Challenges with Estimating Long-Term Overall Survival in Extensive Stage Small-Cell Lung Cancer: A Validation-Based Case Study.

Objective: The study aimed to explore methods and highlight the challenges of extrapolating the overall survival (OS) of immunotherapy-based treatment in first-line extensive stage small-cell lung cancer (ES-SCLC). Methods: Standard parametric survival models, spline models, landmark models, mixture and non-mixture cure models, and Markov models were fitted to 2-year data of the CASPIAN Phase 3 randomised trial of PD-L1 inhibitor durvalumab added to platinum-based chemotherapy (NCT03043872). Extrapolations were compared with updated 3-year data from the same trial and the plausibility of long-term estimates assessed. Results: All models used provided a reasonable fit to the observed Kaplan-Meier (K-M) survival data. The model which provided the best fit to the updated CASPIAN data was the mixture cure model. In contrast, the landmark analysis provided the least accurate fit to model survival. Estimated mean OS differed substantially across models and ranged from (in years) 1.41 (landmark model) to 4.81 (mixture cure model) for durvalumab plus etoposide and platinum and from 1.01 (landmark model) to 2.00 (mixture cure model) for etoposide and platinum. Conclusion: While most models may provide a good fit to K-M data, it is crucial to assess beyond the statistical goodness-of-fit and consider the clinical plausibility of the long-term predictions. The more complex cure models demonstrated the best predictive ability at 3 years, potentially providing a better representation of the underlying method of action of immunotherapy; however, consideration of the models' clinical plausibility and cure assumptions need further research and validation. Our findings underscore the significance of adopting a clinical perspective when selecting the most appropriate approach to model long-term survival, particularly when considering the use of more complex models.

A Systematised Literature Review of Real-World Treatment Patterns and Outcomes in Unresectable Advanced or Metastatic Biliary Tract Cancer.

BACKGROUND: Biliary tract cancers are rare aggressive malignancies typically diagnosed when the disease is metastatic or unresectable, precluding curative treatment. OBJECTIVE: We aimed to identify treatment guidelines, real-world treatment patterns, and outcomes for unresectable advanced or metastatic biliary tract cancers in adult patients. METHODS: Databases (MEDLINE, Embase, Cochrane Database of Systematic Reviews) were systematically searched between 1 January, 2000 and 25 November, 2021, and supplemented by hand searches. Eligible records were (1) treatment guidelines and (2) observational studies reporting real-world treatment outcomes, for unresectable advanced or metastatic biliary tract cancers. Only studies performed in the UK, Germany, France, Australia, Canada and South Korea were extracted, to moderate the number of records for synthesis while maintaining representation of a wide range of biliary tract cancer incidences. RESULTS: A total of 66 relevant unique full-text records were extracted, including 16 treatment guidelines and 50 observational studies. Among guidelines, chemotherapies were most strongly recommended at first line (1L); the combination of gemcitabine and cisplatin (GEMCIS) was recommended as the standard of care in 1L. Recommendations for systemic chemotherapy in the second line (2L) conflicted because of uncertainties around survival benefit. Guidelines on further lines of treatment included a range of locoregional modalities and stenting or best supportive care without providing clear recommendations because of data paucity. Fifty observational studies reporting real-world treatment outcomes were extracted, of which 25 (50%) and 9 (18%) reported outcomes in 1L and 2L, respectively; 22 (44%) reported outcomes for treatments described as 'palliative'. In 1L, outcomes for systemic chemotherapy were most frequently described (23/25 studies), and GEMCIS was the most common systemic chemotherapy used (10/23 studies) in line with guidelines. Median overall survival with 1L systemic chemotherapy was < 12 months in most studies (16/23; range 4.7-22.3 months). Most 2L studies (10/11) described outcomes for systemic chemotherapy, most commonly for fluoropyrimidine-based regimen (5/10 studies). Median overall survival with 2L systemic chemotherapy was < 12 months in 5/10 studies (range 4.9-21.5 months). Median progression-free survival was reported more rarely than median overall survival. Some studies with small sample sizes or specifically selected patient populations (e.g. higher performance status, or patients who had already responded to treatment) achieved higher median overall survival. CONCLUSIONS: At the time of this review, treatment options for unresectable advanced or metastatic biliary tract cancers confer poor real-world survival. For over a decade, GEMCIS remained the 1L standard of care, highlighting the lack of therapeutic innovation in this indication and the urgent unmet need for novel treatments with improved outcomes in this aggressive condition. Additional observational studies are needed to further understand the effectiveness of currently available treatments, as well as newly available therapies including the addition of immunotherapy in the evolving treatment landscape.

