The Quebec Semantic Memory Battery: Development, Standardization, and Psychometric Assessment of a Semantic Memory Battery in French.

OBJECTIVE: People with aphasia often experience semantic memory (SM) impairment. To improve diagnostic outcomes, SM tasks should recruit various sensory input channels (oral, written, and pictographic), permitting accessible, complete evaluation. There is a need for SM batteries for French-speaking Quebecers that use multiple input channels. The present study, therefore, describes the development of a novel French-language semantic battery: la Batterie québécoise de la mémoire sémantique (BQMS), the assessment of the BQMS's psychometric properties, and the establishment of normative data for the BQMS. METHOD: We first developed eight SM tasks. Following a pilot validation study, we determined the BQMS's reliability and validity, to ensure consistent, accurate detection of SM impairment. Among French-speaking Quebecers with cerebrovascular aphasia (n = 10), people with the semantic variant of Primary Progressive Aphasia (n = 4), and healthy controls (n = 14), we examined its convergent validity, concurrent validity, test-retest reliability, and internal consistency. Finally, we established normative data for the BQMS by calculating cut-off scores per task that indicate SM impairment (in 93 cognitively healthy French-speaking Quebecers), stratified by sociodemographic variables associated with performance. RESULTS: The BQMS shows high concurrent, discriminant, and convergent validity, as well as good test-retest reliability and internal consistency. The cut-off score indicating SM impairment ranged from the 2nd to 25th percentiles (stratified by task, age, and sex). CONCLUSIONS: The BQMS's psychometric properties indicate that it could be a valuable clinical tool for detecting SM impairment. Our normative data will help clinicians detect such impairments.

Diagnostic accuracy and clinical impact of MRI-based technologies for patients with non-alcoholic fatty liver disease: systematic review and economic evaluation.

Background: Magnetic resonance imaging-based technologies are non-invasive diagnostic tests that can be used to assess non-alcoholic fatty liver disease. Objectives: The study objectives were to assess the diagnostic test accuracy, clinical impact and cost-effectiveness of two magnetic resonance imaging-based technologies (LiverMultiScan and magnetic resonance elastography) for patients with non-alcoholic fatty liver disease for whom advanced fibrosis or cirrhosis had not been diagnosed and who had indeterminate results from fibrosis testing, or for whom transient elastography or acoustic radiation force impulse was unsuitable, or who had discordant results from fibrosis testing. Data sources: The data sources searched were MEDLINE, MEDLINE Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Embase, Cochrane Database of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects and the Health Technology Assessment. Methods: A systematic review was conducted using established methods. Diagnostic test accuracy estimates were calculated using bivariate models and a summary receiver operating characteristic curve was calculated using a hierarchical model. A simple decision-tree model was developed to generate cost-effectiveness results. Results: The diagnostic test accuracy review (13 studies) and the clinical impact review (11 studies) only included one study that provided evidence for patients who had indeterminate or discordant results from fibrosis testing. No studies of patients for whom transient elastography or acoustic radiation force impulse were unsuitable were identified. Depending on fibrosis level, relevant published LiverMultiScan diagnostic test accuracy results ranged from 50% to 88% (sensitivity) and from 42% to 75% (specificity). No magnetic resonance elastography diagnostic test accuracy data were available for the specific population of interest. Results from the clinical impact review suggested that acceptability of LiverMultiScan was generally positive. To explore how the decision to proceed to biopsy is influenced by magnetic resonance imaging-based technologies, the External Assessment Group presented cost-effectiveness analyses for LiverMultiScan plus biopsy versus biopsy only. Base-case incremental cost-effectiveness ratio per quality-adjusted life year gained results for seven of the eight diagnostic test strategies considered showed that LiverMultiScan plus biopsy was dominated by biopsy only; for the remaining strategy (Brunt grade ≥2), the incremental cost-effectiveness ratio per quality-adjusted life year gained was £1,266,511. Results from threshold and scenario analyses demonstrated that External Assessment Group base-case results were robust to plausible variations in the magnitude of key parameters. Limitations: Diagnostic test accuracy, clinical impact and cost-effectiveness data for magnetic resonance imaging-based technologies for the population that is the focus of this assessment were limited. Conclusions: Magnetic resonance imaging-based technologies may be useful to identify patients who may benefit from additional testing in the form of liver biopsy and those for whom this additional testing may not be necessary. However, there is a paucity of diagnostic test accuracy and clinical impact data for patients who have indeterminate results from fibrosis testing, for whom transient elastography or acoustic radiation force impulse are unsuitable or who had discordant results from fibrosis testing. Given the External Assessment Group cost-effectiveness analyses assumptions, the use of LiverMultiScan and magnetic resonance elastography for assessing non-alcoholic fatty liver disease for patients with inconclusive results from previous fibrosis testing is unlikely to be a cost-effective use of National Health Service resources compared with liver biopsy only. Study registration: This study is registered as PROSPERO CRD42021286891. Funding: Funding for this study was provided by the Evidence Synthesis Programme of the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 10. See the NIHR Journals Library website for further project information.

Non-alcoholic fatty liver disease includes a range of conditions that are caused by a build-up of fat in the liver, and not by alcohol consumption. This build-up of fat can cause inflammation. Persistent inflammation can cause scar tissue (fibrosis) to develop. It is important to identify patients with fibrosis because severe fibrosis can cause permanent liver damage (cirrhosis), which can lead to liver failure and liver cancer. In the National Health Service, patients with non-alcoholic fatty liver disease undergo tests to determine whether they have fibrosis. The test results are not always accurate and multiple tests can give conflicting results. Some of the tests may not be suitable for patients who have a very high body mass index. In the National Health Service, a liver biopsy may be offered to patients with inconclusive or conflicting test results or to those patients for whom other tests are unsuitable. However, liver biopsy is expensive, and is associated with side-effects such as pain and bleeding. Magnetic resonance imaging-based testing could be used as an extra test to help clinicians assess non-alcoholic fatty liver disease and identify patients who may need a liver biopsy. We assessed two magnetic resonance imaging-based diagnostic tests, LiverMultiScan and magnetic resonance elastography. LiverMultiScan is imaging software that is used alongside magnetic resonance imaging to measure markers of liver disease. Magnetic resonance elastography is used in some National Health Service centres to assess liver fibrosis; however, magnetic resonance elastography requires more equipment than just an magnetic resonance imaging scanner. We reviewed all studies examining how well LiverMultiScan and magnetic resonance elastography assess patients with non-alcoholic fatty liver disease. We also built an economic model to estimate the costs and benefits of using LiverMultiScan to identify patients who should be sent for a biopsy. Results from the model showed that LiverMultiScan may not provide good value for money to the National Health Service.

Onasemnogene Abeparvovec for Treating Pre-symptomatic Spinal Muscular Atrophy: An External Assessment Group Perspective of the Partial Review of NICE Highly Specialised Technology Evaluation 15.

