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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. [ABSTRACT FROM AUTHOR]

Background: The CLN2 Clinical Rating Scale evaluates disease progression in CLN2 disease, an ultra-rare, neurodegenerative disorder with late infantile onset. To validate the Clinical Rating Scale, a comparison with the Pediatric Quality of Life Inventory (PedsQL) was conducted utilising clinical trial data investigating cerliponase alfa use in CLN2 disease. Methods: Linear regression and mixed effects models were used to investigate the relationship between the Clinical Rating Scale and PedsQL using open-label, single-arm, phase 1/2 (NCT01907087) and ongoing extension study (NCT02485899) data of 23 children with CLN2 disease treated with cerliponase alfa for ≥96 weeks. Results: Correlations between the four Clinical Rating Scale domains were low. Linear mixed effects analyses showed significant correlation between PedsQL and Clinical Rating Scale (Total score or motor-language [ML] score adjusted p-values <0.05), driven by the relationship with the PedsQL Physical domain. A statistically significant relationship was identified between the Clinical Rating Scale motor domain and PedsQL (Total score: adjusted p-value = 0.048, parameter estimate [PE] = 8.10; Physical domain score: adjusted p-value = 0.012; PE = 13.79). Conclusions: Each domain of the Clinical Rating Scale provides unique information on disease state. Validity of the scale is supported by its relationship with the PedsQL. Among the four domains of the Clinical Rating Scale, motor has the highest correlation to PedsQL, suggesting motor function as a driver of patients' quality of life. The lack of association between the remaining domains of the Clinical Rating Scale and PedsQL suggests that additional disease-specific measures may be needed to fully capture the quality of life impact of CLN2 disease. Trial registration: NCT01907087, NCT02485899. [ABSTRACT FROM AUTHOR]

Background: Utility studies enable preference-based quantification of a disease's impact on patients' health-related quality of life (HRQoL). It is often difficult to obtain utility values for rare, neurodegenerative conditions due to cognitive burden of direct elicitation methods, and the limited size of patient/caregiver populations. CLN2 disease (neuronal ceroid lipofuscinosis type 2) is an ultra-rare, progressive condition, for which there are no published utility data fully capturing all disease stages. This case study demonstrates how utility values can be estimated for ultra-rare paediatric diseases by asking clinicians to complete EQ-5D-5L questionnaires based on vignettes describing the stages of CLN2 disease.Methods: An indirect elicitation method using proxy-reporting by clinical experts was adopted. Eighteen vignettes were developed, describing nine progressive disease stages as defined by motor and language domain scores of the CLN2 Clinical Rating Scale, in individuals treated with cerliponase alfa or standard care. Eight clinical experts with experience of treating CLN2 disease with cerliponase alfa and current standard care completed the proxy version 2 EQ-5D-5L online after reading these vignettes. Resulting scores were converted to EQ-5D-5L utility values for each disease stage, using UK, German and Spanish value sets.Results: Utility values, which are typically anchored by 0 (equivalent to death) and 1 (full health), decreased with CLN2 disease progression (results spanned the maximum range of the utility scale). Assigned utility values were consistently higher for patients receiving cerliponase alfa than standard care; differences were statistically significant for the 6 most severe disease stages (p < 0.05). Analysis of the individual dimensions of the EQ-5D-5L showed that greatest differences between patients treated with cerliponase alfa and standard care occurred in the pain dimension (differences in mean scores ranged between no difference and 1.8), with notable differences also observed in the anxiety/depression dimension (differences in mean scores ranged between 0.1 and 1.0).Conclusions: This study demonstrates a feasible methodology for eliciting utility values in CLN2 disease, indicating HRQoL declines with disease progression. Vignettes describing patients receiving cerliponase alfa were consistently assigned higher utility values for the same disease state, suggesting this treatment improves HRQoL compared with standard care. Trial registration NCT01907087, NCT02485899. [ABSTRACT FROM AUTHOR]

Objectives: To identify challenges that affect the feasibility and rigor of economic models in rare diseases and strategies that manufacturers have employed in health technology assessment submissions to demonstrate the value of new orphan products that have limited study data.Methods: Targeted reviews of PubMed, the National Institute for Health and Care Excellence's (NICE's) Highly Specialised Technologies (HST), and the Scottish Medicines Consortium's (SMC's) ultra-orphan submissions were performed.Results: A total of 19 PubMed studies, 3 published NICE HSTs, and 11 ultra-orphan SMC submissions were eligible for inclusion. In rare diseases, a number of different factors may affect the model's ability to comply with good practice recommendations. Many products for the treatment of rare diseases have an incomplete efficacy and safety profile at product launch. In addition, there is often limited available natural history and epidemiology data. Information on the direct and indirect cost burden of an orphan disease also may be limited, making it difficult to estimate the potential economic benefit of treatment. These challenges can prevent accurate estimation of a new product's benefits in relation to costs. Approaches that can address such challenges include using patient and/or clinician feedback to inform model assumptions; data from disease analogues; epidemiological techniques, such as matching-adjusted indirect comparison; and long-term data collection.Conclusions: Modeling in rare diseases is often challenging; however, a number of approaches are available to support the development of model structures and the collation of input parameters and to manage uncertainty. [ABSTRACT FROM AUTHOR]

