Joshua Ray

Roche (Switzerland)

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Andrew Palmer

University of Tasmania

William J. Valentine

Universitas Patria Artha

Sreeram Ramagopalan

Peacocks Medical Group (United Kingdom)

Stéphane Roze

Southwestern Medical Center

Vivek Subbiah

The University of Texas MD Anderson Cancer Center

Cormac Sammon

People's History Museum

V. Foos

Health Economics and Outcomes Research (United Kingdom)

Kristian Thorlund

McMaster University

Samantha Wilkinson

Roche (United Kingdom)

Noman Paracha

Bayer (Switzerland)

Cooperative Institutions

Roche (Switzerland)

Health Economics and Outcomes Research (United Kingdom)

Roche (United Kingdom)

Ibero American University

Cardiff University

University College London

Cytel (United States)

University of York

University of Washington

University of Sheffield

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Prospective Utility Study of Patients with Multiple Cardiovascular Events

Value in Health (2016)

Rhys Pockett Phil McEwan Joshua Ray Irwin Tran S.D. Shutler

Unstable angina

Stroke

Demographics

10.1016/j.jval.2016.09.2408

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Citations (0)

Accounting for Uncertainty in Decision Analytic Models Using Rank Preserving Structural Failure Time Modeling: Application to Parametric Survival Models

Value in Health (2017)

Iain Bennett Noman Paracha Keith R. Abrams Joshua Ray

Rank Preserving Structural Failure Time models are one of the most commonly used statistical methods to adjust for treatment switching in oncology clinical trials. The method is often applied in a decision analytic model without appropriately accounting for additional uncertainty when determining the allocation of health care resources. The aim of the study is to describe novel approaches to adequately account for uncertainty when using a Rank Preserving Structural Failure Time model in a decision analytic model.Using two examples, we tested and compared the performance of the novel Test-based method with the resampling bootstrap method and with the conventional approach of no adjustment. In the first example, we simulated life expectancy using a simple decision analytic model based on a hypothetical oncology trial with treatment switching. In the second example, we applied the adjustment method on published data when no individual patient data were available.Mean estimates of overall and incremental life expectancy were similar across methods. However, the bootstrapped and test-based estimates consistently produced greater estimates of uncertainty compared with the estimate without any adjustment applied. Similar results were observed when using the test based approach on a published data showing that failing to adjust for uncertainty led to smaller confidence intervals.Both the bootstrapping and test-based approaches provide a solution to appropriately incorporate uncertainty, with the benefit that the latter can implemented by researchers in the absence of individual patient data.

Bootstrapping (finance)

Resampling

Rank (graph theory)

Nominal level

10.1016/j.jval.2017.07.008

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Citations (5)

OP208 Did Health Technology Assessments Make the Wrong Call? Quantitative Bias Analysis: Alectinib versus Ceritinib in Non-Small Cell Lung Cancer

International Journal of Technology Assessment in Health Care (2021)

Samantha Wilkinson Alind Gupta E. V. Mackay Paul Arora Kristian Thorlund

Introduction The German health technology assessment (HTA) rejected additional benefit of alectinib for second line (2L) ALK+ NSCLC, citing possible biases from missing ECOG performance status data and unmeasured confounding in real-world evidence (RWE) for 2L ceritinib that was submitted as a comparator to the single arm alectinib trial. Alectinib was approved in the US and therefore US post-launch RWE can be used to evaluate this HTA decision. Methods We compared the real-world effectiveness of alectinib with ceritinib in 2L post-crizotinib ALK+ NSCLC using the nationwide Flatiron Health electronic health record (EHR)-derived de-identified database. Using quantitative bias analysis (QBA), we estimated the strength of (i) unmeasured confounding and (ii) deviation from missing-at-random (MAR) assumptions needed to nullify any overall survival (OS) benefit. Results Alectinib had significantly longer median OS than ceritinib in complete case analysis. The estimated effect size (Hazard Ratio: 0.55) was robust to risk ratios of unmeasured confounder-outcome and confounder-exposure associations of <2.4. Based on tipping point analysis, missing baseline ECOG performance status for ceritinib-treated patients (49% missing) would need to be more than 3.4-times worse than expected under MAR to nullify the OS benefit observed for alectinib. Conclusions Only implausible levels of bias reversed our conclusions. These methods could provide a framework to explore uncertainty and aid decision-making for HTAs to enable patient access to innovative therapies.

