Optically addressable molecular spins for quantum information processing.

Spin-bearing molecules are promising building blocks for quantum technologies as they can be chemically tuned, assembled into scalable arrays, and readily incorporated into diverse device architectures. In molecular systems, optically addressing ground-state spins would enable a wide range of applications in quantum information science, as has been demonstrated for solid-state defects. However, this important functionality has remained elusive for molecules. Here, we demonstrate such optical addressability in a series of synthesized organometallic, chromium(IV) molecules. These compounds display a ground-state spin that can be initialized and read out using light and coherently manipulated with microwaves. In addition, through atomistic modification of the molecular structure, we vary the spin and optical properties of these compounds, indicating promise for designer quantum systems synthesized from the bottom-up.

Spin Fine Structure Reveals Biexciton Geometry in an Organic Semiconductor.

In organic semiconductors, biexcitons are key intermediates in carrier multiplication and exciton annihilation. Their local geometry governs their electronic properties and yet has been challenging to determine. Here, we access the structure of the recently discovered S=2 quintet biexciton state in an organic semiconductor using broadband optically detected magnetic resonance. We correlate the experimentally extracted spin structure with the molecular crystal geometry to identify the specific molecular pairings on which biexciton states reside.

Systematic review of the effectiveness of community-based self-management interventions among primary care COPD patients.

COPD self-management reduces hospital admissions and improves health-related quality of life (HRQoL). However, whilst most patients are managed in primary care, the majority of self-management trials have recruited participants with more severe disease from secondary care. We report the findings of a systematic review of the effectiveness of community-based self-management interventions in primary care patients with COPD. We systematically searched eleven electronic databases and identified 12 eligible randomised controlled trials with seven included in meta-analyses for HRQoL, anxiety and depression. We report no difference in HRQoL at final follow-up (St George's Respiratory Questionnaire total score -0.29; 95%CI -2.09, 1.51; I2 0%), nor any difference in anxiety or depression. In conclusion, supported self-management interventions delivered in the community to patients from primary care do not appear to be effective. Further research is recommended to identify effective self-management interventions suitable for primary care populations, particularly those with milder disease.

Site-selective measurement of coupled spin pairs in an organic semiconductor.

From organic electronics to biological systems, understanding the role of intermolecular interactions between spin pairs is a key challenge. Here we show how such pairs can be selectively addressed with combined spin and optical sensitivity. We demonstrate this for bound pairs of spin-triplet excitations formed by singlet fission, with direct applicability across a wide range of synthetic and biological systems. We show that the site sensitivity of exchange coupling allows distinct triplet pairs to be resonantly addressed at different magnetic fields, tuning them between optically bright singlet ([Formula: see text]) and dark triplet quintet ([Formula: see text]) configurations: This induces narrow holes in a broad optical emission spectrum, uncovering exchange-specific luminescence. Using fields up to 60 T, we identify three distinct triplet-pair sites, with exchange couplings varying over an order of magnitude (0.3-5 meV), each with its own luminescence spectrum, coexisting in a single material. Our results reveal how site selectivity can be achieved for organic spin pairs in a broad range of systems.

Room temperature magneto-optic effect in silicon light-emitting diodes.

In weakly spin-orbit coupled materials, the spin-selective nature of recombination can give rise to large magnetic-field effects, e.g. on the electro-luminescence of molecular semiconductors. Although silicon has weak spin-orbit coupling, observing spin-dependent recombination through magneto-electroluminescence is challenging: silicon's indirect band-gap causes an inefficient emission and it is difficult to separate spin-dependent phenomena from classical magneto-resistance effects. Here we overcome these challenges and measure magneto-electroluminescence in silicon light-emitting diodes fabricated via gas immersion laser doping. These devices allow us to achieve efficient emission while retaining a well-defined geometry, thus suppressing classical magnetoresistance effects to a few percent. We find that electroluminescence can be enhanced by up to 300% near room temperature in a seven Tesla magnetic field, showing that the control of the spin degree of freedom can have a strong impact on the efficiency of silicon LEDs.

Epigenetic biomarkers in progression from non-dysplastic Barrett's oesophagus to oesophageal adenocarcinoma: a systematic review protocol.

