Cost-Effectiveness of Robot-Assisted Radical Cystectomy vs Open Radical Cystectomy for Patients With Bladder Cancer.

Importance: The value to payers of robot-assisted radical cystectomy with intracorporeal urinary diversion (iRARC) when compared with open radical cystectomy (ORC) for patients with bladder cancer is unclear. Objectives: To compare the cost-effectiveness of iRARC with that of ORC. Design, Setting, and Participants: This economic evaluation used individual patient data from a randomized clinical trial at 9 surgical centers in the United Kingdom. Patients with nonmetastatic bladder cancer were recruited from March 20, 2017, to January 29, 2020. The analysis used a health service perspective and a 90-day time horizon, with supplementary analyses exploring patient benefits up to 1 year. Deterministic and probabilistic sensitivity analyses were undertaken. Data were analyzed from January 13, 2022, to March 10, 2023. Interventions: Patients were randomized to receive either iRARC (n = 169) or ORC (n = 169). Main Outcomes and Measures: Costs of surgery were calculated using surgery timings and equipment costs, with other hospital data based on counts of activity. Quality-adjusted life-years were calculated from European Quality of Life 5-Dimension 5-Level instrument responses. Prespecified subgroup analyses were undertaken based on patient characteristics and type of diversion. Results: A total of 305 patients with available outcome data were included in the analysis, with a mean (SD) age of 68.3 (8.1) years, and of whom 241 (79.0%) were men. Robot-assisted radical cystectomy was associated with statistically significant reductions in admissions to intensive therapy (6.35% [95% CI, 0.42%-12.28%]), and readmissions to hospital (14.56% [95% CI, 5.00%-24.11%]), but increases in theater time (31.35 [95% CI, 13.67-49.02] minutes). The additional cost of iRARC per patient was £1124 (95% CI, -£576 to £2824 [US $1622 (95% CI, -$831 to $4075)]) with an associated gain in quality-adjusted life-years of 0.01124 (95% CI, 0.00391-0.01857). The incremental cost-effectiveness ratio was £100 008 (US $144 312) per quality-adjusted life-year gained. Robot-assisted radical cystectomy had a much higher probability of being cost-effective for subgroups defined by age, tumor stage, and performance status. Conclusions and Relevance: In this economic evaluation of surgery for patients with bladder cancer, iRARC reduced short-term morbidity and some associated costs. While the resulting cost-effectiveness ratio was in excess of thresholds used by many publicly funded health systems, patient subgroups were identified for which iRARC had a high probability of being cost-effective. Trial Registration: ClinicalTrials.gov Identifier: NCT03049410.

Intravitreal ranibizumab versus aflibercept versus bevacizumab for macular oedema due to central retinal vein occlusion: the LEAVO non-inferiority three-arm RCT.