Alectinib

Ceritinib

10.1017/s0266462321000787

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The value of innovation: association between improvements in survival of advanced and metastatic non-small cell lung cancer and targeted and immunotherapy

BMC Medicine (2021)

Sreeram Ramagopalan Thomas P. Leahy Joshua Ray Samantha Wilkinson Cormac Sammon

Significant improvements in mortality among patients with non-small cell lung cancer (NSCLC) in the USA over the past two decades have been reported based on Surveillance, Epidemiology, and End Results (SEER) data. The timing of these improvements led to suggestions that they result from the introduction of new treatments; however, few studies have directly investigated this. The aim of this study was to investigate the extent to which population level improvements in survival of advanced and/or metastatic NSCLC (admNSCLC) patients were associated with changes in treatment patterns.We utilized a de-identified database to select three cohorts of patients with admNSCLC: (1) patients with non-oncogene (EGFR/ALK/ROS1/BRAF) positive tumors, (2) patients with ALK-positive (ALK+) tumors, and (3) patients with EGFR-positive (EGFR+) tumors. All patients were diagnosed with admNSCLC between 2012 and 2019. Multivariable Cox models adjusting for baseline characteristics and receipt of targeted and immunotherapy were utilized to explore the relationship between these variables and changes in the hazard of death by calendar year in each cohort.We included 28,154 admNSCLC patients with non-oncogene positive tumors, 598 with ALK+ tumors, and 2464 with EGFR+ tumors eligible for analysis. After adjustment for differences in baseline characteristics, the hazard of death in patients who had non-oncogene positive tumors diagnosed in 2015, 2016, 2017, 2018 ,and 2019 was observed to be 12%, 11%, 17%, 20%, and 21% lower respectively than that for those diagnosed in 2012. Upon additionally adjusting for receipt of first line or second line immunotherapy, the decrease in the hazard of death by calendar year was no longer observed, suggesting improvements in survival observed over time may be explained by the introduction of these treatments. Similarly, decreases in the hazard of death were only observed in patients with ALK+ tumors diagnosed between 2017 and 2019 relative to 2012 but were no longer observed following adjustment for the use of 1st and later generation ALK inhibitors. Among patients with EGFR+ tumors, the hazard of death did not improve significantly over time.Our findings expand on the SEER data and provide additional evidence suggesting improvements in survival of patients with advanced and metastatic NSCLC over the past decade could be explained by the change in treatment patterns over this period.

10.1186/s12916-021-02070-w

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Citations (18)

[Cost-effectiveness of trastuzumab in the treatment of early stages breast cancer patients, in Portugal].

PubMed (2010)

