Cost-effectiveness of treating relapsed or refractory 3L+ follicular lymphoma with axicabtagene ciloleucel vs mosunetuzumab in the United States.

Introduction: Novel therapies for 3L+ relapsed/refractory (r/r) follicular lymphoma (FL) have been approved recently by the US Food and Drug Administration including anti-CD19 CAR-T therapies such as axicabtagene ciloleucel (axi-cel) and CD20 × CD3 T-cell-engaging bispecific monoclonal antibodies such as mosunetuzumab (mosun). The objective of this study was to assess the cost-effectiveness of axi-cel compared to mosun in 3L+ r/r FL patients from a US third-party payer perspective. Methods: A three-state (progression-free, progressed disease, and death) partitioned-survival model was used to compare two treatments over a lifetime horizon in a hypothetical cohort of US adults (age ≥18) receiving 3L+ treatment for r/r FL. ZUMA-5 and GO29781 trial data were used to inform progression-free survival (PFS) and overall survival (OS). Mosun survival was modeled via hazard ratios (HRs) applied to axi-cel survival curves. The PFS HR value was estimated via a matching-adjusted indirect comparison (MAIC) based on mosun pseudo-individual patient data and adjusted axi-cel data to account for trial populations differences. One-way sensitivity analysis (OWSA) and probabilistic sensitivity analyses (PSA) were conducted. Scenario analyses included: 1) the mosun HRs were applied to the weighted (adjusted) ZUMA-5 24-month data to most exactly reflect the MAIC, 2) mosun HR values were applied to axi-cel 48-month follow-up data, and 3) recent axi-cel health state utility values in diffuse large B-cell lymphoma patients. Results: The analysis estimated increases of 1.82 LY and 1.89 QALY for axi-cel compared to mosun. PFS for axi-cel patients was 6.42 LY vs. 1.60 LY for mosun. Increase of $257,113 in the progression-free state was driven by one-time axi-cel treatment costs. Total incremental costs for axi-cel were $204,377, resulting in an ICER of $108,307/QALY gained. The OWSA led to ICERs ranging from $240,255 to $75,624, with all but two parameters falling below $150,000/QALY. In the PSA, axi-cel had an 64% probability of being cost-effective across 5,000 iterations using a $150,000 willingness-to-pay threshold. Scenarios one and two resulted in ICERs of $105,353 and $102,695, respectively. Discussion: This study finds that axi-cel is cost-effective compared to mosun at the commonly cited $150,000/QALY US willingness-to-pay threshold, with robust results across a range of sensitivity analyses accounting for parameter uncertainty.

Bleeding risk in patients prescribed dual antiplatelet therapy and triple therapy after coronary interventions: the ADAPTT retrospective population-based cohort studies.

