A Cost-Effectiveness Framework for Amyotrophic Lateral Sclerosis, Applied to Riluzole.

OBJECTIVES: Reexamine cost-effectiveness of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) in light of recent advances in disease staging and understanding of stage-specific drug effect. METHODS: ALS was staged according to the "fine'til 9" (FT9) staging method. Stage-specific health utilities (EQ-5D, US valuation) were estimated from an institutional cohort, whereas literature informed costs and transition probabilities. Costs at 2018 prices were disaggregated into recurring costs (RCs) and "one-off" transition/"tollgate" costs (TCs). Five- and 10-year horizons starting in stage 1 disease were examined from healthcare sector and societal perspectives using Markov models to evaluate riluzole use, at a threshold of $100 000/quality-adjusted life year (QALY). Probabilistic and deterministic sensitivity analyses were conducted. RESULTS: Mean EQ-5D utilities for stages 0 to 4 were 0.79, 0.74, 0.63, 0.54, and 0.46, respectively. From the healthcare sector perspective at the 5-year horizon, riluzole use contributed to 0.182 QALY gained at the cost difference of $12 348 ($5403 riluzole cost, $8870 RC and -$1925 TC differences), translating to an incremental cost-effectiveness ratio (ICER) of $67 658/QALY. Transition probability variation contributed considerably to ICER uncertainty (-30.2% to +90.0%). ICER was sensitive to drug price and RCs, whereas higher TCs modestly reduced ICER due to delayed tollgates. CONCLUSION: This study provides a framework for health economic studies of ALS treatments using FT9 staging. Prospective stage-specific and disaggregated cost measurement is warranted for accurate future cost-effectiveness analyses. Appropriate separation of TCs from RCs substantially mitigates the high burden of background cost of care on the ICER.

Economic Studies in Motor Neurone Disease: A Systematic Methodological Review.

BACKGROUND: Motor neurone disease (MND) is a devastating condition which greatly diminishes patients' quality of life and limits life expectancy. Health technology appraisals of future interventions in MND need robust data on costs and utilities. Existing economic evaluations have been noted to be limited and fraught with challenges. OBJECTIVE: The aim of this study was to identify and critique methodological aspects of all published economic evaluations, cost studies, and utility studies in MND. METHODS: We systematically reviewed all relevant published studies in English from 1946 until January 2016, searching the databases of Medline, EMBASE, Econlit, NHS Economic Evaluation Database (NHS EED) and the Health Economics Evaluation Database (HEED). Key data were extracted and synthesised narratively. RESULTS: A total of 1830 articles were identified, of which 15 economic evaluations, 23 cost and 3 utility studies were included. Most economic studies focused on riluzole (n = 9). Six studies modelled the progressive decline in motor function using a Markov design but did not include mutually exclusive health states. Cost estimates for a number of evaluations were based on expert opinion and were hampered by high variability and location-specific characteristics. Few cost studies reported disease-stage-specific costs (n = 3) or fully captured indirect costs. Utilities in three studies of MND patients used the EuroQol EQ-5D questionnaire or standard gamble, but included potentially unrepresentative cohorts and did not consider any health impacts on caregivers. CONCLUSION: Economic evaluations in MND suffer from significant methodological issues such as a lack of data, uncertainty with the disease course and use of inappropriate modelling framework. Limitations may be addressed through the collection of detailed and representative data from large cohorts of patients.

Cost effectiveness of treatments for amyotrophic lateral sclerosis: a review of the literature.

Amyotrophic lateral sclerosis (ALS) is a difficult to diagnose, fatal, progressive degenerative disease with an average survival time of 2 to 5 years. Percutaneous endoscopic gastrotomy (PEG) and bi-level intermittent positive pressure (BIPAP) ventilation may be the major interventions leading to longer survival of patients with ALS. Riluzole has been shown to have modest effects on survival (as opposed to functional) gains and is currently the only drug approved for the treatment of ALS. There is conflicting evidence with regard to the ability of recombinant human insulin-like growth factor (rhIGF-I) to retard ALS progression. Mechanical ventilation (via a tracheostomy tube) is expensive, but is widely used in later stage patients with ALS in the US. A review of nine cost-effectiveness studies of riluzole and one of rhIGF-I found the following: drug costs and survival gains are the major drivers of cost effectiveness; survival gains are estimated from truncated databases with a high degree of uncertainty; more accurate stage-specific utility weights based on patients who agreed to treatment are needed; case incidence-based evaluations should be carried out; cost-effectiveness ratios are insensitive to discount rates; employment and caregiver issues or externalities have been widely ignored; threshold acceptance cost-effectiveness values are ill-defined and evaluations are not generalisable to other countries because of cost and treatment style differences. On account of the high degree of uncertainty pertaining to survival gains and the relatively high costs per life years or quality-adjusted life-years gained, and while acknowledging that not every therapy has to be cost effective (e.g. orphan drugs), it is still inconclusive as to whether or not riluzole or rhIGF-1 can be considered as cost-effective therapies for ALS.

The cost utility analysis of riluzole for the treatment of amyotrophic lateral sclerosis in the UK.