As part of the National Institute for Health and Care Excellence (NICE) highly specialised technology (HST) evaluation programme, Novartis submitted evidence to support the use of onasemnogene abeparvovec as a treatment option for patients with pre-symptomatic 5q spinal muscular atrophy (SMA) with a bi-allelic mutation in the survival of motor neuron (SMN) 1 gene and up to three copies of the SMN2 gene. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the External Assessment Group (EAG). This article summarises the EAG's review of the evidence submitted by the company and provides an overview of the NICE Evaluation Committee's final decision, published in April 2023. The primary source of evidence for this evaluation was the SPR1NT trial, a single-arm trial including 29 babies. The EAG and committee considered that the SPR1NT trial results suggested that onasemnogene abeparvovec is effective in treating pre-symptomatic SMA; however, long-term efficacy data were unavailable and efficacy in babies aged over 6 weeks remained uncertain. Cost-effectiveness analyses conducted by the company and the EAG (using a discounted price for onasemnogene abeparvovec) explored various assumptions; all analyses generated incremental cost-effectiveness ratios (ICERs) that were less than £100,000 per quality-adjusted life-year (QALY) gained. The committee recommended onasemnogene abeparvovec as an option for treating pre-symptomatic 5q SMA with a bi-allelic mutation in the SMN1 gene and up to three copies of the SMN2 gene in babies aged ≤ 12 months only if the company provides it according to the commercial arrangement (i.e. simple discount patient access scheme).

Modelling tool to support decision-making in the NHS Health Check programme: workshops, systematic review and co-production with users.

BACKGROUND: Local authorities in England commission the NHS Health Check programme to invite everyone aged 40-74 years without pre-existing conditions for risk assessment and eventual intervention, if needed. However, the programme's effectiveness, cost-effectiveness and equity impact remain uncertain. AIM: To develop a validated open-access flexible web-based model that enables local commissioners to quantify the cost-effectiveness and potential for equitable population health gain of the NHS Health Check programme. OBJECTIVES: The objectives were as follows: (1) co-produce with stakeholders the desirable features of the user-friendly model; (2) update the evidence base to support model and scenario development; (3) further develop our computational model to allow for developments and changes to the NHS Health Check programme and the diseases it addresses; (4) assess the effectiveness, cost-effectiveness and equity of alternative strategies for implementation to illustrate the use of the tool; and (5) propose a sustainability and implementation plan to deploy our user-friendly computational model at the local level. DESIGN: Co-production workshops surveying the best-performing local authorities and a systematic literature review of strategies to increase uptake of screening programmes informed model use and development. We then co-produced the workHORSE (working Health Outcomes Research Simulation Environment) model to estimate the health, economic and equity impact of different NHS Health Check programme implementations, using illustrative-use cases. SETTING: Local authorities in England. PARTICIPANTS: Stakeholders from local authorities, Public Health England, the NHS, the British Heart Foundation, academia and other organisations participated in the workshops. For the local authorities survey, we invited 16 of the best-performing local authorities in England. INTERVENTIONS: The user interface allows users to vary key parameters that represent programme activities (i.e. invitation, uptake, prescriptions and referrals). Scenarios can be compared with each other. MAIN OUTCOME MEASURES: Disease cases and case-years prevented or postponed, incremental cost-effectiveness ratios, net monetary benefit and change in slope index of inequality. RESULTS: The survey of best-performing local authorities revealed a diversity of effective approaches to maximise the coverage and uptake of NHS Health Check programme, with no distinct 'best buy'. The umbrella literature review identified a range of effective single interventions. However, these generally need to be combined to maximally improve uptake and health gains. A validated dynamic, stochastic microsimulation model, built on robust epidemiology, enabled service options analysis. Analyses of three contrasting illustrative cases estimated the health, economic and equity impact of optimising the Health Checks, and the added value of obtaining detailed local data. Optimising the programme in Liverpool can become cost-effective and equitable, but simply changing the invitation method will require other programme changes to improve its performance. Detailed data inputs can benefit local analysis. LIMITATIONS: Although the approach is extremely flexible, it is complex and requires substantial amounts of data, alongside expertise to both maintain and run. CONCLUSIONS: Our project showed that the workHORSE model could be used to estimate the health, economic and equity impact comprehensively at local authority level. It has the potential for further development as a commissioning tool and to stimulate broader discussions on the role of these tools in real-world decision-making. FUTURE WORK: Future work should focus on improving user interactions with the model, modelling simulation standards, and adapting workHORSE for evaluation, design and implementation support. STUDY REGISTRATION: This study is registered as PROSPERO CRD42019132087. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 35. See the NIHR Journals Library website for further project information.

The NHS Health Check programme is available for adults aged 40­74 years in England to find the early risk of heart disease, cancers, lung disease and dementia, and lower that risk. However, some studies have suggested that the current scheme could perhaps be improved. We systematically looked at previous studies to understand what makes a screening programme successful. We also contacted local authorities with the best NHS Health Check programmes to find out how they were being delivered so well. The most successful local authorities highlighted a wide variety of methods for achieving success. All had concrete plans in place for delivery, including different approaches for encouraging more adults to participate. We further developed our existing computer model into a web-based tool [workHORSE (working Health Outcomes Research Simulation Environment)]. This tool can help those responsible for commissioning NHS Health Checks to further improve the delivery of their local programme. We held four workshops with relevant professionals to develop the workHORSE model. These workshops resulted in a useful 'real-world' tool for local commissioners: a tool that can calculate the current and potential future benefits of different programmes. We used the model to show how commissioners can explore and compare a variety of different programmes. We found that combining several improvements can be useful. However, this provides modest benefits in improving health and value for money. At the same time, the impact on reducing inequalities is less clear and depends on the interventions used. Our results suggest that: a variety of successful approaches can be used to help increase the uptake of screening programmes such as NHS Health Checksjointly developing a computer model with end-users leads to a more user-friendly and relevant model to improve the programmethe stage is now set for further work to identify the best approach in each local area.

A systematic review of health state utility values for thyroid cancer.

PURPOSE: Health state utility values are commonly used to inform economic evaluations and determine the cost-effectiveness of an intervention. The aim of this systematic review is to summarise the utility values available to represent the health-related quality of life (HRQoL) of patients with thyroid cancer. METHODS: Eight electronic databases were searched from January 1999 to April 2019 for studies which included assessment of HRQoL for patients with thyroid cancer. Utility estimates derived from multiple sources (EuroQol questionnaire 5-dimension (EQ-5D), time trade-off [TTO] and standard gamble [SG] methods) were extracted. In addition, utility estimates were generated by mapping from SF-36 and EORTC QLQ-30 to the EQ-5D-3L UK value set using published mapping algorithms. RESULTS: Searches identified 33 eligible studies. Twenty-six studies reported HRQoL for patients with differentiated thyroid cancer and seven studies for patients with general thyroid cancer. We identified studies which used different methods and tools to quantify the HRQoL in patients with thyroid cancer, such as the EQ-5D-3L, SF-36, EORTC QLQ-30 and SG and TTO techniques to estimate utility values. Utility estimates range from 0.205 (patients with low-risk differentiated thyroid cancer) to utility values approximate to the average UK population (following successful thyroidectomy surgery and radioiodine treatment). Utility estimates for different health states, across thyroid cancer sub-types and interventions are presented. CONCLUSION: A catalogue of utility values is provided for use when carrying out economic modelling of thyroid cancer; by including mapped values, this approach broadens the scope of health states that can be considered within cost-effectiveness modelling.

Prophylactic removal of impacted mandibular third molars: a systematic review and economic evaluation.