INTRODUCTION: Barrett's oesophagus (BO), a metaplastic condition affecting the lower oesophagus due to long-standing gastro-oesophageal reflux and chronic inflammation, is a precursor lesion for oesophageal adenocarcinoma (OADC). There is no clinical test to predict which patients with BO will progress to OADC. The British Society of Gastroenterology recommends endoscopic surveillance of patients with BO. Epigenetic changes have been well characterised in the neoplastic progression of ulcerative colitis to colonic carcinoma, another gastrointestinal cancer associated with chronic inflammation. This systematic review protocol aims to identify and evaluate studies which examine epigenetic biomarkers in BO and their association with progression to OADC. METHODS AND ANALYSIS: All prospective and retrospective primary studies, and existing systematic reviews investigating epigenetic markers including DNA methylation, histone modification, chromatin remodelling, micro and non-coding RNAs of all types will be eligible for inclusion. Eligible patients are those over the age of 18 with BO, BO with dysplasia, OADC or unspecified oesophageal cancer. A comprehensive search of bibliographic databases using combinations of text and index words relating to the population, prognostic markers and outcome will be undertaken with no language restrictions. Results will be screened by 2 independent reviewers and data extracted using a standardised proforma. The quality and risk of bias of individual studies will be assessed using the Quality in Prognostic Studies (QUIPS) tool. A narrative synthesis of all evidence will be performed with key findings tabulated. Meta-analysis will be considered where studies and reported outcomes are considered sufficiently homogeneous, both clinically and methodologically. Findings will be interpreted in the context of the quality of included studies. The systematic review will be reported according to PRISMA guidelines. ETHICS AND DISSEMINATION: This is a systematic review of completed studies and no ethical approval is required. Findings from the full systematic review will be submitted for publication and presentation at national and international conferences which will inform future research on risk stratification in patients with BO. REVIEW REGISTRATION NUMBER: CRD42016038654.

The Effects of Different Aspirin Dosing Frequencies and the Timing of Aspirin Intake in Primary and Secondary Prevention of Cardiovascular Disease: A Systematic Review.

Enhancing the effectiveness of aspirin by tailoring administration regimens is an important question among health professionals. We conducted a systematic review to evaluate the evidence on the effects of different aspirin regimens in terms of timing (chronotherapy) or frequency of dosing in the prevention of cardiovascular disease. Only two out of the 28 included studies reported long-term cardiovascular outcomes, highlighting an evidence gap that future research should address. The remaining 26 studies used surrogate outcomes.

Patients' experiences of deep brain stimulation for Parkinson's disease: a qualitative systematic review and synthesis.

OBJECTIVE: To review and synthesise qualitative research studies that have explored patients' experience of deep brain stimulation (DBS) in advanced Parkinson's disease (PD). DESIGN: Systematic review and meta-synthesis of 7 original papers, using metaethnography. SETTING: Studies conducted in Denmark, France and Sweden. PARTICIPANTS: 116 patients who had undergone DBS and 9 spouses of patients. RESULTS: Prior to surgery, the experience of advancing PD is one of considerable loss and a feeling of loss of control. There are significant hopes for what DBS can bring. Following surgery, a sense of euphoria is described by many, although this does not persist and there is a need for significant transitions following this. We suggest that normality as a concept is core to the experience of DBS and that a sense of control may be a key condition for normality. Experience of DBS for patients and spouses, and of the transitions that they must undertake, is influenced by their hopes of what surgery will enable them to achieve, or regain (ie, a new normality). CONCLUSIONS: There is a need for further qualitative research to understand the nature of these transitions to inform how best patients and their spouses can be supported by healthcare professionals before, during and after DBS. In assessing the outcomes of DBS and other treatments in advanced PD, we should consider how to capture holistic concepts such as normality and control. Studies that examine the outcomes of DBS require longer term follow-up.

Cost-effectiveness of transcatheter aortic valve implantation (TAVI) for aortic stenosis in patients who are high risk or contraindicated for surgery: a model-based economic evaluation.

