Generating health technology assessment evidence for rare diseases

Objectives: Rare diseases are often heterogeneous in their progression and response to treatment, with only a small population for study. This provides challenges for evidence generation to support HTA, so novel research methods are required. Methods: Discussion with an expert panel was augmented with references and case studies to explore robust approaches for HTA evidence generation for rare disease treatments. Results: Traditional RCTs can be modified using sequential, three-stage or adaptive designs to gain more power from a small patient population or to focus trial design. However, such designs need to maintain important design aspects such as randomization and blinding and be analyzed to take account of the multiple analyses performed. N-of-1 trials use within-patient randomization to test repeat periods of treatment and control until a response is clear. Such trials could be particularly valuable for rare diseases and when prospectively planned across several patients and analyzed using Bayesian techniques, a population effect can be estimated that might be of value to HTA. When the optimal outcome is unclear in a rare disease, disease specific patient reported outcomes can elucidate impacts on patients’ functioning and wellbeing. Likewise, qualitative research can be used to elicit patients’ perspectives, with just a small number of patients. Conclusions: International consensus is needed on ways to improve evidence collection and assessment of technologies for rare diseases, which recognize the value of novel study designs and analyses in a setting where the outcomes and effects of importance are yet to be agreed.</p

Strain Measurements of Chondrules and Refraction Inclusion in Allende

This study uses traditional strain measurement techniques, combined with X-ray computerized tomography (CT), to evaluate petrographic evidence in the Allende CV3 chondrite for preferred orientation and to measure strain in three dimensions. The existence of petrofabrics and lineations was first observed in carbonaceous meteorites in the 1960's. Yet, fifty years later only a few studies have reported that meteorites record such features. Impacts are often cited as the mechanism for this feature, although plastic deformation from overburden and nebular imbrication have also been proposed. Previous work conducted on the Leoville CV3 and the Parnallee LL3 chondrites, exhibited a minimum uniaxial shortening of 33% and 21%, respectively. Petrofabrics in Allende CV3 have been looked at before; previous workers using Electron Back Scatter Diffraction (EBSD) found a major-axis alignment of olivine inside dark inclusions and an "augen"-like preferred orientation of olivine grains around more competent chondrule

Evidence for impact induced pressure gradients on the Allende CV3 parent body: Consequences for fluid and volatile transport

Carbonaceous chondrites, such as those associated with the Vigarano (CV) parent body, exhibit a diverse range of oxidative/reduced alteration mineralogy (McSween, 1977). Although fluids are often cited as the medium by which this occurs (Rubin, 2012), a mechanism to explain how this fluid migrates, and why some meteorite subtypes from the same planetary body are more oxidized than others remains elusive. In our study we examined a slab of the well-known Allende (CV3OxA) meteorite. Using several petrological techniques (e.g., Fry's and Flinn) and Computerized Tomography (CT) we discover it exhibits a strong penetrative planar fabric, resulting from strain partitioning among its major components: Calcium–Aluminum-rich Inclusions (CAIs) (64.5%CT) > matrix (21.5%Fry) > chondrules (17.6%CT). In addition to the planar fabric, we found a strong lineation defined by the alignment of the maximum elongation of flattened particles interpreted to have developed by an impact event. The existence of a lineation could either be non-coaxial deformation, or the result of a mechanically heterogeneous target material. In the later case it could have formed due to discontinuous patches of sub-surface ice and/or fabrics developed through prior impact compaction (MacPherson and Krot, 2014), which would have encouraged preferential flow within the target material immediately following the impact, compacting pore spaces. We suggest that structurally controlled movement of alteration fluids in the asteroid parent body along pressure gradients contributed to the formation of secondary minerals, which may have ultimately lead to the different oxidized subtypes

