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.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men, is less associated with smoking, but occurs at a younger age than sporadic tumours. OBJECTIVES: To assess the clinical effectiveness of single-agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcomes were overall survival and progression-free survival. Secondary outcomes included response rate, symptom palliation, toxicity, and health-related quality of life. SEARCH METHODS: We conducted electronic searches of the Cochrane Register of Controlled Trials (CENTRAL) (2020, Issue 7), MEDLINE (1946 to 27th July 2020), Embase (1980 to 27th July 2020), and ISI Web of Science (1899 to 27th July 2020). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (July 2020); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. SELECTION CRITERIA: Parallel-group randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. DATA COLLECTION AND ANALYSIS: Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. MAIN RESULTS: Twenty-two trials met the inclusion criteria. Ten of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 3023, of whom approximately 2563 were of Asian origin. Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo. Erlotinib was used in eight trials, gefitinib in nine trials, afatinib in two trials, cetuximab in two trials, and icotinib in one trial. The findings of FASTACT 2 suggested a clinical benefit for OS for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, as did the Han 2017 trial for gefitinib plus cytotoxic chemotherapy, but both results were based on a small number of participants (n = 97 and 122, respectively). For progression-free survival (PFS), a pooled analysis of four trials showed evidence of clinical benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.31; 95% confidence interval (CI) 0.25 to 0.39 ; 583 participants ; high-certainty evidence). A pooled analysis of two trials of gefitinib versus paclitaxel plus carboplatin showed evidence of clinical benefit for PFS for gefitinib (HR 0.39; 95% CI 0.32 to 0.48 ; 491 participants high-certainty evidence), and a pooled analysis of two trials of gefitinib versus pemetrexed plus carboplatin with pemetrexed maintenance also showed evidence of clinical benefit for PFS for gefitinib (HR 0.59; 95% CI 0.46 to 0.74, 371 participants ; moderate-certainty evidence). Afatinib showed evidence of clinical benefit for PFS when compared with chemotherapy in a pooled analysis of two trials (HR 0.42; 95% CI 0.34 to 0.53, 709 participants high-certainty evidence). All but one small trial showed a corresponding improvement in response rate with tyrosine-kinase inhibitor (TKI) compared to chemotherapy. Commonly reported grade 3/4 adverse events associated with afatinib, erlotinib, gefitinib and icotinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms; fatigue and anorexia were also associated with some chemotherapies. Seven trials reported on health-related quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, two trials showed improvement in one or more indices for the TKI compared to chemotherapy. The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. AUTHORS' CONCLUSIONS: Erlotinib, gefitinib, afatinib and icotinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged PFS compared to cytotoxic chemotherapy. We found a beneficial effect of the TKI compared to cytotoxic chemotherapy in adverse effect and health-related quality of life. We found limited evidence for increased OS for the TKI when compared with standard chemotherapy, but the majority of the included trials allowed participants to switch treatments on disease progression, which will have a confounding effect on any OS analysis. Single agent-TKI remains the standard of care and the benefit of combining a TKI and chemotherapy remains uncertain as the evidence is based on small patient numbers. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, afatinib or icotinib and is associated with greater toxicity. There are no data supporting the use of monoclonal antibody therapy. Icotinib is not available outside China.

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.

A systematic review of lenvatinib and sorafenib for treating progressive, locally advanced or metastatic, differentiated thyroid cancer after treatment with radioactive iodine.