BACKGROUND: Calcific aortic stenosis (AS) is a common valvular heart disease. Patients with severe symptomatic AS typically survive less than 3 years. In such patients, intervention with surgical aortic valve replacement (SAVR) may increase survival. However, in some patients SAVR is associated with a high operative risk and medical management is considered appropriate. Transcatheter aortic valve implantation (TAVI) is a relatively recent technique to avoid the invasiveness of open surgery. This procedure has been used for the treatment of patients with severe AS who are unsuitable for SAVR (because it is too high risk and/or for other reasons such as suffering from porcelain aorta) and is increasingly being considered for other patients. OBJECTIVES: To determine the cost-effectiveness of TAVI being made available for patients who are high risk or contraindicated for SAVR through a review of existing economic evaluations and development of a model. DATA SOURCES AND REVIEW METHODS: Bibliographic databases [MEDLINE, EMBASE, The Cochrane Library, Health Technology Assessment (HTA), Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database (EED), Centre for Reviews and Dissemination HTA, DARE and NHS EED], guideline resources, current trials registers, websites/grey literature and manufacturers' websites, and consultation with clinical experts were used to identify studies for the review and information for the model. Databases were searched from 2007 to November 2010. A model was built to assess the cost-effectiveness of TAVI separately in patients suitable and unsuitable for SAVR, together with overall results for the effect of making TAVI available. Substantial deterministic sensitivity analysis was carried out together with probabilistic sensitivity analysis. RESULTS: No fully published cost-effectiveness studies were found. Modelling patients not suitable for SAVR, the base-case results show TAVI as more costly but more effective than medical management, with an incremental cost-effectiveness ratio (ICER) of £12,900 per quality-adjusted life-year (QALY). The ICER was below £20,000 per QALY for over 99% of model runs in the probabilistic sensitivity analysis. For patients suitable for SAVR, the comparator with TAVI is a mixture of SAVR and medical management. TAVI is both more costly and less effective than this comparator assuming that most patients would receive SAVR in the absence of TAVI. This is robust to a number of assumption changes about the effects of treatment, but sensitive to assumptions about the proportion of patients receiving SAVR in the comparator. If the use of TAVI is extended to include more patients suitable for SAVR, the overall results from the model become less favourable for TAVI. LIMITATIONS: The modelling involves extrapolation of short-term data and the comparison between TAVI and SAVR is not based on randomised data. More trial data on the latter have been published since the modelling was undertaken. CONCLUSIONS: The results for TAVI compared with medical management in patients unsuitable for surgery are reasonably robust and suggest that TAVI is likely to be cost-effective. For patients suitable for SAVR, TAVI could be both more costly and less effective than SAVR. The overall results suggest that, if a very substantial majority of TAVI patients are those unsuitable for SAVR, the cost-effectiveness of a broad policy of introducing TAVI may fall below £20,000 per QALY. Future work required includes the incorporation of new data made available after completion of this work. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Prucalopride for the treatment of women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of prucalopride for the treatment of women with chronic constipation in whom standard laxative regimens have failed to provide adequate relief. The ERG report is based on the manufacturer's submission (MS) to the National Institute for Health and Clinical Excellence as part of the single technology appraisal process. In the submission, quality-of-life data [Patient Assessment of Constipation Quality of Life (PAC-QOL) and Patient Assessment of Constipation Symptoms (PAC-SYM) questionnaires] from trials of prucalopride were extrapolated to EQ-5D (European Quality of Life-5 Dimensions) data and used to inform effectiveness in an economic model. Response rates to prucalopride were derived from observed response rates in trials, defined as the proportion of patients achieving an average of three or more spontaneous complete bowel movements over the 4- or 12-week trial periods. Adult (18-64 years) and elderly (≥ 65 years) patients were considered separately in the model. Cost-effectiveness was determined from estimated improvements in EQ-5D and anticipated response rates, adjusted for baseline severity of chronic constipation. The ERG considered that the patients participating in these trials were not representative of those in the licensed indication. They were not all refractory to laxatives, and baseline EQ-5D scores showed a large spread in quality of life, with many patients experiencing little baseline dissatisfaction. The mapping of quality-of-life data from trials (PAC-QOL and PAC-SYM data) to EQ-5D was unclear and invalidated. The assumption of the long-term effectiveness and safety of prucalopride to 1 year was considered unjustified. There was no justification or sources given for coefficients used to predict effectiveness in the economic model, and no costs other than the cost of prucalopride were incorporated into the model. Owing to the many areas of uncertainty, particularly the effectiveness of prucalopride in the licensed patient group and its long-term effectiveness and safety, it was considered that the MS provided no evidence for whether prucalopride is effective or not in women with laxative-refractory chronic constipation. Further subgroup analysis of the actual patient group of interest may have better guided decision-making. However, long-term efficacy data, with validated estimates of quality of life incorporated in a well-founded model, would be important for an evidence-based judgement to be made.

Palivizumab for immunoprophylaxis of respiratory syncytial virus (RSV) bronchiolitis in high-risk infants and young children: a systematic review and additional economic modelling of subgroup analyses.

