Illustrating the financial consequences of outcome-based payment models from a payers perspective- the case of autologous gene therapy atidarsagene autotemcel (Libmeldy®).

OBJECTIVE: To illustrate the financial consequences of implementing different managed entry agreements ((MEA) for the Dutch healthcare system for autologous gene therapy atidarsagene autotemcel (AA, Libmeldy®), while also providing a first systematic guidance on how to construct MEAs to aid future reimbursement decision-making and create patient access to high-cost, one-off potentially curative therapies. METHODS: Three payment models were compared: (1) an arbitrary 60% price discount, (2) an outcome-based spread payment with discounts, and (3) an outcome-based spread payment linked to a willingness to pay model with discounts. Financial consequences were estimated for full responders (A), patients responding according to the predicted clinical pathway presented in HTA reports (B), and unstable responders (C). The associated costs for an average patient during the timeframe of the payment agreement, the total budget impact, and associated benefits expressed in quality-adjusted life-years of the patient population were calculated. RESULTS: When patients responded according to the predicted clinical pathway presented in HTA reports (Scenario B), implementing outcome-based reimbursement models (models 2 and 3) had lower associated budget impacts while gaining similar benefits compared to the discount (Scenario 1, €8,9 million to €6,6 million vs. €9.2 million). In the case of unstable responders (Scenario C), costs for payers are lower in the outcome-based scenarios (€4.1 million and €3.0 million, Scenario 2.C and 3.C, respectively) compared to implementing the discount (€9.2 million, Scenario 1.C). CONCLUSION: Outcome-based models can mitigate the financial risk of reimbursing AA. This can be considerably beneficial over simple discounts when clinical performance was similar to or worse than predicted.

Longitudinal volumetric analysis of gray matter atrophy in metachromatic leukodystrophy.

Metachromatic leukodystrophy (MLD) is an inherited lysosomal storage disorder characterized by arylsulfatase A (ASA) deficiency, leading to sulfatide accumulation and myelin degeneration in the central nervous system. While primarily considered a white matter (WM) disease, gray matter (GM) is also affected in MLD, and hematopoietic stem cell transplantation (HSCT) may have limited effect on GM atrophy. We cross-sectionally and longitudinally studied GM volumes using volumetric MRI in a cohort of 36 (late-infantile, juvenile and adult type) MLD patients containing untreated and HSCT treated subjects. Cerebrum, cortical GM, (total) CSF, cerebellum, deep gray matter (DGM) (excluding thalamus) and thalamus volumes were analyzed. Longitudinal correlations with measures of cognitive and motor functioning were assessed. Cross-sectionally, juvenile and adult type patients (infantiles excluded based on limited numbers) were compared with controls at earliest scan, before possible treatment. Patients had lower cerebrum, cortical GM, DGM and thalamus volumes. Differences were most pronounced for adult type patients. Longitudinal analyses showed substantial and progressive atrophy of all regions and increase of CSF in untreated patients. Similar, albeit less pronounced, effects were seen in treated patients for cerebrum, cortical GM, CSF and thalamus volumes. Deterioration in motor performance (all patients) was related to atrophy, and increase of CSF, in all regions. Cognitive functioning (data available for treated patients) was related to cerebral, cortical GM and thalamus atrophy; and to CSF increase. Our findings illustrate the importance of recognizing GM pathology as a potentially substantial, clinically relevant part of MLD, apparently less amenable to treatment.

Newborn screening in metachromatic leukodystrophy - European consensus-based recommendations on clinical management.

INTRODUCTION: Metachromatic leukodystrophy (MLD) is a rare autosomal recessive lysosomal storage disorder resulting from arylsulfatase A enzyme deficiency, leading to toxic sulfatide accumulation. As a result affected individuals exhibit progressive neurodegeneration. Treatments such as hematopoietic stem cell transplantation (HSCT) and gene therapy are effective when administered pre-symptomatically. Newborn screening (NBS) for MLD has recently been shown to be technically feasible and is indicated because of available treatment options. However, there is a lack of guidance on how to monitor and manage identified cases. This study aims to establish consensus among international experts in MLD and patient advocates on clinical management for NBS-identified MLD cases. METHODS: A real-time Delphi procedure using eDELPHI software with 22 experts in MLD was performed. Questions, based on a literature review and workshops, were answered during a seven-week period. Three levels of consensus were defined: A) 100%, B) 75-99%, and C) 50-74% or >75% but >25% neutral votes. Recommendations were categorized by agreement level, from strongly recommended to suggested. Patient advocates participated in discussions and were involved in the final consensus. RESULTS: The study presents 57 statements guiding clinical management of NBS-identified MLD patients. Key recommendations include timely communication by MLD experts with identified families, treating early-onset MLD with gene therapy and late-onset MLD with HSCT, as well as pre-treatment monitoring schemes. Specific knowledge gaps were identified, urging prioritized research for future evidence-based guidelines. DISCUSSION: Consensus-based recommendations for NBS in MLD will enhance harmonized management and facilitate integration in national screening programs. Structured data collection and monitoring of screening programs are crucial for evidence generation and future guideline development. Involving patient representatives in the development of recommendations seems essential for NBS programs.

