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.

Severity-Adjusted Probability of Being Cost Effective Abstract Background In the context of priority setting, a differential cost-effectiveness threshold can be used to reflect a higher societal willingness to pay for quality-adjusted life-year gains in the worse off. However, uncertainty in the estimate of severity can lead to problems when evaluating the outcomes of cost-effectiveness analyses. Objectives This study standardizes the assessment of severity, integrates its uncertainty with the uncertainty in cost-effectiveness results and provides decision makers with a new estimate: the severity-adjusted probability of being cost effective. Methods Severity is expressed in proportional and absolute shortfall and estimated using life tables and country-specific EQ-5D values. We use the three severity-based cost-effectiveness thresholds (€20.000, €50.000 and €80.000, per QALY) adopted in The Netherlands. We exemplify procedures of integrating uncertainty with a stylized example of a hypothetical oncology treatment. Results Applying our methods, taking into account the uncertainty in the cost-effectiveness results and in the estimation of severity identifies the likelihood of an intervention being cost effective when there is uncertainty about the appropriate severity-based cost-effectiveness threshold. Conclusions Higher willingness-to-pay thresholds for severe diseases are implemented in countries to reflect societal concerns for an equitable distribution of resources. However, the estimates of severity are uncertain, patient populations are heterogeneous, and this can be accounted for with the severity-adjusted probability of being cost effective proposed in this study. The application to the Netherlands suggests that not adopting the new method could result in incorrect decisions in the reimbursement of new health technologies.

Estimating Lifetime Benefits Associated with Immuno-Oncology Therapies: Challenges and Approaches for Overall Survival Extrapolations Abstract Background Standard parametric survival models are commonly used to estimate long-term survival in oncology health technology assessments; however, they can inadequately represent the complex pattern of hazard functions or underlying mechanism of action (MoA) of immuno-oncology (IO) treatments. Objective The aim of this study was to explore methods for extrapolating overall survival (OS) and provide insights on model selection in the context of the underlying MoA of IO treatments. Methods Standard parametric, flexible parametric, cure, parametric mixture and landmark models were applied to data from ATLANTIC (NCT02087423; data cut-off [DCO] 3 June 2016). The goodness of fit of each model was compared using the observed survival and hazard functions, together with the plausibility of corresponding model extrapolation beyond the trial period. Extrapolations were compared with updated data from ATLANTIC (DCO 7 November 2017) for validation. Results A close fit to the observed OS was seen with all models; however, projections beyond the trial period differed. Estimated mean OS differed substantially across models. The cure models provided the best fit for the new DCO. Conclusions Standard parametric models fitted to the initial ATLANTIC DCO generally underestimated longer-term OS, compared with the later DCO. Cure, parametric mixture and response-based landmark models predicted that larger proportions of patients with metastatic non-small cell lung cancer receiving IO treatments may experience long-term survival, which was more in keeping with the observed data. Further research using more mature OS data for IO treatments is needed.

Valuation of EQ-5D-5L Health States in Poland: the First EQ-VT-Based Study in Central and Eastern Europe Abstract Objective Cost-utility analyses are becoming increasingly important in Central and Eastern Europe. We aimed to develop a Polish utility tariff for EQ-5D-5L health states. Methods Face-to-face, computer-assisted interviews were collected in a representative sample. Each respondent followed a standardised protocol to collect ten composite time trade-off and seven discrete choice experiment observations. In the Bayesian approach, several model specifications were compared based on model fit, the usability of the final value set and how they reflect the elicitation procedure (e.g. censoring). A hybrid approach (using composite time trade-off and discrete choice experiment data) was employed in the final set, which was compared with the existing ones: EQ-5D-3L and EQ-5D-5L cross-walk. Results Data from 1252 respondents (11,480 composite time trade-off valuations and 8764 discrete choice experiment pairs) were collected over the period June to October 2016. The final model accounted for random parameters, error scaling with fat tails, censoring at − 1, unwillingness to trade in time trade-off by the religious people and Cauchy distribution in discrete choice experiments. Pain/discomfort impacts the utility most: the disutility equals 0.575 when at level 5. In the value set, 4.4% of EQ-5D-5L states are worse than dead. The new value set has a comparable range (minimum of − 0.590 compared to − 0.523) and the same ordering of the first three dimensions (pain/discomfort, mobility, self-care) as the EQ-5D-3L value set and the EQ-5D-5L cross-walk value set. Moreover, it is more sensitive to a moderate decline in health. Conclusions The new value set supports consistency with past decisions in cost-utility studies, while offering a better assessment of even moderate improvements in health. It could represent an option for Central and Eastern Europe countries lacking their own value sets.