Background: Bleeding among populations undergoing percutaneous coronary intervention or coronary artery bypass grafting and among conservatively managed patients with acute coronary syndrome exposed to different dual antiplatelet therapy and triple therapy (i.e. dual antiplatelet therapy plus an anticoagulant) has not been previously quantified. Objectives: The objectives were to estimate hazard ratios for bleeding for different antiplatelet and triple therapy regimens, estimate resources and the associated costs of treating bleeding events, and to extend existing economic models of the cost-effectiveness of dual antiplatelet therapy. Design: The study was designed as three retrospective population-based cohort studies emulating target randomised controlled trials. Setting: The study was set in primary and secondary care in England from 2010 to 2017. Participants: Participants were patients aged ≥ 18 years undergoing coronary artery bypass grafting or emergency percutaneous coronary intervention (for acute coronary syndrome), or conservatively managed patients with acute coronary syndrome. Data sources: Data were sourced from linked Clinical Practice Research Datalink and Hospital Episode Statistics. Interventions: Coronary artery bypass grafting and conservatively managed acute coronary syndrome: aspirin (reference) compared with aspirin and clopidogrel. Percutaneous coronary intervention: aspirin and clopidogrel (reference) compared with aspirin and prasugrel (ST elevation myocardial infarction only) or aspirin and ticagrelor. Main outcome measures: Primary outcome: any bleeding events up to 12 months after the index event. Secondary outcomes: major or minor bleeding, all-cause and cardiovascular mortality, mortality from bleeding, myocardial infarction, stroke, additional coronary intervention and major adverse cardiovascular events. Results: The incidence of any bleeding was 5% among coronary artery bypass graft patients, 10% among conservatively managed acute coronary syndrome patients and 9% among emergency percutaneous coronary intervention patients, compared with 18% among patients prescribed triple therapy. Among coronary artery bypass grafting and conservatively managed acute coronary syndrome patients, dual antiplatelet therapy, compared with aspirin, increased the hazards of any bleeding (coronary artery bypass grafting: hazard ratio 1.43, 95% confidence interval 1.21 to 1.69; conservatively-managed acute coronary syndrome: hazard ratio 1.72, 95% confidence interval 1.15 to 2.57) and major adverse cardiovascular events (coronary artery bypass grafting: hazard ratio 2.06, 95% confidence interval 1.23 to 3.46; conservatively-managed acute coronary syndrome: hazard ratio 1.57, 95% confidence interval 1.38 to 1.78). Among emergency percutaneous coronary intervention patients, dual antiplatelet therapy with ticagrelor, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.47, 95% confidence interval 1.19 to 1.82), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.06, 95% confidence interval 0.89 to 1.27). Among ST elevation myocardial infarction percutaneous coronary intervention patients, dual antiplatelet therapy with prasugrel, compared with dual antiplatelet therapy with clopidogrel, increased the hazard of any bleeding (hazard ratio 1.48, 95% confidence interval 1.02 to 2.12), but did not reduce the incidence of major adverse cardiovascular events (hazard ratio 1.10, 95% confidence interval 0.80 to 1.51). Health-care costs in the first year did not differ between dual antiplatelet therapy with clopidogrel and aspirin monotherapy among either coronary artery bypass grafting patients (mean difference £94, 95% confidence interval -£155 to £763) or conservatively managed acute coronary syndrome patients (mean difference £610, 95% confidence interval -£626 to £1516), but among emergency percutaneous coronary intervention patients were higher for those receiving dual antiplatelet therapy with ticagrelor than for those receiving dual antiplatelet therapy with clopidogrel, although for only patients on concurrent proton pump inhibitors (mean difference £1145, 95% confidence interval £269 to £2195). Conclusions: This study suggests that more potent dual antiplatelet therapy may increase the risk of bleeding without reducing the incidence of major adverse cardiovascular events. These results should be carefully considered by clinicians and decision-makers alongside randomised controlled trial evidence when making recommendations about dual antiplatelet therapy. Limitations: The estimates for bleeding and major adverse cardiovascular events may be biased from unmeasured confounding and the exclusion of an eligible subgroup of patients who could not be assigned an intervention. Because of these limitations, a formal cost-effectiveness analysis could not be conducted. Future work: Future work should explore the feasibility of using other UK data sets of routinely collected data, less susceptible to bias, to estimate the benefit and harm of antiplatelet interventions. Trial registration: This trial is registered as ISRCTN76607611. Funding: This project was funded by 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. 8. See the NIHR Journals Library website for further project information.

People who have a heart attack are treated with a stent to open up the blocked artery that caused the heart attack, with surgery to bypass the blocked artery or with medication only. Whatever the treatment, they are prescribed one or more antiplatelet drugs, either aspirin only or aspirin and an additional antiplatelet (clopidogrel, prasugrel or ticagrelor), for 12 months after the heart attack. Antiplatelets are given to prevent another heart attack, but increase the risk of bleeding. We used a large general practice database and a database describing patients' attendances and admissions to hospital to determine how many people bleed with different antiplatelet combinations. We found that, overall, up to 1 in 10 people taking antiplatelets (rising to 2 in 10 if also taking an anticoagulant such as warfarin or dabigatran) reported a bleed. Among patients treated with surgery or medication only, we compared aspirin only (which is a less potent therapy) with aspirin and clopidogrel (a more potent therapy). Among patients treated with stents, we compared aspirin and clopidogrel (less potent therapy) with aspirin and prasugrel or ticagrelor (more potent therapy). In all three populations, the more potent therapy increased the risk of bleeding by about one and a half times, but this was not offset by a reduced risk of having a subsequent heart attack. This may be explained by low adherence to the medication: between one-third and almost half of all patients did not adhere to their regimen, and non-adherence was generally higher among patients taking a more potent therapy. It may also be explained by bias inherent in the study, for example if the groups prescribed different antiplatelet regimens had different risks of having another heart attack. Nevertheless, the results show that doctors should be cautious about prescribing more potent antiplatelet therapy because it may increase serious bleeds without necessarily reducing the number of heart attacks.

End-of-life cost trajectories and the trade-off between treatment costs and life-extension: Findings from the Cost and Medical Care of Patients with Advanced Serious Illness (COMPASS) cohort study.

