The Impact of Hospital Costing Methods on Cost-Effectiveness Analysis: A Case Study’

Tisagenlecleucel for the Treatment of Relapsed or Refractory B-cell Acute Lymphoblastic Leukaemia in People Aged up to 25 Years: An Evidence Review Group Perspective of a NICE Single Technology Appraisal Abstract As part of the National Institute for Health and Care Excellence’s (NICE’s) Single Technology Appraisal (STA) process, Novartis submitted evidence on the clinical effectiveness and cost-effectiveness of tisagenlecleucel for treating paediatric and young adult patients (under the age of 25 years) with relapsed or refractory (r/r) B-cell acute lymphoblastic leukaemia (ALL). This article presents a summary of the Evidence Review Group’s (ERG’s) independent review of the evidence submission, the committee’s deliberations, and the subsequent development of NICE guidance for the use of tisagenlecleucel on the National Health Service (NHS) in England. Tisagenlecleucel is a chimeric antigen receptor-modified T-cell (CAR-T) product, the first of this emerging therapeutic class to be considered by NICE in this indication. The company’s evidence submission was based upon three single-arm, phase II studies: ELIANA, ENSIGN, and B2101J. These trials demonstrated a beneficial effect of tisagenlecleucel, with significant extensions in event-free survival (EFS) and overall survival (OS) compared to historical control datasets on blinatumomab and salvage chemotherapy. Adverse events were common; 77% of patients suffered from cytokine release syndrome (CRS), 56% of whom required intensive care unit-level care. The ERG did not consider clofarabine monotherapy an appropriate proxy for salvage chemotherapy. The company presented a hybrid cost-effectiveness model, combining a decision tree and three-state partitioned survival model structure. The majority of quality-adjusted life-years (QALYs) gained were generated through additional life-years in the extrapolated ‘long-term survival’ phase of the model, where patients were assumed to be ‘cured’. The ERG considered the results to be subject to substantial uncertainty, due in part to immature trial data, unresolved long-term treatment effects, and a lack of appropriate comparator data. The ERG implemented a number of changes to the company’s model in an alternative base case, producing deterministic incremental cost-effectiveness ratios (ICERs) of £45,397 per QALY gained versus salvage chemotherapy, and £27,732 versus blinatumomab. The probabilistic model produced ICERs of £48,265 per QALY gained versus salvage chemotherapy, and £29,501 versus blinatumomab. The committee considered the ERG’s analysis to be most closely aligned with their preferred assumptions, and did not consider tisagenlecleucel to meet both of the end-of-life (EoL) criteria. In recognition of the innovative nature of tisagenlecleucel, and the present immaturity of ongoing clinical trials, the committee considered further data collection would be valuable in resolving uncertainties around OS, the technology’s novel mechanism of action, and the management of CRS and B-cell aplasia. The committee therefore recommended tisagenlecleucel for use in the Cancer Drugs Fund (CDF) until the conclusion of the ELIANA study (June 2023). This appraisal highlighted the difficulty of interpreting EoL criteria in the context of curative therapies and the valuation of cure versus extension of life. Further clarification of NICE’s position in these situations may be necessary to ensure consistency and equity in their decision-making.

Cost-Effectiveness Analysis of Non-Statin Lipid-Modifying Agents for Secondary Cardiovascular Disease Prevention Among Statin-Treated Patients in Thailand Abstract Background Using non-statin lipid-modifying agents in combination with statin therapy provides additional benefits for cardiovascular disease (CVD) risk reduction, but their value for money has only been evaluated in high-income countries (HICs). Furthermore, studies mainly derive effectiveness data from a single trial or older meta-analyses. Objectives Our study used data from the most recent network meta-analysis (NMA) and local parameters to assess the cost effectiveness of non-statin agents in statin-treated patients with a history of CVD. Methods A published Markov model was adopted to investigate lifetime outcomes: (1) number of recurrent CVD events prevented, (2) quality-adjusted life-years (QALYs) gained, (3) costs and (4) incremental cost-effectiveness ratios (ICERs) of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) and ezetimibe added to statin therapy. Event rates and effectiveness inputs were obtained from the NMA. Cost and utility data were gathered from published studies conducted in Thailand. A series of sensitivity analyses were performed. Results Patients receiving PCSK9i and ezetimibe experienced fewer recurrent CVD events (number needed to treat [NNT] 17 and 30) and more QALYs (0.168 and 0.096 QALYs gained per person). However, under the societal perspective and at current acquisition costs in 2018, ICERs of both agents were $US1,223,995 and 27,361 per QALY gained, respectively. Based on threshold analyses, the costs need to be reduced by 97 and 85%, respectively, for PCSK9i and ezetimibe to be cost-effective. Conclusions Despite the proven effectiveness of PCSK9i and ezetimibe, the costs of these agents need to reduce to a much greater extent than in HICs to be cost-effective in Thailand.

