A Model-Based Economic Evaluation of Hypothetical Treatments for Amyotrophic Lateral Sclerosis in the UK: Implications for Pricing of New and Emerging Health Technologies.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease which leads to loss of muscle function and paralysis. Historically, clinical drug development has been unsuccessful, but promising disease-modifying therapies (DMTs) may be on the horizon. OBJECTIVES: The aims of this study were to estimate survival, quality-adjusted life-years (QALYs) and costs under current care, and to explore the conditions under which new therapies might be considered cost effective. METHODS: We developed a health economic model to evaluate the cost effectiveness of future ALS treatments from a UK National Health Service and Personal Social Services perspective over a lifetime horizon using data from the ALS-CarE study. Costs were valued at 2021/22 prices. Two hypothetical interventions were evaluated: a DMT which delays progression and mortality, and a symptomatic therapy which improves utility only. Sensitivity analysis was conducted to identify key drivers of cost effectiveness. RESULTS: Starting from King's stage 2, patients receiving current care accrue an estimated 2.27 life-years, 0.75 QALYs and lifetime costs of £68,047. Assuming a 50% reduction in progression rates and a UK-converted estimate of the price of edaravone, the incremental cost-effectiveness ratio for a new DMT versus current care is likely to exceed £735,000 per QALY gained. Symptomatic therapies may be more likely to achieve acceptable levels of cost effectiveness. CONCLUSIONS: Regardless of efficacy, DMTs may struggle to demonstrate cost effectiveness, even at a low price. The cost effectiveness of DMTs is likely to be strongly influenced by drug price, the magnitude and durability of relative treatment effects, treatment starting/stopping rules and any additional utility benefits over current care.

Cost-effectiveness of acceptance and commitment therapy for people living with motor neuron disease, and their health-related quality of life.

BACKGROUND: Given the degenerative nature of the condition, people living with motor neuron disease (MND) experience high levels of psychological distress. The purpose of this research was to investigate the cost-effectiveness of acceptance and commitment therapy (ACT), adapted for the specific needs of this population, for improving quality of life. METHODS: A trial-based cost-utility analysis over a 9-month period was conducted comparing ACT plus usual care (n = 97) versus usual care alone (n = 94) from the perspective of the National Health Service. In the primary analysis, quality-adjusted life years (QALYs) were computed using health utilities generated from the EQ-5D-5L questionnaire. Sensitivity analyses and subgroup analyses were also carried out. RESULTS: Difference in costs was statistically significant between the two arms, driven mainly by the intervention costs. Effects measured by EQ-5D-5L were not statistically significantly different between the two arms. The incremental cost-effectiveness was above the £20,000 to £30,000 per QALY gained threshold used in the UK. However, the difference in effects was statistically significant when measured by the McGill Quality of Life-Revised (MQOL-R) questionnaire. The intervention was cost-effective in a subgroup experiencing medium deterioration in motor neuron symptoms. CONCLUSIONS: Despite the intervention being cost-ineffective in the primary analysis, the significant difference in the effects measured by MQOL-R, the low costs of the intervention, the results in the subgroup analysis, and the fact that ACT was shown to improve the quality of life for people living with MND, suggest that ACT could be incorporated into MND clinical services.

Individual participant data from digital sources informed and improved precision in the evaluation of predictive biomarkers in Bayesian network meta-analysis.

OBJECTIVES: We aimed to develop a network meta-analytic model for the evaluation of treatment effectiveness within predictive biomarker subgroups, by combining evidence from individual participant data (IPD) from digital sources (in the absence of randomized controlled trials) and aggregate data (AD). STUDY DESIGN AND SETTING: A Bayesian framework was developed for modeling time-to-event data to evaluate predictive biomarkers. IPD were sourced from electronic health records, using a target trial emulation approach, or digitized Kaplan-Meier curves. The model is illustrated using two examples: breast cancer with a hormone receptor biomarker, and metastatic colorectal cancer with the Kirsten Rat Sarcoma (KRAS) biomarker. RESULTS: The model allowed for the estimation of treatment effects in two subgroups of patients defined by their biomarker status. Effectiveness of taxanes did not differ in hormone receptor positive and negative breast cancer patients. Epidermal growth factor receptor inhibitors were more effective than chemotherapy in KRAS wild type colorectal cancer patients but not in patients with KRAS mutant status. Use of IPD reduced uncertainty of the subgroup-specific treatment effect estimates by up to 49%. CONCLUSION: Utilization of IPD allowed for more detailed evaluation of predictive biomarkers and cancer therapies and improved precision of the estimates compared to use of AD alone.

A systematic review of whole disease models for informing healthcare resource allocation decisions.