BACKGROUND: Treatment with radioactive iodine is effective for many patients with progressive, locally advanced or metastatic, differentiated thyroid cancer. However, some patients become refractory to treatment. These types of patients are considered to have radioactive iodine refractory differentiated thyroid cancer (RR-DTC). METHODS: We searched Embase, MEDLINE, PubMed and the Cochrane Library from January 1999 through January 2017. Reference lists of included studies and ongoing trial registries were also searched. Reports of randomized controlled trials (RCTs), prospective observational studies, and systematic reviews/indirect comparisons were eligible for inclusion. In the absence of direct clinical trial evidence comparing lenvatinib versus sorafenib, we assessed the feasibility of conducting an indirect comparison to obtain estimates of the relative efficacy and safety of these two treatments. RESULTS: Of 2364 citations, in total, 93 papers reporting on 2 RCTs (primary evidence), 9 observational studies and 13 evidence reviews (supporting evidence) were identified. Compared to placebo, RCT evidence demonstrated improvements with lenvatinib or sorafenib in median progression-free survival (PFS) and objective tumour response rate (ORR). Overall survival (OS) was confounded by high treatment crossover (≥75%) in both trials. Adverse events (AEs) were more common with lenvatinib or sorafenib than with placebo but the most common AEs associated with each drug differed. Primarily due to differences in the survival risk profiles of patients in the placebo arms of the RCTs, we considered it inappropriate to indirectly compare the effectiveness of lenvatinib versus sorafenib. ORR and AE findings for lenvatinib and sorafenib from the supporting evidence were broadly in line with RCT evidence. Health-related quality of life (HRQoL) data were limited. CONCLUSIONS: Lenvatinib and sorafenib are more efficacious than placebo (a proxy for best supportive care) for treating RR-DTC. Uncertainty surrounds the extent of the impact on OS and HRQoL. Lenvatinib could not reliably be compared with sorafenib. Choice of treatment is therefore likely to depend on an individual patient's circumstances.

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.

A systematic review of the diagnostic accuracy of automated tests for cognitive impairment.

OBJECTIVE: The aim of this review is to determine whether automated computerised tests accurately identify patients with progressive cognitive impairment and, if so, to investigate their role in monitoring disease progression and/or response to treatment. METHODS: Six electronic databases (Medline, Embase, Cochrane, Institute for Scientific Information, PsycINFO, and ProQuest) were searched from January 2005 to August 2015 to identify papers for inclusion. Studies assessing the diagnostic accuracy of automated computerised tests for mild cognitive impairment (MCI) and early dementia against a reference standard were included. Where possible, sensitivity, specificity, positive predictive value, negative predictive value, and likelihood ratios were calculated. The Quality Assessment of Diagnostic Accuracy Studies tool was used to assess risk of bias. RESULTS: Sixteen studies assessing 11 diagnostic tools for MCI and early dementia were included. No studies were eligible for inclusion in the review of tools for monitoring progressive disease and response to treatment. 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 statistical analysis was not possible. CONCLUSION: Some tests have shown promising results for identifying MCI and early dementia. However, concerns over small sample sizes, lack of replicability of studies, and lack of evidence available make it difficult to make recommendations on the clinical use of the computerised tests for diagnosing, monitoring progression, and treatment response for MCI and early dementia. Research is required to establish stable cut-off points for automated computerised tests used to diagnose patients with MCI or early dementia.