Contrasting Size Distributions of Chondrules and Inclusions in Allende CV3

There are several leading theories on the processes that led to the formation of chondrites, e.g., sorting by mass, by X-winds, turbulent concentration, and by photophoresis. The juxtaposition of refractory inclusions (CAIs) and less refractory chondrules is central to these theories and there is much to be learned from their relative size distributions. There have been a number of studies into size distributions of particles in chondrites but only on relatively small scales primarily for chondrules, and rarely for both Calcium Aluminum-rich Inclusions (CAIs) and chondrules in the same sample. We have implemented macro-scale (25 cm diameter sample) and high-resolution microscale sampling of the Allende CV3 chondrite to create a complete data set of size frequencies for CAIs and chondrules

Particle size distributions in chondritic meteorites: Evidence for pre-planetesimal histories

Magnesium-rich silicate chondrules and calcium-, aluminum-rich refractory inclusions (CAIs) are fundamental components of primitive chondritic meteorites. It has been suggested that concentration of these early-formed particles by nebular sorting processes may lead to accretion of planetesimals, the planetary bodies that represent the building blocks of the terrestrial planets. In this case, the size distributions of the particles may constrain the accretion process. Here we present new particle size distribution data for Northwest Africa 5717, a primitive ordinary chondrite (ungrouped 3.05) and the well-known carbonaceous chondrite Allende (CV3). Instead of the relatively narrow size distributions obtained in previous studies (Ebel et al., 2016, Friedrich et al., 2015, Paque and Cuzzi, 1997, and references therein), we observed broad size distributions for all particle types in both meteorites. Detailed microscopic image analysis of Allende shows differences in the size distributions of chondrule subtypes, but collectively these subpopulations comprise a composite “chondrule” size distribution that is similar to the broad size distribution found for CAIs. Also, we find accretionary ‘dust’ rims on only a subset (∼15–20%) of the chondrules contained in Allende, which indicates that subpopulations of chondrules experienced distinct histories prior to planetary accretion. For the rimmed subset, we find positive correlation between rim thickness and chondrule size. The remarkable similarity between the size distributions of various subgroups of particles, both with and without fine grained rims, implies a common size sorting process. Chondrite classification schemes, astrophysical disk models that predict a narrow chondrule size population and/or a common localized formation event, and conventional particle analysis methods must all be critically reevaluated. We support the idea that distinct “lithologies” in NWA 5717 are nebular aggregates of chondrules. If ≥cm-sized aggregates of chondrules can form it will have implications for planet formation and suggests the sticking stage is where the preferential size physics is operating

Genetic Testing in Emerging Economies (GenTEE)

Drivers, barriers and opportunities for genetic testing services in emerging economies: the GenTEE (Genetic Testing in Emerging Economies) project Background: Due to the epidemiological transition in the emerging economies of China, East Asia, India, Latin America, the Middle East and South Africa, these economies are facing (i) an increasing proportion of morbidity and mortality due to congenital and genetic conditions, (ii) a rising need for genetic services to improve patient outcomes and overall population health. These economies are facing the challenge how: (i) to ensure the successful translation of genetic/genomics laboratory and academic research into quality assured pathways, (ii) to develop a service delivery infrastructure that leads to equitable and affordable access to high quality genetic/genomic testing services. Objectives: (i) to document and compare current practices and the state of genetic service provision in eight emerging economies: Argentina, Brazil, China, Egypt, India, Oman, Philippines and South Africa, (ii) to identify current knowledge gaps and unmet service needs. The GenTEE international project is intended to inform policy decisions for the challenges of delivering equitable high quality genetic services and to promote international collaboration for capacity building. Methods: (i) a standardized survey that is the first of its worldwide that allows comparison of services internationally across a number of key dimensions by using a core set of indicators, selected by the GenTEE consortium for their relevance and comparability, (ii) capacity building demonstration projects. To date, the GenTEE project has completed its survey that maps the current state of genetic services in the participating countries and identifies current drivers, barriers and opportunities for genetic services development. Results: There is no equitable access to genetic services in all countries mainly due to financial barriers (underfunded fragmented public services, out-of-pocket expenses tend to be the norm for genetic testing services), geographical barriers (concentration of services in main cities) and skill gaps, resulting in inequitable services or delayed access. The development of services in the private sector is opportunistic and mostly technology and market driven. There is a marked lack of standard operating procedures and agreed quality assessment processes for new technologies. Discussion: International collaborative networks can provide support for capacity building and help to strengthen the provision of quality genetic/genomic services in emerging economies.JRC.I.1-Chemical Assessment and Testin