BACKGROUND: Few studies have assessed how patient preferences influence end-of-life costs. AIM: To estimate mean monthly healthcare costs in 2019 Singapore Dollars (SGD) at five time points within the last year of life and identify how patients' preferences for the trade-off between treatment cost containment and life-extension and other factors affect these costs. DESIGN: Mean monthly costs were quantified in the last 1, 3, 6, 9, and 12-months before death. Univariate and multivariate analyses were conducted. SETTING/PARTICIPANTS: Billing records for 286 deceased participants in the Cost and Medical Care of Patients with Advanced Serious Illness (COMPASS) cancer cohort study in Singapore. RESULTS: Mean monthly costs were $5140 (95% CI: $4750; $5520) in the 12-months before death and rose to $8350 (95% CI: $7110; $9590) 1-month before death. Participants preferring higher cost containment/less life-extension defied the trend of increasing costs closer to death (mean monthly costs of $4630 (95% CI: $3690; $ 5580) and $4850 (95% CI: $2850; $6850) (12-months and 1-month before death respectively). Participants preferring lower cost containment/more life-extension had costs that were $1050 (95% CI: $49; $2051) and $5220 (95% CI: $2320; $8130) higher than those preferring lower costs/less life-extension 12-months and 1-month before death respectively. CONCLUSIONS: On average, cancer patients in Singapore can expect to spend $61,680 in the last year of life. Of broader relevance is that patient preferences and other observable factors clearly influence these costs, suggesting that policymakers and patients can better predict and budget for end-of-life costs by considering these factors.

Economic burden of asthma in Singapore.

BACKGROUND AND OBJECTIVE: Up-to-date economic burden of asthma in Singapore is currently unknown. METHODS: We quantify the per capita and total annual costs of asthma for adults and children by level of symptom control (uncontrolled, partly controlled, and well controlled) via a cross-sectional online survey administered to a national web panel. Participants were asked about healthcare utilisation, days missed from work, and reduced productivity due to their symptoms. These values were then monetised and multiplied by prevalence estimates of adult and child asthmatics to generate total costs. RESULTS: A total of 300 adults and 221 parents of children with asthma were included in analysis. The total annual cost of adult asthma was estimated to be SGD 1.74 billion (US$1.25 billion) with 42% coming from the uncontrolled group, 45% from the partly controlled group, and 13% from the well-controlled group. For children, the total cost is SGD 0.35 billion (US$0.25 billion), with 64%, 26% and 10% coming from each group respectively. Combined, the annual economic burden of asthma in Singapore is SGD 2.09 billion (US$1.50 billion) with 79% due to productivity losses. CONCLUSION: Poorly controlled asthma imposes a significant economic burden. Therefore, better control of disease has the potential to generate not only health improvements, but also medical expenditure savings and productivity gains.

A randomized controlled trial testing the effects of a positive front-of-pack label with or without a physical activity equivalent label on food purchases.

BACKGROUND: Positive front-of-pack (FOP) labels, including Singapore's Healthier Choice Symbol (HCS), target a subset of healthier products whose consumption is to be encouraged. However, this may inadvertently lead to excess caloric intake, which could be addressed by including an additional label identifying calories per serving. We test this hypothesis by adding a Physical Activity Equivalent (PAE) label, an indicator of calorie content, to all products available in an on-line grocery store. METHODS: We conducted a randomized controlled trial using a 3 arm within-subject crossover design in adult Singapore residents recruited online. Participants shopped once in each condition in an experimental online grocery store in random order: 1) no FOP label (Control); 2) Select products displaying HCS labels (HCS-only); 3) Condition 2 with additional information displaying PAEs per serving on every product (HCS+PAE). 117 participants were recruited and data from 317 shops were analyzed. We used first-differenced regressions to assess the impact of the conditions on calories per serving (primary) and on other measures of diet quality. RESULTS: The HCS-only condition led to a statistically significant five-percentage point increase in the proportion of HCS products purchased (95% CI, 1%: 9%). However, neither the HCS-only (3.45; 95% CI, -12.52: 19.43) nor HCS + PAE (8.14; 95% CI, -5.25: 21.54) condition led to a change in the number of calories per serving purchased or changes in other measures of diet quality. CONCLUSIONS: Positive labels, like the HCS, are likely to increase purchases of labelled products. However, these changes may not lead to improvements in diet quality or calorie intake. Combining positive labels with additional PAE information does not appear to address this concern.