First-line treatment of advanced epidermal growth factor receptor (EGFR) mutation positive non-squamous non-small cell lung cancer.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutation positive (M+) non-small cell lung cancer (NSCLC) is emerging as an important subtype of lung cancer comprising 10% to 15% of non-squamous tumours. This subtype is more common in women than men and is less associated with smoking. OBJECTIVES: To assess the clinical effectiveness of single -agent or combination EGFR therapies used in the first-line treatment of people with locally advanced or metastatic EGFR M+ NSCLC compared with other cytotoxic chemotherapy (CTX) agents used alone or in combination, or best supportive care (BSC). The primary outcome was overall survival. Secondary outcomes included progression-free survival, response rate, toxicity, and quality of life. SEARCH METHODS: We conducted electronic searches of the the Cochrane Register of Controlled Trials (CENTRAL) (2015, Issue 6), MEDLINE (1946 to 1 June 2015), EMBASE (1980 to 1 June 2015), and ISI Web of Science (1899 to 1 June 2015). We also searched the conference abstracts of the American Society for Clinical Oncology and the European Society for Medical Oncology (1 June 2015); Evidence Review Group submissions to the National Institute for Health and Care Excellence; and the reference lists of retrieved articles. SELECTION CRITERIA: Parallel randomised controlled trials comparing EGFR-targeted agents (alone or in combination with cytotoxic agents or BSC) with cytotoxic chemotherapy (single or doublet) or BSC in chemotherapy-naive patients with locally advanced or metastatic (stage IIIB or IV) EGFR M+ NSCLC unsuitable for treatment with curative intent. DATA COLLECTION AND ANALYSIS: Two review authors independently identified articles, extracted data, and carried out the 'Risk of bias' assessment. We conducted meta-analyses using a fixed-effect model unless there was substantial heterogeneity, in which case we also performed a random-effects analysis as a sensitivity analysis. MAIN RESULTS: Nineteen trials met the inclusion criteria. Seven of these exclusively recruited people with EGFR M+ NSCLC; the remainder recruited a mixed population and reported results for people with EGFR M+ NSCLC as subgroup analyses. The number of participants with EGFR M+ tumours totalled 2317, of whom 1700 were of Asian origin.Overall survival (OS) data showed inconsistent results between the included trials that compared EGFR-targeted treatments against cytotoxic chemotherapy or placebo.Erlotinib was the intervention treatment used in eight trials, gefitinib in seven trials, afatinib in two trials, and cetuximab in two trials. The findings of one trial (FASTACT 2) did report a statistically significant OS gain for participants treated with erlotinib plus cytotoxic chemotherapy when compared to cytotoxic chemotherapy alone, but this result was based on a small number of participants (n = 97). For progression-free survival (PFS), a pooled analysis of 3 trials (n = 378) demonstrated a statistically significant benefit for erlotinib compared with cytotoxic chemotherapy (hazard ratio (HR) 0.30; 95% confidence interval (CI) 0.24 to 0.38).In a pooled analysis with 491 participants administered gefitinib, 2 trials (IPASS and NEJSG) demonstrated a statistically significant PFS benefit of gefitinib compared with cytotoxic chemotherapy (HR 0.39; 95% CI 0.32 to 0.48).Afatinib (n = 709) showed a statistically significant PFS benefit when compared with chemotherapy in a pooled analysis of 2 trials (HR 0.42; 95% CI 0.34 to 0.53).Commonly reported grade 3/4 adverse events for afatinib, erlotinib, and gefitinib monotherapy were rash and diarrhoea. Myelosuppression was consistently worse in the chemotherapy arms, fatigue and anorexia were also associated with some chemotherapies.No statistically significant PFS or OS benefit for cetuximab plus cytotoxic chemotherapy (n = 81) compared to chemotherapy alone was reported in either of the two trials.Six trials reported on quality of life and symptom improvement using different methodologies. For each of erlotinib, gefitinib, and afatinib, 2 trials showed improvement in one or more indices for the tyrosine-kinase inhibitor (TKI) compared to chemotherapy.The quality of evidence was high for the comparisons of erlotinib and gefitinib with cytotoxic chemotherapy and for the comparison of afatinib with cytotoxic chemotherapy. AUTHORS' CONCLUSIONS: Erlotinib, gefitinib, and afatinib are all active agents in EGFR M+ NSCLC patients, and demonstrate an increased tumour response rate and prolonged progression-free survival compared to cytotoxic chemotherapy. We also found a beneficial effect of the TKI compared to cytotoxic chemotherapy. However, we found no increase in overall survival for the TKI when compared with standard chemotherapy. Cytotoxic chemotherapy is less effective in EGFR M+ NSCLC than erlotinib, gefitinib, or afatinib and is associated with greater toxicity. There were no data supporting the use of monoclonal antibody therapy.

A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer.

Our aim was to evaluate the clinical effectiveness of chemotherapy treatments currently licensed in Europe and recommended by the National Institute for Health and Care Excellence (NICE) for the first-line treatment of adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC). A systematic search of MEDLINE, EMBASE and the Cochrane Library for randomised controlled trials (RCTs) published from 2001 to 2010 was carried out. Relative treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using standard meta-analysis and mixed treatment comparison methodology. A total of 23 RCTs were included: 18 trials compared platinum-based chemotherapy, two compared pemetrexed and three compared gefitinib. There are no statistically significant differences in OS between any of the four third-generation chemotherapy regimens. There is statistically significant evidence that pemetrexed+platinum increases OS compared with gemcitabine+platinum. There are no statistically significant differences in OS between gefitinib and docetaxel+platinum or between gefitinib and paclitaxel+platinum. There is a statistically significant improvement in PFS with gefitinib compared with docetaxel+platinum and gefitinib compared with paclitaxel+platinum. Due to reduced generic pricing, third-generation chemotherapy regimens (except vinorelbine) are still competitive options for most patients. This research provides a comprehensive evidence base, which clinicians and decision-makers can use when deciding on the optimal first-line chemotherapy treatment regimen for patients diagnosed with locally advanced or metastatic NSCLC.