Cost-effectiveness of Simvastatin plus Ezetimibe for Cardiovascular Prevention in CKD:Results of the Study of Heart and Renal Protection (SHARP)

Background Simvastatin, 20 mg, plus ezetimibe, 10 mg, daily (simvastatin plus ezetimibe) reduced major atherosclerotic events in patients with moderate to severe chronic kidney disease (CKD) in the Study of Heart and Renal Protection (SHARP), but its cost-effectiveness is unknown. Study Design Cost-effectiveness of simvastatin plus ezetimibe in SHARP, a randomized controlled trial. Setting & Population 9,270 patients with CKD randomly assigned to simvastatin plus ezetimibe versus placebo; participants in categories by 5-year cardiovascular risk (low, = 20%) and CKD stage (3, 4, 5 not on dialysis, or on dialysis therapy). Model, Perspective, & Timeline Assessment during SHARP follow-up from the UK perspective; long-term projections. Intervention Simvastatin plus ezetimibe (2015 UK 1.19 pound per day) during 4.9 years median follow-up in SHARP; scenario analyses with high-intensity statin regimens (2015 UK 0.05- pound 1.06 pound per day). Outcomes Additional health care costs per major atherosclerotic event avoided and per quality-adjusted life-year (QALY) gained. Results In SHARP, the proportional reductions per 1 mmol/L of low-density lipoprotein (LDL) cholesterol reduction with simvastatin plus ezetimibe in all major atherosclerotic events of 20% (95% CI, 6%-32%) and in the costs of vascular hospital episodes of 17% (95% CI, 4%-28%) were similar across participant categories by cardiovascular risk and CKD stage. The 5-year reduction in major atherosclerotic events per 1,000 participants ranged from 10 in low-risk to 58 in high-risk patients and from 28 in CKD stage 3 to 36 in patients on dialysis therapy. The net cost per major atherosclerotic event avoided with simvastatin plus ezetimibe compared to no LDL-lowering regimen ranged from 157,060 pound in patients at low risk to 15,230 pound in those at high risk (30,500- pound 39,600 pound per QALY); and from 47,280 pound in CKD stage 3 to 28,180 pound in patients on dialysis therapy (13,000- pound 43,300 pound per QALY). In scenario analyses, generic high-intensity statin regimens were estimated to yield similar benefits at substantially lower cost. Limitations High-intensity statin-alone regimens were not studied in SHARP. Conclusions Simvastatin plus ezetimibe prevented atherosclerotic events in SHARP, but other less costly statin regimens are likely to be more cost-effective for reducing cardiovascular risk in CKD. (C) 2016 The Authors. Published by Elsevier Inc. on behalf of the National Kidney Foundation, Inc

The Challenge of Transparency and Validation in Health Economic Decision Modelling:A View from Mount Hood

Transparency in health economic decision modelling is important for engendering confidence in the models and in the reliability of model-based cost-effectiveness analyses. The Mount Hood Diabetes Challenge Network has taken a lead in promoting transparency through validation with biennial conferences in which diabetes modelling groups meet to compare simulated outcomes of pre-specified scenarios often based on the results of pivotal clinical trials. Model registration is a potential method for promoting transparency, while also reducing the duplication of effort. An important network initiative is the ongoing construction of a diabetes model registry (https://www.mthooddiabeteschallenge.com). Following the 2012 International Society for Pharmacoeconomics and Outcomes Research and the Society of Medical Decision Making (ISPOR-SMDM) guidelines, we recommend that modelling groups provide technical and non-technical documentation sufficient to enable model reproduction, but not necessarily provide the model code. We also request that modelling groups upload documentation on the methods and outcomes of validation efforts, and run reference case simulations so that model outcomes can be compared. In this paper, we discuss conflicting definitions of transparency in health economic modelling, and describe the ongoing development of a registry of economic models for diabetes through the Mount Hood Diabetes Challenge Network, its objectives and potential further developments, and highlight the challenges in its construction and maintenance. The support of key stakeholders such as decision-making bodies and journals is key to ensuring the success of this and other registries. In the absence of public funding, the development of a network of modellers is of huge value in enhancing transparency, whether through registries or other means

