A systematic review of clinical effectiveness and safety for historical and current treatment options for metachromatic leukodystrophy in children, including atidarsagene autotemcel.

OBJECTIVE: To understand the benefit-risk profile for historical and current treatments for MLD. METHODS: A systematic review was conducted on the effectiveness, safety, and costs of MLD treatments: allogeneic haematopoietic stem cell transplantation (HSCT) and atidarsagene autotemcel (arsa-cel) according to best practice. RESULTS: A total of 6940 titles and abstracts were retrieved from the literature searches and 26 from other sources. From these, 35 manuscripts reporting on a total of 12 studies were selected for inclusion in the review. There were no controlled multi-armed trials. However, we provide observations comparing two interventional therapies (alloHSCT and arsa-cel) and each of these to standard/supportive care (natural history). There were no benefits for survival, gross motor function and cognitive function for LI patients receiving alloHSCT, as patients experienced disease progression similar to LI natural history. For juvenile patients receiving alloHSCT, no differences in survival were observed versus natural history, however stabilisation of cognitive and motor function were reported for some patients (particularly for pre- or minimally-symptomatic LJ patients), while others experienced disease progression. Furthermore, alloHSCT was associated with severe complications such as treatment-related mortality, graft versus host disease, and re-transplantation in both LI and EJ treated patients. Most LI and EJ patients treated with arsa-cel appeared to have normal development, preservation, or slower progression of gross motor function and cognitive function, in contrast to the rapid decline observed in natural history patients. A survival benefit for arsa-cel versus natural history and versus alloHSCT was observed in LI patients.LI and EJ patients treated with arsa-cel had better gross motor function and cognitive function compared to alloHSCT, which had limited effect on motor and cognitive decline. No data has been reported for arsa-cel treatment of LJ patients. CONCLUSIONS: Overall, this systematic review indicates that compared to NHx and HSCT, treatment with arsa-cel results in clinically relevant benefits in LI and EJ MLD patients by preserving cognitive function and motor development in most patients, and increased survival for LI patients. Nevertheless, further research is required to confirm these findings, given they are based on results from non-RCT studies.

An international study of caregiver-reported burden and quality of life in metachromatic leukodystrophy.

BACKGROUND: Metachromatic leukodystrophy (MLD) is an autosomal recessive lysosomal disorder caused by mutations in the arylsulfatase A gene. Until now, there has been little information on the burden of MLD on patients and their caregivers. This multinational study aims to quantify caregiver-related impacts of MLD across several key domains including symptoms, treatment burden, time investment, social and emotional well-being, and professional and financial impact. RESULTS: Data were collected through moderator-assisted web survey and telephone interviews. The survey was developed with extensive input from clinical experts and MLD patient advocacy groups. The EQ-5D-5L questionnaire was administered during follow-up interviews. The total sample consisted of parents of MLD patients in the US (n = 10), France (n = 10), Germany (n = 6), UK (n = 5), Belgium (n = 1), and Norway (n = 2). The impact of MLD is evident from the EQ-5D-5L scores, which indicate utility values for caregivers below respective national population norms and a higher proportion of caregivers reporting problems with anxiety/depression. Time involved for care was demonstrated by a mean of 4.1 inpatient and 29.6 outpatient hospital visits in the previous 12-month period. These commitments place stress on familial relationships with 50% of caregivers reporting their child's MLD diagnosis had negatively impacted their relationship with their spouse/partner. Professionally, 76.5% of caregivers stopped working or switched to part-time employment following their child's MLD diagnosis, and most acknowledged caring for their child had affected their potential for career progression or promotion. Differences are also observed based on late infantile versus juvenile onset MLD, time since diagnosis, and for transplanted patients versus those who received palliative care only. CONCLUSIONS: This multinational study demonstrates that MLD consistently negatively affects many aspects of caregivers' lives including health, relationships, and professional status, irrespective of location. We expect that the results of this study are generalizable to other countries. This study enhances our understanding of MLD caregiver impacts, which could improve patient care and assist in identifying support for individuals with MLD and their families.

Development of the multi-attribute Adolescent Health Utility Measure (AHUM).