Economic evaluation of nebulized magnesium sulphate in acute severe asthma in children.

OBJECTIVES: The aim of this study was to estimate the cost-effectiveness of nebulized magnesium sulphate (MgSO4) in acute asthma in children from the perspective of the UK National Health Service and personal social services. METHODS: An economic evaluation was conducted based on evidence from a randomized placebo controlled multi-center trial of nebulized MgSO4 in severe acute asthma in children. Participants comprised 508 children aged 2-16 years presenting to an emergency department or a children's assessment unit with severe acute asthma across thirty hospitals in the United Kingdom. Children were randomly allocated to receive nebulized salbutamol and ipratropium bromide mixed with either 2.5 ml of isotonic MgSO4 or 2.5 ml of isotonic saline on three occasions at 20-min intervals. Cost-effectiveness outcomes were constructed around the Yung Asthma Severity Score (ASS) after 60 min of treatment; whilst cost-utility outcomes were constructed around the quality-adjusted life-year (QALY) metric. The nonparametric bootstrap method was used to present cost-effectiveness acceptability curves at alternative cost-effectiveness thresholds for either: (i) a unit reduction in ASS; or (ii) an additional QALY. RESULTS: MgSO4 had a 75.1 percent probability of being cost-effective at a GBP 1,000 (EUR 1,148) per unit decrement in ASS threshold, an 88.0 percent probability of being more effective (in terms of reducing the ASS) and a 36.6 percent probability of being less costly. MgSO4 also had a 67.6 percent probability of being cost-effective at a GBP 20,000 (EUR 22,957) per QALY gained threshold, an 8.5 percent probability of being more effective (in terms of generating increased QALYs) and a 69.1 percent probability of being less costly. Sensitivity analyses showed that the results of the economic evaluation were particularly sensitive to the methods used for QALY estimation. CONCLUSIONS: The probability of cost-effectiveness of nebulized isotonic MgSO4, given as an adjuvant to standard treatment of severe acute asthma in children, is less than 70 percent across accepted cost-effectiveness thresholds for an additional QALY.

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.

Trastuzumab Deruxtecan for Treating HER2-Positive Unresectable or Metastatic Breast Cancer After Two or More Anti-HER2 Therapies: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

The National Institute for Health and Care Excellence (NICE) provides guidance to improve health and social care in England and Wales. NICE invited Daiichi Sankyo to submit evidence for the use of trastuzumab deruxtecan (T-DXd) for treating human epidermal growth factor 2 (HER2)-positive unresectable or metastatic breast cancer (UBC/MBC) after two or more anti-HER2 therapies, in accordance with NICE's Single Technology Appraisal process. The Liverpool Reviews and Implementation Group, part of the University of Liverpool, was commissioned to act as the Evidence Review Group (ERG). This article summarises the ERG's review of the evidence submitted by the company and provides an overview of the NICE Appraisal Committee's (AC's) final decision made in May 2021. Results from the company's base-case fully incremental analysis showed that, compared with T-DXd, eribulin and vinorelbine were dominated and the incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained versus capecitabine was £47,230. The ERG scenario analyses generated a range of ICERs, with the highest being a scenario relating to a comparison of T-DXd versus capecitabine (£78,142 per QALY gained). The ERG considered that due to a lack of appropriate clinical effectiveness evidence, the relative effectiveness of T-DXd versus any comparator treatment could not be determined with any degree of certainty. The NICE AC agreed that the modelling of overall survival was highly uncertain and concluded that treatment with T-DXd could not be recommended for routine use within the National Health Service (NHS). T-DXd was, however, recommended for use within the Cancer Drugs Fund, provided Managed Access Agreement conditions were followed.

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).

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.