BACKGROUND: Whole disease models (WDM) are large-scale, system-level models which can evaluate multiple decision questions across an entire care pathway. Whilst this type of model can offer several advantages as a platform for undertaking economic analyses, the availability and quality of existing WDMs is unknown. OBJECTIVES: This systematic review aimed to identify existing WDMs to explore which disease areas they cover, to critically assess the quality of these models and provide recommendations for future research. METHODS: An electronic search was performed on multiple databases (MEDLINE, EMBASE, the NHS Economic Evaluation Database and the Health Technology Assessment database) on 23rd July 2023. Two independent reviewers selected studies for inclusion. Study quality was assessed using the National Institute for Health and Care Excellence (NICE) appraisal checklist for economic evaluations. Model characteristics were descriptively summarised. RESULTS: Forty-four WDMs were identified, of which thirty-two were developed after 2010. The main disease areas covered by existing WDMs are heart disease, cancer, acquired immune deficiency syndrome and metabolic disease. The quality of included WDMs is generally low. Common limitations included failure to consider the harms and costs of adverse events (AEs) of interventions, lack of probabilistic sensitivity analysis (PSA) and poor reporting. CONCLUSIONS: There has been an increase in the number of WDMs since 2010. However, their quality is generally low which means they may require significant modification before they could be re-used, such as modelling AEs of interventions and incorporation of PSA. Sufficient details of the WDMs need to be reported to allow future reuse/adaptation.

A model-based economic analysis of the CFHealthHub intervention to support adherence to inhaled medications for people with cystic fibrosis in the UK.

BACKGROUND: Adherence to preventative inhaled therapies in people with cystic fibrosis (CF) is low, resulting in potentially avoidable health losses and the need for costly rescue therapies. OBJECTIVES: To estimate the cost-effectiveness of the CFHealthHub (CFHH) intervention to support adherence to inhaled medications. METHODS: A state transition model was developed to assess the cost-effectiveness of the CFHH intervention versus usual care from the perspective of the UK National Health Service and Personal Social Services over a lifetime horizon. Costs and health outcomes were discounted at a rate of 3.5 percent per annum. Costs were valued at 2021/22 prices. The model structure includes health states defined by survival status, level of lung function, and transplant history. Treatment effects were modeled by changing the probabilities of transitioning between lung function states and reducing exacerbation rates. Model parameters were informed by the CFHH trial, CF Registry data, routine cost databases, literature, and expert opinion. Deterministic and probabilistic sensitivity analyses were undertaken to assess uncertainty. RESULTS: The CFHH intervention is expected to generate additional health gains and cost savings compared with usual care. Assuming that it is delivered for 10 years, the CFHH intervention is expected to generate 0.17 additional quality-adjusted life years and cost savings of GBP 1,600 (EUR 1,662) per patient. CONCLUSIONS: The CFHH intervention is expected to dominate usual care, irrespective of the duration over which the intervention is delivered. The modeled benefits and cost savings are smaller than initially expected and are sensitive to relative treatment effects on lung function.

Self-management intervention to reduce pulmonary exacerbations by supporting treatment adherence in adults with cystic fibrosis: a randomised controlled trial.

INTRODUCTION: Recurrent pulmonary exacerbations lead to progressive lung damage in cystic fibrosis (CF). Inhaled medications (mucoactive agents and antibiotics) help prevent exacerbations, but objectively measured adherence is low. We investigated whether a multi-component (complex) self-management intervention to support adherence would reduce exacerbation rates over 12 months. METHODS: Between October 2017 and May 2018, adults with CF (aged ≥16 years; 19 UK centres) were randomised to the intervention (data-logging nebulisers, a digital platform and behavioural change sessions with trained clinical interventionists) or usual care (data-logging nebulisers). Outcomes included pulmonary exacerbations (primary outcome), objectively measured adherence, body mass index (BMI), lung function (FEV1) and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Analyses were by intent to treat over 12 months. RESULTS: Among intervention (n=304) and usual care (n=303) participants (51% female, median age 31 years), 88% completed 12-month follow-up. Mean exacerbation rate was 1.63/year with intervention and 1.77/year with usual care (adjusted ratio 0.96; 95% CI 0.83 to 1.12; p=0.64). Adjusted mean differences (95% CI) were in favour of the intervention versus usual care for objectively measured adherence (9.5% (8.6% to 10.4%)) and BMI (0.3 (0.1 to 0.6) kg/m2), with no difference for %FEV1 (1.4 (-0.2 to 3.0)). Seven CFQ-R subscales showed no between-group difference, but treatment burden reduced for the intervention (3.9 (1.2 to 6.7) points). No intervention-related serious adverse events occurred. CONCLUSIONS: While pulmonary exacerbations and FEV1 did not show statistically significant differences, the intervention achieved higher objectively measured adherence versus usual care. The adherence difference might be inadequate to influence exacerbations, though higher BMI and lower perceived CF treatment burden were observed.

Estimation of Transition Probabilities for State-Transition Models: A Review of NICE Appraisals.

State transition models are used to inform health technology reimbursement decisions. Within state transition models, the movement of patients between the model health states over discrete time intervals is determined by transition probabilities (TPs). Estimating TPs presents numerous issues, including missing data for specific transitions, data incongruence and uncertainty around extrapolation. Inappropriately estimated TPs could result in biased models. There is limited guidance on how to address common issues associated with TP estimation. To assess current methods for estimating TPs and to identify issues that may introduce bias, we reviewed National Institute for Health and Care Excellence Technology Appraisals published from 1 January, 2019 to 27 May, 2020. Twenty-eight models (from 26 Technology Appraisals) were included in the review. Several methods for estimating TPs were identified: survival analysis (n = 11); count method (n = 9); multi-state modelling (n = 7); logistic regression (n = 2); negative binomial regression (n = 2); Poisson regression (n = 1); and calibration (n = 1). Evidence Review Groups identified several issues relating to TP estimation within these models, including important transitions being excluded (n = 5); potential selection bias when estimating TPs for post-randomisation health states (n = 2); issues concerning the use of multiple data sources (n = 4); potential biases resulting from the use of data from different populations (n = 2), and inappropriate assumptions around extrapolation (n = 3). These issues remained unresolved in almost every instance. Failing to address these issues may bias model results and lead to sub-optimal decision making. Further research is recommended to address these methodological problems.