OBJECTIVE: Obtain utilities (preferences) for a generalizable set of health states experienced by older children and adolescents who receive therapy for chronic health conditions. METHODS: A health state classification system, the Adolescent Health Utility Measure (AHUM), was developed based on generic health status measures and input from children with Hunter syndrome and their caregivers. The AHUM contains six dimensions with 4-7 severity levels: self-care, pain, mobility, strenuous activities, self-image, and health perceptions. Using the time trade off (TTO) approach, a UK population sample provided utilities for 62 of 16,800 AHUM states. A mixed effects model was used to estimate utilities for the AHUM states. The AHUM was applied to trial NCT00069641 of idursulfase for Hunter syndrome and its extension (NCT00630747). RESULTS: Observations (i.e., utilities) totaled 3,744 (12*312 participants), with between 43 to 60 for each health state except for the best and worst states which had 312 observations. The mean utilities for the best and worst AHUM states were 0.99 and 0.41, respectively. The random effects model was statistically significant (p < 0.0001; adjusted R2 = 0.361; RMSE = 0.194). When AHUM utilities were applied to the idursulfase trial, mean utilities in the idursulfase weekly and placebo groups improved +0.087 and +0.006, respectively, from baseline to week 53. In the extension, when all patients received idursulfase, the utilities in the treatment group remained stable and the placebo group improved +0.039. DISCUSSION: The AHUM health state classification system may be used in future research to enable calculation of quality-adjust life expectancy for applicable health conditions.

Enteral nutrition and oral nutrition supplements: a review of the economics literature.

BACKGROUND: We sought to review the economics literature on enteral nutrition (EN) and oral nutrition supplements (ONS) against the background of an ongoing clinical guideline development. METHODS: We searched the Health Economic Evaluations Database, the NHS Economic Evaluation Database, and the Cochrane Database of Systematic Reviews. RESULTS: Enteral vs parenteral nutrition was found to be the most common comparison undertaken. The randomized trial evidence suggests that, in some groups of patients, EN is better in terms of clinical endpoints and/or length of hospital stay. This should translate into a lower mean cost for EN, given the reduced daily cost. These studies should be treated with caution because of their small sample size and poor quality. Costing was often crude and poorly reported, tending to focus on the narrow costs of the nutrition supplements. Only 1 study of a nutrition supplement in the community setting was found. CONCLUSIONS: There is some evidence to indicate economic advantages of enteral over parenteral nutrition and of immune-enhancing supplements relative to control diet. There is a lack of well-designed studies taking a broad view of relevant comparators, costs, and outcomes. The cost-effectiveness of different forms of nutrition in different patient groups remains to be established.

A cost-effectiveness analysis of eletriptan 40 and 80 mg versus sumatriptan 50 and 100 mg in the acute treatment of migraine.

OBJECTIVES: This article explores the application of cost-effectiveness analysis in a comparison of eletriptan and sumatriptan in the acute treatment of migraine. METHODS: The study employs data from a randomized, double-blind, placebo-controlled clinical trial comparison of oral eletriptan (40 and 80 mg) and oral sumatriptan (50 and 100 mg). Analyses were undertaken using two composite measures of treatment outcome constructed to reflect the requirements of patients more comprehensively than the conventional efficacy indicator of headache response at 2 hours. On the cost side of the equation, reflecting the health-care system perspective of the analysis, drug costs for initial dosing, second dosing for nonresponse, and recurrence and rescue medication were taken into account. RESULTS: The analysis found that eletriptan treatment resulted in lower costs per successfully treated attack than those of sumatriptan under both outcome criteria. CONCLUSION: Further refinement of outcomes measurement in migraine would be valuable and eletriptan has a potentially important role to play in the cost-effective management of the disorder.

Design, analysis and presentation of multinational economic studies: the need for guidance.

Over the last decade, there has been a proliferation in the number of economic evaluations of pharmaceuticals to meet the growing demand for information about the economic benefits of healthcare technologies. The majority of these studies have been commissioned by pharmaceutical companies for the purposes of drawing attention to the resource and quality-of-life aspects of new or existing products. Such information has become important in overcoming a new obstacle, namely the demonstration of cost effectiveness (the so-called 'fourth hurdle'), in addition to the three well-established criteria of quality, tolerability and efficacy. To ensure the maintenance of standards, guidance for economic evaluations has emerged lately in the form of guidelines, regulations, principles, policies and positions. Drummond outlined three purposes of these guidelines, as follows: as a requirement prior to reimbursement, as statements of methodological standards, and as a statement of ethical standards. Such guidelines are designed to assist both the economic analyst and the decision-maker. In laying out the state of the art regarding the methodology of economic evaluation, guidelines assist the analyst in performing high-quality, scientifically valid studies, and assist the decision-maker in properly interpreting and assessing their quality. In response to these growing requirements for cost-effectiveness data globally, it has become increasingly common for economic evaluations to be conducted on an international scale. However, the recommendations in pharmacoeconomics guidelines regarding the manner in which these multinational economic evaluations should be designed, analysed and presented are too limited to be of any real value. This article examines the various issues that must be taken into consideration when conducting multinational studies, and provides a review of the techniques and approaches that have been suggested to date. It concludes with recommendations for potential inclusion in future sets of pharmacoeconomic guidelines.