Inventory of current practices regarding hematopoietic stem cell transplantation in metachromatic leukodystrophy in Europe and neighboring countries.

BACKGROUND: For decades, early allogeneic stem cell transplantation (HSCT) has been used to slow neurological decline in metachromatic leukodystrophy (MLD). There is lack of consensus regarding who may benefit, and guidelines are lacking. Clinical practice relies on limited literature and expert opinions. The European Reference Network for Rare Neurological Diseases (ERN-RND) and the MLD initiative facilitate expert panels for treatment advice, but some countries are underrepresented. This study explores organizational and clinical HSCT practices for MLD in Europe and neighboring countries to enhance optimization and harmonization of cross-border MLD care. METHODS: A web-based EUSurvey was distributed through the ERN-RND and the European Society for Blood and Marrow Transplantation Inborn Errors Working Party. Personal invitations were sent to 89 physicians (43 countries) with neurological/metabolic/hematological expertise. The results were analyzed and visualized using Microsoft Excel and IBM SPSS statistics. RESULTS: Of the 30 countries represented by 42 respondents, 23 countries offer HSCT for MLD. The treatment is usually available in 1-3 centers per country (18/23, 78%). Most countries have no or very few MLD patients transplanted during the past 1-5 years. The eligibility criteria regarding MLD subtype, motor function, IQ, and MRI largely differ across countries. CONCLUSION: HSCT for MLD is available in most European countries, but uncertainties exist in Eastern and South-Eastern Europe. Applied eligibility criteria and management vary and may not align with the latest scientific insights, indicating physicians' struggle in providing evidence-based care. Interaction between local physicians and international experts is crucial for adequate treatment decision-making and cross-border care in the rapidly changing MLD field.

Adaptive behavior assessed by Vineland-3 as comprehensive outcome measure in vanishing white matter.

OBJECTIVES: Investigate the results and usability of the Vineland-3 as an outcome measure in vanishing white matter patients. METHODS: A cross-sectional investigation of the Vineland-3 based on interviews with caregivers, the Health Utilities Index, and the modified Rankin Scale in 64 vanishing white matter patients. RESULTS: Adaptive behavior measured with the Vineland-3 is impaired in the vast majority of vanishing white matter patients and significantly impacts daily life. Typically, the daily living skills domain is most severely affected and the socialization domain is the least affected. Based on the metric properties and the clinical relevance, the standard scores for the daily living skills domain and Adaptive Behavior Composite have the best properties to be used as an outcome measure. INTERPRETATION: The Vineland-3 appears to be a useful outcome measure to explore and quantify complex cognitive, behavioral, and psychiatric impairments affecting daily functioning in vanishing white matter. Further research should address the longitudinal evaluation of this tool and its additional value to standard neuropsychological and clinical examination.

Core protocol development for phase 2/3 clinical trials in the leukodystrophy vanishing white matter: a consensus statement by the VWM consortium and patient advocates.