The Cost Effectiveness of Immunoglobulin vs. Hematopoietic Stem Cell Transplantation for CIDP.

Background: Intravenous immunoglobulin (IVIG) is effective as standard first line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), but some patients remain dependent on its long-term use. Recently, we have reported that autologous non-myeloablative hematopoietic stem cell transplantation (HSCT) is an effective second line therapy for CIDP. Objectives: To compare the cost of chronic IVIG vs. autologous HSCT (a one-time therapy), we collected data on patients with CIDP undergoing HSCT between 2017 and 2019. This was compared with published literature on the costs and efficacy defined by the Inflammatory Neuropathy Cause And Treatment (INCAT) disability score, Medical Research Council (MRC) sum score, hand grip strength, and SF-36 quality of life (QOL) for CIDP. Methods: Between 2017 and 2019, nineteen patients with chronic CIDP (mean disease treatment duration prior to HSCT of 6 years) underwent autologous HSCT with mean cost of $108,577 per patient (range $56,327-277,119, standard deviation $53,092). After HSCT, 80% of patients remain IVIG and immune treatment free for up to 5 years. In comparison, published cost of IVIG treatment in the USA for an average CIDP patient exceeds $136,000 per year. Despite remaining treatment free, HSCT demonstrated greater improvement in efficacy compared to immunoglobulins. Recommendations: Given the long-term treatment-free remission and better outcome measurements, autologous HSCT is more cost effective than long-term IVIG treatment in patients with chronic CIDP. However, costs will depend on patient selection, the HSCT regimen, and regional variations. Further analysis of the health economics, i.e., cost/outcome ratio, of HSCT as therapy for chronically IVIG dependent CIDP is warranted.

Modelling approaches for histology-independent cancer drugs to inform NICE appraisals: a systematic review and decision-framework.

BACKGROUND: The first histology-independent marketing authorisation in Europe was granted in 2019. This was the first time that a cancer treatment was approved based on a common biomarker rather than the location in the body at which the tumour originated. This research aims to explore the implications for National Institute for Health and Care Excellence appraisals. METHODS: Targeted reviews were undertaken to determine the type of evidence that is likely to be available at the point of marketing authorisation and the analyses required to support National Institute for Health and Care Excellence appraisals. Several challenges were identified concerning the design and conduct of trials for histology-independent products, the greater levels of heterogeneity within the licensed population and the use of surrogate end points. We identified approaches to address these challenges by reviewing key statistical literature that focuses on the design and analysis of histology-independent trials and by undertaking a systematic review to evaluate the use of response end points as surrogate outcomes for survival end points. We developed a decision framework to help to inform approval and research policies for histology-independent products. The framework explored the uncertainties and risks associated with different approval policies, including the role of further data collection, pricing schemes and stratified decision-making. RESULTS: We found that the potential for heterogeneity in treatment effects, across tumour types or other characteristics, is likely to be a central issue for National Institute for Health and Care Excellence appraisals. Bayesian hierarchical methods may serve as a useful vehicle to assess the level of heterogeneity across tumours and to estimate the pooled treatment effects for each tumour, which can inform whether or not the assumption of homogeneity is reasonable. Our review suggests that response end points may not be reliable surrogates for survival end points. However, a surrogate-based modelling approach, which captures all relevant uncertainty, may be preferable to the use of immature survival data. Several additional sources of heterogeneity were identified as presenting potential challenges to National Institute for Health and Care Excellence appraisal, including the cost of testing, baseline risk, quality of life and routine management costs. We concluded that a range of alternative approaches will be required to address different sources of heterogeneity to support National Institute for Health and Care Excellence appraisals. An exemplar case study was developed to illustrate the nature of the assessments that may be required. CONCLUSIONS: Adequately designed and analysed basket studies that assess the homogeneity of outcomes and allow borrowing of information across baskets, where appropriate, are recommended. Where there is evidence of heterogeneity in treatment effects and estimates of cost-effectiveness, consideration should be given to optimised recommendations. Routine presentation of the scale of the consequences of heterogeneity and decision uncertainty may provide an important additional approach to the assessments specified in the current National Institute for Health and Care Excellence methods guide. FURTHER RESEARCH: Further exploration of Bayesian hierarchical methods could help to inform decision-makers on whether or not there is sufficient evidence of homogeneity to support pooled analyses. Further research is also required to determine the appropriate basis for apportioning genomic testing costs where there are multiple targets and to address the challenges of uncontrolled Phase II studies, including the role and use of surrogate end points. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Evidence Synthesis programme and will be published in full in Health Technology Assessment; Vol. 25, No. 76. See the NIHR Journals Library website for further project information.