BACKGROUND: Impacted third molars are third molars that are blocked, by soft tissue or bone, from fully erupting through the gum. This can cause pain and disease. The treatment options for people with impacted third molars are removal or retention with standard care. If there are pathological changes, the current National Institute for Health and Care Excellence guidance states that the impacted third molar should be removed. OBJECTIVE: The objective of this study was to appraise the clinical effectiveness and cost-effectiveness of the prophylactic removal of impacted mandibular third molars compared with retention of, and standard care for, impacted third molars. METHODS: Five electronic databases were searched (1999 to 29 April 2016) to identify relevant evidence [The Cochrane Library (searched 4 April 2016 and 29 April 2016), MEDLINE (searched 4 April 2016 and 29 April 2016), EMBASE (searched 4 April 2016 and 29 April 2016), EconLit (searched 4 April 2016 and 29 April 2016) and NHS Economic Evaluation Database (searched 4 April 2016)]. Studies that compared the prophylactic removal of impacted mandibular third molars with retention and standard care or studies that assessed the outcomes from either approach were included. The clinical outcomes considered were pathology associated with retention, post-operative complications following extraction and adverse effects of treatment. Cost-effectiveness outcomes included UK costs and health-related quality-of-life measures. In addition, the assessment group constructed a de novo economic model to compare the cost-effectiveness of a prophylactic removal strategy with that of retention and standard care. RESULTS: The clinical review identified four cohort studies and nine systematic reviews. In the two studies that reported on surgical complications, no serious complications were reported. Pathological changes due to retention of asymptomatic impacted mandibular third molars were reported by three studies. In these studies, the extraction rate for retained impacted mandibular third molars varied from 5.5% to 31.4%; this variation can be explained by the differing follow-up periods (i.e. 1 and 5 years). The findings from this review are consistent with the findings from previous systematic reviews. Two published cost-effectiveness studies were identified. The authors of both studies concluded that, to their knowledge, there is currently no economic evidence to support the prophylactic removal of impacted mandibular third molars. The results generated by the assessment group's lifetime economic model indicated that the incremental cost-effectiveness ratio per quality-adjusted life-year gained for the comparison of a prophylactic removal strategy with a retention and standard care strategy is £11,741 for people aged 20 years with asymptomatic impacted mandibular third molars. The incremental cost per person associated with prophylactic extraction is £55.71, with an incremental quality-adjusted life-year gain of 0.005 per person. The base-case incremental cost-effectiveness ratio per quality-adjusted life-year gained was found to be robust when a range of sensitivity and scenario analyses were carried out. LIMITATIONS: Limitations of the study included that no head-to-head trials comparing the effectiveness of prophylactic removal of impacted mandibular third molars with retention and standard care were identified with the assessment group model that was built on observational data. Utility data on impacted mandibular third molars and their symptoms are lacking. CONCLUSIONS: The evidence comparing the prophylactic removal of impacted mandibular third molars with retention and standard care is very limited. However, the results from an exploratory assessment group model, which uses available evidence on symptom development and extraction rates of retained impacted mandibular third molars, suggest that prophylactic removal may be the more cost-effective strategy. FUTURE WORK: Effectiveness evidence is lacking. Head-to-head trials comparing the prophylactic removal of trouble-free impacted mandibular third molars with retention and watchful waiting are required. If this is not possible, routine clinical data, using common definitions and outcome reporting methods, should be collected. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016037776. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 30. See the NIHR Journals Library website for further project information.

Third molars, commonly known as wisdom teeth, may come through the gum (erupt) without any problems, usually during young adulthood (aged 18­24 years). However, in some cases they are unable to erupt because they are poorly aligned or obstructed by other teeth, gums or bone. They are then referred to as 'impacted'. Historically, dentists often recommended that these teeth be removed, so as not to cause problems later in life. This is referred to as 'prophylactic' removal. In 2000, the National Institute for Health and Care Excellence reviewed this practice and recommended that these teeth should not be removed if they are not bothersome to the person. Many dentists and oral surgeons have disagreed with this decision, believing that it is more difficult to remove these teeth later in life, and that there are more complications for the patient if they are removed later in life. Our review group carried out a systematic review of the available clinical effectiveness and cost-effectiveness evidence of the prophylactic removal of impacted third molars. The review identified four clinical studies, none of which provided strong evidence for or against the prophylactic removal of these teeth. These findings are similar to those of nine previous reviews. There is also very little research reported that relates to the cost-effectiveness of the procedure, with only three studies identified. With the available evidence on the rates of extraction and the symptoms experienced by people who keep their impacted mandibular third molar, we built an exploratory economic model to assess the cost-effectiveness of recommending prophylactic removal compared with that of recommending watchful waiting. Results from the model suggested that a prophylactic removal strategy costs more than a watchful waiting strategy, but leads to improvements in quality of life. When the costs and quality-of-life measures that are associated with the two strategies are compared, the resulting statistic is £11,741 per quality-adjusted life-year gained, which would probably be good value for money for the NHS.

Engaging with stakeholders to inform the development of a decision-support tool for the NHS health check programme: qualitative study.

BACKGROUND: The NHS Health Check Programme is a risk-reduction programme offered to all adults in England aged 40-74 years. Previous studies mainly focused on patient perspectives and programme delivery; however, delivery varies, and costs are substantial. We were therefore working with key stakeholders to develop and co-produce an NHS Health Check Programme modelling tool (workHORSE) for commissioners to quantify local effectiveness, cost-effectiveness, and equity. Here we report on Workshop 1, which specifically aimed to facilitate engagement with stakeholders; develop a shared understanding of current Health Check implementation; identify what is working well, less well, and future hopes; and explore features to include in the tool. METHODS: This qualitative study identified key stakeholders across the UK via networking and snowball techniques. The stakeholders spanned local organisations (NHS commissioners, GPs, and academics), third sector and national organisations (Public Health England and The National Institute for Health and Care Excellence). We used the validated Hovmand "group model building" approach to engage stakeholders in a series of pre-piloted, structured, small group exercises. We then used Framework Analysis to analyse responses. RESULTS: Fifteen stakeholders participated in workshop 1. Stakeholders identified continued financial and political support for the NHS Health Check Programme. However, many stakeholders highlighted issues concerning lack of data on processes and outcomes, variability in quality of delivery, and suboptimal public engagement. Stakeholders' hopes included maximising coverage, uptake, and referrals, and producing additional evidence on population health, equity, and economic impacts. Key model suggestions focused on developing good-practice template scenarios, analysis of broader prevention activities at local level, accessible local data, broader economic perspectives, and fit-for-purpose outputs. CONCLUSIONS: A shared understanding of current implementations of the NHS Health Check Programme was developed. Stakeholders demonstrated their commitment to the NHS Health Check Programme whilst highlighting the perceived requirements for enhancing the service and discussed how the modelling tool could be instrumental in this process. These suggestions for improvement informed subsequent workshops and model development.

Lead-I ECG for detecting atrial fibrillation in patients with an irregular pulse using single time point testing: a systematic review and economic evaluation.