Abstract: Growing demand for tissues and organs for transplantation and the inability to meet this need using by autogeneic (from the host) or allogeneic (from the same species) sources has led to the rapid development of tissue engineering as an alternative. Tissue engineering aims to replace or facilitate the regrowth of damaged or diseased tissue by applying a combination of biomaterials, cells and bioactive molecules. This review focuses on synthetic polymers that have been used for tissue growth scaffold fabrication and their applications in both cell and extracellular matrix support and controlling the release of cell growth and differentiation supporting drugs. [Copyright &y& Elsevier]

Background: Morquio A (MPS IVA) is a rare disease characterised by a deficiency of N-acetylgalactosamine-6 sulfatase (GALNS) and presenting with short stature, abnormal gait, cervical spine instability and shortened lifespan. Purpose: To prepare a systematic review of the prevalence of Morquio A in multiple countries and suggest recommendations for reporting rare diseases. Methods: Medline, Medline In-Process, Medline Daily Update, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database and PROSPERO were searched from inception to October 2013 to identify relevant information on the epidemiology of Morquio A. Forty Patient Organisation Representatives (POR) and Key Opinion Leaders (KOL) across 24 countries were contacted for data. Observational studies were included and case reports were excluded. Searches were performed without date or language restriction. Two researchers independently screened and extracted data. Quality of study reporting was assessed using a checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology). Point or birth prevalence was stratified according to diagnostic method and discussed narratively. Results: In total 9,074 records were retrieved from searching and 25 studies were included for data extraction. Twenty out of 40 KOL and POR responded (50%) and 9 provided data (23%). Point prevalence of Morquio A was 1 per 926,000 in Australia, 1 per 1,872,000 in Malaysia and 1 per 599,000 in UK and Morquio (unclassified) was 1 per 323, 000 in Denmark. Birth prevalence of Morquio A (using recommended diagnostic methods) ranged from 1 per 71,000 in UAE to 1 per 500,000 in Japan. All results were compromised by poor study reporting and internal validity. Conclusions: The review highlighted that there is a misunderstanding of the definitions for prevalence and incidence in the field; that studies were poorly reported (diagnostic methods and patient characteristics) and that no suitable quality assessment tool exists. Overestimation and underestimation of prevalence data can occur. Bespoke reporting guidelines and a quality assessment tool specifically for prevalence of rare diseases are recommended. [ABSTRACT FROM AUTHOR]

Background: Morquio A (MPS IVA) is a rare disease characterised by a deficiency of N-acetylgalactosamine-6 sulfatase (GALNS) and presenting with short stature, abnormal gait, cervical spine instability and shortened lifespan.Purpose: To prepare a systematic review of the prevalence of Morquio A in multiple countries and suggest recommendations for reporting rare diseases.Methods: Medline, Medline In-Process, Medline Daily Update, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database and PROSPERO were searched from inception to October 2013 to identify relevant information on the epidemiology of Morquio A. Forty Patient Organisation Representatives (POR) and Key Opinion Leaders (KOL) across 24 countries were contacted for data. Observational studies were included and case reports were excluded. Searches were performed without date or language restriction. Two researchers independently screened and extracted data. Quality of study reporting was assessed using a checklist adapted from STROBE (STrengthening the Reporting of OBservational studies in Epidemiology). Point or birth prevalence was stratified according to diagnostic method and discussed narratively.Results: In total 9,074 records were retrieved from searching and 25 studies were included for data extraction. Twenty out of 40 KOL and POR responded (50%) and 9 provided data (23%). Point prevalence of Morquio A was 1 per 926,000 in Australia, 1 per 1,872,000 in Malaysia and 1 per 599,000 in UK and Morquio (unclassified) was 1 per 323, 000 in Denmark. Birth prevalence of Morquio A (using recommended diagnostic methods) ranged from 1 per 71,000 in UAE to 1 per 500,000 in Japan. All results were compromised by poor study reporting and internal validity.Conclusions: The review highlighted that there is a misunderstanding of the definitions for prevalence and incidence in the field; that studies were poorly reported (diagnostic methods and patient characteristics) and that no suitable quality assessment tool exists. Overestimation and underestimation of prevalence data can occur. Bespoke reporting guidelines and a quality assessment tool specifically for prevalence of rare diseases are recommended. [ABSTRACT FROM AUTHOR]