Real-world treatment patterns and outcomes in small-cell lung cancer: a systematic literature review.

BACKGROUND: Small-cell lung cancer (SCLC) accounts for 12-15% of lung cancers and is associated with poor survival outcomes and high symptom burden. This study employed a broad, systematic search strategy and timeframe to identify evidence on real-world treatment patterns and outcomes for SCLC outside the USA, including understanding sub-populations such as extensive-stage (ES) or limited-stage (LS) disease. METHODS: Databases (MEDLINE, Embase, and EBM reviews) were searched for journal articles published in the English language between 1 January 2000-1 March 2020 and supplemented by hand searching of conference abstracts and posters presented at conferences between 1 January 2016-1 March 2020 reporting real-world treatment outcomes in patients with SCLC. A targeted clinical guideline review was also completed. RESULTS: One-hundred studies provided quantitative data; 57 were available as full-text articles, whilst the remaining 43 were presented as abstracts or posters. The majority (80 studies, 80%) of included studies reported treatment in the first-line setting, where platinum-based chemotherapy and chemoradiotherapy was the most commonly used treatment strategy, in line with current treatment guidelines in SCLC. First-line treatments were found to have a high response rate; however, most patients relapsed early. No studies reported treatment or outcomes with immune-oncology therapies. Second-line treatment options were very limited, and primarily consisted of either re-treatment with first-line regimen or topotecan, but the prognosis for these patients remained poor. Outcomes were particularly poor amongst those with ES or relapsed disease vs. LS disease. CONCLUSIONS: SCLC treatment patterns and short survival outcomes have remained constant over the previous 20 years. Due to the search timeframe, none of the studies identified reported on the impact of recently approved immune-oncology therapies in SCLC. Further data is needed on the impact of immunotherapies on treatment patterns and real-world outcomes in SCLC.

Evaluating Partitioned Survival and Markov Decision-Analytic Modeling Approaches for Use in Cost-Effectiveness Analysis: Estimating and Comparing Survival Outcomes.

OBJECTIVE: The objective of this study was to assess long-term survival outcomes for nivolumab and everolimus in renal cell carcinoma predicted by three model structures, a partitioned survival model (PSM) and two variations of a semi-Markov model (SMM), for use in cost-effectiveness analyses. METHODS: Three economic model structures were developed and populated using parametric curves fitted to patient-level data from the CheckMate 025 trial. Models consisted of three health states: progression-free, progressed disease, and death. The PSM estimated state occupancy using an area under-the-curve approach from overall survival (OS) and progression-free survival (PFS) curves. The SMMs derived transition probabilities to calculate patient flow between health states. One SMM assumed that post-progression survival (PPS) was independent of PFS duration (PPS Markov); the second SMM assumed differences in PPS based on PFS duration (PPS-PFS Markov). RESULTS: All models provide a reasonable fit to the observed OS data at 2 years. For estimating cost effectiveness, however, a more relevant comparison is between estimates of OS over the modeling horizon, because this will likely impact differences in costs and quality-adjusted life-years. Estimates of the incremental mean survival benefit of nivolumab versus everolimus over 20 years were 6.6 months (PSM), 7.6 months (PPS Markov), and 7.4 months (PPS-PFS Markov), reflecting non-trivial differences of + 14% and + 11%, respectively, compared with PSM. CONCLUSIONS: The evidence from this study and previous work highlights the importance of the assumptions underlying any model structure, and the need to validate assumptions regarding survival and the application of treatment effects against what is known about the characteristics of the disease.