In May 2017, the US Food and Drug Administration granted the first approval for a cancer treatment based on a common biomarker rather than the location in the body at which the tumour originated (the tumour site); that is, a site-agnostic or 'histology-independent' indication was granted. Research from the National Institute for Health and Care Excellence suggests that there are approximately 20 technologies currently in development for histology-independent indications. The first marketing authorisation was granted in Europe in 2019. Histology-independent treatments have the potential to have important effects in patient populations for whom there are currently limited or no available treatment options. However, it is also important to ensure that the use of these treatments in the NHS is supported by systematic and robust assessments of clinical evidence (i.e. how well the medicine or treatment works) and economic evidence (i.e. the medicine's value for money). These assessments are undertaken by the National Institute for Health and Care Excellence, usually for treatments targeting specific tumours sites. However, a histology-independent marketing authorisation would probably include many tumour sites and it is not possible for the National Institute for Health and Care Excellence to conduct a separate assessment for each tumour site for which the treatment could be beneficial. As a result, the National Institute for Health and Care Excellence needs to consider how these products can be appropriately assessed without creating unnecessary delays in patient access. This research explores the extent to which the National Institute for Health and Care Excellence's existing approaches for assessing clinical and economic value can be applied to histology-independent indications, and any changes that might be required. We explore the nature and amount of evidence that is typically available at the point of initial marketing authorisation and develop recommendations to establish the evidence and analyses required to help inform the National Institute for Health and Care Excellence's decisions. We use case studies to highlight possible challenges and to explore ways that these challenges might be addressed. This research will help to inform future National Institute for Health and Care Excellence policy on how to appraise cancer drugs with histology-independent indications. It will also inform the development of guidance for those developing these treatments to help their understanding of the clinical effectiveness and cost-effectiveness assessments that will be required to inform the National Institute for Health and Care Excellence's appraisals.

Cost and health impacts of adherence to the National Institute for Health and Care Excellence schizophrenia guideline recommendations.

BACKGROUND: Discrepancies between the National Institute for Health and Care Excellence (NICE) schizophrenia guideline recommendations and current clinical practice in the UK have been reported. AIMS: We aim to assess whether it is cost-effective to improve adherence to the NICE schizophrenia guideline recommendations, compared with current practice. METHOD: A previously developed whole-disease model for schizophrenia, using the discrete event simulation method, was adapted to assess the cost and health impacts of adherence to the NICE recommendations. Three scenarios to improve adherence to the clinical guidelines were modelled: universal provision of cognitive-behavioural therapy for patients at clinical high risk of psychosis, universal provision of family intervention for patients with first-episode psychosis and prompt provision of clozapine for patients with treatment-resistant schizophrenia. The primary outcomes were lifetime costs and quality-adjusted life-years gained. RESULTS: The results suggest full adherence to the guideline recommendations would decrease cost and improve quality-adjusted life-years. Based on the NICE willingness-to-pay threshold of £20 000-£30 000 per quality-adjusted life-year gained, prompt provision of clozapine for patients with treatment-resistant schizophrenia results in the greatest net monetary benefit, followed by universal provision of cognitive-behavioural therapy for patients at clinical high risk of psychosis, and universal provision of family intervention for patients with first-episode psychosis. CONCLUSIONS: Our results suggest that adherence to guideline recommendations would decrease cost and improve quality-adjusted life-years. Greater investment is needed to improve guideline adherence and therefore improve patient quality of life and realise potential cost savings.

A systematic review of meta-analyses assessing the validity of tumour response endpoints as surrogates for progression-free or overall survival in cancer.

BACKGROUND: Tumour response endpoints, such as overall response rate (ORR) and complete response (CR), are increasingly used in cancer trials. However, the validity of response-based surrogates is unclear. This systematic review summarises meta-analyses assessing the association between response-based outcomes and overall survival (OS), progression-free survival (PFS) or time-to-progression (TTP). METHODS: Five databases were searched to March 2019. Meta-analyses reporting correlation or regression between response-based outcomes and OS, PFS or TTP were summarised. RESULTS: The systematic review included 63 studies across 20 cancer types, most commonly non-small cell lung cancer (NSCLC), colorectal cancer (CRC) and breast cancer. The strength of association between ORR or CR and either PFS or OS varied widely between and within studies, with no clear pattern by cancer type. The association between ORR and OS appeared weaker and more variable than that between ORR and PFS, both for associations between absolute endpoints and associations between treatment effects. CONCLUSIONS: This systematic review suggests that response-based endpoints, such as ORR and CR, may not be reliable surrogates for PFS or OS. Where it is necessary to use tumour response to predict treatment effects on survival outcomes, it is important to fully reflect all statistical uncertainty in the surrogate relationship.

Health economics and patient outcomes of hematopoietic stem cell transplantation versus disease-modifying therapies for relapsing remitting multiple sclerosis in the United States of America.