BACKGROUND: Respiratory syncytial virus (RSV) is a seasonal infectious disease, with epidemics occurring annually from October to March in the UK. It is a very common infection in infants and young children and can lead to hospitalisation, particularly in those who are premature or who have chronic lung disease (CLD) or congenital heart disease (CHD). Palivizumab (Synagis®, MedImmune) is a monoclonal antibody designed to provide passive immunity against RSV and thereby prevent or reduce the severity of RSV infection. It is licensed for the prevention of serious lower respiratory tract infection caused by RSV in children at high risk. While it is recognised that a policy of using palivizumab for all children who meet the licensed indication does not meet conventional UK standards of cost-effectiveness, most clinicians feel that its use is justified in some children. OBJECTIVES: To use systematic review evidence to estimate the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of children with or without CLD or CHD who are at high risk of serious morbidity from RSV infection. DATA SOURCES: A systematic review of the literature and an economic evaluation was carried out. The bibliographic databases included the Cochrane Library [Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), Database of Abstracts of Reviews of Effects (DARE) and Health Technology Assessment (HTA)] and five other databases, from inception to 2009. Research registries of ongoing trials including Current Controlled Trials metaRegister, Clinical Trials.gov and the National Institute for Health Research Clinical Research Network Portfolio were also searched. REVIEW METHODS: Searches were conducted for prognostic and hospitalisation studies covering 1950-2009 (the original report searches conducted in 2007 covering the period 1950-2007 were rerun in August 2009 to cover the period 2007-9) and the database of all references from the original report was sifted to find any relevant studies that may have been missed. The risk factors identified from the systematic review of included studies were analysed and synthesised using stata. The base-case decision tree model developed in the original HTA journal publication [Health Technol Assess 2008;12(36)] was used to derive the cost-effectiveness of immunoprophylaxis of RSV using palivizumab in different subgroups of pre-term infants and young children who are at high risk of serious morbidity from RSV infection. Cost-effective spectra of prophylaxis with palivizumab compared with no prophylaxis for children without CLD/CHD, children with CLD, children with acyanotic CHD and children with cyanotic CHD were derived. RESULTS: Thirteen studies were included in this analysis. Analysis of 16,128 subgroups showed that prophylaxis with palivizumab may be cost-effective [at a willingness-to-pay threshold of £30,000/quality-adjusted life-year (QALY)] for some subgroups. For example, for children without CLD or CHD, the cost-effective subgroups included children under 6 weeks old at the start of the RSV season who had at least two other risk factors that were considered in this report and were born at 24 weeks gestational age (GA) or less, but did not include children who were > 9 months old at the start of the RSV season or had a GA of > 32 weeks. For children with CLD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 28 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with acyanotic CHD, the cost-effective subgroups included children < 6 months old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 21 months old at the start of the RSV season. For children with cyanotic CHD, the cost-effective subgroups included children < 6 weeks old at the start of the RSV season who were born at 24 weeks GA or less, but did not include children who were > 12 months old at the start of the RSV season. LIMITATIONS: The poor quality of the studies feeding numerical results into this analysis means that the true cost-effectiveness may vary considerably from that estimated here. There is a risk that the relatively high mathematical precision of the point estimates of cost-effectiveness may be quite inaccurate because of poor-quality inputs. CONCLUSIONS: Prophylaxis with palivizumab does not represent good value for money based on the current UK incremental cost-effectiveness ratio threshold of £30,000/QALY when used unselectively in children without CLD/CHD or children with CLD or CHD. This subgroup analysis showed that prophylaxis with palivizumab may be cost-effective (at a willingness-to-pay threshold of £30,000/QALY) for some subgroups. In summary, the cost-effective subgroups for children who had no CLD or CHD must contain at least two other risk factors apart from GA and birth age. The cost-effective subgroups for children who had CLD or CHD do not necessarily need to have any other risk factors. Future research should be directed towards conducting much larger, better powered and better reported studies to derive better estimates of the risk factor effect sizes. FUNDING: This report was funded by the HTA programme of the National Institute for Health Research.

Clinical effectiveness and cost-effectiveness of stem cell transplantation in the management of acute leukaemia: a systematic review.