This study reports the results of a long-term economic evaluation of riluzole in the treatment of amyotrophic lateral sclerosis (ALS) versus best supportive care in the United Kingdom. The aim was to assess the cost implications of the life extension offered by riluzole through cost utility analysis based on patient assessed utilities of different health states.A Markov model was used to assess the cost-effectiveness of Rilutek with best supportive care. Transition possibilities and the distribution of patients by health states were taken from a cohort of 954 patients drawn from a large randomised, double blind, placebo-controlled, multicentre trial between 1992 and 1994 in the first 18 months and used to extrapolate the model to assess the long-term prolongation of life. Four distinct health states were used corresponding to mild, moderate, severe and terminal states. Costs associated with Rilutek included the acquisition cost and bi-monthly monitoring for raised ALT levels. Patient assessed utilities were collected by use of the standard gamble technique. 77 patients were entered into the study from two centres (King's, London and Preston) in the UK. Mean utilities for each of the health states was generated and, given that the data were skewed, a sensitivity analysis was undertaken with the median utility values. The implications of life extension offered by riluzole versus best supportive care were assessed both in terms of life extension projected and quality adjusted survival using patient based utilities. Using the Markov model and the transitional probabilities the base case cost per life year gained was estimated at pound sterlings 14,370 and applying Standard Gamble utility scores, the base case cost per QALY was assessed as pound sterlings 20,904. The effect of discounting costs and benefits altered the cost effectiveness analysis to pound sterlings 17,760 per life year gained while a sensitivity analysis around median or mean scores for the utility weight resulted in a range of pound sterlings 19,020 to pound sterlings 25,794 per QALY gained.

Slowing down ALS--is this good or bad?

The availability of a drug that provides modest relief in ALS without altering its inevitable progression and end, has posed new ethical and economic problems for patients, caregivers and physicians. Early evidence suggests that riluzole does provide a short additional quality of life and economic benefit for patient and society. However, there is a clear need for additional therapies, even if the benefit is minor.

ALS/MND and the perspective of health economics.

In health care, choices are constantly being made about alternative uses of scarce resources, and health economics offers a framework for analysing these choices and for improving resource allocation. In cost-effectiveness analysis, the costs and consequences of alternatives are systematically measured and compared, with the objective of achieving maximum health gain with the available resources. Treatment options for patients with ALS/MND are severely limited, but riluzole has been shown to offer modest improvements in survival. However, decision-makers are likely to want convincing evidence on the cost-effectiveness of this therapy before recommending widespread adoption. Here, some initial estimates of cost-effectiveness are provided, using published effectiveness data and considering only the costs of therapy and of tracheostomy. Compared with placebo, the incremental cost per life year gained of 50 mg/day of riluzole is pound sterling 45630, and of 100 mg/day is pound sterling 44890. Increasing the estimated costs of tracheostomy reduces the cost per life year gained of 50 mg/day to pound sterling 34940. However, if quality of life during the increased period of survival is 80% of full health, the cost per quality adjusted life year gained of 50 mg/day becomes pound sterling 57040. These cost-effectiveness ratios are well in excess of the range that is normally considered to be acceptable in UK health technology assessment. However, the comparatively small number of ALS/MND patients and the lack of treatment alternatives should also be considered. Meanwhile, better information on costs is required in order to produce more precise estimates of cost-effectiveness.

Service provision for patients with ALS/MND: a cost-effective multidisciplinary approach.

Optimal management of patients with ALS/MND requires a team approach, with early referral to paramedical services for clinical assessment and prompt intervention. As the condition progresses, a flexible approach to management must be adopted by the medical team, with an ability to intervene at very short notice. We have developed an efficient multi-disciplinary clinic that services the ALS/MND population of Ireland by combining the existing infrastructure of community services with a hospital-based specialist clinic. The clinic operates on a weekly basis, and is staffed by a core team including a neurologist, a liaison nurse, and the director of the ALS/MND Association. On-site and same-day physiotherapy, occupational therapy and speech therapy is available, as is pulmonary evaluation. All patients utilising the clinical services are automatically included on the Irish Register of Motor Neurone Disease, and are tracked by the liaison nurse. The core members of the clinic interact regularly with paramedical staff within the community, ensuring that necessary community services are made available within 1-2 weeks of the clinic visit. Equipment necessary for the patient's well being is made available free of charge by the Irish Motor Neurone Disease Association, following an appropriate request from the regional para-medical staff. We have thus demonstrated that an effective multi- disciplinary care service for ALS/MND can be developed at modest cost by close personal liaison between the existing health care structures and core members of a multidisciplinary team.

Factors influencing a patient's decision regarding riluzole: an early experience.

Riluzole is the first drug to be approved in the United States for the treatment of amyotrophic lateral sclerosis (ALS). During the first 8 months of the drug's availability by prescription, its use was discussed with 46 patients with probable or definite ALS as defined by the E1 Escorial criteria. Seventeen of the patients (37%) chose to take riluzole while 29 (63%) refused. Increased duration of symptoms, increased time since diagnosis, and participation in either the insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) trials were all associated with decreased likelihood of starting the drug. The most common reason given for not wanting to take the medication was insufficient benefit.