OBJECTIVE: To estimate differences in treatment costs and health outcomes between non-myeloablative hematopoietic stem cell transplantation (HSCT) and disease-modifying therapies (DMTs) for the treatment of relapsing-remitting multiple sclerosis (RRMS). METHODS: We collected data on costs and reimbursements for patients who underwent HSCT for RRMS at Northwestern Memorial Hospital in Chicago (USA) between January 2017 and January 2019. The costs of HSCT were compared against those for DMTs in the United States, obtained from the literature. We also conducted a literature review to interpret the cost comparisons in terms of disease control and patients' wellbeing defined as no evidence of disease activity (NEDA), neurologic disability by the Expanded Disability Status Scale (EDSS), and quality of life by the short form SF-36, respectively. RESULTS: Outside of the data, herein, no other studies on cost of HSCT for RRMS were found in the literature. HSCT mean total costs, based on our own hospital, were $85,184 (range $70,635 to $120,260). Mean revenue collected was $95,268 (range $16,544 to $173,204). In comparison, according to the literature, 2019 DMT costs in the USA ranged from $80,000 to $100,000 per year per patient. Compared to DMTs, studies of HSCT reported greater improvement in no evidence of disease activity, disability, and quality of life. LIMITATIONS: Costs of HSCT would be expected to vary by conditioning regimen utilized, patient selection, center experience, and regional variation. No cost data on other HSCT regimens or on the three most recently licensed DMTs, alemtuzumab, ocrelizumab, and cladribine, are available. Randomized trials for cost comparisons are missing and variations in HSCT designs, populations, and methodology preclude more precise cost estimates. CONCLUSION: Costs of non-myeloablative HSCT after which DMTs are indefinitely discontinued, are approximately the same cost as those for one year of prescription DMTs. Since DMTs assessed in this analysis are given on an ongoing basis, whilst HSCT is not, HSCT is expected to produce long-term cost-savings. When considered alongside the available clinical evidence, which suggests that HSCT may generate more health gains than DMTs, HSCT is likely to represent a cost-effective use of resources. Model-based health economic analyses are required to substantiate this conclusion.

Systematic review of the methods of health economic models assessing antipsychotic medication for schizophrenia.

BACKGROUND: Numerous economic models have assessed the cost-effectiveness of antipsychotic medications in schizophrenia. It is important to understand what key impacts of antipsychotic medications were considered in the existing models and limitations of existing models in order to inform the development of future models. OBJECTIVES: This systematic review aims to identify which clinical benefits, clinical harms, costs and cost savings of antipsychotic medication have been considered by existing models, to assess quality of existing models and to suggest good practice recommendations for future economic models of antipsychotic medications. METHODS: An electronic search was performed on multiple databases (MEDLINE, EMBASE, PsycInfo, Cochrane database of systematic reviews, The NHS Economic Evaluation Database and Health Technology Assessment database) to identify economic models of schizophrenia published between 2005-2020. Two independent reviewers selected studies for inclusion. Study quality was assessed using the National Institute for Health and Care Excellence (NICE) checklist and the Cooper hierarchy. Key impacts of antipsychotic medications considered by exiting models were descriptively summarised. RESULTS: Sixty models were included. Existing models varied greatly in key impacts of antipsychotic medication included in the model, especially in clinical outcomes used for assessing reduction in psychotic symptoms and types of adverse events considered in the model. Quality of existing models was generally low due to failure to capture the health and cost impact of adverse events of antipsychotic medications and input data not obtained from best available source. Good practices for modelling antipsychotic medications are suggested. DISCUSSIONS: This review highlights inconsistency in key impacts considered by different models, and limitations of the existing models. Recommendations on future research are provided.

Evaluation of the Cost-effectiveness of Services for Schizophrenia in the UK Across the Entire Care Pathway in a Single Whole-Disease Model.

Importance: The existing economic models for schizophrenia often have 3 limitations; namely, they do not cover nonpharmacologic interventions, they report inconsistent conclusions for antipsychotics, and they have poor methodologic quality. Objectives: To develop a whole-disease model for schizophrenia and use it to inform resource allocation decisions across the entire care pathway for schizophrenia in the UK. Design, Setting, and Participants: This decision analytical model used a whole-disease model to simulate the entire disease and treatment pathway among a simulated cohort of 200 000 individuals at clinical high risk of psychoses or with a diagnosis of psychosis or schizophrenia being treated in primary, secondary, and tertiary care in the UK. Data were collected March 2016 to December 2018 and analyzed December 2018 to April 2019. Exposures: The whole-disease model used discrete event simulation; its structure and input data were informed by published literature and expert opinion. Analyses were conducted from the perspective of the National Health Service and Personal Social Services over a lifetime horizon. Key interventions assessed included cognitive behavioral therapy, antipsychotic medication, family intervention, inpatient care, and crisis resolution and home treatment team. Main Outcomes and Measures: Life-time costs and quality-adjusted life-years. Results: In the simulated cohort of 200 000 individuals (mean [SD] age, 23.5 [5.1] years; 120 800 [60.4%] men), 66 400 (33.2%) were not at risk of psychosis, 69 800 (34.9%) were at clinical high risk of psychosis, and 63 800 (31.9%) had psychosis. The results of the whole-disease model suggest the following interventions are likely to be cost-effective at a willingness-to-pay threshold of £20 000 ($25 552) per quality-adjusted life-year: practice as usual plus cognitive behavioral therapy for individuals at clinical high risk of psychosis (probability vs practice as usual alone, 0.96); a mix of hospital admission and crisis resolution and home treatment team for individuals with acute psychosis (probability vs hospital admission alone, 0.99); amisulpride (probability vs all other antipsychotics, 0.39), risperidone (probability vs all other antipsychotics, 0.30), or olanzapine (probability vs all other antipsychotics, 0.17) combined with family intervention for individuals with first-episode psychosis (probability vs family intervention or medication alone, 0.58); and clozapine for individuals with treatment-resistant schizophrenia (probability vs other medications, 0.81). Conclusions and Relevance: The results of this study suggest that the current schizophrenia service configuration is not optimal. Cost savings and/or additional quality-adjusted life-years may be gained by replacing current interventions with more cost-effective interventions.