Pegcetacoplan for Treating Paroxysmal Nocturnal Haemoglobinuria: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of the Single Technology Appraisal (STA) process, the UK National Institute for Health and Care Excellence (NICE) invited Apellis Pharmaceuticals/Sobi to submit evidence for the clinical and cost effectiveness of pegcetacoplan versus eculizumab and pegcetacoplan versus ravulizumab for treating paroxysmal nocturnal haemoglobinuria (PNH) in adults whose anaemia is uncontrolled after treatment with a C5 inhibitor. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned as the Evidence Review Group (ERG). The company pursued a low incremental cost-effectiveness ratio (ICER) Fast Track Appraisal (FTA). This was a form of STA processed in a shorter time frame and designed for technologies with company base-case ICER < £10,000 per quality-adjusted life-year (QALY) gained and most plausible ICER < £20,000 per QALY gained. This article summarises the ERG's review of the company's evidence submission, and the NICE Appraisal Committee's (AC's) final decision. The company presented clinical evidence from the PEGASUS trial that assessed the efficacy of pegcetacoplan versus eculizumab. At Week 16, patients in the pegcetacoplan arm had statistically significantly greater change from baseline in haemoglobin levels and a higher rate of transfusion avoidance than patients in the eculizumab arm. Using the PEGASUS trial and Study 302 data (a non-inferiority trial that assessed ravulizumab versus eculizumab), the company conducted an anchored matching-adjusted indirect comparison (MAIC) to indirectly estimate the efficacy of pegcetacoplan versus ravulizumab. The company identified key differences between trial designs and populations that could not be adjusted for using anchored MAIC methods. The company and ERG agreed that the anchored MAIC results were not robust and should not inform decision making. In the absence of robust indirect estimates, the company assumed that ravulizumab had equivalent efficacy to eculizumab in the PEGASUS trial population. Results from the company base-case cost-effectiveness analysis showed that treatment with pegcetacoplan dominated eculizumab and ravulizumab. The ERG considered that the long-term effectiveness of pegcetacoplan was uncertain and ran a scenario assuming that after 1 year the efficacy of pegcetacoplan would be the same as eculizumab; treatment with pegcetacoplan continued to dominate eculizumab and ravulizumab. The AC noted that treatment with pegcetacoplan had lower total costs than treatment with eculizumab or ravulizumab because it is self-administered and reduces the need for blood transfusions. If the assumption that ravulizumab has equivalent efficacy to eculizumab does not hold, then this will affect the estimate of the cost effectiveness of pegcetacoplan versus ravulizumab; however, the AC was satisfied that the assumption was reasonable. The AC recommended pegcetacoplan as an option for the treatment of PNH in adults who have uncontrolled anaemia despite treatment with a stable dose of a C5 inhibitor for ≥ 3 months. Pegcetacoplan was the first technology recommended by NICE via the low ICER FTA process.

Association of Food and Nonalcoholic Beverage Marketing With Children and Adolescents' Eating Behaviors and Health: A Systematic Review and Meta-analysis.

Importance: There is widespread interest in the effect of food marketing on children; however, the comprehensive global evidence reviews are now dated. Objective: To quantify the association of food and nonalcoholic beverage marketing with behavioral and health outcomes in children and adolescents to inform updated World Health Organization guidelines. Data Sources: Twenty-two databases were searched (including MEDLINE, CINAHL, Web of Science, Embase, and The Cochrane Library) with a publication date limit from January 2009 through March 2020. Study Selection: Preferred Reporting Items for Systematic Reviews and Meta-Analyses reporting guidelines were followed. Inclusion criteria were primary studies assessing the association of food marketing with specified outcomes in children and adolescents (aged 0-19 years). Exclusion criteria were qualitative studies or those on advertising of infant formula. Of 31 063 articles identified, 96 articles were eligible for inclusion in the systematic review, and 80 articles in the meta-analysis (19 372 participants). Data Extraction and Synthesis: Two reviewers independently extracted data. Random-effects models were used for meta-analyses; meta-regressions, sensitivity analyses, and P curve analyses were also performed. Where appropriate, pooling was conducted using combining P values and vote counting by direction of effect. Grading of Recommendations Assessment, Development, and Evaluation was used to judge certainty of evidence. Main Outcomes and Measures: Critical outcomes were intake, choice, preference, and purchasing. Important outcomes were purchase requests, dental caries, body weight, and diet-related noncommunicable diseases. Results: Participants totaled 19 372 from 80 included articles. Food marketing was associated with significant increases in intake (standardized mean difference [SMD], 0.25; 95% CI, 0.15-0.35; P < .001), choice (odds ratio, 1.77; 95% CI, 1.26-2.50; P < .001), and preference (SMD, 0.30; 95% CI, 0.12-0.49; P = .001). Substantial heterogeneity (all >76%) was unexplained by sensitivity or moderator analyses. The combination of P values for purchase requests was significant but no clear evidence was found for an association of marketing with purchasing. Data on dental health and body weight outcomes were scarce. The certainty of evidence was graded as very low to moderate for intake and choice, and very low for preference and purchasing. Conclusions and Relevance: In this systematic review and meta-analysis, food marketing was associated with increased intake, choice, preference, and purchase requests in children and adolescents. Implementation of policies to restrict children's exposure is expected to benefit child health.