The association of self-blame with treatment preferences in a multi-country cohort of advanced cancer patients from the APPROACH study.

OBJECTIVE: To understand the prevalence of behavioral and characterological self-blame and their associations with stated preferences for life-extension and the use of pain-relief medication in a multi-country cohort of advanced cancer patients. METHODS: The prevalence of self-blame and reasons participants attributed to their diagnosis was assessed in a sample of 968 advanced cancer patients enrolled in one of five sites from four Asian countries of the multi-country cross-sectional survey titled APRROACH. Ordered probit and Firth logistic regressions were used to determine associations between each type of self-blame and two treatment-related outcomes: participants' stated preference for life-extension and the use of pain-relief medication in the last 24 h. RESULTS: Behavioral and characterological self-blame were reported by 41% and 49% of the participants respectively, with only 19% and 2% of participants providing a logically consistent reason for the two types of self-blame. We observed no statistically significant differences in stated preferences for life-extension for either type of self-blame and in the use of pain-relief medication for participants reporting behavioral self-blame. However, participants reporting characterological self-blame were 9.7% (95% CI, 2.0% to 17.3%; p = 0.014) more likely to report using pain-relief medication compared to participants not reporting characterological self-blame. CONCLUSIONS: A substantial proportion of patients report self-blame and those reporting characterological self-blame appear more likely to use pain medication. Therefore, developing interventions aimed at reducing characterological self-blame might help patients receive only appropriate treatments as opposed to treatments pursued in response to feelings of self-blame.

Clinical and cost-effectiveness of a diabetes education and behavioural weight management programme versus a diabetes education programme in adults with a recent diagnosis of type 2 diabetes: study protocol for the Glucose Lowering through Weight management (GLoW) randomised controlled trial.

INTRODUCTION: People with type 2 diabetes (T2D) can improve glycaemic control or even achieve remission through weight loss and reduce their use of medication and risk of cardiovascular disease. The Glucose Lowering through Weight management (GLoW) trial will evaluate whether a tailored diabetes education and behavioural weight management programme (DEW) is more effective and cost-effective than a diabetes education (DE) programme in helping people with overweight or obesity and a recent diagnosis of T2D to lower their blood glucose, lose weight and improve other markers of cardiovascular risk. METHODS AND ANALYSIS: This study is a pragmatic, randomised, single-blind, parallel group, two-arm, superiority trial. We will recruit 576 adults with body mass index>25 kg/m2 and diagnosis of T2D in the past 3 years and randomise them to a tailored DEW or a DE programme. Participants will attend measurement appointments at a local general practitioner practice or research centre at baseline, 6 and 12 months. The primary outcome is 12-month change in glycated haemoglobin. The effect of the intervention on the primary outcome will be estimated and tested using a linear regression model (analysis of covariance) including randomisation group and adjusted for baseline value of the outcome and the randomisation stratifiers. Participants will be included in the group to which they were randomised, under the intention-to-treat principle. Secondary outcomes include 6-month and 12-month changes in body weight, body fat percentage, systolic and diastolic blood pressure and lipid profile; probability of achieving good glycaemic control; probability of achieving remission from diabetes; probability of losing 5% and 10% body weight and modelled cardiovascular risk (UKPDS). An intention-to-treat within-trial cost-effectiveness analysis will be conducted from NHS and societal perspectives using participant-level data. Qualitative interviews will be conducted with participants to understand why and how the programme achieved its results and how participants manage their weight after the programme ends. ETHICS AND DISSEMINATION: Ethical approval was received from East of Scotland Research Ethics Service on 15 May 2018 (18/ES/0048). This protocol (V.3) was approved on 19 June 2019. Findings will be published in peer-reviewed scientific journals and communicated to other stakeholders as appropriate. TRIAL REGISTRATION NUMBER: ISRCTN18399564.

Randomized trial evaluating the effectiveness of within versus across-category front-of-package lower-calorie labelling on food demand.