BACKGROUND: Acute leukaemia is a group of rapidly progressing cancers of bone marrow and blood classified as either acute myeloid leukaemia (AML) or acute lymphoblastic leukaemia (ALL). Haemopoietic stem cell transplantation (SCT) has developed as an adjunct to or replacement for conventional chemotherapy with the aim of improving survival and quality of life. OBJECTIVES: A systematic overview of the best available evidence on the clinical effectiveness and cost-effectiveness of SCT in the treatment of acute leukaemia. DATA SOURCES: Clinical effectiveness: electronic databases, including MEDLINE, EMBASE and the Cochrane Library, were searched from inception to December 2008 to identify published systematic reviews and meta-analyses. Cochrane CENTRAL, MEDLINE, EMBASE and Science Citation Index (SCI) were searched from 1997 to March 2009 to identify primary studies. Cost-effectiveness: MEDLINE, EMBASE, Database of Abstracts of Reviews of Effects (DARE) and NHS Economic Evaluation Database (NHS EED) were searched from inception to January 2009. STUDY SELECTION: Potentially relevant papers were retrieved and independently checked against predefined criteria by two reviewers (one in the case of the cost-effectiveness review). STUDY APPRAISAL: Included reviews and meta-analyses were critically appraised and data extracted and narratively presented. Included randomised controlled trials (RCTs) and donor versus no donor (DvND) studies were mapped to the evidence covered in existing systematic reviews and meta-analyses according to a framework of 12 decision problems (DPs): DP1 related to SCT in adults with AML in first complete remission (CR1); DP2 to adults with AML in second or subsequent remission or with refractory disease (CR2+); DP3 to children with AML in CR1; DP4 to children with AML in CR2+; DP5 to adults with ALL in CR1; DP6 to adults with ALL in CR2+; DP7 to children with ALL in CR1; DP8 to children with ALL in CR2+; DP9 to comparison of different sources of stem cells in transplantation; DP10 to different conditioning regimens; DP11 to the use of purging in autologous SCT; and DP12 to the use of T-cell depletion in allogeneic SCT. RESULTS: Fifteen systematic reviews/meta-analyses met the inclusion criteria for the review of clinical effectiveness, thirteen of which were published from 2004 onwards. Taking into account the timing of their publications, most reviews appeared to have omitted an appreciable proportion of potentially available evidence. The best available evidence for effectiveness of allogeneic SCT using stem cells from matched sibling donors came from DvND studies: there was sufficient evidence to support the use of allogeneic SCT in DP1 (except in good-risk patients), DP3 (role of risk stratification unclear) and DP5 (role of risk stratification unclear). There was conflicting evidence in DP7 and a paucity of evidence from DvND studies for all decision problems concerning patient groups in CR2+. The best available evidence for effectiveness of autologous SCT came from RCTs: overall, evidence suggested that autologous SCT was either similar to or less effective than chemotherapy. There was a paucity of evidence from published reviews of RCTs for DPs 9-12. Nineteen studies met the inclusion criteria in the cost-effectiveness review, most reporting only cost information and only one incorporating an economic model. Although there is a wealth of information on costs and some information on cost-effectiveness of allogeneic SCT in adults with AML (DPs 1 and 2), there is very limited evidence on relative costs and cost-effectiveness for other DPs. LIMITATIONS: Time and resources did not permit critical appraisal of the primary studies on which the reviews/meta-analyses reviewed were based; there were substantial differences in methodologies, and consequently quantitative synthesis of data was neither planned in the protocol nor carried out; some of the studies were quite old and might not reflect current practice; and a number of the studies might not be applicable to the UK. CONCLUSIONS: Bearing in mind the limitations, existing evidence suggests that sibling donor allogeneic SCT may be more effective than chemotherapy in adult AML (except in good-risk patients) in CR1, childhood AML in CR1 and adult ALL in CR1, and that autologous SCT is equal to or less effective than chemotherapy. No firm conclusions could be drawn regarding the cost-effectiveness of SCT in the UK NHS owing to the limitations given above. Future research should include the impact of the treatments on patients' quality of life as well as information on health service use and costs associated with SCT from the perspective of the UK NHS.

Certolizumab pegol (CIMZIA®) for the treatment of rheumatoid arthritis.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of certolizumab pegol (CZP) for adults with active rheumatoid arthritis (RA) that have not responded adequately to treatment with conventional disease modifying anti-rheumatic drugs (DMARDs) including methotrexate (MTX), in accordance with the licensed indication, based upon the evidence submission from the manufacturer to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The outcome measures included American College of Rheumatology (ACR) 20, 50 and 70 response rates and quality of life measures after 3 months and 6 months of treatment. The ERG examined the submission's search strategies and considered they appeared comprehensive and that it was unlikely that relevant studies would have been missed. Only English language studies were considered in the submission and non-English language studies relevant to the decision problem may possibly have been ignored. The ERG analysed the first submitted economic model so as to itemise in detail clarification points that were brought to the attention of the manufacturer. In response the manufacturer submitted a modified cost-effectiveness analysis. The ERG undertook further analysis of this second model and other additional submitted evidence. The clinical evidence was derived from two multicentre blinded randomised controlled trials (RCTs) comparing CZP + MTX to placebo + MTX (the RAPID 1 and RAPID 2 trials). RAPID 1 lasted 52 weeks with 982 patients and RAPID 2 24 weeks with 619 patients. Evidence for clinical effectiveness of CZP in mono-therapy came from the 24-week FAST4WARD trial with 220 patients that compared CZP (400 mg every 4 weeks) versus placebo. The three key RCTs demonstrated statistically significant superiority of CZP + MTX versus placebo + MTX and of CZP versus placebo with respect to a variety of outcomes including ACR 20, ACR 50 and ACR 70 measures and quality of life measures at 3 and 6 months. On the basis of results from the indirect comparison meta-analyses, the manufacturer suggested that CZP may be at least as effective as other 'biological' DMARD (bDMARD) comparators and, in a few ACR measures at 3 and 6 months, more effective. CZP is an effective therapy for adult RA patients whose disease has failed to respond adequately to cDMARDs including MTX or who are intolerant of MTX. The cost-effectiveness of CZP relative to other bDMARDs is unclear because the economic modelling undertaken may have ignored relevant effectiveness data and potential differences between trial populations, and so may have included effectiveness results that were biased in favour of CZP; underestimated uncertainty in the relative effectiveness of compared DMARDs; and ignored the potential influence of differences between bDMARDs with regard to adverse events and their related costs and health impacts. The NICE guidance issued in October 2009 states that: the Committee is minded not to recommend certolizumab pegol as a treatment option for people with RA; and the Committee recommends that NICE asks the manufacturer of CZP for more information on the clinical effectiveness and cost-effectiveness of CZP for the treatment of people with RA. On receipt of this information and details of a patient access scheme NICE issued final guidance recommending CZP, under certain criteria, as a treatment option for people with RA.