Pembrolizumab for Treating Relapsed or Refractory Classical Hodgkin Lymphoma: An Evidence Review Group Perspective of a NICE Single Technology Appraisal Abstract As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme; MSD) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of patients with relapsed or refractory classical Hodgkin lymphoma (RRcHL) who did not respond to treatment with brentuximab vedotin. Kleijnen Systematic Reviews Ltd, in collaboration with Maastricht University Medical Centre+, was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company’s submission to NICE. According to the NICE scope, pembrolizumab was compared with single or combination chemotherapy. Comparisons were undertaken in two populations: patients who did and did not receive prior autologous stem cell transplant (autoSCT; populations 1 and 2, respectively). Despite it having been recommended by NICE in population 1 at the time the ERG received the company submission, nivolumab was not included as a comparator. No studies directly comparing pembrolizumab and its comparators were identified. One ongoing, single-arm study of the efficacy and safety of pembrolizumab (KEYNOTE-087) and one comparative observational study (Cheah et al., 2016) were used to inform the comparative effectiveness of pembrolizumab and standard of care (SoC), using indirect comparisons in both populations. Almost all analyses showed significant PFS and overall response rate benefits for pembrolizumab versus SoC, but due to being based on indirect comparison, were likely to contain systematic error. The economic evaluation therefore suffered from substantial uncertainty in any estimates of cost effectiveness. Furthermore, there was a lack of evidence on the uptake and timing of allogeneic stem cell transplant, and alternative assumptions had a significant impact on cost effectiveness. Immature survival data from KEYNOTE-087 exacerbated this issue and necessitated the use of alternative data sources for longer-term extrapolation of survival. Some issues identified in the company’s analyses were amended by the ERG. The revised ERG deterministic base-case incremental cost-effectiveness ratios based on the company’s second Appraisal Consultation Document response for pembrolizumab versus SoC (with a commercial access agreement) for populations 1 and 2 were £54,325 and £62,527 per quality-adjusted life-year gained, respectively. There was substantial uncertainty around these ICERs, especially in population 2. NICE did not recommend pembrolizumab as an option for treating RRcHL in population 1, but recommended pembrolizumab for use within the Cancer Drugs Fund in population 2.

Decision Models for Assessing the Cost Effectiveness of Treatments for Pediatric Drug-Resistant Epilepsy: A Systematic Review of Economic Evaluations Abstract Background Drug-resistant epilepsy affects about one-third of children with epilepsy and is associated with high costs to the healthcare system, yet the cost effectiveness of most treatments is unclear. Use of cannabis-based products for epilepsy is increasing, and the cost effectiveness of such strategies relative to conventional pharmacologic treatments must be considered. Objective The objective of this systematic review was to identify economic evaluations of cannabis-based treatments for pediatric drug-resistant epilepsy. We also sought to identify and appraise decision models that have been used in economic evaluations of pharmacologic treatments (i.e., antiepileptic drugs) in this population. Methods Electronic searches of MEDLINE, EMBASE, and the Cochrane library, as well as a targeted grey literature search, were undertaken (11 June 2018). Model-based full economic evaluations involving cannabis-based treatments or pharmacologic treatments for drug-resistant epilepsy in children were eligible for inclusion. Two independent reviewers selected studies for inclusion, and study quality was assessed by use of the Drummond and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) checklists. Study findings, as well as model characteristics, are narratively summarized. Results Nine economic evaluations involving children with drug-resistant epilepsy were identified; however, none involved cannabis-based treatments. All studies involved pharmacologic treatments compared with other pharmacologic treatments or non-pharmacologic treatments (i.e., ketogenic diet, epilepsy surgery, vagus nerve stimulation). Few studies have assessed the cost effectiveness of pharmacologic treatments in specific drug-resistant epilepsy syndromes, including Dravet and Lennox-Gastaut syndromes. Five included studies involved use of Markov models with a similar structure (i.e., health states based on seizure frequency relative to baseline). There was a wide range of methodological quality, and few studies fully addressed context-specific issues such as weight gain and treatment switching. Conclusion Whether cannabis-based treatments for pediatric drug-resistant epilepsy represent good value for money has yet to be investigated. Economic evaluations of such treatments are needed and should address issues of particular importance in pediatric epilepsy, including weight gain over time, switching or discontinuation of treatments, effectiveness of interventions and comparators, and long-term effectiveness beyond the duration of available clinical studies. PROSPERO Registration CRD42018099591.