BACKGROUND: The leukodystrophy "Vanishing White Matter" (VWM) is an orphan disease with neurological decline and high mortality. Currently, VWM has no approved treatments, but advances in understanding pathophysiology have led to identification of promising therapies. Several investigational medicinal products are either in or about to enter clinical trial phase. Clinical trials in VWM pose serious challenges, as VWM has an episodic disease course; disease phenotype is highly heterogeneous and predictable only for early onset; and study power is limited by the small patient numbers. To address these challenges and accelerate therapy delivery, the VWM Consortium, a group of academic clinicians with expertise in VWM, decided to develop a core protocol to function as a template for trials, to improve trial design and facilitate sharing of control data, while permitting flexibility regarding other trial details. Overall aims of the core protocol are to collect safety, tolerability, and efficacy data for treatment assessment and marketing authorization. METHODS: To develop the core protocol, the VWM Consortium designated a committee, including clinician members of the VWM Consortium, family and patient group advocates, and experts in statistics, clinical trial design and alliancing with industries. We drafted three age-specific protocols, to stratify into more homogeneous patient groups, of ages ≥ 18 years, ≥ 6 to < 18 years and < 6 years. We chose double-blind, randomized, placebo-controlled design for patients aged ≥ 6 years; and open-label non-randomized natural-history-controlled design for patients < 6 years. The protocol describes study populations, age-specific endpoints, inclusion and exclusion criteria, study schedules, sample size determinations, and statistical considerations. DISCUSSION: The core protocol provides a shared uniformity across trials, enables a pool of shared controls, and reduces the total number of patients necessary per trial, limiting the number of patients on placebo. All VWM clinical trials are suggested to adhere to the core protocol. Other trial components such as choice of primary outcome, pharmacokinetics, pharmacodynamics, and biomarkers are flexible and unconstrained by the core protocol. Each sponsor is responsible for their trial execution, while the control data are handled by a shared research organization. This core protocol benefits the efficiency of parallel and consecutive trials in VWM, and we hope accelerates time to availability of treatments for VWM. TRIAL REGISTRATION: NA. From a scientific and ethical perspective, it is strongly recommended that all interventional trials using this core protocol are registered in a clinical trial register.

Recognizing early MRI signs (or their absence) is crucial in diagnosing metachromatic leukodystrophy.

OBJECTIVES: Metachromatic leukodystrophy (MLD) has characteristic white matter (WM) changes on brain MRI, which often trigger biochemical and genetic confirmation of the diagnosis. In early or pre-symptomatic disease stages, these typical MRI changes might be absent, hampering early diagnosis. This study aims to describe the characteristics of MRI WM abnormalities at diagnosis, related to clinical presentation. METHODS: We retrospectively reviewed brain MRIs of MLD patients followed in 2 centers at the time of diagnosis regarding MLD MRI score and presence of tigroid pattern. In addition, MLD subtype, symptom status, CNS/PNS phenotype, motor/cognitive/mixed phenotype, and the presence of CNS symptoms were evaluated. RESULTS: We included 104 brain MRIs from patients with late-infantile (n = 43), early-juvenile (n = 24), late-juvenile (n = 20) and adult (n = 17) onset. Involvement of the corpus callosum was a characteristic early MRI sign and was present in 71% of the symptomatic late-infantile patients, 94% of the symptomatic early-juvenile patients and 100% of the symptomatic late-juvenile and adult patients. Symptomatic early-juvenile, late-juvenile and adult patients generally had WM abnormalities on MRI suggestive of MLD. By contrast, 47% of the early-symptomatic late-infantile patients had no or only mild WM abnormalities on MRI, even in the presence of CNS symptoms including pyramidal signs. INTERPRETATION: Patients with late-infantile MLD may have no or only mild, nonspecific abnormalities at brain MRI, partly suggestive of 'delayed myelination', even with clear clinical symptoms. This may lead to significant diagnostic delay. Knowledge of these early MRI signs (or their absence) is important for fast diagnosis.

Modified Delphi procedure-based expert consensus on endpoints for an international disease registry for Metachromatic Leukodystrophy: The European Metachromatic Leukodystrophy initiative (MLDi).

BACKGROUND: Metachromatic Leukodystrophy (MLD) is a rare lysosomal disorder. Patients suffer from relentless neurological deterioration leading to premature death. Recently, new treatment modalities, including gene therapy and enzyme replacement therapy, have been developed. Those advances increase the need for high-quality research infrastructure to adequately compare treatments, execute post-marketing surveillance, and perform health technology assessments (HTA). To facilitate this, a group of MLD experts started the MLD initiative (MLDi) and initiated an academia-led European MLD registry: the MLDi. An expert-based consensus procedure, namely a modified Delphi procedure, was used to determine the data elements required to answer academic, regulatory, and HTA research questions. RESULTS: Three distinct sets of data elements were defined by the 13-member expert panel. The minimal set (n = 13) contained demographics and basic disease characteristics. The core set (n = 55) included functional status scores in terms of motor, manual, speech and eating abilities, and causal and supportive treatment characteristics. Health-related quality of life scores were included that were also deemed necessary for HTA. The optional set (n = 31) contained additional clinical aspects, such as findings at neurological examination, detailed motor function, presence of peripheral neuropathy, gall bladder involvement and micturition. CONCLUSION: Using a modified Delphi procedure with physicians from the main expert centers, consensus was reached on a core set of data that can be collected retrospectively and prospectively. With this consensus-based approach, an important step towards harmonization was made. This unique dataset will support knowledge about the disease and facilitate regulatory requirements related to the launch of new treatments.