BACKGROUND: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and is associated with an increased risk of stroke and congestive heart failure. Lead-I electrocardiogram (ECG) devices are handheld instruments that can be used to detect AF at a single time point in people who present with relevant signs or symptoms. OBJECTIVE: To assess the diagnostic test accuracy, clinical impact and cost-effectiveness of using single time point lead-I ECG devices for the detection of AF in people presenting to primary care with relevant signs or symptoms, and who have an irregular pulse compared with using manual pulse palpation (MPP) followed by a 12-lead ECG in primary or secondary care. DATA SOURCES: MEDLINE, MEDLINE Epub Ahead of Print and MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, PubMed, Cochrane Databases of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects and the Health Technology Assessment Database. METHODS: The systematic review methods followed published guidance. Two reviewers screened the search results (database inception to April 2018), extracted data and assessed the quality of the included studies. Summary estimates of diagnostic accuracy were calculated using bivariate models. An economic model consisting of a decision tree and two cohort Markov models was developed to evaluate the cost-effectiveness of lead-I ECG devices. RESULTS: No studies were identified that evaluated the use of lead-I ECG devices for patients with signs or symptoms of AF. Therefore, the diagnostic accuracy and clinical impact results presented are derived from an asymptomatic population (used as a proxy for people with signs or symptoms of AF). The summary sensitivity of lead-I ECG devices was 93.9% [95% confidence interval (CI) 86.2% to 97.4%] and summary specificity was 96.5% (95% CI 90.4% to 98.8%). One study reported limited clinical outcome data. Acceptability of lead-I ECG devices was reported in four studies, with generally positive views. The de novo economic model yielded incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) gained. The results of the pairwise analysis show that all lead-I ECG devices generated ICERs per QALY gained below the £20,000-30,000 threshold. Kardia Mobile (AliveCor Ltd, Mountain View, CA, USA) is the most cost-effective option in a full incremental analysis. LIMITATIONS: No published data evaluating the diagnostic accuracy, clinical impact or cost-effectiveness of lead-I ECG devices for the population of interest are available. CONCLUSIONS: Single time point lead-I ECG devices for the detection of AF in people with signs or symptoms of AF and an irregular pulse appear to be a cost-effective use of NHS resources compared with MPP followed by a 12-lead ECG in primary or secondary care, given the assumptions used in the base-case model. FUTURE WORK: Studies assessing how the use of lead-I ECG devices in this population affects the number of people diagnosed with AF when compared with current practice would be useful. STUDY REGISTRATION: This study is registered as PROSPERO CRD42018090375. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Atrial fibrillation (AF) is the most common type of abnormal heart rhythm. People with AF are more likely to have a serious stroke or die than people without the condition. Many people go to their general practitioner (GP) with the signs or symptoms commonly linked to AF, such as feeling dizzy, being short of breath, feeling tired and having heart palpitations. GPs check for AF by taking the patient's pulse by hand. If the GP thinks that the patient might have AF, a 12-lead electrocardiogram (ECG) test is arranged. Lead-I (i.e. one lead) ECGs are handheld electronic devices that could detect AF more accurately than a manual pulse check. If GPs were to routinely use lead-I ECG devices, people with suspected AF could receive treatment while waiting for the AF diagnosis to be confirmed by a 12-lead ECG. This study aimed to assess whether or not the use of lead-I ECGs in GP surgeries could benefit these patients and offer good value for money to the NHS. All studies that examined how well lead-I ECGs identified people with AF were reviewed, and the economic value of using these devices was assessed. No evidence was found that examined the use of lead-I ECGs for people with signs or symptoms of AF. As an alternative, evidence for the use of lead-I ECGs for people with no symptoms of AF was searched for and these data were used to assess value for money. The study found that using a manual pulse check followed by a lead-I ECG offers value for money when compared with a manual pulse check followed by a 12-lead ECG. This is mostly because patients with AF can begin treatment earlier when a GP has access to a lead-I ECG device.

Lenvatinib and sorafenib for differentiated thyroid cancer after radioactive iodine: a systematic review and economic evaluation.

BACKGROUND: Thyroid cancer is a rare cancer, accounting for only 1% of all malignancies in England and Wales. Differentiated thyroid cancer (DTC) accounts for ≈94% of all thyroid cancers. Patients with DTC often require treatment with radioactive iodine. Treatment for DTC that is refractory to radioactive iodine [radioactive iodine-refractory DTC (RR-DTC)] is often limited to best supportive care (BSC). OBJECTIVES: We aimed to assess the clinical effectiveness and cost-effectiveness of lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany) for the treatment of patients with RR-DTC. DATA SOURCES: EMBASE, MEDLINE, PubMed, The Cochrane Library and EconLit were searched (date range 1999 to 10 January 2017; searched on 10 January 2017). The bibliographies of retrieved citations were also examined. REVIEW METHODS: We searched for randomised controlled trials (RCTs), systematic reviews, prospective observational studies and economic evaluations of lenvatinib or sorafenib. In the absence of relevant economic evaluations, we constructed a de novo economic model to compare the cost-effectiveness of lenvatinib and sorafenib with that of BSC. RESULTS: Two RCTs were identified: SELECT (Study of [E7080] LEnvatinib in 131I-refractory differentiated Cancer of the Thyroid) and DECISION (StuDy of sorafEnib in loCally advanced or metastatIc patientS with radioactive Iodine-refractory thyrOid caNcer). Lenvatinib and sorafenib were both reported to improve median progression-free survival (PFS) compared with placebo: 18.3 months (lenvatinib) vs. 3.6 months (placebo) and 10.8 months (sorafenib) vs. 5.8 months (placebo). Patient crossover was high (≥ 75%) in both trials, confounding estimates of overall survival (OS). Using OS data adjusted for crossover, trial authors reported a statistically significant improvement in OS for patients treated with lenvatinib compared with those given placebo (SELECT) but not for patients treated with sorafenib compared with those given placebo (DECISION). Both lenvatinib and sorafenib increased the incidence of adverse events (AEs), and dose reductions were required (for > 60% of patients). The results from nine prospective observational studies and 13 systematic reviews of lenvatinib or sorafenib were broadly comparable to those from the RCTs. Health-related quality-of-life (HRQoL) data were collected only in DECISION. We considered the feasibility of comparing lenvatinib with sorafenib via an indirect comparison but concluded that this would not be appropriate because of differences in trial and participant characteristics, risk profiles of the participants in the placebo arms and because the proportional hazard assumption was violated for five of the six survival outcomes available from the trials. In the base-case economic analysis, using list prices only, the cost-effectiveness comparison of lenvatinib versus BSC yields an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £65,872, and the comparison of sorafenib versus BSC yields an ICER of £85,644 per QALY gained. The deterministic sensitivity analyses show that none of the variations lowered the base-case ICERs to < £50,000 per QALY gained. LIMITATIONS: We consider that it is not possible to compare the clinical effectiveness or cost-effectiveness of lenvatinib and sorafenib. CONCLUSIONS: Compared with placebo/BSC, treatment with lenvatinib or sorafenib results in an improvement in PFS, objective tumour response rate and possibly OS, but dose modifications were required to treat AEs. Both treatments exhibit estimated ICERs of > £50,000 per QALY gained. Further research should include examination of the effects of lenvatinib, sorafenib and BSC (including HRQoL) for both symptomatic and asymptomatic patients, and the positioning of treatments in the treatment pathway. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017055516. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

WHAT WAS THE PROBLEM?: Differentiated thyroid cancer is a common type of thyroid cancer. For many patients, radioactive iodine is an effective treatment; however, for some patients, the treatment stops working or becomes unsafe. Two new drugs, lenvatinib (Lenvima®; Eisai Ltd, Hertfordshire, UK) and sorafenib (Nexar®; Bayer HealthCare, Leverkusen, Germany), may be new treatment options. WHAT DID WE DO?: We reviewed the clinical evidence of lenvatinib and sorafenib. We also estimated the costs and benefits of treatment. WHAT DID WE FIND?: Compared with no treatment, treatment with lenvatinib or sorafenib may increase the time that people live with thyroid cancer before their disease gets worse; however, both drugs are expensive and may have unpleasant side effects. WHAT DOES THIS MEAN?: At their published (undiscounted) prices, lenvatinib or sorafenib may not be considered to provide good value for money to the NHS.