Cost Effectiveness of Advanced Pharmacy Services Provided in the Community and Primary Care Settings: A Systematic Review Abstract Background Pharmacists working in community and primary care are increasingly developing advanced skills to provide enhanced services, particularly in dealing with minor acute illness. These services can potentially free-up primary care physicians’ time; however, it is not clear whether they are sufficiently cost effective to be recommended for wider provision in the UK. Objective The aim of this study was to review published economic evaluations of enhanced pharmacy services in the community and primary care settings. Methods We undertook a systematic review of economic evaluations of enhanced pharmacy services to inform NICE guidelines for emergency and acute care. The review protocol was developed and agreed with the guideline committee. The National Health Service Economic Evaluation Database, Health Technology Assessment Database, Health Economic Evaluations Database, MEDLINE and EMBASE were searched in December 2016 and the search was updated in March 2018. Studies were assessed for applicability and methodological quality using the NICE Economic Evaluation Checklist. Results Of 3124 records, 13 studies published in 14 papers were included. The studies were conducted in the UK, Spain, The Netherlands, Australia, Italy and Canada. Settings included community pharmacies, primary care/general practice surgeries and patients’ homes. Most of the studies were assessed as partially applicable with potentially serious limitations. Services provided in community and primary care settings were found to be either dominant or cost effective, at a £20,000 per quality-adjusted life-year threshold, compared with usual care. Those delivered in the patient’s home were not found to be cost effective. Conclusions Advanced pharmacy services appear to be cost effective when delivered in community and primary care settings, but not in domiciliary settings. Expansion in the provision of these services in community and primary care can be recommended for wider implementation.

Adoption of Cost Effectiveness-Driven Value-Based Formularies in Private Health Insurance from 2010 to 2013 Abstract Background and Objective It is unclear whether private insurance benefit designs align with the most widely used ex-US definition of value, the incremental cost-effectiveness ratio (ICER). A large Pacific Northwest private insurance plan explicitly implemented a tiered formulary based on cost-effectiveness estimates of individual drugs in 2010, resulting in cost savings to the plan without negatively affecting patient health service utilization. Given the pressures of rising costs, we investigate whether employer-based private health insurance plans have adopted value-based cost-sharing approaches that are in line with cost-effectiveness estimates. Methods At the drug level, we identified five drug tier designations (0–4) that are tied to increasing ICER ranges in a large claims dataset from 2010 to 2013. We used a random effects model to evaluate whether out-of-pocket (OOP) cost levels and trends were associated with drug value designation, controlling for generic status and list price, and whether the associations varied by insurance plan type and insurance market concentration, as measured by the Herfindahl-Hirschman Index (HHI). We also estimated the weighted mean cost effectiveness of the drug claims in the sample by year and generic status using the formulary’s cost-effectiveness value ranges. Results The 2010 volume weighted mean OOP cost for a 30-day supply of drugs in tiers 0 through 4 were $US6.87, $US22.62, $US62.22, $US57.36, and $US59.85, respectively (2013 US dollars). OOP costs for cost-saving and preventive drugs (tier 0) decreased 5% annually from 2010 to 2013 (p < 0.01); OOP costs for drugs costing under $US10,000/quality-adjusted life-year (QALY) (tier 1) decreased 4.5% annually (p < 0.01) and OOP costs for drugs costing over $US50,000/QALY (tier 3) and $US150,000/QALY (tier 4) decreased by 2.4% and 2.2%, respectively (p < 0.01 and p = 0.046). OOP costs for drugs valued between $US10,000 and $US50,000/QALY did not change significantly (p = 0.31). Average ICER estimates increased for generic drugs and did not change for brand name drugs. Conclusion OOP costs for prescription drugs are decreasing across value levels, with OOP costs for higher-value drugs generally decreasing at a faster rate than lower-value drugs. The relationship between cost sharing and value remains tenuous, however, particularly at higher ICER levels, likely reflecting the persistence of traditional formulary structures and increasing use of generic drugs over brand name drugs.

Structural Design and Data Requirements for Simulation Modelling in HIV/AIDS: A Narrative Review Abstract Born out of a necessity for fiscal sustainability, simulation modeling is playing an increasingly prominent role in setting priorities for combination implementation strategies for HIV treatment and prevention globally. The design of a model and the data inputted into it are central factors in ensuring credible inferences. We executed a narrative review of a set of dynamic HIV transmission models to comprehensively synthesize and compare the structural design and the quality of evidence used to support each model. We included 19 models representing both generalized and concentrated epidemics, classified as compartmental, agent-based, individual-based microsimulation or hybrid in our review. We focused on four structural components (population construction; model entry, exit and HIV care engagement; HIV disease progression; and the force of HIV infection), and two analytical components (model calibration/validation; and health economic evaluation, including uncertainty analysis). While the models we reviewed focused on a variety of individual interventions and their combinations, their structural designs were relatively homogenous across three of the four focal components, with key structural elements influenced by model type and epidemiological context. In contrast, model entry, exit and HIV care engagement tended to differ most across models, with some health system interactions—particularly HIV testing—not modeled explicitly in many contexts. The quality of data used in the models and the transparency with which the data was presented differed substantially across model components. Representative and high-quality data on health service delivery were most commonly not accessed or were unavailable. The structure of an HIV model should ideally fit its epidemiological context and be able to capture all efficacious treatment and prevention services relevant to a robust combination implementation strategy. Developing standardized guidelines on evidence syntheses for health economic evaluation would improve transparency and help prioritize data collection to reduce decision uncertainty.