BACKGROUND: Licensed ranibizumab (0.5 mg/0.05 ml Lucentis®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea®; Bayer AG, Leverkusen, Germany) and unlicensed bevacizumab (1.25 mg/0.05 ml Avastin®; F. Hoffmann-La Roche AG, Basel, Switzerland) are used to treat macula oedema due to central retinal vein occlusion, but their relative clinical effectiveness, cost-effectiveness and impact on the UK NHS and Personal Social Services have never been directly compared over the typical disease treatment period. OBJECTIVE: The objective was to compare the clinical effectiveness and cost-effectiveness of three intravitreal antivascular endothelial growth factor agents for the management of macula oedema due to central retinal vein occlusion. DESIGN: This was a three-arm, double-masked, randomised controlled non-inferiority trial. SETTING: The trial was set in 44 UK NHS ophthalmology departments, between 2014 and 2018. PARTICIPANTS: A total of 463 patients with visual impairment due to macula oedema secondary to central retinal vein occlusion were included in the trial. INTERVENTIONS: The participants were treated with repeated intravitreal injections of ranibizumab (n = 155), aflibercept (n = 154) or bevacizumab (n = 154). MAIN OUTCOME MEASURES: The primary outcome was an increase in the best corrected visual acuity letter score from baseline to 100 weeks in the trial eye. The null hypothesis that aflibercept and bevacizumab are each inferior to ranibizumab was tested with a non-inferiority margin of -5 visual acuity letters over 100 weeks. Secondary outcomes included additional visual acuity, and imaging outcomes, Visual Function Questionnaire-25, EuroQol-5 Dimensions with and without a vision bolt-on, and drug side effects. Cost-effectiveness was estimated using treatment costs and Visual Function Questionnaire-Utility Index to measure quality-adjusted life-years. RESULTS: The adjusted mean changes at 100 weeks in the best corrected visual acuity letter scores were as follows - ranibizumab, 12.5 letters (standard deviation 21.1 letters); aflibercept, 15.1 letters (standard deviation 18.7 letters); and bevacizumab, 9.8 letters (standard deviation 21.4 letters). Aflibercept was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference 2.23 letters, 95% confidence interval -2.17 to 6.63 letters; p = 0.0006), but not superior. The study was unable to demonstrate that bevacizumab was non-inferior to ranibizumab in the intention-to-treat population (adjusted mean best corrected visual acuity difference -1.73 letters, 95% confidence interval -6.12 to 2.67 letters; p = 0.071). A post hoc analysis was unable to demonstrate that bevacizumab was non-inferior to aflibercept in the intention-to-treat population (adjusted mean best corrected visual acuity difference was -3.96 letters, 95% confidence interval -8.34 to 0.42 letters; p = 0.32). All per-protocol population results were the same. Fewer injections were required with aflibercept (10.0) than with ranibizumab (11.8) (difference in means -1.8, 95% confidence interval -2.9 to -0.8). A post hoc analysis showed that more bevacizumab than aflibercept injections were required (difference in means 1.6, 95% confidence interval 0.5 to 2.7). There were no new safety concerns. The model- and trial-based cost-effectiveness analyses estimated that bevacizumab was the most cost-effective treatment at a threshold of £20,000-30,000 per quality-adjusted life-year. LIMITATIONS: The comparison of aflibercept and bevacizumab was a post hoc analysis. CONCLUSION: The study showed aflibercept to be non-inferior to ranibizumab. However, the possibility that bevacizumab is worse than ranibizumab and aflibercept by 5 visual acuity letters cannot be ruled out. Bevacizumab is an economically attractive treatment alternative and would lead to substantial cost savings to the NHS and other health-care systems. However, uncertainty about its relative effectiveness should be discussed comprehensively with patients, their representatives and funders before treatment is considered. FUTURE WORK: To obtain extensive patient feedback and discuss with all stakeholders future bevacizumab NHS use. TRIAL REGISTRATION: Current Controlled Trials ISRCTN13623634. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 38. See the NIHR Journals Library website for further project information.

The eye functions like a camera. The retina, at the back of the eye, is the camera film, and the centre, the macula, allows us to see fine details. Approximately 6500 people each year in England and Wales are affected by fluid leaking out of congested tiny blood vessels, causing macular swelling or oedema. The cause is blockage of the main vein that normally drains blood from the retina. Three drugs, injected into the eye in tiny amounts every 4­8 weeks, have been shown to improve the vision of people with this condition. Two drugs, ranibizumab (0.5 mg/0.05 ml Lucentis^®; Novartis International AG, Basel, Switzerland) and aflibercept (2 mg/0.05 ml Eylea^®; Bayer AG, Leverkusen, Germany), are licensed for UK use, but the third, bevacizumab (1.25 mg/0.05 ml Avastin^®; F. Hoffmann-La Roche AG, Basel, Switzerland), is not, even though it is much cheaper and used extensively worldwide. To our knowledge, no trials have compared the three drugs over the typical 2-year treatment period. This multicentre, Phase III, double-masked, randomised controlled non-inferiority trial comparing the clinical effectiveness and cost-effectiveness of intravitreal therapy with ranibizumab (Lucentis) versus aflibercept (Eylea) versus bevacizumab (Avastin) for macular oedema due to central retinal Vein Occlusion (LEAVO) was designed to compare ranibizumab, aflibercept and bevacizumab in this type of macular oedema. The trial showed that all three drugs improved vision a lot, but bevacizumab improved vision to a slightly lesser degree than the other two drugs. All patients should be aware of these findings before considering their treatment options. A comparison of the costs and benefits of ranibizumab, aflibercept and bevacizumab, using data from the trial and other sources, found that all three led to similar improvements in quality of life. Because aflibercept and ranibizumab are so much more expensive, they may be poor value for money. If patients, their representatives and funders all agree, it may be possible to treat this type of macular oedema with bevacizumab, which is cheaper, keeping the other agents available if needed.

Cost Effectiveness of Ranibizumab vs Aflibercept vs Bevacizumab for the Treatment of Macular Oedema Due to Central Retinal Vein Occlusion: The LEAVO Study.