Cost-Effectiveness Analysis of Abatacept Compared with Adalimumab on Background Methotrexate in Biologic-Naive Adult Patients with Rheumatoid Arthritis and Poor Prognosis.

OBJECTIVES: To assess cost effectiveness of abatacept versus adalimumab, each administered with methotrexate, in treating patients with rheumatoid arthritis (RA) stratified according to baseline anticitrullinated protein antibody (ACPA) levels (marker of poor prognosis in RA). METHODS: A payer-perspective cost-effectiveness model simulated disease progression in patients with RA who had previously failed conventional disease-modifying antirheumatic drugs and were starting biologic therapy. Patients commenced treatment with abatacept or adalimumab plus methotrexate and were evaluated after 6 months. Therapy continuation was based on the European League Against Rheumatism treatment response; disease progression was based on the Health Assessment Questionnaire Disability Index score. These score changes were used to estimate health state utilities and direct medical costs. Quality-adjusted life-years (QALYs) and incremental cost per QALY gained were calculated by baseline ACPA groups (Q1, 28-234 AU/ml; Q2, 235-609 AU/ml; Q3, 613-1045 AU/ml; and Q4, 1060-4894 AU/ml). Scenario analysis and one-way and probabilistic sensitivity analyses were used to evaluate robustness of model assumptions. RESULTS: Abatacept resulted in QALY gain versus adalimumab in ACPA Q1, Q3, and Q4; between-treatment difference (difference: Q1, -0.115 Q2, -0.009 Q3, 0.045; and Q4, 0.279). Total lifetime discounted cost was higher for abatacept versus adalimumab in most quartiles (Q2, £77,612 vs. £77,546; Q3, £74,441 vs. £73,263; and Q4, £78,428 vs. £76,696) because of longer time on treatment. Incremental cost per QALY for abatacept (vs. adalimumab) was the lowest in the high ACPA titer group (Q4, £6200/QALY), followed by the next lowest titer group (Q3, £26,272/QALY). CONCLUSIONS: Abatacept is a cost effective alternative to adalimumab in patients with RA with high ACPA levels.

Cost-effectiveness of nivolumab in patients with advanced renal cell carcinoma treated in the United States.

BACKGROUND: We evaluated the cost-effectiveness of nivolumab versus everolimus in patients with advanced renal cell carcinoma (RCC) from a US payer perspective. METHODS: A partitioned survival model consisting of three health states, progression-free survival (PFS), progressive disease, and death, was developed to evaluate the cost-effectiveness of intravenous nivolumab versus oral everolimus over a lifetime. The proportion of patients in each state was calculated based on parametric distributions fitted to PFS and overall survival (OS) data from CheckMate 025 (N = 821), a large randomized phase 3 trial of nivolumab versus everolimus for advanced RCC. Health state utility data were derived from CheckMate 025 EQ-5D data. Scenario analyses and deterministic and probabilistic sensitivity analyses assessed the impact of uncertainty in model inputs on outcomes. RESULTS: Over a 25-year lifetime horizon, treatment with nivolumab resulted in a gain of 0.64 quality-adjusted life-years (QALYs) versus everolimus. Nivolumab had greater total costs versus everolimus ($US197,089 vs. $US163,902), mainly due to higher acquisition costs. The incremental cost-utility ratio (ICUR), a measure of incremental costs divided by incremental QALYs, was $US51,714 per QALY gained for nivolumab versus everolimus, and an incremental cost-effectiveness ratio was $US44,576 per life-year gained for nivolumab versus everolimus. In sensitivity analyses, average body weight had the greatest impact on the ICUR for nivolumab versus everolimus (base case $US51,714; range $US8863-$US94,566). At a $US150,000 willingness-to-pay (WTP) threshold, nivolumab had a 91.7% probability of being cost-effective versus everolimus. CONCLUSIONS: In the United States, at a WTP threshold of $US150,000 per QALY, nivolumab was found to be cost-effective. Key drivers of cost-effectiveness were survival inputs for OS and the average weight of patients; the latter directly affects nivolumab drug acquisition cost.