BACKGROUND: Several front-of-pack (FOP) labels identify healthier options by comparing foods within product categories. Alternative approaches label healthier options by comparing across categories. Which approach is superior remains unknown. The objective of this study was to test the effect of a within-category versus across-category FOP lower calorie label on 1) the percentage of labeled products purchased, 2) several measures of calories purchased (total, per dollar and per serving), and 3) total spending. We also tested the moderating effects of hunger and mood on purchasing patterns. METHODS: Using an online grocery store, we conducted a 3 × 3 crossover trial involving actual purchases with 146 participants randomly exposed to: 1) no labeling control; 2) within-category lower calorie labels, and; 3) across-category lower calorie labels. We labeled the 20% of products with the lowest calories per serving within or across categories. Purchases were compared using a fixed effects regression on first-differenced outcomes. RESULTS: Relative to the control condition, there was a 3 percentage point increase (p = 0.01) in labelled products purchased in the within-category arm and a non-significant decrease of 1 percentage point (p = 0.711) in the across-category arm. There was no significant difference in the proportion of labeled products purchased between the two labelling conditions. Neither strategy resulted in reductions in any measure of calories purchased or in total spending. When limited to beverages, there was a 398 cal reduction (p = 0.01) in the within-category arm and a 438 cal reduction (p < 0.01) in the across-category arm versus the control. Mood and hunger did not modify the effects for either strategy. CONCLUSIONS: Results provide evidence that both labelling strategies have the potential to influence food purchasing patterns. However, we cannot definitely state that one labelling approach is superior or even that an increase in the proportion of labelled products purchased will lead to a reduction in calories purchased. TRIAL REGISTRATION: The American Economic Association's registry for randomized controlled trials, RCT ID: AEARCTR-0002325; Prospectively Registered October 06, 2017. In compliance with ICMJE policy, the trial was also registered on Clinicaltrials.gov, RCT ID: [NCT04165447]. Retrospectively Registered 11 November 2019.

The effect of implicit and explicit taxes on the purchasing of 'high-in-calorie' products: A randomized controlled trial.

Public health taxes on less healthy food and beverage products have been shown to be effective in various settings. However, it is unclear if observed reductions in the quantity of taxed products purchased is a result of price increases due to the tax or the accompanying messaging and if the effects are influenced by the level of support for such taxes within the population. 941 adults residing in Singapore were randomized and asked to shop in one of four versions of a fully functional on-line experimental grocery store: 1) no tax control; 2) implicit tax showing only post-tax prices (i.e., 20 % higher than control prices) on high-in-calorie products; 3) fake tax showing pre-tax prices and a label falsely indicating that the price includes a 20 % tax on high-in-calorie products; and 4) explicit tax showing the same label as in 3) and an actual 20 % price increase applied to the high-in-calorie products. The proportion of high-in-calorie products purchased was 14 % in the control arm. We were unable to reject the null hypothesis of no effect in the implicit tax arm compared to control (0.08, 95 % CI -3.31 to 1.77) or in the fake tax arm compared to the control (2.59, 95 % CI -5.04 to 0.00) but observed a statistically significant 3.35 percentage point decrease (95 % CI -6.01 to -0.5) in the explicit tax arm compared to control. We were unable to reject the null hypothesis of no effect in any of the outcomes related to diet quality. Individuals who support the tax showed greater responsiveness to the explicit and fake taxes compared to those who do not (price elasticities of demand of -1.38 and -0.51 respectively). Results suggest that reductions in the proportions of high-in-calorie products purchased may be largely attributable to explicit messaging rather than to price increases. However, even when effective, policymakers should recognize that changes in purchasing patterns may not improve diet quality and that results may not generalize to other areas where levels of support differ.

Impacts of genomics on the health and social costs of intellectual disability.

BACKGROUND: This study provides an integrated assessment of the economic and social impacts of genomic sequencing for the detection of monogenic disorders resulting in intellectual disability (ID). METHODS: Multiple knowledge bases were cross-referenced and analysed to compile a reference list of monogenic disorders associated with ID. Multiple literature searches were used to quantify the health and social costs for the care of people with ID. Health and social expenditures and the current cost of whole-exome sequencing and whole-genome sequencing were quantified in relation to the more common causes of ID and their impact on lifespan. RESULTS: On average, individuals with ID incur annual costs in terms of health costs, disability support, lost income and other social costs of US$172 000, accumulating to many millions of dollars over a lifetime. CONCLUSION: The diagnosis of monogenic disorders through genomic testing provides the opportunity to improve the diagnosis and management, and to reduce the costs of ID through informed reproductive decisions, reductions in unproductive diagnostic tests and increasingly targeted therapies.

Cost-effectiveness of Intravitreal Ranibizumab With Verteporfin Photodynamic Therapy Compared With Ranibizumab Monotherapy for Patients With Polypoidal Choroidal Vasculopathy.