Lead-I ECG for detecting atrial fibrillation in patients attending primary care with an irregular pulse using single-time point testing: A systematic review and economic evaluation.

BACKGROUND: Atrial fibrillation (AF) is the most common type of cardiac arrhythmia and is associated with increased risk of stroke and congestive heart failure. Lead-I electrocardiogram (ECG) devices are handheld instruments that can detect AF at a single-time point. PURPOSE: To assess the diagnostic test accuracy, clinical impact and cost effectiveness of single-time point lead-I ECG devices compared with manual pulse palpation (MPP) followed by a 12-lead ECG for the detection of AF in symptomatic primary care patients with an irregular pulse. METHODS: Electronic databases (MEDLINE, MEDLINE Epub Ahead of Print and MEDLINE In-Process, EMBASE, PubMed and Cochrane Databases of Systematic Reviews, Cochrane Central Database of Controlled Trials, Database of Abstracts of Reviews of Effects, Health Technology Assessment Database) were searched to March 2018. Two reviewers screened the search results, extracted data and assessed study quality. Summary estimates of diagnostic accuracy were calculated using bivariate models. Cost-effectiveness was evaluated using an economic model consisting of a decision tree and two cohort Markov models. RESULTS: Diagnostic accuracy The diagnostic accuracy (13 publications reporting on nine studies) and clinical impact (24 publications reporting on 19 studies) results are derived from an asymptomatic population (used as a proxy for people with signs or symptoms of AF). The summary sensitivity of lead-I ECG devices was 93.9% (95% confidence interval [CI]: 86.2% to 97.4%) and summary specificity was 96.5% (95% CI: 90.4% to 98.8%). Cost effectiveness The de novo economic model yielded incremental cost effectiveness ratios (ICERs) per quality adjusted life year (QALY) gained. The results of the pairwise analysis show that all lead-I ECG devices generate ICERs per QALY gained below the £20,000-£30,000 threshold. Kardia Mobile is the most cost effective option in a full incremental analysis. Lead-I ECG tests may identify more AF cases than the standard diagnostic pathway. This comes at a higher cost but with greater patient benefit in terms of mortality and quality of life. LIMITATIONS: No published data evaluating the diagnostic accuracy, clinical impact or cost effectiveness of lead-I ECG devices for the target population are available. CONCLUSIONS: The use of single-time point lead-I ECG devices in primary care for the detection of AF in people with signs or symptoms of AF and an irregular pulse appears to be a cost effective use of NHS resources compared with MPP followed by a 12-lead ECG, given the assumptions used in the base case model. REGISTRATION: The protocol for this review is registered on PROSPERO as CRD42018090375.

Cladribine Tablets for the First-Line Treatment of Relapsing-Remitting Multiple Sclerosis: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal process, the National Institute for Health and Care Excellence invited Merck to submit evidence for the clinical and cost effectiveness of cladribine tablets (cladribine) for the treatment of relapsing-remitting multiple sclerosis (RRMS). Rapidly evolving severe (RES) and sub-optimally treated (SOT) RRMS were specified by the National Institute for Health and Care Excellence as subgroups of interest. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group. This article summarises the Evidence Review Group's review of the company's evidence submission for cladribine and the Appraisal Committee's final decision. The final scope issued by the National Institute for Health and Care Excellence listed the following disease-modifying treatments as comparators: alemtuzumab, daclizumab, fingolimod and natalizumab. At the time of the company submission, a licence was anticipated for low-dose cladribine. The main clinical evidence (the CLARITY trial) in the company submission focused on the efficacy of low-dose cladribine vs. placebo. The CLARITY trial showed a statistically significant reduction in relapse rate for cladribine in the RES-RRMS subgroup (n = 50) but not in the SOT-RRMS subgroup (n = 19). Cladribine showed a numerical, but not a statistically significant, advantage in delaying disability progression at 6 months in the RES-RRMS subgroup. Disability progression benefits could not be estimated for those in the SOT-RRMS subgroup because of few events. The Evidence Review Group's main concern regarding the clinical evidence was the small sample size of the subgroups. To compare the effectiveness of cladribine to other disease-modifying treatments, the company conducted network meta-analyses, which showed cladribine and its comparators to be equally effective. The Evidence Review Group considered the results of the disease-modifying treatments to be unreliable because few trials were in the network. The company's cost-effectiveness evidence showed cladribine to be cheaper and more effective than other disease-modifying treatments in the RES-RRMS arm and the SOT-RRMS arm. The results were most sensitive to treatment effect on disability progression at 6 months. The Evidence Review Group was concerned that there was insufficient evidence to conclude that cladribine was superior to placebo in delaying disability progression. The Evidence Review Group amended the company's economic model to allow alternative estimates for the treatment effect of cladribine and its comparators on relapse rate and disability progression at 6 months. The Evidence Review Group made other changes to the company model. After implementing all the amendments, cladribine remained cost effective in the RES-RRMS and SOT-RRMS subgroups. The Appraisal Committee recognised the uncertainty in the available data but concluded that cladribine could be considered a cost-effective use of National Health Service resources.

What Is the Evidence from Past National Institute of Health and Care Excellence Single-Technology Appraisals Regarding Company Submissions with Base-Case Incremental Cost-Effectiveness Ratios of Less Than £10,000/QALY?

BACKGROUND: The National Institute for Health and Care Excellence has recently proposed that company submissions with a base-case incremental cost-effectiveness ratio (ICER) of less than £10,000/quality-adjusted life-year (QALY) might be eligible for a "fast-track" appraisal. OBJECTIVES: To explore outcomes relating to previously conducted single-technology appraisals (STAs) with base-case ICERs of less than £10,000/QALY. METHODS: All STAs with published guidance from 2009 to 2016 were included; those with company base-case ICERs of less than £10,000/QALY were identified and analyzed. A secondary analysis was also conducted for those with a company base-case ICER of £10,000 to £15,000/QALY. Relevant data were extracted and presented in a narrative and in tables. RESULTS: In total, 15% (26 of 171) of STAs included a company submission with a base-case ICER of less than £10,000/QALY. Of these, 73% (19 of 26) were given positive recommendations after the first Appraisal Committee (AC) meeting, whereas 27% (7 of 26) were initially given a Minded No before receiving a positive recommendation in the final appraisal determination, albeit with restricted recommendations for three technologies. Five STAs had company base-case ICERs of £10,000 to £15,000/QALY and all received a positive recommendation after the first AC meeting. CONCLUSIONS: Most previous STAs with a company base-case ICER of £10,000 or even £15,000/QALY received a positive recommendation after the first AC meeting, but a number of them proved more complicated and required detailed appraisal, which influenced the final recommendation. This finding might have implications for the proposed fast-track process of the National Institute for Health and Care Excellence.