A cost-effectiveness and budget impact analysis of first-line fidaxomicin for patients with Clostridium difficile infection (CDI) in Germany.

PURPOSE: Clostridium difficile infection (CDI) represents a significant economic healthcare burden, especially the cost of recurrent disease. Fidaxomicin produced significantly lower recurrence rates and higher sustained cure rates in clinical trials. We evaluated the cost-effectiveness and budget impact of fidaxomicin compared with vancomycin in Germany in the first-line treatment of patient subgroups with CDI at increased risk of recurrence. METHODS: A semi-Markov model was used to compare the cost-effectiveness and budget impact of fidaxomicin vs. vancomycin from a payer perspective in Germany. The model cycle length was 10 days. The time horizon was 1 year. Model inputs were probability of clinical cure, 30-day probability of recurrence, and 30-day attributable mortality based on evidence from two randomized controlled trials comparing fidaxomicin and vancomycin in patients with CDI. Cost-effectiveness outcomes were cost per quality-adjusted life year gained, cost per bed-day saved, and cost per recurrence avoided. RESULTS: Despite higher drug acquisition costs, fidaxomicin was dominant in the cancer subgroup (less costly and more effective) and cost-effective in the other subgroups, with incremental cost-effectiveness ratios vs. vancomycin ranging from €26,900 to €44,500. Hospitalization costs of the first-line treatment of CDI with fidaxomicin vs. vancomycin were lower in every patient subgroup, resulting in budget impacts ranging from -€1325 (in patients ≥65 years) to -€2438 (in cancer patients). Reductions in the cost of treating recurrence with fidaxomicin ranged from -€574.32 per patient in those receiving concomitant antibiotics to -€1500.68 per patient in renally impaired patients. CONCLUSIONS: In patient subgroups with CDI at increased recurrence risk, fidaxomicin was cost-effective vs. vancomycin, and less costly and more effective in patients with cancer.

Mydriasert pupillary dilation for cataract surgery: an economic and clinical study.

BACKGROUND: Mydriasert is an insoluble ophthalmic insert indicated for mydriasis prior to cataract surgery, which gradually releases the active ingredients: tropicamide (0.25 mg) and phenylephrine (5.38 mg). This study aimed to evaluate the cost of Mydriasert compared with conventional mydriatic eye drops to induce pupil dilation prior to cataract surgery using a budget impact model. METHODS: A cohort-based, decision tree, budget impact model was developed to estimate the drug, consumable and staff costs for achieving mydriasis with Mydriasert compared to mydriatic eye drops (tropicamide [1%] plus phenylephrine [10%]). Insights from structured interviews with clinicians (n = 5) experienced in using both Mydriasert and mydriatic eye drops and results from the current clinical study of patients undergoing cataract surgery (n = 144) at a Greater London district general hospital were used to obtain key input parameters for the model, and to validate the model approach. RESULTS: The base case analysis in a cohort of 1763 patients undergoing cataract surgery showed that when Mydriasert substituted mydriatic eye drops, annual total costs decreased by 18% and annual total nurse time decreased from 235.1 hours to 44.1 hours over one year (2012-2013). CONCLUSIONS: This study demonstrated that despite its higher unit cost than mydriatic eye drops, Mydriasert resulted in overall savings in health-care costs, mainly associated with reduced nursing time. The economic model developed could assist National Health Service managers and local payers to estimate the budget impact of the introduction of Mydriasert into different clinical settings.

Cost-effectiveness of metformin plus vildagliptin compared with metformin plus sulphonylurea for the treatment of patients with type 2 diabetes mellitus: a Portuguese healthcare system perspective.