Rituximab for the treatment of relapsed/refractory chronic lymphocytic leukaemia.

This paper presents a summary of the evidence review group (ERG) report on the clinical effectiveness and cost-effectiveness of rituximab with chemotherapy compared to chemotherapy only for the treatment of relapsed/refractory chronic lymphocytic leukaemia (CLL) based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. Evidence was available in the form of one open-label, ongoing, unpublished randomised controlled trial (RCT), REACH (Rituximab in the Study of Relapsed Chronic Lymphocytic Leukemia), conducted by the manufacturer, which compared rituximab with a fludarabine and cyclophosphamide combination (R-FC) to fludarabine and cyclophosphamide (FC) only. REACH was scheduled to run for 8 years; however, the data provided were immature, with a median observation time at the time of data analysis of 2.1 years. REACH provided evidence of prolonged progression free survival with R-FC compared to FC (10 months, investigators' data), but no evidence of an overall survival benefit with R-FC. Patients refractory to fludarabine and with prior rituximab exposure were excluded from REACH and no controlled studies were identified by the ERG for these patient groups. The ERG had concerns about the structure of the economic model submitted by the manufacturer, which did not allow improvement in quality of life from treatment while in a progressed state. The manufacturer's model further assumed a divergence in cumulative deaths between the R-FC and FC treatment arms from the outset, which did not accord with observed data from REACH. When the survival advantage was removed, the manufacturer's base-case incremental cost-effectiveness ratio (ICER) changed from 15,593 pounds to between 40,000 pounds and 42,000 pounds per quality-adjusted life-year (QALY). With no survival advantage, the ICER became sensitive to changes in utility. There was no good empirical evidence on the utility of CLL patients in different states. Allowing for the possibility of a survival advantage with rituximab (although not supported by current evidence), the ERG performed further modelling, which found that rituximab would be cost-effective at 20,000 pounds/QALY (30,000 pounds/QALY) if a reduction in survival advantage relative to the manufacturer's base case of 40% (80%) was assumed. The guidance issued by NICE in July 2010 as a result of the STA recommends rituximab with FC for people with relapsed or refractory chronic lymphocytic leukaemia, except when the condition is refractory to fludarabine or where there has been previous treatment with rituximab.

Cetuximab for the first-line treatment of metastatic colorectal cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of cetuximab for the first-line treatment of metastatic colorectal cancer (mCRC), in accordance with the licensed indication, based upon the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The ERG project ran between 22 January 2008 and 4 November 2008. The clinical evidence came from two unpublished randomised controlled trials (RCTs) of cetuximab plus chemotherapy versus chemotherapy alone in the first-line treatment of mCRC. A third RCT submitted later compared cetuximab with irinotecan in combination with 5-fluorouracil (5-FU) and folinic acid (FA) and cetuximab with oxaliplatin in combination with 5-FU and FA in patients with mCRC with liver metastases only. No published economic evaluations of cetuximab for first-line chemotherapy in mCRC were identified in the submission. A de novo model examined the cost-effectiveness of cetuximab in patients with mCRC that was epidermal growth factor receptor positive, k-ras wild type and with liver metastases. The main source of clinical effectiveness evidence came from the first two RCTs which provided follow up information for 1-2 years. Secondary information was used to estimate survival for a further 22 years. The model focused on the patients for whom the treatment had been licensed. This limited the applicability of the model to the NHS setting in which patients would be a mixture of k-ras wild type and mutations and also a mixture of patients with liver metastases and other metastases. The difference in progression-free survival for the two trials was between 0.5 to 1.2 months over a 7-10 month period. Eight months' treatment with cetuximab, given as an initial loading dose and then weekly until progression, would cost around 22,932 pounds for an average man and 18,427 pounds for an average woman. It is uncertain whether this constitutes good value for money. The guidance issued by NICE on 25 September 2008 stated that cetuximab was not recommended for the first-line treatment of mCRC and people currently receiving cetuximab for the first-line treatment of mCRC should have the option to continue treatment until they and their clinicians consider it appropriate to stop.