The Clinical and Cost Effectiveness of Inotuzumab Ozogamicin for the Treatment of Adult Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia: An Evidence Review Group Evaluation of a NICE Single Technology Appraisal Abstract The National Institute for Health and Care Excellence (NICE) invited Pfizer, the manufacturer of inotuzumab ozogamicin (henceforth inotuzumab), to submit clinical- and cost-effectiveness evidence for inotuzumab as part of NICE’s single technology appraisal process. The Centre for Reviews and Dissemination and the Centre for Health Economics, both at the University of York, were commissioned as the independent evidence review group (ERG). The clinical-effectiveness data were from a multicentre randomised controlled trial that compared inotuzumab with standard of care (SoC), where SoC was the investigator’s choice of chemotherapy. Inotuzumab demonstrated statistically significant improvements in response rates or in the proportion of patients progressing to haematopoietic stem cell transplant (HSCT) but failed to meet the second primary objective of longer overall survival. Treatment-emergent adverse events were more frequent in the SoC arm, except veno-occlusive disease, which was more frequent in the inotuzumab arm. The company’s economic model split patients into three post-hoc subgroups and used a partitioned survival approach within each group, with a cure assumption 3 years after receiving HSCT. In contrast with the trial results, the economic model estimated substantial improvement in survival with inotuzumab compared with SoC, providing an additional 5.2 life-years and 2.2 quality-adjusted life-years (QALYs) using a discount rate of 1.5% per annum. The ERG’s critique highlighted a number of concerns, including the use of a post-hoc post-randomisation patient subset for extrapolation, the choice of a 1.5% discount rate, the complexity of the parametric modelling, the assumption of further treatment benefit post-HSCT, the nature of the cure assumption, and the length of inpatient stay while receiving treatment. The combination of the ERG’s adjustments resulted in an incremental cost-effectiveness ratio (ICER) of £122,174 per QALY gained using Kaplan–Meier survival estimates and £114,078 per QALY gained with parametric survival models fit to the trial data. The final determination of the appraisal followed four NICE Appraisal Committee meetings, an appeal by the company and other stakeholders, two patient access schemes, and a company response to each appraisal consultation. The final ICER post-consultation was between £33,749 and £37,497 per QALY gained compared with SoC (excluding the confidential discount for blinatumomab received as subsequent therapy). The Appraisal Committee concluded that the ICER for inotuzumab was within the range usually considered cost effective for end-of-life care and recommended inotuzumab within its licensed indication.

Cost Effectiveness of Elderly Pneumococcal Vaccination in Presence of Higher-Valent Pneumococcal Conjugate Childhood Vaccination: Systematic Literature Review with Focus on Methods and Assumptions Abstract Background Previous systematic reviews concluded that pneumococcal vaccination in the elderly was cost effective. However, recently published economic evaluations state that it may not be cost effective when children are vaccinated with higher-valent pneumococcal conjugate vaccines. The literature suggests that the outcomes of vaccination in the elderly are strongly influenced by the vaccine effectiveness (VE) against the vaccine-type pneumococcal diseases (PD) and the impact of childhood vaccination on the vaccine-type PD incidence in the elderly, but the extent remains unclear. Methods We conducted a systematic literature search of cost-effectiveness studies on vaccination in the elderly in the PubMed database starting from 2006. We included studies that consider the presence of a childhood vaccination with pneumococcal conjugate vaccine (PCV) 10 and PCV13. We focus on methods and assumptions used in modeling VE and epidemiology of PD over time. Results Twenty-eight economic evaluations underwent full-text review and data extraction. Thirteen were selected for quality assessment. The studies with a higher quality score provide evidence that vaccinating the elderly with PCV13 is not cost effective, when an ongoing rapid decline in the incidence of PCV13-type PD is modeled. A moderate persistence of PCV13 serotypes, in particular due to PCV10 childhood vaccination, makes vaccination of the elderly with PCV13 more attractive. There is no agreement that combining PCV13 with polysaccharide vaccine PPSV23 is cost effective. PPSV23 is attractive when it is effective against non-invasive PD. Conclusion Methodological approaches and assumptions in modeling VE and the indirect effects of childhood vaccination have a major impact on outcomes of decision-analytic models and cost-effectiveness estimates. Considering recently observed trends in the epidemiology of pneumococcal serotypes, there is currently inconclusive evidence regarding the cost effectiveness of pneumococcal vaccination of the elderly due to lack of studies that model key serotypes such as serotype 3 separately from other groups of serotypes.