OBJECTIVE: To evaluate the cost-effectiveness of vildagliptin plus metformin vs generic sulphonylurea plus metformin in patients with type 2 diabetes mellitus, not controlled with metformin, from a Portuguese healthcare system perspective. METHODS: A cost-effectiveness model was constructed using risk equations from the UK Prospective Diabetes Study Outcomes Model with a 10,000-patient cohort and a lifetime horizon. The model predicted microvascular and macrovascular complications and mortality in yearly cycles. Patients entered the model as metformin monotherapy failures and switched to alternative treatments (metformin plus basal-bolus insulin and subsequently metformin plus intensive insulin) when glycated hemoglobin A1c >7.5% was reached. Baseline patient characteristics and clinical variables were derived from a Portuguese epidemiological study. Cost estimates were based on direct medical costs only. One-way and probabilistic sensitivity analyses were conducted to test the robustness of the model. RESULTS: There were fewer non-fatal diabetes-related adverse events (AEs) in patients treated with metformin plus vildagliptin compared with patients treated with metformin plus sulphonylurea (6752 vs 6815). Addition of vildagliptin compared with sulphonylurea led to increased drug acquisition costs but reduced costs of AEs, managing morbidities, and monitoring patients. Treatment with metformin plus vildagliptin yielded a mean per-patient gain of 0.1279 quality-adjusted life years (QALYs) and a mean per-patient increase in total cost of €1161, giving an incremental cost-effectiveness ratio (ICER) of €9072 per QALY. Univariate analyses showed that ICER values were robust and ranged from €4195 to €16,052 per QALY when different parameters were varied. LIMITATIONS: The model excluded several diabetes-related morbidities, such as peripheral neuropathy and ulceration, and did not model second events. Patients were presumed to enter the model with no diabetes-related complications. CONCLUSION: Treatment with metformin plus vildagliptin compared with metformin plus sulphonylurea is expected to result in a lower incidence of diabetes-related AEs and to be a cost-effective treatment strategy.

Mifamurtide for high-grade, resectable, nonmetastatic osteosarcoma following surgical resection: a cost-effectiveness analysis.

OBJECTIVES: Mifamurtide is an immune macrophage stimulant that when added to standard chemotherapy has demonstrated survival benefit for newly diagnosed osteosarcoma. The objectives of this study were to investigate the cost-effectiveness of adding mifamurtide to standard three- or four-agent chemotherapy for high-grade, resectable, nonmetastatic osteosarcoma following surgical resection and the issues of obtaining robust cost-effectiveness estimates for ultra-orphan drugs, given the shortage of data. METHODS: An economic evaluation was conducted from the perspective of the UK's National Health Service as part of the manufacturer's submission to the National Institute for Health and Care Excellence. The disease process was simplified to a transition through a series of health states, modeled by using a Markov approach. Data to inform the model were derived from patient-level data of Study INT-0133, published literature, and expert opinion. The final efficacy measure was life-years gained (LYG), and utilities were used to obtain quality-adjusted life-years (QALYs). RESULTS: For a 60-year time frame and a discount rate of 3.5% for outcomes, patients receiving mifamurtide benefited from an average additional 1.57 years of life and 1.34 QALYs, compared with patients receiving chemotherapy alone, giving an incremental cost-effectiveness ratio (ICER) of £58,737 per LYG and £68,734 per QALY. Because treatment effects were both substantial in restoring health and sustained over a very long period, the National Institute for Health and Care Excellence changed its guidance to allow a discount of 1.5% for outcomes to be applied in these special circumstances. By using this discount factor, it was found that patients receiving mifamurtide had an average additional 2.58 years of life and 2.20 QALYs compared with patients receiving chemotherapy alone, resulting in an ICER of £35,765 per LYG and £41,933 per QALY. CONCLUSION: Mifamurtide's ICER is cost-effective compared with that of other orphan and ultra-orphan drugs, for which prices and corresponding cost-effectiveness estimates are high.