Paclitaxel as Albumin-Bound Nanoparticles with Gemcitabine for Untreated Metastatic Pancreatic Cancer: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the single technology appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited Celgene Ltd to submit clinical and cost-effectiveness evidence for paclitaxel as albumin-bound nanoparticles (Nab-Pac) in combination with gemcitabine (Nab-Pac + Gem) for patients with untreated metastatic pancreatic cancer. The STA was a review of NICE's 2015 guidance (TA360) in which Nab-Pac + Gem was not recommended for patients with untreated metastatic pancreatic cancer. The review was prompted by a proposed Patient Access Scheme (PAS) discount on the price of Nab-Pac and new evidence that might lead to a change in the guidance. The Liverpool Reviews and Implementation Group at the University of Liverpool was the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission for Nab-Pac + Gem, and the Appraisal Committee (AC) decision. The final scope issued by NICE listed three comparators: gemcitabine monotherapy (Gem), gemcitabine in combination with capecitabine (Gem + Cap), and a combination of oxaliplatin, irinotecan, leucovorin and fluorouracil (FOLFIRINOX). Clinical evidence for the comparison of Nab-Pac + Gem versus Gem was from the phase III CA046 randomized controlled trial. Analysis of progression-free survival (PFS) and overall survival (OS) showed statistically significant improvement for patients treated with Nab-Pac + Gem versus Gem. Clinical evidence for the comparison of Nab-Pac + Gem versus FOLFIRINOX and versus Gem + Cap was derived from a network meta-analysis (NMA). Results of the NMA did not indicate a statistically significant difference in OS or PFS for the comparison of Nab-Pac + Gem versus either Gem + Cap or FOLFIRINOX. The ERG's main concerns with the clinical effectiveness evidence were difficulties in identifying the patient population for whom treatment with Nab-Pac + Gem is most appropriate, and violation of the proportional hazards (PH) assumption in the CA046 trial. The ERG highlighted methodological issues in the cost-effectiveness analysis pertaining to the modelling of survival outcomes, estimation of drug costs and double counting of adverse-event disutilities. The AC accepted all the ERG's amendments to the company's cost-effectiveness model; however, these did not make important differences to the incremental cost-effectiveness ratios (ICERs). The company's base-case ICER was £46,932 per quality-adjusted life-year (QALY) gained for the comparison of Nab-Pac + Gem versus Gem. Treatment with Nab-Pac + Gem was dominated both by treatment with Gem + Cap and with FOLFIRINOX in the company's base case. The AC concluded that the most plausible ICER for treatment with Nab-Pac + Gem versus Gem was in the range of £41,000-£46,000 per QALY gained. The AC concluded that Nab-Pac + Gem was not cost effective compared with Gem + Cap or FOLFIRINOX, and accepted that treatment with Nab-Pac + Gem met the end-of-life criteria versus Gem but did not consider Nab-Pac + Gem to meet the end-of-life criteria compared with Gem + Cap or FOLFIRINOX. The AC also concluded that although patients who would receive Nab-Pac + Gem rather than FOLFIRINOX or Gem + Cap were difficult to distinguish, they were identifiable in clinical practice. The AC recommended treatment with Nab-Pac + Gem for patients with untreated metastatic pancreatic cancer for whom other combination chemotherapies were unsuitable and who would otherwise receive Gem.

Pegylated Liposomal Irinotecan Hydrochloride Trihydrate for Treating Pancreatic Cancer After Gemcitabine: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Shire Pharmaceuticals) of pegylated liposomal irinotecan hydrochloride trihydrate (liposomal irinotecan) to submit clinical and cost-effectiveness evidence for its use in combination with 5-fluorouracil (5-FU) and folic acid/leucovorin (LV) for treating patients with pancreatic cancer following prior treatment with gemcitabine as part of the institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's evidence, the ERG review and the resulting NICE guidance (TA440), issued on 26 April 2017. Clinical evidence for liposomal irinotecan + 5-FU/LV versus 5-FU/LV was derived from 236 patients with metastatic pancreatic cancer in the multinational, open-label, randomised controlled NAPOLI-1 trial. Results from analyses of progression-free survival and overall survival showed statistically significant improvements for patients treated with liposomal irinotecan + 5-FU/LV compared with those treated with 5-FU/LV. However, 5-FU/LV alone is rarely used in National Health Service clinical practice for patients with metastatic pancreatic cancer previously treated with gemcitabine. The company, ERG and Appraisal Committee (AC) all agreed that oxaliplatin + 5-FU/LV is the most commonly used treatment. Oxaliplatin + 5-FU/LV was compared with 5-FU/LV in two trials identified by the company. However, the company and the ERG both considered attempts to compare the efficacy of liposomal irinotecan + 5-FU/LV with oxaliplatin + 5-FU/LV to be methodologically flawed; not only was there heterogeneity between trials and their populations but also the proportional hazards assumption required to conduct a robust indirect treatment comparison (ITC) was violated. Nonetheless, data derived from an ITC were used to inform the company's economic model. Using the discounted patient access scheme price for liposomal irinotecan + 5-FU/LV, the company reported an incremental cost-effectiveness ratio (ICER) per quality-adjusted life-year (QALY) gained of £54,412 for the comparison with oxaliplatin + 5-FU/LV. The ERG considered that the company's base-case cost-effectiveness results for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV were underestimates and should be interpreted with extreme caution. Following implementation of a number of model amendments, the ERG's modified exploratory ICER for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV was £106,898 per QALY gained. The AC accepted the majority of the ERG's amendments to the model, and also highlighted that the total QALYs for oxaliplatin + 5-FU/LV were lower than for 5-FU/LV in the company's model, which the AC considered to be clinically implausible. The AC therefore considered results from exploratory analyses, undertaken by the ERG, which included altering the QALY difference between liposomal irinotecan + 5-FU/LV and oxaliplatin + 5-FU/LV by ± 10%. These analyses resulted in ICERs for the comparison of liposomal irinotecan + 5-FU/LV versus oxaliplatin + 5-FU/LV of between £201,019 per QALY gained to liposomal irinotecan + 5-FU/LV being dominated by oxaliplatin + 5-FU/LV. Therefore, despite uncertainty around the clinical-effectiveness evidence and cost-effectiveness results, the AC was confident that the ICER was in excess of £50,000 per QALY gained. The final guidance issued by NICE is that liposomal irinotecan + 5-FU/LV is not recommended within its marketing authorisation for treating metastatic adenocarcinoma of the pancreas in adults whose disease has progressed after gemcitabine-based therapy.