A Systematic Review of Economic Models Across the Entire Schizophrenia Pathway.

BACKGROUND: Schizophrenia is associated with a high economic burden. Economic models can help to inform resource allocation decisions to maximise benefits to patients. OBJECTIVES: This systematic review aims to assess the availability, quality and consistency of conclusions of health economic models evaluating the cost effectiveness of interventions for schizophrenia. METHODS: An electronic search was performed on multiple databases (MEDLINE, EMBASE, PsycINFO, Cochrane database of systematic reviews, NHS Economic Evaluation Database and Health Technology Assessment database) to identify economic models of interventions for schizophrenia published between 2005 and 2020. Two independent reviewers selected studies for inclusion. Study quality was assessed using the National Institute for Health and Care Excellence (NICE) checklist and the Cooper hierarchy. Model characteristics and conclusions were descriptively summarised. RESULTS: Seventy-three models met inclusion criteria. Seventy-eight percent of existing models assessed antipsychotics; however, due to inconsistent conclusions reported by different studies, no antipsychotic can be considered clearly cost effective compared with the others. A very limited number of models suggest that the following non-pharmacological interventions might be cost effective: psychosocial interventions, stratified tests, employment intervention and intensive intervention to improve liaison between primary and secondary care. The quality of included models is generally low due to use of a short time horizon, omission of adverse events of interventions, poor data quality and potential conflicts of interest. CONCLUSIONS: This review highlights a lack of models for non-pharmacological interventions, and limitations of the existing models, including low quality and inconsistency in conclusions. Recommendations on future modelling approaches for schizophrenia are provided.

Statistical Methods for Adjusting Estimates of Treatment Effectiveness for Patient Nonadherence in the Context of Time-to-Event Outcomes and Health Technology Assessment: A Systematic Review of Methodological Papers.

Introduction. Medication nonadherence can have a significant negative impact on treatment effectiveness. Standard intention-to-treat analyses conducted alongside clinical trials do not make adjustments for nonadherence. Several methods have been developed that attempt to estimate what treatment effectiveness would have been in the absence of nonadherence. However, health technology assessment (HTA) needs to consider effectiveness under real-world conditions, where nonadherence levels typically differ from those observed in trials. With this analytical requirement in mind, we conducted a review to identify methods for adjusting estimates of treatment effectiveness in the presence of patient nonadherence to assess their suitability for use in HTA. Methods. A "Comprehensive Pearl Growing" technique, with citation searching and reference checking, was applied across 7 electronic databases to identify methodological papers for adjusting time-to-event outcomes for nonadherence using individual patient data. A narrative synthesis of identified methods was conducted. Methods were assessed in terms of their ability to reestimate effectiveness based on alternative, suboptimal adherence levels. Results. Twenty relevant methodological papers covering 12 methods and 8 extensions to those methods were identified. Methods are broadly classified into 4 groups: 1) simple methods, 2) principal stratification methods, 3) generalized methods (g-methods), and 4) pharmacometrics-based methods using pharmacokinetics and pharmacodynamics (PKPD) analysis. Each method makes specific assumptions and has associated limitations. Five of the 12 methods are capable of adjusting for real-world nonadherence, with only g-methods and PKPD considered appropriate for HTA. Conclusion. A range of statistical methods is available for adjusting estimates of treatment effectiveness for nonadherence, but most are not suitable for use in HTA. G-methods and PKPD appear to be more appropriate to estimate effectiveness in the presence of real-world adherence.

Tumour profiling tests to guide adjuvant chemotherapy decisions in early breast cancer: a systematic review and economic analysis.

