cochrane Library, Database of Abstracts of Reviews of Effects, and Health Technology Assessment. The synthesis studies were evaluated using the "Questionnaire to assess the relevance and credibility of the NMA." RESULTS: Eleven NMAs evaluating NOACs among adults with nonvalvular AF were identified. Most NMAs included three large phase III randomized controlled trials, comparing NOACs to adjusted-dose warfarin (Randomized Evaluation of Long-Term Anticoagulation Therapy [RE-LY], Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF], and Apixaban for Reduction of Stroke and Other Thromboembolic Events in Atrial Fibrillation [ARISTOTLE]). The main differences identified related to potential treatment effect modifiers regarding the mean time spent in therapeutic range (TTR) in the warfarin arm, the risk of stroke or systemic embolism across the trials (mean CHADS2 score: C = congestive heart failure, H = hypertension, A = older than age 75 years, D = diabetes mellitus, S2 = prior stroke or history of transient ischemic attack) or primary versus secondary prevention, and type of populations used in the analysis. Kansal et al. [Kansal AR, Sharma M, Bradley-Kennedy C, et al. Dabigatran versus rivaroxaban for the prevention of stroke and systemic embolism in atrial fibrillation in Canada: comparative efficacy and cost-effectiveness. Thromb Haemost 2012;108:672-82] appropriately adjusted the ROCKET-AF TTR to match the RE-LY population on the basis of individual patient data. Meta-regressions are not expected to minimize confounding bias given limited data, whereas subgroup analyses had some impact on the point estimates for the treatment comparisons. CONCLUSIONS: Results of the synthesis studies were generally comparable and suggested that the NOACs had similar efficacy, although some differences were identified depending on the outcome. The extent to which differences in the distribution of TTR, CHADS2 score, or primary versus secondary prevention biased the results remains unclear.

Cost-effectiveness of dabigatran versus vitamin K antagonists for the prevention of stroke in patients with atrial fibrillation: a French payer perspective.

BACKGROUND: Atrial fibrillation is the main cause of stroke, but the risk can be reduced, usually with vitamin K antagonists (VKAs) such as warfarin. The RE-LY atrial fibrillation study demonstrated that the rates of stroke and systemic embolism with dabigatran (an oral direct thrombin inhibitor) were similar to or lower than those with warfarin. AIMS: To estimate the cost-effectiveness, from a French payer perspective, of dabigatran (150 or 110mg bid for patients