Sorafenib for the treatment of advanced hepatocellular carcinoma.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of sorafenib according to its licensed indication for advanced hepatocellular carcinoma (HCC). The ERG report was based on the manufacturer's submission to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The licensed indication for sorafenib specifies advanced HCC patients for whom locoregional intervention and surgery are unsuitable or had been unsuccessful. The clinical evidence came from a multicentre randomised controlled trial (Sorafenib HCC Assessment Randomized Protocol; SHARP) of sorafenib plus best supportive care versus placebo plus best supportive care, with 602 participants of a predominantly European ethnicity broadly comparable to the UK population. The submitted evidence indicated that for advanced HCC patients with Child-Pugh grade A liver function and relatively good Eastern Cooperative Oncology Group performance status, sorafenib on average improves overall survival by 83 days relative to placebo, and also increases time-to-radiological disease progression. Sorafenib therapy had little or no effect on time-to-symptom progression or on quality of life as measured using a disease-specific questionnaire. Sorafenib treatment was associated with increased incidence of hypertension and of gastrointestinal and dermatological problems. However, the therapy was reasonably well tolerated and, in SHARP, withdrawals from treatment due to adverse events were similar in the sorafenib and placebo arms, although more temporary reductions in dose were required in the sorafenib than in the placebo group. In the base case, the manufacturer's submitted economic analysis generated a deterministic incremental cost-effectiveness ratio (ICER) of 64,754 pounds per quality-adjusted life-year (QALY). The ERG extracted individual patient data for overall survival and disease progression, reran the economic model to check the submitted cost-effectiveness results, and performed new analyses which the ERG considered relevant to the decision problem; these analyses delivered ICERs between 76,000 pounds/QALY and 86,000 pounds/QALY. The guidance issued by NICE (7 May 2009) stated that sorafenib, within its licensed indication, is not recommended for the treatment of advanced (Barcelona-Clínic Liver Cancer stage C) HCC patients for whom surgical or locoregional therapies have failed or are not suitable, and people currently receiving sorafenib for the treatment of HCC should have the option to continue treatment until they and their clinician consider it appropriate to stop. Subsequently the manufacturer submitted a patient access scheme to the Department of Health. The base-case ICER submitted by the manufacturer for this scheme was 51,899 pounds/QALY. When the ERG reran the model with inputs considered relevant to the decision problem the ICER estimates ranged between 53,000 pounds to 58,000 pounds/QALY and substantially higher values depending on the nature of the sensitivity analyses. NICE considered the impact of the patient access scheme and determined that it was not sufficient to alter the guidance.

Immunoprophylaxis against respiratory syncytial virus (RSV) with palivizumab in children: a systematic review and economic evaluation.

OBJECTIVES: To systematically review the effectiveness and cost-effectiveness of palivizumab for the prevention of respiratory syncytial virus (RSV) in children and examine prognostic factors to determine whether subgroups can be identified with important differences in cost-effectiveness. DATA SOURCES: Bibliographic databases were searched from inception to March 2007 for literature on the effectiveness and cost-effectiveness of prophylaxis with palivizumab. REVIEW METHODS: The literature was systematically reviewed and current economic evaluations were analysed to identify which parameters were driving the different cost-effectiveness estimates. A probabilistic decision-analytical model was built to assess the cost-effectiveness of prophylaxis with palivizumab for children at risk of RSV infection and the parameters populated with the best estimates thought most applicable to the UK. We also constructed a new model, the Birmingham Economic Evaluation (BrumEE). Cost-effectiveness analyses were undertaken from both NHS and societal perspectives. RESULTS: Two randomised controlled trials (RCTs) were identified. Prophylaxis with palivizumab for preterm infants without chronic lung disease (CLD) or children with CLD resulted in a 55% reduction in RSV hospital admission: 4.8% (48/1002) in the palivizumab group and 10.6% (53/500) in the no prophylaxis group (p = 0.0004). Prophylaxis with palivizumab was associated with a 45% reduction in hospitalisation rate RSV among children with coronary heart disease (CHD). Hospitalisation rates for RSV were 5.3% (34/639) in the palivizumab group and 9.7% (63/648) in the no prophylaxis group (p = 0.003). Of existing economic evaluations, 3 systematic reviews and 18 primary studies were identified. All the systematic reviews concluded that the potential costs of palivizumab were far in excess of any potential savings achieved by decreasing hospital admission rates, and that the use of palivizumab was unlikely to be cost-effective in all children for whom it is recommended, but that its continued use for particularly high-risk children may be justified. The incremental cost-effectiveness ratios (ICERs) of the primary studies varied 17-fold for life-years gained (LYG), from 25,800 pounds/LYG to 404,900 pounds/LYG, and several hundred-fold for quality-adjusted life-years (QALYs), from 3200 pounds/QALY to 1,489,700 pounds/QALY for preterm infants without CLD or children with CLD. For children with CHD, the ICER varied from 5300 pounds/LYG to 7900 pounds/LYG and from 7500 pounds/QALY to 68,700 pounds/QALY. An analysis of what led to the discrepant ICERs showed that the assumed mortality rate for RSV infection was the most important driver. The results of the BrumEE confirm that palivizumab does not reach conventional levels of cost-effectiveness in any of the licensed indications if used for all eligible children. CONCLUSIONS: Prophylaxis with palivizumab is clinically effective for the reducing the risk of serious lower respiratory tract infection caused by RSV infection and requiring hospitalisation in high-risk children, but if used unselectively in the licensed population, the ICER is double that considered to represent good value for money in the UK. The BrumEE shows that prophylaxis with palivizumab may be cost-effective (based on a threshold of 30,000 pounds/QALY) for children with CLD when the children have two or more additional risk factors. Future research should initially focus on reviewing systematically the major uncertainties for patient subgroups with CLD and CHD and then on primary research to address the important uncertainties that remain.