High intra- and inter-observer reliability of planning implant size in MRI-based patient-specific instrumentation for total knee arthroplasty.

PURPOSE: Patient-specific instrumentation (PSI) in total knee arthroplasty (TKA) uses individually designed disposable guides to determine intraoperative bone cuts. The manufacturer provides the surgeon with proposed planning which can be modified and should be approved by the surgeon before the guides are produced. This study aims to assess the intra- and inter-observer reliability among preoperative planning by orthopaedic surgeons using PSI. The authors hypothesize a high intra- and inter-observer reliability in planning TKA using PSI. METHODS: Four orthopaedic surgeons modified and approved 40 preoperative MRI-based PSI plannings three times. The surgeons were blinded to their own and each other's results. Intra- and inter-observer reliability was obtained for planned implant size, resection, and position of the implant. RESULTS: Intra-observer reliability Intraclass Correlation Coefficients (ICC) were excellent for femoral and tibial implant size with a range of 0.948-0.995 and 0.919-0.988, respectively. Inter-observer reliability for femoral and tibial implant size showed an ICC range of 0.953-0.982 and 0.839-0.951, respectively. Next to implant size, intra- and inter-observer reliability demonstrated good to an excellent agreement (ICC > 0.75) for 7 out of 12 remaining parameters and 6 out of 12 remaining parameters, respectively. CONCLUSION: Preoperative planning of TKA implant size using MRI-based PSI showed excellent intra- and inter-observer reliability. Further research on the comparison of predicted implant size preoperatively to intraoperative results is needed.

Consistency in patient-reported outcome measures after total knee arthroplasty using patient-specific instrumentation: a 5-year follow-up of 200 consecutive cases.

PURPOSE: The purpose of this study was to evaluate the 5-year follow-up results of the first 200 total knee arthroplasties (TKA) performed by one high-volume surgeon, using patient-specific information (PSI). To date, there has been no other research into the mid-term follow-up of TKA performed using PSI. MATERIALS AND METHODS: A total of 184 consecutive patients (200 TKA) were evaluated. Outcome measures included implant survival rate, adverse events, and the following patient-reported outcome measures (PROMs); Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Oxford Knee Score (OKS), Pain Visual Analogue Score (VAS) and EuroQol-5D Score (EQ-5D). RESULTS: Revision surgery was performed for late secondary prosthetic joint infection (n = 1, total revision), aseptic loosening (n = 1, tibial component revision), instability (n = 1, isolated polyethylene insert exchange), and polyethylene insert breakage (n = 1, isolated polyethylene insert exchange). Other adverse events were as follows: debridement, antibiotics and implant retention for early prosthetic joint infection (n = 1), surgical debridement for haemarthrosis (n = 1), superficial wound infection (n = 2), thromboembolic events (n = 2), compartment syndrome (n = 1), and nerve injury (n = 2). All median outcome scores for patient reported outcome measures at 5 years improved significantly compared with the preoperative values (p ≤ 0.05). Median outcome scores were not significantly different between 1- and 5-year moments of follow-up, except for a significant decrease of EQ-VAS (p ≤ 0.05) between these two follow-up moments. CONCLUSION: PROMs are consistent for 5-year follow-up of TKA using PSI. After 5 years of follow-up, revision surgery for any reason occurred in four patients (2%). LEVEL OF EVIDENCE: III.

The Role of the Social Network in Access to Psychosocial Services for Migrant Elderly-A Qualitative Study.