Importance: The EVEREST II trial showed that for patients with polypoidal choroidal vasculopathy (PCV), intravitreal ranibizumab in combination with verteporfin photodynamic therapy improves visual acuity relative to ranibizumab monotherapy. However, whether combination therapy is incrementally cost-effective relative to monotherapy during a lifetime is unclear. Objective: To assess the incremental cost-effectiveness of combination therapy compared with ranibizumab monotherapy in patients with PCV. Design, Setting, and Participants: This model-based, economic evaluation used 2018 unit cost data from a tertiary eye hospital in Singapore, first- and second-year outcomes and resource use data from a multicenter trial across various Asian countries (EVEREST II) to model a hypothetical cohort of patients with symptomatic PCV. Scenario analyses and deterministic and probabilistic sensitivity analyses were performed to examine uncertainty. Data were collected from October 2018 through April 2019 and analyzed from March through October 2019. Interventions: This model used data from the EVEREST II trial, in which all participants were given 0.5 mg of intravitreal ranibizumab once every 4 weeks for the first 3 months. Subsequent administration occurred as needed. For participants receiving combination therapy, standard fluence (50 J/cm3) photodynamic therapy with 6-mg/m2 verteporfin was administered once during the first 3 months and thereafter as needed. Main Outcomes and Measures: Incremental cost per quality-adjusted life-year (QALY) gained for combination therapy relative to monotherapy for patients with PCV. Results: In this model based on a cohort of 1000 patients aged 68 years, a patient with PCV incurred a total cost in Singapore dollars (SGD) of 92 327 (US $67 399) with combination therapy and SGD 92 371 (US $67 431) with monotherapy during a lifetime horizon, generating a modest cost savings of SGD 44 (US $32) per patient undergoing combination therapy. Lifetime QALYs were estimated to be 7.87 for combination therapy and 7.85 for monotherapy, for an incremental gain of 0.02 QALYs. Combination therapy remained cost-saving or cost-effective in all lifetime scenarios modeled, but during shorter time horizons and at lower monotherapy costs, it may not be cost-effective. Conclusions and Relevance: This study found combination therapy to be a dominant (more effective and less costly) strategy, being similar in costs and slightly more effective than ranibizumab monotherapy during a lifetime horizon. However, decreasing the time horizon to less than 10 years and/or reductions in the cost of monotherapy may result in combination therapy no longer being cost-effective.

Beyond cost-effectiveness: A five-step framework for appraising the value of health technologies in Asia-Pacific.

Given resource constraints and the potential for increasingly high-cost, cost-effective medicines to become available, policymakers require strategies that go beyond cost-effectiveness when making resource allocation decisions. This manuscript presents a five-step framework that complements traditional health technology assessment (HTA) guidance documents that policymakers in Asia-Pacific and elsewhere may consider when setting up HTA guidelines and/or evaluating whether or not to subsidize a medicine or other health innovations. The framework recommends that subsidy decisions be based on five criteria: the relative burden of the condition as compared with other conditions (step 1), comparative and cost-effectiveness of the medicine (steps 2 and 3), the short-term impact on the budget (step 4), and other considerations including patient and societal preferences (step 5). Our approach, which is a complement to traditional HTA guidance documents, is not prescriptive but provides an evidence-based framework that HTA agencies in Asia-Pacific can follow as they aim to deliver value-based medicines to their constituents.

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis.

OBJECTIVES: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients. MATERIALS AND METHODS: We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted. RESULTS: A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time. CONCLUSIONS: This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.

A Randomized Controlled Trial Evaluating the Relative Effectiveness of the Multiple Traffic Light and Nutri-Score Front of Package Nutrition Labels.

The objective of this trial was to test two promising front-of-pack nutrition labels, 1) the United Kingdom's Multiple Traffic Lights (MTL) label and 2) France's Nutri-Score (NS), relative to a no-label control. We hypothesized that both labels would improve diet quality but NS would be more effective due to its greater simplicity. We tested this hypothesis via an online grocery store using a 3 × 3 crossover (within-person) design with 154 participants. Outcomes assessed via within person regression models include a modified Alternative Healthy Eating Index (AHEI)-2010 (primary), average Nutri-Score, calories purchased, and singular measures of diet quality of purchase orders. Results show that both labels significantly improve modified AHEI scores relative to Control but neither is statistically superior using this measure. NS performed statistically better than MTL and Control based on average Nutri-Score, yet, unlike MTL it did not statistically reduce calories or sugar from beverages. This suggest that NS may be preferred if the goal is to improve overall diet quality but, because calories are clearly displayed on the label, MTL may perform better if the goal is to reduce total energy intake.