Talimogene Laherparepvec for Treating Metastatic Melanoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) invited the manufacturer (Amgen) of talimogene laherparepvec (T-VEC) to submit clinical and cost-effectiveness evidence for previously untreated advanced (unresectable or metastatic) melanoma as part of the Institute's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group (LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG). This article presents a summary of the company's submission of T-VEC, the ERG review and the resulting NICE guidance (TA410), issued in September 2016. T-VEC is an oncolytic virus therapy granted a marketing authorisation by the European Commission for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral disease. Clinical evidence for T-VEC versus granulocyte-macrophage colony-stimulating factor (GM-CSF) was derived from the multinational, open-label randomised controlled OPTiM trial [Oncovex (GM-CSF) Pivotal Trial in Melanoma]. In accordance with T-VEC's marketing authorisation, the company's submission focused primarily on 249 patients with stage IIIB to stage IV/M1a disease who constituted 57% of the overall trial population (T-VEC, n = 163 and GM-CSF, n = 86). Results from analyses of durable response rate, objective response rate, time to treatment failure and overall survival all showed marked and statistically significant improvements for patients treated with T-VEC compared with those treated with GM-CSF. However, GM-CSF is not used to treat melanoma in clinical practice. It was not possible to compare treatment with T-VEC with an appropriate comparator using conventionally accepted methods due to the absence of comparative head-to-head data or trials with sufficient common comparators. Therefore, the company compared T-VEC with ipilimumab using what it described as modified Korn and two-step Korn methods. Results from these analyses suggested that treatment with T-VEC was at least as effective as treatment with ipilimumab. Using the discounted patient access scheme (PAS) price for T-VEC and list price for ipilimumab, the company reported incremental cost-effectiveness ratios (ICERs) per quality-adjusted life-year (QALY) gained. For the comparison of treatment with T-VEC versus ipilimumab, the ICER per QALY gained was -£16,367 using the modified Korn method and -£60,271 using the two-step Korn method. The NICE Appraisal Committee (AC) agreed with the ERG that the company's methods for estimating clinical effectiveness of T-VEC versus ipilimumab were flawed and therefore produced unreliable results for modelling progression in stage IIIB to stage IVM1a melanoma. The AC concluded that the clinical and cost effectiveness of treatment with T-VEC compared with ipilimumab is unknown in patients with stage IIIB to stage IV/M1a disease. However, the AC considered that T-VEC may be a reasonable option for treating patients who are unsuitable for treatment with systemically administered immunotherapies (such as ipilimumab). T-VEC was therefore recommended by NICE as a treatment option for adults with unresectable, regionally or distantly metastatic (stage IIIB to stage IVM1a) melanoma that has not spread to bone, brain, lung or other internal organs, only if treatment with systemically administered immunotherapies is not suitable and the company provides T-VEC at the agreed discounted PAS price.

Automated tests for diagnosing and monitoring cognitive impairment: a diagnostic accuracy review.

BACKGROUND: Cognitive impairment is a growing public health concern, and is one of the most distinctive characteristics of all dementias. The timely recognition of dementia syndromes can be beneficial, as some causes of dementia are treatable and are fully or partially reversible. Several automated cognitive assessment tools for assessing mild cognitive impairment (MCI) and early dementia are now available. Proponents of these tests cite as benefits the tests' repeatability and robustness and the saving of clinicians' time. However, the use of these tools to diagnose and/or monitor progressive cognitive impairment or response to treatment has not yet been evaluated. OBJECTIVES: The aim of this review was to determine whether or not automated computerised tests could accurately identify patients with progressive cognitive impairment in MCI and dementia and, if so, to investigate their role in monitoring disease progression and/or response to treatment. DATA SOURCES: Five electronic databases (MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science and PsycINFO), plus ProQuest, were searched from 2005 to August 2015. The bibliographies of retrieved citations were also examined. Trial and research registers were searched for ongoing studies and reviews. A second search was run to identify individual test costs and acquisition costs for the various tools identified in the review. REVIEW METHODS: Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently by two reviewers. Data were extracted and assessed for risk of bias by one reviewer and independently checked for accuracy by a second. The results of the data extraction and quality assessment for each study are presented in structured tables and as a narrative summary. RESULTS: The electronic searching of databases, including ProQuest, resulted in 13,542 unique citations. The titles and abstracts of these were screened and 399 articles were shortlisted for full-text assessment. Sixteen studies were included in the diagnostic accuracy review. No studies were eligible for inclusion in the review of tools for monitoring progressive disease. Eleven automated computerised tests were assessed in the 16 included studies. The overall quality of the studies was good; however, the wide range of tests assessed and the non-standardised reporting of diagnostic accuracy outcomes meant that meaningful synthesis or statistical analysis was not possible. LIMITATIONS: The main limitation of this review is the substantial heterogeneity of the tests assessed in the included studies. As a result, no meta-analyses could be undertaken. CONCLUSION: The quantity of information available is insufficient to be able to make recommendations on the clinical use of the computerised tests for diagnosing and monitoring MCI and early dementia progression. The value of these tests also depends on the costs of acquisition, training, administration and scoring. FUTURE WORK: Research is required to establish stable cut-off points for automated computerised tests that are used to diagnose patients with MCI or early dementia. Additionally, the costs associated with acquiring and using these tests in clinical practice should be estimated. STUDY REGISTRATION: The study is registered as PROSPERO CRD42015025410. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The clinical effectiveness and cost-effectiveness of the PROGENSA® prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation.

BACKGROUND: There is no single definitive test to identify prostate cancer in men. Biopsies are commonly used to obtain samples of prostate tissue for histopathological examination. However, this approach frequently misses cases of cancer, meaning that repeat biopsies may be necessary to obtain a diagnosis. The PROGENSA(®) prostate cancer antigen 3 (PCA3) assay (Hologic Gen-Probe, Marlborough, MA, USA) and the Prostate Health Index (phi; Beckman Coulter Inc., Brea, CA, USA) are two new tests (a urine test and a blood test, respectively) that are designed to be used to help clinicians decide whether or not to recommend a repeat biopsy. OBJECTIVE: To evaluate the clinical effectiveness and cost-effectiveness of the PCA3 assay and the phi in the diagnosis of prostate cancer. DATA SOURCES: Multiple publication databases and trial registers were searched in May 2014 (from 2000 to May 2014), including MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, Medion, Aggressive Research Intelligence Facility database, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number Register and World Health Organization International Clinical Trials Registry Platform. REVIEW METHODS: The assessment of clinical effectiveness involved three separate systematic reviews, namely reviews of the analytical validity, the clinical validity of these tests and the clinical utility of these tests. The assessment of cost-effectiveness comprised a systematic review of full economic evaluations and the development of a de novo economic model. SETTING: The perspective of the evaluation was the NHS in England and Wales. PARTICIPANTS: Men suspected of having prostate cancer for whom the results of an initial prostate biopsy were negative or equivocal. INTERVENTIONS: The use of the PCA3 score or phi in combination with existing tests (including histopathology results, prostate-specific antigen level and digital rectal examination), multiparametric magnetic resonance imaging and clinical judgement. RESULTS: In addition to documents published by the manufacturers, six studies were identified for inclusion in the analytical validity review. The review identified issues concerning the precision of the PCA3 assay measurements. It also highlighted issues relating to the storage requirements and stability of samples intended for analysis using the phi assay. Fifteen studies met the inclusion criteria for the clinical validity review. These studies reported results for 10 different clinical comparisons. There was insufficient evidence to enable the identification of appropriate test threshold values for use in a clinical setting. In addition, the implications of adding either the PCA3 assay or the phi to clinical assessment were not clear. Furthermore, the addition of the PCA3 assay or the phi to clinical assessment plus magnetic resonance imaging was not found to improve discrimination. No published papers met the inclusion criteria for either the clinical utility review or the cost-effectiveness review. The results from the cost-effectiveness analyses indicated that using either the PCA3 assay or the phi in the NHS was not cost-effective. LIMITATIONS: The main limitations of the systematic review of clinical validity are that the review conclusions are over-reliant on findings from one study, the descriptions of clinical assessment vary widely within reviewed studies and many of the reported results for the clinical validity outcomes do not include either standard errors or confidence intervals. CONCLUSIONS: The clinical benefit of using the PCA3 assay or the phi in combination with existing tests, scans and clinical judgement has not yet been confirmed. The results from the cost-effectiveness analyses indicate that the use of these tests in the NHS would not be cost-effective. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014009595. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

A scoping study to explore the cost-effectiveness of next-generation sequencing compared with traditional genetic testing for the diagnosis of learning disabilities in children.