BACKGROUND: Breast cancer and its treatment can have an impact on health-related quality of life and survival. Tumour profiling tests aim to identify whether or not women need chemotherapy owing to their risk of relapse. OBJECTIVES: To conduct a systematic review of the effectiveness and cost-effectiveness of the tumour profiling tests oncotype DX® (Genomic Health, Inc., Redwood City, CA, USA), MammaPrint® (Agendia, Inc., Amsterdam, the Netherlands), Prosigna® (NanoString Technologies, Inc., Seattle, WA, USA), EndoPredict® (Myriad Genetics Ltd, London, UK) and immunohistochemistry 4 (IHC4). To develop a health economic model to assess the cost-effectiveness of these tests compared with clinical tools to guide the use of adjuvant chemotherapy in early-stage breast cancer from the perspective of the NHS and Personal Social Services. DESIGN: A systematic review and health economic analysis were conducted. REVIEW METHODS: The systematic review was partially an update of a 2013 review. Nine databases were searched in February 2017. The review included studies assessing clinical effectiveness in people with oestrogen receptor-positive, human epidermal growth factor receptor 2-negative, stage I or II cancer with zero to three positive lymph nodes. The economic analysis included a review of existing analyses and the development of a de novo model. RESULTS: A total of 153 studies were identified. Only one completed randomised controlled trial (RCT) using a tumour profiling test in clinical practice was identified: Microarray In Node-negative Disease may Avoid ChemoTherapy (MINDACT) for MammaPrint. Other studies suggest that all the tests can provide information on the risk of relapse; however, results were more varied in lymph node-positive (LN+) patients than in lymph node-negative (LN0) patients. There is limited and varying evidence that oncotype DX and MammaPrint can predict benefit from chemotherapy. The net change in the percentage of patients with a chemotherapy recommendation or decision pre/post test ranged from an increase of 1% to a decrease of 23% among UK studies and a decrease of 0% to 64% across European studies. The health economic analysis suggests that the incremental cost-effectiveness ratios for the tests versus current practice are broadly favourable for the following scenarios: (1) oncotype DX, for the LN0 subgroup with a Nottingham Prognostic Index (NPI) of > 3.4 and the one to three positive lymph nodes (LN1-3) subgroup (if a predictive benefit is assumed); (2) IHC4 plus clinical factors (IHC4+C), for all patient subgroups; (3) Prosigna, for the LN0 subgroup with a NPI of > 3.4 and the LN1-3 subgroup; (4) EndoPredict Clinical, for the LN1-3 subgroup only; and (5) MammaPrint, for no subgroups. LIMITATIONS: There was only one completed RCT using a tumour profiling test in clinical practice. Except for oncotype DX in the LN0 group with a NPI score of > 3.4 (clinical intermediate risk), evidence surrounding pre- and post-test chemotherapy probabilities is subject to considerable uncertainty. There is uncertainty regarding whether or not oncotype DX and MammaPrint are predictive of chemotherapy benefit. The MammaPrint analysis uses a different data source to the other four tests. The Translational substudy of the Arimidex, Tamoxifen, Alone or in Combination (TransATAC) study (used in the economic modelling) has a number of limitations. CONCLUSIONS: The review suggests that all the tests can provide prognostic information on the risk of relapse; results were more varied in LN+ patients than in LN0 patients. There is limited and varying evidence that oncotype DX and MammaPrint are predictive of chemotherapy benefit. Health economic analyses indicate that some tests may have a favourable cost-effectiveness profile for certain patient subgroups; all estimates are subject to uncertainty. More evidence is needed on the prediction of chemotherapy benefit, long-term impacts and changes in UK pre-/post-chemotherapy decisions. STUDY REGISTRATION: This study is registered as PROSPERO CRD42017059561. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Breast cancer is the most commonly diagnosed cancer in women in England and Wales. Breast cancer, and its treatment, can have an impact on a person's health-related quality of life and survival. Tumour profiling tests are used before chemotherapy. They test small samples of a patient's tumour (removed during surgery) to find out whether the genes in it mean that a person has a high or low risk of the disease returning (relapse). If the risk is low, the patient may be able to avoid having chemotherapy and, therefore, avoid its side effects. Some tests might also be able to identify which patients will respond to chemotherapy. This study looked at the evidence for five tumour profiling tests. A total of 153 studies were identified. This study considered the results and the quality of the studies to find out if the tests are helpful. Most studies had design flaws (e.g. some patients had already had chemotherapy) that meant that the studies were of low quality overall. The results suggest that all of the tests can give information on the risk of relapse; however, some tests may be less useful in patients whose disease has spread to the lymph nodes (lymph node-positive disease). There was limited and varying evidence about whether or not two of these tests can also predict which patients will respond to chemotherapy. This study also looked at whether or not these tests represent good value for money for the NHS through cost-effectiveness analyses. The analyses showed that some of the tests may represent a good use of NHS resources for some patient groups; however, there was still a lot of uncertainty about this.

Cabozantinib and vandetanib for unresectable locally advanced or metastatic medullary thyroid cancer: a systematic review and economic model.