Cost Effectiveness of Blinatumomab Versus Inotuzumab Ozogamicin in Adult Patients with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukemia in the United States Abstract Background and Objective The TOWER and INO-VATE-ALL trials demonstrated the efficacy and safety of blinatumomab and inotuzumab ozogamicin (inotuzumab), respectively, versus standard-of-care (SOC) chemotherapy in adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). The cost effectiveness of blinatumomab versus inotuzumab has not previously been examined. Methods Cost effectiveness of blinatumomab versus inotuzumab in R/R B-cell precursor ALL patients with one or no prior salvage therapy from a United States (US) payer perspective was estimated using a partitioned survival model. Health outcomes were estimated based on published aggregate data from INO-VATE-ALL and individual patient data from TOWER weighted to match patients in INO-VATE-ALL using matching adjusted indirect comparison (MAIC). Analyses were conducted using five approaches relating to use of anchored versus unanchored comparisons of health outcomes and, for the anchored comparisons, the reference treatment to which treatment effects on health outcomes were applied. Estimates from TOWER including the probabilities of complete remission and allogeneic stem-cell transplant (allo-SCT), overall and event-free survival, utilities, duration of therapy, and use of subsequent therapies were MAIC adjusted to match INO-VATE-ALL. Costs of treatment, adverse events, allo-SCT, subsequent therapies, and terminal care were from published sources. A 50-year time horizon and 3% annual discount rate were used. Results Incremental costs for blinatumomab versus inotuzumab ranged from US$7023 to US$36,244, depending on the approach used for estimating relative effectiveness. Incremental quality-adjusted life-years (QALYs) ranged from 0.54 to 1.78. Cost effectiveness for blinatumomab versus inotuzumab ranged from US$4006 to US$20,737 per QALY gained. Conclusions Blinatumomab is estimated to be cost effective versus inotuzumab in R/R B-cell precursor ALL adults who have received one or no prior salvage therapy from a US payer perspective.

Value Assessment and Quantitative Benefit-Risk Modelling of Biosimilar Infliximab for Crohn’s Disease Abstract Background and Objective Regulatory approval of biosimilars often depends on extrapolating evidence from one clinical indication to all of those of the originator biologic. We aimed to develop a quantitative benefit-risk analysis to assess whether the resulting increase in the uncertainty in the clinical performance of biosimilars (i.e. risk) may be countered by their lower pricing (benefit). Methods A 1-year decision-analytic model was developed for the biosimilar infliximab (Inflectra®) for Crohn’s disease. The perspective was that of the National Health Service in the UK and costs were valued to 2015/16. A hypothetical cohort of biologic-naïve patients with moderate-to-severe Crohn’s disease was simulated through the model. Immunogenicity to infliximab was a key modifier, influencing rates of non-response and infusion reactions. Net health benefit was estimated based on quality-adjusted life-years. A range of sensitivity analyses tested the robustness of the results and explored how the biosimilar price must respond to varying immunogenicity to remain the preferred option. Results The base-case analysis predicted a positive incremental net health benefit of 0.04 (95% central range 0.00–0.09) favouring the biosimilar, based on 0.803 quality-adjusted life-years, and costs of £18,087 and £19,176 for the biosimilar and originator, respectively. Two-way sensitivity analyses suggested that if 50% of patients developed antibodies, the value-based price of £410 per vial must be lower than that of the originator (£420), but remain higher than the actual market price (£378). Conclusions The model supports the use of Inflecta® for Crohn’s disease in the UK, and provides a framework for the quantitative evaluation of biosimilars in the context of a health technology assessment. Value-based pricing using this methodology could protect health systems from the potential risks of biosimilars where they are untested in the approved populations.

Correction to: Cost-Effectiveness Analysis of Patiromer and Spironolactone Therapy in Heart Failure Patients with Hyperkalemia Correction to Bounthavong M, Butler J, Dolan CM, Dunn JD, Fisher KA, Oestreicher N, Pitt B, Hauptman PJ, Veenstra DL.