Cardiovascular magnetic resonance in emergency patients with multivessel disease or unobstructed coronary arteries: a cost-effectiveness analysis in the UK.

OBJECTIVE: To identify the key drivers of cost-effectiveness for cardiovascular magnetic resonance (CMR) when patients activate the primary percutaneous coronary intervention (PPCI) pathway. DESIGN: Economic decision models for two patient subgroups populated from secondary sources, each with a 1 year time horizon from the perspective of the National Health Service (NHS) and personal social services in the UK. SETTING: Usual care (with or without CMR) in the NHS. PARTICIPANTS: Patients who activated the PPCI pathway, and for Model 1: underwent an emergency coronary angiogram and PPCI, and were found to have multivessel coronary artery disease. For Model 2: underwent an emergency coronary angiogram and were found to have unobstructed coronary arteries. INTERVENTIONS: Model 1 (multivessel disease) compared two different ischaemia testing methods, CMR or fractional flow reserve (FFR), versus stress echocardiography. Model 2 (unobstructed arteries) compared CMR with standard echocardiography versus standard echocardiography alone. MAIN OUTCOME MEASURES: Key drivers of cost-effectiveness for CMR, incremental costs and quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios. RESULTS: In both models, the incremental costs and QALYs between CMR (or FFR, Model 1) versus no CMR (stress echocardiography, Model 1 and standard echocardiography, Model 2) were small (CMR: -£64 (95% CI -£232 to £187)/FFR: £360 (95% CI -£116 to £844) and CMR/FFR: 0.0012 QALYs (95% CI -0.0076 to 0.0093)) and (£98 (95% CI -£199 to £488) and 0.0005 QALYs (95% CI -0.0050 to 0.0077)), respectively. The diagnostic accuracy of the tests was the key driver of cost-effectiveness for both patient groups. CONCLUSIONS: If CMR were introduced for all subgroups of patients who activate the PPCI pathway, it is likely that diagnostic accuracy would be a key determinant of its cost-effectiveness. Further research is needed to definitively answer whether revascularisation guided by CMR or FFR leads to different clinical outcomes in acute coronary syndrome patients with multivessel disease.

Comprehensive ascertainment of bleeding in patients prescribed different combinations of dual antiplatelet therapy (DAPT) and triple therapy (TT) in the UK: study protocol for three population-based cohort studies emulating 'target trials' (the ADAPTT Study).

INTRODUCTION: 'Real world' bleeding in patients exposed to different regimens of dual antiplatelet therapy (DAPT) and triple therapy (TT, DAPT plus an anticoagulant) have a clinical and economic impact but have not been previously quantified. METHODS AND ANALYSIS: We will use linked Clinical Practice Research Datalink (CPRD) and Hospital Episode Statistics (HES) data to assemble populations eligible for three 'target trials' in patient groups: percutaneous coronary intervention (PCI); coronary artery bypass grafting (CABG); conservatively managed (medication only) acute coronary syndrome (ACS). Patients ≥18 years old will be eligible if, in CPRD records, they have: ≥1 year of data before the index event; no prescription for DAPT or anticoagulants in the preceding 3 months; a prescription for aspirin or DAPT within 2 months after discharge from the index event. The primary outcome will be any bleeding event (CPRD or HES) up to 12 months after the index event. We will estimate adjusted HR for time to first bleeding event comparing: aspirin and clopidogrel (reference) versus aspirin and prasugrel or aspirin and ticagrelor after PCI; and aspirin (reference) versus aspirin and clopidogrel after CABG and ACS. We will describe rates of bleeding in patients prescribed TT (DAPT plus an anticoagulant). Potential confounders will be identified systematically using literature review, semistructured interviews with clinicians and a short survey of clinicians. We will conduct sensitivity analyses addressing the robustness of results to the study's main limitation-that we will not be able to identify the intervention group for patients whose bleeding event occurs before a DAPT prescription in CPRD. ETHICS AND DISSEMINATION: This protocol was approved by the Independent Scientific Advisory Committee for the UK Medicines and Healthcare Products Regulatory Agency Database Research (protocol 16_126R) and the South West Cornwall and Plymouth Research Ethics Committee (17/SW/0092). The findings will be presented in peer-reviewed journals, lay summaries and briefing papers to commissioners/other stakeholders. TRIAL REGISTRATION NUMBER: 76607611; Pre-results.