Ana Macedo Isabel Monteiro Sofia Andrade A Cirrincione Joshua Ray

Despite the important advances observed in the last 25 years in the comprehension of the clinical and biological nature of breast cancer and its treatment, this disease remains a significant cause of cancer morbidity and mortality worldwide. The clinical trial Hera has demonstrated the safety and efficacy of trastuzumab in the treatment of HER2 positive (HER2+) breast cancer patients, in early stages, subsequent to surgery, chemotherapy (neoadjuvante or adjuvant) and radiotherapy, if applied.To evaluate the cost-effectiveness of 1-year trastuzumab treatment versus standard care (observation following standard adjuvant chemotherapy), in patients with HER2+ breast cancer in early stages from the societal and the Portuguese National Health Service (NHS) perspectives.A 5-state Markov model with annual transition cycles was developed to estimate the long term health and economic outcomes of HER2+ early breast cáncer patients based on HERA clinical trial results. Portuguese NHS resource use and costs were estimated from a consensus expert panel and published unit costs, respectively. Clinical and economic outcomes were discounted at 3% per annum. The incremental cost-effectiveness ratios per life year gained (LYG) and per quality adjusted life year (QALY) gained were estimated. One-way sensitivity analysis was performed.Considering a 45 year time horizon, treatment with trastuzumab was estimated to increase discounted life expectancy by 2,114 life years and quality-adjusted life expectancy by 2,009 QALYs compared to standard care. Direct and indirect costs were projected to be 61.839 euro and 19.759 euro with trastuzumab and 40.559 euro and 25.392 euro with standard of care. These results corresponded to incremental cost-effectiveness ratios of 10.067 euro and 10.595 euro assuming direct costs only, and of 7.400 euro and 7.789 euro including indirect costs, per life year gained and per QALY gained, respectively.The 1-year trastuzumab use as adjuvant therapy in HER-2+ early breast cancer patients improves survival and can be considered a cost effective therapy with a high degree of certainty in the Portuguese setting.

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Citations (13)

Exenatide versus insulin glargine in patients with type 2 diabetes in the UK: a model of long-term clinical and cost outcomes

Current Medical Research and Opinion (2007)

Joshua Ray Kristina S. Boye Nicole Yurgin William J. Valentine S. Roze

Objectives: The aim of this study was to evaluate the long-term clinical and economic outcomes associated with exenatide or insulin glargine, added to oral therapy in individuals with type 2 diabetes inadequately controlled with combination oral agents in the UK setting.Methods: A published and validated computer simulation model of diabetes was used to project long-term complications, life expectancy, quality-adjusted life expectancy and direct medical costs. Probabilities of diabetes-related complications were derived from published sources. Treatment effects and patient characteristics were extracted from a recent randomised controlled trial comparing exenatide with insulin glargine. Simulations incorporated published quality of life utilities and UK-specific costs from 2004. Pharmacy costs for exenatide were based on 20, 40, 60, 80 and 100% of the US value (as no price for the UK was available at the time of analysis). Future costs and clinical benefits were discounted at 3.5% annually. Sensitivity analyses were performed.Results: In the base–case analysis exenatide was associated with improvements in life expectancy of 0.057 years and in quality-adjusted life expectancy of 0.442 quality-adjusted life years (QALYs) versus insulin glargine. Long-term projections demonstrated that exenatide was associated with a lower cumulative incidence of most cardiovascular disease (CVD) complications and CVD-related death than insulin glargine. Using the range of cost values, evaluation results showed that exenatide is likely to fall in a range between dominant (cost and life saving) at 20% of the US price and cost-effective (with an ICER of £22 420 per QALY gained) at 100% of the US price, versus insulin glargine.Conclusions: Based on the findings of a recent clinical trial, long-term projections indicated that exenatide is likely to be associated with improvement in life expectancy and quality-adjusted life expectancy compared to insulin glargine. The results from this modelling analysis suggest that that exenatide is likely to represent good value for money by generally accepted standards in the UK setting in individuals with type 2 diabetes inadequately controlled on oral therapy.

10.1185/030079907x178685

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Citations (59)

Prospective utility study of patients with multiple cardiovascular events

Journal of Medical Economics (2018)