BACKGROUND: Medullary thyroid cancer (MTC) is a rare form of cancer that affects patients' health-related quality of life (HRQoL) and survival. Cabozantinib (Cometriq®; Ipsen, Paris, France) and vandetanib (Caprelsa®; Sanofi Genzyme, Cambridge, MA, USA) are currently the treatment modality of choice for treating unresectable progressive and symptomatic MTC. OBJECTIVES: (1) To evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. (2) To estimate the incremental cost-effectiveness of cabozantinib and vandetanib versus each other and best supportive care. (3) To identify key areas for primary research. (4) To estimate the overall cost of these treatments in England. DATA SOURCES: Peer-reviewed publications (searched from inception to November 2016), European Public Assessment Reports and manufacturers' submissions. REVIEW METHODS: A systematic review [including a network meta-analysis (NMA)] was conducted to evaluate the clinical effectiveness and safety of cabozantinib and vandetanib. The economic analysis included a review of existing analyses and the development of a de novo model. RESULTS: The systematic review identified two placebo-controlled trials. The Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid Cancer (EXAM) trial evaluated the efficacy and safety of cabozantinib in patients with unresectable locally advanced, metastatic and progressive MTC. The ZETA trial evaluated the efficacy and safety of vandetanib in patients with unresectable locally advanced or metastatic MTC. Both drugs significantly improved progression-free survival (PFS) more than the placebo (p < 0.001). The NMA suggested that, within the symptomatic and progressive MTC population, the effects on PFS were similar (vandetanib vs. cabozantinib: hazard ratio 1.14, 95% credible interval 0.41 to 3.09). Neither trial demonstrated a significant overall survival benefit for cabozantinib or vandetanib versus placebo, although data from ZETA were subject to potential confounding. Both cabozantinib and vandetanib demonstrated significantly better objective response rates and calcitonin (CTN) and carcinoembryonic antigen (CEA) response rates than placebo. Both cabozantinib and vandetanib produced frequent adverse events, often leading to dose interruption or reduction. The assessment group model indicates that, within the EU-label population (symptomatic and progressive MTC), the incremental cost-effectiveness ratios (ICERs) for cabozantinib and vandetanib are > £138,000 per quality-adjusted life-year (QALY) gained. Within the restricted EU-label population (symptomatic and progressive MTC with CEA/CTN doubling times of ≤ 24 months), the ICER for vandetanib is expected to be > £66,000 per QALY gained. The maximum annual budget impact within the symptomatic and progressive population is estimated to be ≈£2.35M for cabozantinib and ≈£5.53M for vandetanib. The costs of vandetanib in the restricted EU-label population are expected to be lower. LIMITATIONS: The intention-to-treat populations of the EXAM and ZETA trials are notably different. The analyses of ZETA subgroups may be subject to confounding as a result of differences in baseline characteristics and open-label vandetanib use. Attempts to statistically adjust for treatment switching were unsuccessful. No HRQoL evidence was identified for the MTC population. CONCLUSIONS: The identified trials suggest that cabozantinib and vandetanib improve PFS more than the placebo; however, significant OS benefits were not demonstrated. The economic analyses indicate that within the EU-label population, the ICERs for cabozantinib and vandetanib are > £138,000 per QALY gained. Within the restricted EU-label population, the ICER for vandetanib is expected to be > £66,000 per QALY gained. FUTURE RESEARCH PRIORITIES: (1) Primary research assessing the long-term effectiveness of cabozantinib and vandetanib within relevant subgroups. (2) Reanalyses of the ZETA trial to investigate the impact of adjusting for open-label vandetanib use using appropriate statistical methods. (3) Studies assessing the impact of MTC on HRQoL. STUDY REGISTRATION: This study is registered as PROSPERO CRD42016050403. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Medullary thyroid carcinoma (MTC) is a rare form of cancer that presents as a mass of tumours in the thyroid gland of the neck. MTC affects both patients' health-related quality of life and survival. Targeted therapies (cabozantinib and vandetanib) are currently used to treat unresectable progressive and symptomatic MTC. The evidence for the use of cabozantinib and vandetanib in patients with unresectable locally advanced or metastatic MTC was reviewed, and two clinical trials were identified. The trials suggest that both drugs improve progression-free survival. Neither trial demonstrated significant survival benefits for cabozantinib or vandetanib. Both drugs produced frequent adverse events, often leading to dose interruption or reduction. Whether or not these therapies represent good value for money for the NHS was also assessed. Analyses indicate that the incremental cost-effectiveness ratios (ICERs) (a measure of cost-effectiveness) for cabozantinib and vandetanib versus best supportive care (BSC) in patients with symptomatic and progressive MTC are > £138,000 per quality-adjusted life-year (QALY) gained. Within a subgroup of patients with symptomatic and progressive MTC and carcinoembryonic antigen and/or calcitonin doubling times of ≤ 24 months, the ICER for vandetanib versus BSC remains > £66,000 per QALY gained.

Ibrutinib for Treating Relapsed or Refractory Mantle Cell Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal.

As part of its Single Technology Appraisal process, the UK National Institute for Health and Care Excellence (NICE) invited the manufacturer of ibrutinib (Janssen) to submit evidence on the clinical effectiveness and cost effectiveness of ibrutinib for the treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL). The School of Health and Related Research Technology Assessment Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence contained within the company's submission to NICE. The clinical effectiveness evidence for ibrutinib included one randomised controlled trial comparing ibrutinib and temsirolimus and two single-arm studies. The company's indirect comparison of ibrutinib versus rituximab plus chemotherapy (R-chemo) produced a hazard ratio (HR) for progression-free survival (PFS) of 0.28. The ERG's random effects network meta-analysis (NMA) indicated that the treatment effect on PFS was highly uncertain (HR 0.27; 95% credible interval (CrI) 0.06-1.26). The company's Markov model assessed the cost effectiveness of ibrutinib versus R-chemo for the treatment of R/R MCL from the perspective of the National Health Service (NHS) and Personal Social Services over a lifetime horizon. Based on a re-run of the company's model by the ERG, the incremental cost-effectiveness ratio (ICER) for ibrutinib versus R-chemo [including the company's original patient access scheme (PAS)] was expected to be £76,014 per quality-adjusted life-year (QALY) gained. The ERG had several concerns regarding the company's model structure and the evidence used to inform its parameters. The ERG's preferred analysis, which used the ERG's NMA and the observed Kaplan-Meier curve for time to ibrutinib discontinuation and excluded long-term disutilities for R-chemo, produced ICERs of £63,340 per QALY gained for the overall R/R MCL population and of £44,711 per QALY gained for patients with one prior treatment. Following an updated PAS and consideration of evidence from a later data-cut of the RAY trial, the appraisal committee concluded that the most plausible ICER for the one prior treatment subgroup was likely to be lower than the company's estimate of £49,848 per QALY gained. The company's ICER for the overall R/R MCL population was higher, at £62,650 per QALY gained. The committee recommended ibrutinib as an option for treating R/R MCL in adults only if they have received only one previous line of therapy and the company provides ibrutinib with the discount agreed in the commercial access agreement with NHS England.