Multi-Centre Micro-Costing of Roux-En-Y Gastric Bypass, Sleeve Gastrectomy and Adjustable Gastric Banding Procedures for the Treatment of Severe, Complex Obesity.

BACKGROUND: There is a growing interest in comparing the effectiveness and costs of alternative forms of bariatric surgery. We aimed to examine the per-patient, procedural costs of Roux-en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) and adjustable gastric banding (AGB) in the United Kingdom. METHODS: Multi-centre (two National Health Service; NHS and one private hospital) micro-costing, using a time-and-motion study. Prospective collection of surgery times, staff quantities, equipment, instruments and consumables for 12 patients (four RYGB, five SG, three AGB) from patients' first surgeon interaction on the day of surgery to departure from the theatre recovery area. Costs were attached to quantities and mean costs compared. Sensitivity and scenario analyses assessed the impact of varying surgery inputs and consideration of additional plausible factors respectively on total costs. RESULTS: Mean procedural costs were £5002 for RYGB, £4306 for SG and £2527 for AGB. Varying staff seniority or altering procedure times had small impacts on costs (± 4-6%). Reducing prices of consumables by 20% reduced costs by 10-13%. Accounting for differences in surgical technique by altering the number of staple reloads used impacted costs by ± 7-10%. Adjusted total costs from scenario analyses were similar to NHS tariffs for RYGB and SG (difference of £51 and -£119 respectively) but were much lower for AGB (difference of £1982). CONCLUSIONS: These detailed costs will allow for more precise reimbursement of bariatric surgery and support comprehensive assessments of cost-effectiveness. Additional work to investigate costs of post-surgical care, re-operations and life-long support received by patients following surgery is required.

Mapping the EORTC-QLQ-C30 to the EQ-5D-3L: An Assessment of Existing and Newly Developed Algorithms.

OBJECTIVES: To assess the external validity of mapping algorithms for predicting EQ-5D-3L utility values from EORTC QLQ-C30 responses not previously validated and to assess whether statistical models not previously applied are better suited for mapping the EORTC QLQ-C30 to the EQ-5D-3L. METHODS: In total, 3866 observations for 1719 patients from a longitudinal study (Cancer 2015) were used to validate existing algorithms. Predictive accuracy was compared to previously validated algorithms using root mean squared error, mean absolute error across the EQ-5D-3L range, and for 10 tumor-type specific samples as well as using differences between estimated quality-adjusted life years. Thirteen new algorithms were estimated using a subset of the Cancer 2015 data (3203 observations for 1419 patients) applying various linear, response mapping, beta, and mixture models. Validation was performed using 2 data sets composed of patients with varying disease severity not used in the estimation and all available algorithms ranked on their performance. RESULTS: None of the 5 existing algorithms offer an improvement in predictive accuracy over preferred algorithms from previous validation studies. Of the newly estimated algorithms, a 2-part beta model performed the best across the validation criteria and in data sets composed of patients with different levels of disease severity. Validation results did, however, vary widely between the 2 data sets, and the most accurate algorithm appears to depend on health state severity as the distribution of observed EQ-5D-3L values varies. Linear models performed better for patients in relatively good health, whereas beta, mixture, and response mapping models performed better for patients in worse health. CONCLUSION: The most appropriate mapping algorithm to apply in practice may depend on the disease severity of the patient sample whose utility values are being predicted.

Using "Big Data" in the Cost-Effectiveness Analysis of Next-Generation Sequencing Technologies: Challenges and Potential Solutions.

Next-generation sequencing (NGS) is considered to be a prominent example of "big data" because of the quantity and complexity of data it produces and because it presents an opportunity to use powerful information sources that could reduce clinical and health economic uncertainty at a patient level. One obstacle to translating NGS into routine health care has been a lack of clinical trials evaluating NGS technologies, which could be used to populate cost-effectiveness analyses (CEAs). A key question is whether big data can be used to partially support CEAs of NGS. This question has been brought into sharp focus with the creation of large national sequencing initiatives. In this article we summarize the main methodological and practical challenges of using big data as an input into CEAs of NGS. Our focus is on the challenges of using large observational datasets and cohort studies and linking these data to the genomic information obtained from NGS, as is being pursued in the conduct of large genomic sequencing initiatives. We propose potential solutions to these key challenges. We conclude that the use of genomic big data to support and inform CEAs of NGS technologies holds great promise. Nevertheless, health economists face substantial challenges when using these data and must be cognizant of them before big data can be confidently used to produce evidence on the cost-effectiveness of NGS.