Systematic review of the effect of policies to restrict the marketing of foods and non-alcoholic beverages to which children are exposed.

This systematic review examined the effectiveness of policies restricting the marketing of foods and/or non-alcoholic beverages to children to inform updated World Health Organization (WHO) guidelines. Databases were searched to March 2020. Inclusion criteria were primary studies of any design assessing implemented policies to restrict food marketing to children (0-19 years). Critical outcomes were exposure to and power of marketing, dietary intake, choice, preference, and purchasing. Important outcomes were purchase requests, dental caries, body weight, diet-related noncommunicable diseases, product change, and unintended consequences. Forty-four observational studies met inclusion criteria; most were moderate quality. Pooling was conducted using vote counting by direction of effect, and GRADE was used to judge evidence certainty. Evidence suggests food marketing policies may result in reduced purchases of unhealthy foods and in unintended consequences favorable for public health. Desirable or potentially desirable (for public health) effects of policies on food marketing exposure and power were also found. Evidence on diet and product change was very limited. The certainty of evidence was very low for four outcomes (exposure, power, dietary intake, and product change) and low for two (purchasing and unintended consequences). Policies can effectively limit food marketing to children; policymakers should prioritize mandatory approaches aligned with WHO recommendations.

The National Institute for Health and Clinical Excellence Single Technology Appraisal process: lessons from the first 4 years.

OBJECTIVES: The National Institute for Health and Clinical Excellence (NICE) Single Technology Appraisal (STA) process in the United Kingdom was established in 2005 in order to provide guidance on new technologies as close to their launch as possible. The NICE recommended timeframe for completion of an STA is 34 weeks. The purpose of this study was to map the first 95 STAs to collect information on a range of issues including timelines and appraisal decisions. METHODS: A mapping tool was devised to collect information from the NICE Web site. Data were analyzed by calculating frequencies. Simple descriptive statistics were applied where appropriate. RESULTS: Ninety-five STAs were included in the analysis. Almost one-third (30/95) initially identified topics did not go on to be appraised often due to licensing issues. Timelines were measured for 29 completed STAs. Eight (28%) of these were completed by 37 weeks and 20 (69%) by 42 weeks. When STAs with appeals were excluded, 31% (8/26) were completed by 37 weeks and 85% (22/26) by 42 weeks. The incremental cost-effectiveness ratios reported by manufacturers were consistently lower than those estimated by the evidence review groups. In all, 76% (38/50) of the completed STAs resulted in an approval. CONCLUSIONS: The NICE Web site enabled access to almost all necessary information, although electronic documents were sometimes difficult to locate. One-third of the referred topics were suspended or terminated. The NICE STA process is slower than initially anticipated and this is primarily due to events outside of NICE's direct control.