Abstract:Background: Despite high prevalence of mental problems among elderly migrants in The Netherlands, the use of psychosocial care services by this group is low. Scientific evidence points at the crucial role of social support for mental health and the use of psychosocial services. We therefore explored the role of social networks in the access to psychosocial care among elderly migrants in The Netherlands. Methods: A qualitative study was conducted using semi-structured group interviews and individual interviews. The eight group and eleven individual interviews (respectively n = 58 and n = 11) were conducted in The Netherlands with Turkish, Moroccan, Surinamese, and Dutch elderly. The data were analysed through coding and comparing fragments and recognizing patterns. Results: Support of the social network is important to navigate to psychosocial care and is most frequently provided by children. However, the social network of elderly migrants is generally not able to meet the needs of the elderly. This is mostly due to poor mental health literacy of the social network, taboo, and stigma around mental illness and the busy lives of the social network members. Conclusions: Strategies to address help-seeking barriers should consider mental health literacy in elderly migrants as well as their social networks, and counteract taboos and stigma of mental health problems.

Measurement of lower limb alignment: there are within-person differences between weight-bearing and non-weight-bearing measurement modalities.

PURPOSE: Previous studies have compared weight-bearing mechanical leg axis (MLA) measurements to non-weight-bearing measurement modalities. Most of these studies compared mean or median values and did not analyse within-person differences between measurements. This study evaluates the within-person agreement of MLA measurements between weight-bearing full-length radiographs (FLR) and non-weight-bearing measurement modalities (computer-assisted surgery (CAS) navigation or MRI). MATERIALS AND METHODS: Two independent observers measured the MLA on pre- and postoperative weight-bearing FLR in 168 patients. These measurements were compared to non-weight-bearing measurements obtained by CAS navigation or MRI. Absolute differences in individual subjects were calculated to determine the agreement between measurement modalities. Linear regression was used to evaluate the possibility that other independent variables impact the differences in measurements. RESULTS: A difference was found in preoperative measurements between FLR and CAS navigation (mean of 2.5° with limit of agreement (1.96 SD) of 6.4°), as well as between FLR and MRI measurements (mean of 2.4° with limit of agreement (1.96 SD) of 6.9°). Postoperatively, the mean difference between MLA measured on FLR compared to CAS navigation was 1.5° (limit of agreement (1.96 SD) of 4.6°). Linear regression analysis showed that weight-bearing MLA measurements vary significantly from non-weight-bearing MLA measurements. Differences were more severe in patients with mediolateral instability (p = 0.010), age (p = 0.049) and ≥3° varus or valgus alignment (p = 0.008). CONCLUSION: The clinical importance of this study lies in the finding that there are within-person differences between weight-bearing and non-weight-bearing measurement modalities. This has implications for preoperative planning, performing total knee arthroplasty (TKA), and clinical follow-up after TKA surgery using CAS navigation or patient-specific instrumentation. LEVEL OF EVIDENCE: III.

Patient-specific instruments for total knee arthroplasty can accurately predict the component size as used peroperative.

PURPOSE: Patients-specific instruments (PSI) for implantation of total knee arthroplasty (TKA) can be used to predict the implant size for both the femur and the tibia component. This study aims to determine the impact of approval of the PSI planning for TKA on the frequency of, and reason for intraoperative changes of implant sizes. METHODS: The clinical records of 293 patients operated with MRI- (90.4 %) and CT-based (9.6 %) PSI were reviewed for actual used implant size. Preoperative default planning from the technician and approved planning by the operating surgeon were compared with the intraoperative implanted component size for both the femur and tibia. Intraoperative reason for not following the default sizes was outdated. Furthermore, MRI- and CT-based PSI were compared for these outcomes. RESULTS: In 93.9 and 91.1 % for, respectively, the femur and tibia (n.s.), the surgeon planned size was implanted during surgery. The predicted size of the femur (p < 0.00) and the tibia (p < 0.00) component planned by a technician differed from the implanted component sizes in 62 (21.2 %) and 51 (17.4 %) patients, respectively. In 17 cases, the femoral component size was adapted intraoperative based on the expert opinion of the operating surgeon. In 26 cases, the tibia component was changed during the surgery because of a mediolateral overhang, sclerotic bone, medial or lateral release, limited extension and/or fixed varus deformity. The results between the MRI- and CT-based PSI did not differ (n.s.). CONCLUSIONS: PSI is a tool to help the surgeon to achieve the best possible results during TKA. The planning made by a technician should always be validated and approved by the operating surgeon who has the ultimate responsibility regarding the operation. With PSI, the operating surgeon is able to minimize intraoperative implant size errors in advance to improve operating room efficiency with possible lowering hospital costs per procedure. LEVELS OF EVIDENCE: III.