BACKGROUND: Learning disability (LD) is a serious and lifelong condition characterised by the impairment of cognitive and adaptive skills. Some cases of LD with unidentified causes may be linked to genetic factors. Next-generation sequencing (NGS) techniques are new approaches to genetic testing that are expected to increase diagnostic yield. OBJECTIVES: This scoping study focused on the diagnosis of LD in children and the objectives were to describe current pathways that involve the use of genetic testing; collect stakeholder views on the changes in service provision that would need to be put in place before NGS could be used in clinical practice; describe the new systems and safeguards that would need to be put in place before NGS could be used in clinical practice; and explore the cost-effectiveness of using NGS compared with conventional genetic testing. METHODS: A research advisory group was established. This group provided ongoing support by e-mail and telephone through the lifetime of the study and also contributed face-to-face through a workshop. A detailed review of published studies and reports was undertaken. In addition, information was collected through 33 semistructured interviews with key stakeholders. RESULTS: NGS techniques consist of targeted gene sequencing, whole-exome sequencing (WES) and whole-genome sequencing (WGS). Targeted gene panels, which are the least complex, are in their infancy in clinical settings. Some interviewees thought that during the next 3-5 years targeted gene panels would be superseded by WES. If NGS technologies were to be fully introduced into clinical practice in the future a number of factors would need to be overcome. The main resource-related issues pertaining to service provision are the need for additional computing capacity, more bioinformaticians, more genetic counsellors and also genetics-related training for the public and a wide range of staff. It is also considered that, as the number of children undergoing genetic testing increases, there will be an increase in demand for information and support for families. The main issues relating to systems and safeguards are giving informed consent, sharing unanticipated findings, developing ethical and other frameworks, equity of access, data protection, data storage and data sharing. There is little published evidence on the cost-effectiveness of NGS technologies. The major barriers to determining cost-effectiveness are the uncertainty around diagnostic yield, the heterogeneity of diagnostic pathways and the lack of information on the impact of a diagnosis on health care, social care, educational support needs and the wider family. Furthermore, as NGS techniques are currently being used only in research, costs and benefits to the NHS are unclear. CONCLUSIONS: NGS technologies are at an early stage of development and it is too soon to say whether they can offer value for money to the NHS as part of the LD diagnostic process. Substantial organisational changes, as well as new systems and safeguards, would be required if NGS technologies were to be introduced into NHS clinical practice. Considerable further research is required to establish whether using NGS technologies to diagnose learning disabilities is clinically effective and cost-effective. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Erlotinib and gefitinib for treating non-small cell lung cancer that has progressed following prior chemotherapy (review of NICE technology appraisals 162 and 175): a systematic review and economic evaluation.

BACKGROUND: Lung cancer is the second most diagnosed cancer in the UK. Over 70% of lung cancers are non-small cell lung cancers (NSCLCs). Patients with stage III or IV NSCLC may be offered treatment to improve survival, disease control and quality of life. One-third of these patients receive further treatment following disease progression; these treatments are the focus of this systematic review. OBJECTIVES: To appraise the clinical effectiveness and cost-effectiveness of erlotinib [Tarceva(®), Roche (UK) Ltd] and gefitinib (IRESSA(®), AstraZeneca) compared with each other, docetaxel or best supportive care (BSC) for the treatment of NSCLC after disease progression following prior chemotherapy. The effectiveness of treatment with gefitinib was considered only for patients with epidermal growth factor mutation-positive (EGFR M+) disease. DATA SOURCES: Four electronic databases (EMBASE, MEDLINE, The Cochrane Library, PubMed) were searched for randomised controlled trials (RCTs) and economic evaluations. Manufacturers' evidence submissions to the National Institute for Health and Care Excellence were also considered. REVIEW METHODS: Outcomes for three distinct patient groups based on EGFR mutation status [EGFR M+, epidermal growth factor mutation negative (EGFR M-) and epidermal growth factor mutation status unknown (EGFR unknown)] were considered. Heterogeneity of the data precluded statistical analysis. A de novo economic model was developed to compare treatments (incremental cost per quality-adjusted life-year gained). RESULTS: Twelve trials were included in the review. The use of gefitinib was compared with chemotherapy (n = 6) or BSC (n = 1), and the use of erlotinib was compared with chemotherapy (n = 3) or BSC (n = 1). One trial compared the use of gefitinib with the use of erlotinib. No trials included solely EGFR M+ patients; all data were derived from retrospective subgroup analyses from six RCTs [Kim ST, Uhm JE, Lee J, Sun JM, Sohn I, Kim SW, et al. Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy. Lung Cancer 2012;75:82-8, V-15-32, Tarceva In Treatment of Advanced NSCLC (TITAN), BR.21, IRESSA Survival Evaluation in Lung cancer (ISEL) and IRESSA NSCLC Trial Evaluating REsponse and Survival versus Taxotere (INTEREST)]. These limited data precluded conclusions regarding the clinical effectiveness of any treatment for EGFR M+ patients. For EGFR M- patients, data were derived from the TArceva Italian Lung Optimization tRial (TAILOR) trial and Docetaxel and Erlotinib Lung Cancer Trial (DELTA). Retrospective data were also derived from subgroup analyses of BR.21, Kim et al., TITAN, INTEREST and ISEL. The only statistically significant reported results were for progression-free survival (PFS) for TAILOR and DELTA, and favoured docetaxel over erlotinib [TAILOR hazard ratio (HR) 1.39, 95% confidence interval (CI) 1.06 to 1.82; DELTA HR 1.44, 95% CI 1.08 to 1.92]. In EGFR unknown patients, nine trials (INTEREST, IRESSA as Second-line Therapy in Advanced NSCLC - KoreA, Li, Second-line Indication of Gefitinib in NSCLC, V-15-32, ISEL, DELTA, TITAN and BR.21) reported overall survival data and only one (BR.21) reported a statistically significant result favouring the use of erlotinib over BSC (HR 0.7, 95% CI 0.58 to 0.85). For PFS, BR.21 favoured the use of erlotinib when compared with BSC (HR 0.61, 95% CI 0.51 to 0.74) and the use of gefitinib was favoured when compared with BSC (HR 0.82, 95% CI 0.73 to 0.92) in ISEL. Limitations in the clinical data precluded assessment of cost-effectiveness of treatments for an EGFR M+ population by the Assessment Group (AG). The AG's economic model suggested that for the EGFR M- population, the use of erlotinib was not cost-effective compared with the use of docetaxel and compared with BSC. For EGFR unknown patients, the use of erlotinib was not cost-effective when compared with BSC. CONCLUSIONS/FUTURE WORK: The lack of clinical data available for distinct patient populations limited the conclusions of the assessment. Future trials should distinguish between patients with EGFR M+ and EGFR M- disease. FUNDING: The National Institute for Health Research Health Technology Assessment programme.