European ADPKD Forum multidisciplinary position statement on autosomal dominant polycystic kidney disease care

Autosomal dominant polycystic kidney disease (ADPKD) is a chronic, progressive condition characterised by the development and growth of cysts in the kidneys and other organs and by additional systemic manifestations. Individuals with ADPKD should have access to life-long, multidisciplinary, specialist and patient-centred care involving: 1) A holistic and comprehensive assessment of the manifestations, complications, prognosis and impact of the disease (in physical, psychological and social terms) on the patient and their family; 2) Access to treatment to relieve symptoms, manage complications, preserve kidney function, lower the risk of cardiovascular disease, and maintain quality of life; 3) Information and support to help patients and their families act as fully informed and active partners in care, i.e. to maintain self-management approaches, deal with the impact of the condition, and participate in decision-making regarding healthcare policies, services and research. Building on discussions at an international Roundtable of specialists and patient advocates involved in ADPKD care, this paper sets out 1) The principles for a patient-centred, holistic approach to the organisation and delivery of ADPKD care in practice, with a focus on multi-specialist collaboration and shared-decision making, 2) The rationale and knowledge base for a Route Map for ADPKD care intended to help patients navigate the services available to them and to help stakeholders and decision-makers take practical steps to ensure that all patients with ADPKD can access the comprehensive multi-specialist care to which they are entitled. Further multispecialty collaboration is encouraged to design and implement these services, and to work with patient organisations to promote awareness building, education, and research

Cost-effectiveness of dopamine agonists and monoamine oxidase B inhibitors in Parkinson’s disease

Background: The PD MED study reported small but persistent benefits in patient‐rated mobility scores and quality of life from initiating therapy with levodopa compared with levodopa‐sparing therapies in early Parkinson's disease (PD). Objectives: The objective was to estimate the cost‐effectiveness of levodopa‐sparing therapy (dopamine agonists or monoamine oxidase type B inhibitors compared with levodopa alone. Methods: PD MED is a pragmatic, open‐label randomized, controlled trial in which patients newly diagnosed with PD were randomly assigned between levodopa‐sparing therapy (dopamine agonists or monoamine oxidase type B inhibitors ) and levodopa alone. Mean quality‐adjusted life‐years and costs were calculated for each participant. Differences in mean quality‐adjusted life‐years and costs between levodopa and levodopa‐sparing therapies and between dopamine agonists and monoamine oxidase type B inhibitors were estimated using linear regression. Results: Over a mean observation period of 4 years, levodopa was associated with significantly higher quality‐adjusted life‐years (difference, 0.18; 95% CI, 0.05–0.30; P &lt; 0.01) and lower mean costs (£3390; £2671–£4109; P &lt; 0.01) than levodopa‐sparing therapies, the difference in costs driven by the higher costs of levodopa‐sparing therapies. There were no significant differences in the costs of inpatient, social care, and institutional care between arms. There was no significant difference in quality‐adjusted life‐years between those allocated dopamine agonists and monoamine oxidase type B inhibitors (0.02; −0.17 to 0.13 in favor of dopamine agonists; P = 0.81); however costs were significantly lower for those allocated monoamine oxidase type B inhibitors (£2321; £1628–£3015; P &lt; 0.01) because of the higher costs of dopamine agonists. There were no significant differences between arms for other costs. Conclusions: Initial treatment with levodopa is highly cost‐effective compared with levodopa‐sparing therapies. Monoamine oxidase type B inhibitors, as initial levodopa‐sparing therapy was more cost‐effective, with similar quality‐adjusted life‐years but lower costs than dopamine agonists