Structural neuroimaging in psychosis: a systematic review and economic evaluation.

OBJECTIVES: To establish the clinical effectiveness and cost-effectiveness of structural neuroimaging [structural magnetic resonance imaging (MRI) or computed tomography (CT) scanning] for all patients with psychosis, particularly a first episode of psychosis, relative to the current UK practice of selective screening only where it is clinically indicated. DATA SOURCES: Major electronic databases were searched from inception to November 2006. REVIEW METHODS: A systematic review of studies reporting the additional diagnostic benefit of structural MRI, CT or combinations of these in patients with psychosis was conducted. The economic assessment consisted of a systematic review of economic evaluations and the development of a threshold analysis to predict the gain in quality-adjusted life-years (QALYs) required to make neuroimaging cost-effective at commonly accepted threshold levels (20,000 pounds and 30,000 pounds per QALY). Sensitivity analyses of several parameters including prevalence of psychosis were performed. RESULTS: The systematic review included 24 studies of a diagnostic before-after type of design evaluating the clinical benefit of CT, structural MRI or combinations in treatment-naive, first-episode or unspecified psychotic patients, including one in schizophrenia patients resistant to treatment. Also included was a review of published case reports of misidentification syndromes. Almost all evidence was in patients aged less than 65 years. In most studies, structural neuroimaging identified very little that would influence patient management that was not suspected based on a medical history and/or physical examination and there were more incidental findings. In the four MRI studies, approximately 5% of patients had findings that would influence clinical management, whereas in the CT studies, approximately 0.5% of patients had these findings. The review of misidentification syndromes found that 25% of CT scans affected clinical management, but this may have been a selected and therefore unrepresentative sample. A threshold analysis with a 1-year time horizon was undertaken. This combined the incremental cost of routine scanning with a threshold cost per QALY value of 20,000 pounds and 30,000 pounds to predict the QoL gain required to meet these threshold values. Routine scanning versus selective scanning appears to produce different results for MRI and CT. With MRI scanning the incremental cost is positive, ranging from 37 pounds to 150 pounds; however, when scanning routinely using CT, the result is cost saving, ranging from 7 pounds to 108 pounds with the assumption of a 1% prevalence rate of tumours/cysts or other organic causes amenable to treatment. This means that for the intervention to be viewed as cost-effective, the QALY gain necessary for MRI scanning is 0.002-0.007 and with CT scanning the QALY loss that can be tolerated is between 0.0003 and 0.0054 using a 20,000 pounds threshold value. These estimates were subjected to sensitivity analysis. With a 3-month time delay, MRI remains cost-incurring with a small gain in QoL required for the intervention to be cost-effective; routine scanning with CT remains cost-saving. When the sensitivity of CT is varied to 50%, routine scanning is both cost-incurring or cost-saving depending on the scenario. Finally, the results have been shown to be sensitive to the assumed prevalence rate of brain tumours in a psychotic population. CONCLUSIONS: The evidence to date suggests that if screening with structural neuroimaging was implemented in all patients presenting with psychotic symptoms, little would be found to affect clinical management in addition to that suspected by a full clinical history and neurological examination. From an economic perspective, the outcome is not clear. The strategy of neuroimaging for all is either cost-incurring or cost-saving (dependent upon whether MRI or CT is used) if the prevalence of organic causes is around 1%. However, these values are nested within a number of assumptions, and so have to be interpreted with caution. The main research priorities are to monitor the current use of structural neuroimaging in psychosis in the NHS to identify clinical triggers to its current use and subsequent outcomes; to undertake well-conducted diagnostic before-and-after studies on representative populations to determine the clinical utility of structural neuroimaging in this patient group, and to determine whether the most appropriate structural imaging modality in psychosis should be CT or MRI.