Encorafenib with Binimetinib for the Treatment of Patients with BRAF V600 Mutation-Positive Unresectable or Metastatic Melanoma: 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 (NICE) invited Pierre Fabre to submit evidence for the clinical and cost-effectiveness of encorafenib with binimetinib (Enco + Bini) versus dabrafenib with trametinib (Dab + Tram) as a first-line treatment for advanced (unresectable or metastatic) BRAF V600 mutation-positive melanoma. The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned as the Evidence Review Group (ERG). This article summarises the ERG's review of the company's evidence submission (CS), and the Appraisal Committee's (AC's) final decision. The main clinical evidence in the CS was derived from the COLUMBUS trial and focused on the efficacy of Enco + Bini (encorafenib 450 mg per day plus binimetinib 45 mg twice daily) compared to vemurafenib. The company conducted network meta-analyses (NMAs) to indirectly estimate the relative effects of progression-free survival (PFS), overall survival (OS), adverse events (AEs) and health-related quality of life (HRQoL) for Enco + Bini versus Dab + Tram. None of the results from the NMAs demonstrated a statistically significant difference between the treatment regimens for any outcomes. The ERG advised caution when interpreting the results from the company's NMAs due to limitations relating to the methods. The ERG considered that use of the OS and PFS hazard ratios (HRs) generated by the company's NMAs to model the relative effectiveness of Enco + Bini versus Dab + Tram in the company model was inappropriate as these estimates were not statistically significantly different. The ERG amended the company's economic model to include estimates of equivalent efficacy, safety and HRQoL for Enco + Bini and Dab + Tram. The ERG considered use of different estimates of relative dose intensity to be inappropriate and used the same estimate for both drug combinations. The ERG also concluded that as only the prices of drug combinations were different, a cost comparison was an appropriate method of economic analysis. Using this approach (combined with confidential discounted drug prices for Enco + Bini and Dab + Tram), treatment with Enco + Bini was more cost effective than treatment with Dab + Tram. The AC raised concerns that an absence of evidence of a difference in outcomes between Enco + Bini and Dab + Tram did not constitute evidence of absence. However, as the numerical differences in outcomes generated by the company's networks were small, the AC did not have a preferred approach and considered that both the company's and the ERG's methods of incorporating outcome estimates into the economic model were suitable for decision making. The NICE AC recommended Enco + Bini as a first-line treatment for unresectable or metastatic melanoma with a BRAF V600 mutation.

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.

Brentuximab Vedotin for Treating Relapsed or Refractory CD30-Positive Cutaneous T-Cell Lymphoma: 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 Takeda UK Ltd to submit clinical- and cost-effectiveness evidence for brentuximab vedotin (BV) for treating relapsed or refractory CD30-positive (CD30+) cutaneous T-cell lymphoma (CTCL). The Liverpool Reviews and Implementation Group at the University of Liverpool was commissioned to act as the evidence review group (ERG). This article summarises the ERG's review of the company's submission for BV and the appraisal committee (AC) decision. The principal clinical evidence was derived from a subgroup of patients with advanced-stage CD30+ mycosis fungoides (MF) or primary cutaneous anaplastic large-cell lymphoma (pcALCL) in the phase III ALCANZA randomised controlled trial (RCT). This trial compared BV versus physician's choice (PC) of methotrexate or bexarotene. Evidence from three observational studies was also presented, which included patients with other CTCL subtypes. The ERG's main concerns with the clinical evidence were the lack of RCT evidence for CTCL subtypes other than MF or pcALCL, lack of robust overall survival data (data were immature and confounded by subsequent treatment and treatment crossover on disease progression) and lack of conclusive results from analyses of health-related quality-of-life data. The ERG noted that many areas of uncertainty in the cost-effectiveness analysis were related to the clinical data, arising from the rarity of the condition and its subtypes and the complexity of the treatment pathway. The ERG highlighted that the inclusion of allogeneic stem-cell transplant (alloSCT) as an option in the treatment pathway was based on weak evidence and generated more uncertainty in a disease area that, because of its rarity and diversity, was already highly uncertain. The ERG also lacked confidence in the company's modelling of the post-progression pathway and was concerned that it may not produce reliable results. Results from the company's base-case comparison (including a simple discount patient access scheme [PAS] for BV) showed that treatment with BV dominated PC. The ERG's revisions and scenario analyses highlighted the high level of uncertainty around the company base-case cost-effectiveness results, ranging from BV dominating PC to an incremental cost-effectiveness ratio per quality-adjusted life-year gained of £494,981. The AC concluded that it was appropriate to include alloSCT in the treatment pathway even though data were limited. The AC recommended BV as an option for treating CD30+ CTCL after at least one systemic therapy in adults if they have MF, stage IIB or higher pcALCL or Sézary syndrome and if the company provides BV according to the commercial arrangement (i.e. simple discount PAS).