Pembrolizumab for Locally Advanced or Metastatic Urothelial Cancer Where Cisplatin is Unsuitable: An Evidence Review Group Perspective of a NICE Single Technology Appraisal Abstract As part of its Single Technology Appraisal (STA) process, the National Institute for Health and Care Excellence (NICE) invited the manufacturer (Merck Sharp & Dohme) of pembrolizumab (Keytruda®) to submit evidence of its clinical and cost effectiveness for the treatment of locally advanced or metastatic urothelial cancer where cisplatin is unsuitable. The School of Health and Related Research Technology Appraisal Group at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a detailed review of the evidence for the clinical and cost effectiveness of the technology, based on the company’s submission (CS) to NICE. The clinical effectiveness evidence in the CS for pembrolizumab was based on one phase II, single-arm, open-label, non-randomised study (KEYNOTE-052), while the evidence for the comparator (carboplatin plus gemcitabine) was based on four studies, including one randomised controlled trial and three cohort studies. In the absence of head-to-head trials, the company conducted an indirect treatment comparison for both progression-free survival (PFS) and overall survival (OS), by firstly adjusting cross-study differences using a simulated treatment comparison approach and then synthesizing the evidence based on an assumption of constant hazard ratios using a standard meta-analysis model and time-varying hazard ratios using fractional polynomial models. The treatment effect of pembrolizumab was more favourable in the adjusted population compared with the observed effect in the KEYNOTE-052 study. The company submitted a de novo partitioned survival cohort simulation model, which partitions the OS time into PFS and post-progression survival. The probabilistic incremental cost-effectiveness ratio (ICER) for pembrolizumab compared with carboplatin plus gemcitabine was estimated to be £37,081 per quality-adjusted life-year (QALY) gained, based on the results within the company’s health economic model. Following a critique of the model, for their preferred base case the ERG corrected some minor model errors, chose a progression approach for estimating utilities, and revised the extrapolation of PFS and OS. The ERG’s probabilistic base case ICER was estimated to be £67,068 per QALY gained. The ERG also undertook a range of exploratory sensitivity analyses which suggested that the ICER was highly uncertain. In particular, the choices of extrapolation for the OS of pembrolizumab and the stopping rule for pembrolizumab had the largest impacts on the ICER. The NICE Appraisal Committee recommended pembrolizumab for use within the Cancer Drugs Fund as an option for treating locally advanced or metastatic urothelial carcinoma in adults who have had platinum-containing chemotherapy, provided that pembrolizumab was stopped at 2 years of uninterrupted treatment, or earlier if the disease progresses, and the conditions of the managed access agreement for pembrolizumab are followed.

Mapping the PedsQL™ onto the CHU9D: An Assessment of External Validity in a Large Community-Based Sample Abstract Background Mapping algorithms have been indicated as a second-best solution for estimating health state utilities for the calculation of quality-adjusted life-years within cost-utility analysis when no generic preference-based measure is incorporated into the study. However, the predictive performance of these algorithms may be variable and hence it is important to assess their external validity before application in different settings. Objective The aim of this study was to assess the external validity and generalisability of existing mapping algorithms for predicting preference-based Child Health Utility 9D (CHU9D) utilities from non-preference-based Pediatric Quality of Life Inventory (PedsQL) scores among children and adolescents living with or without disabilities or health conditions. Methods Five existing mapping algorithms, three developed using data from an Australian community population and two using data from a UK population with one or more self-reported health conditions, were externally validated on data from the Longitudinal Study of Australian Children (n = 6623). The predictive accuracy of each mapping algorithm was assessed using the mean absolute error (MAE) and the mean squared error (MSE). Results Values for the MAE (0.0741–0.2302) for all validations were within the range of published estimates. In general, across all ages, the algorithms amongst children and adolescents with disabilities/health conditions (Australia MAE: 0.2085–0.2302; UK MAE: 0.0854–0.1162) performed worse relative to those amongst children and adolescents without disabilities/health conditions (Australia MAE: 0.1424–0.1645; UK MAE: 0.0741–0.0931). Conclusions The published mapping algorithms have acceptable predictive accuracy as measured by MAE and MSE. The findings of this study indicate that the choice of the most appropriate mapping algorithm to apply may vary according to the population under consideration.