BACKGROUND: We aimed to assess the cost effectiveness of intravitreal ranibizumab (Lucentis), aflibercept (Eylea) and bevacizumab (Avastin) for the treatment of macular oedema due to central retinal vein occlusion. METHODS: We calculated costs and quality-adjusted life-years from the UK National Health Service and Personal Social Services perspective. We performed a within-trial analysis using the efficacy, safety, resource use and health utility data from a randomised controlled trial (LEAVO) over 100 weeks. We built a discrete event simulation to model long-term outcomes. We estimated utilities using the Visual-Functioning Questionnaire-Utility Index, EQ-5D and EQ-5D with an additional vision question. We used standard UK costs sources for 2018/19 and a cost of £28 per bevacizumab injection. We discounted costs and quality-adjusted life-years at 3.5% annually. RESULTS: Bevacizumab was the least costly intervention followed by ranibizumab and aflibercept in both the within-trial analysis (bevacizumab: £6292, ranibizumab: £13,014, aflibercept: £14,328) and long-term model (bevacizumab: £18,353, ranibizumab: £30,226, aflibercept: £35,026). Although LEAVO did not demonstrate bevacizumab to be non-inferior for the visual acuity primary outcome, the three interventions generated similar quality-adjusted life-years in both analyses. Bevacizumab was always the most cost-effective intervention at a threshold of £30,000 per quality-adjusted life-year, even using the list price of £243 per injection. CONCLUSIONS: Wider adoption of bevacizumab for the treatment of macular oedema due to central retinal vein occlusion could result in substantial savings to healthcare systems and deliver similar health-related quality of life. However, patients, funders and ophthalmologists should be fully aware that LEAVO could not demonstrate that bevacizumab is non-inferior to the licensed agents.

Mapping From Visual Acuity to EQ-5D, EQ-5D With Vision Bolt-On, and VFQ-UI in Patients With Macular Edema in the LEAVO Trial.

OBJECTIVES: Mappings to convert clinical measures to preference-based measures of health such as the EQ-5D-3L are sometimes required in cost-utility analyses. We developed mappings to convert best-corrected visual acuity (BCVA) to the EQ-5D-3L, the EQ-5D-3L with a vision bolt-on (EQ-5D V), and the Visual Functioning Questionnaire-Utility Index (VFQ-UI) in patients with macular edema caused by central retinal vein occlusion. METHODS: We used data from Lucentis, Eylea, Avastin in vein occlusion (LEAVO), which is a phase-3 randomized controlled trial comparing ranibizumab, aflibercept, and bevacizumab in 463 patients with observations at 6 time points. We estimated adjusted limited dependent variable mixture models consisting of 1 to 4 distributions (components) using BCVA in each eye, age, and sex to predict utility within the components and BCVA as a determinant of component membership. We compared model fit using mean error, mean absolute error, root mean square error, Akaike information criteria, Bayesian information criteria, and visual inspection of mean predicted and observed utilities and cumulative distribution functions. RESULTS: Mean utility scores were 0.82 for the EQ-5D-3L, 0.79 for the EQ-5D V, and 0.88 for the VFQ-UI. The best-fitting models for the EQ-5D and EQ-5D V had 2 components (with means of approximately 0.44 and 0.85), and the best-fitting model for VFQ-UI had 3 components (with means of approximately 0.95, 0.74, and 0.90). CONCLUSIONS: Models with multiple components better predict utility than those with single components. This article provides a valuable addition to the literature, in which previous mappings in visual acuity have been limited to linear regressions, resulting in unfounded assumptions about the distribution of the dependent variable.

Adaptive designs undertaken in clinical research: a review of registered clinical trials.

Adaptive designs have the potential to improve efficiency in the evaluation of new medical treatments in comparison to traditional fixed sample size designs. However, they are still not widely used in practice in clinical research. Little research has been conducted to investigate what adaptive designs are being undertaken. This review highlights the current state of registered adaptive designs and their characteristics. The review looked at phase II, II/III and III trials registered on ClinicalTrials.gov from 29 February 2000 to 1 June 2014, supplemented with trials from the National Institute for Health Research register and known adaptive trials. A range of adaptive design search terms were applied to the trials extracted from each database. Characteristics of the adaptive designs were then recorded including funder, therapeutic area and type of adaptation. The results in the paper suggest that the use of adaptive designs has increased. They seem to be most often used in phase II trials and in oncology. In phase III trials, the most popular form of adaptation is the group sequential design. The review failed to capture all trials with adaptive designs, which suggests that the reporting of adaptive designs, such as in clinical trials registers, needs much improving. We recommend that clinical trial registers should contain sections dedicated to the type and scope of the adaptation and that the term 'adaptive design' should be included in the trial title or at least in the brief summary or design sections.