Rhys Pockett Phil McEwan Joshua Ray Irwin Tran S.D. Shutler

The effects of acute coronary syndrome (ACS) events on health-related quality-of-life (HRQoL) and the time dependency of these effects are unknown. This study aimed to characterize health utilities in ACS patients to aid development of future economic models estimating the cost per quality-adjusted life-year impact of ACS events and potential treatments.Multi-center, non-interventional, longitudinal evaluation of health utility in patients experiencing ACS or stroke events. EuroQol-5 dimension 3 level (EQ-5D-3L) surveys were sent to patients (≥18 years) from three UK centers, 1 month after hospital discharge for myocardial infarction (MI), unstable angina (UA), or stroke. Patient demographics, lifestyle, and baseline utility score were collected in the first survey. Follow-up surveys were sent at 6, 12, 18, and 24 months to prospectively capture utility and subsequent health events. Two methods of patient identification were adopted-prospective, where the patient's qualifying events occurred after the study index date, and retrospective, where the patient's qualifying event occurred prior to the study index date. General healthy population utility values were assumed for pre-event HRQoL.Between January 2011 and March 2014, 2,103 prospectively (n = 1,350)/retrospectively (n = 753) identified patients (mean age = 68.3 years; 67.9% male) responded: MI = 55.9% (n = 1,176), UA = 42.7% (n = 898), stroke = 1.4% (n = 29); 24% had type 2 diabetes. Post-event utility values were lower than general healthy population values, although significant differences in utility between subsequent 6 (n = 1,031, change = -0.002), 12 (n = 1,096, change = -0.008), 18 (n = 1,246, change = -0.007), and 24 (n = 1,277, change = -0.004) month timepoints were not detected. Through multivariate regression analyses, wheelchair use, current smoking, and secondary mental and joint health events were associated with the greatest statistically significant utility decrements.This study indicates that health utility decreases following a cardiovascular event and, although some improvement occurs over the subsequent 24 months, general healthy population utility is not necessarily attained.

Unstable angina

Stroke

EQ-5D

10.1080/13696998.2018.1454453

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Citations (10)

Adjusting Variance Parameters to Incorporate Uncertainty into Health Economics Models Following Treatment Switching

Value in Health (2016)

Joshua Ray Iain Bennett Noman Paracha

10.1016/j.jval.2016.09.265

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PRM155 - JOINT MODELING OF OVERALL SURVIVAL AND PROGRESSION FREE SURVIVAL

Value in Health (2018)

Federico Felizzi Iain Bennett Mark Pletscher Per-Olof Thuresson Noman Paracha

Shape parameter

Log-normal distribution

10.1016/j.jval.2018.09.2275

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Health economic implications of irbesartan plus conventional antihypertensive medications versus conventional blood pressure control alone in patients with type 2 diabetes, hypertension, and renal disease in Switzerland.

Schweizerische medizinische Wochenschrift (2006)

Andrew Palmer Stéphane Roze William J. Valentine Joshua Ray Andreas P. Frei

The aim of this health economic modelling study was to investigate the effect of irbesartan combined with conventional antihypertensive medications compared to conventional antihypertensive therapy alone on the progression of nephropathy in patients with hypertension, type 2 diabetes and microalbuminuria in a Swiss setting.In simulated patients with hypertension and type 2 diabetes, treatment of microalbuminuria with irbesartan 300 mg daily plus conventional antihypertensive medications was compared to a control regimen (conventional medications excluding angiotensin converting enzyme inhibitors, other angiotensin-2-receptor antagonist and dihydropyridine calcium channel blockers). Progression from microalbuminuria to nephropathy, doubling of serum creatinine, ESRD, and all-cause mortality was simulated over a 25-year time horizon using a published Markov model adapted to a Swiss setting. Transition probabilities were based on the Irbesartan in Reduction of Microalbuminuria-2 Study, Irbesartan in Diabetic Nephropathy Trial and other sources. Costs and clinical outcomes were discounted at 5% annually according to Swiss guidelines, and a third party payer perspective was taken.Treatment with irbesartan was projected to improve mean life expectancy by 0.57 years compared to conventional antihypertension treatment (undiscounted 1.22 years). Irbesartan treatment was associated with cost savings of CHF 21,488 per patient over the 25-year time horizon. Sensitivity analysis showed that irbesartan therapy remained dominant to conventional antihypertension treatment over a range of plausible assumptions.Addition of irbesartan to conventional antihypertension therapy was projected to improve life expectancy and reduce costs in hypertensive patients with type 2 diabetes and microalbuminuria in a Swiss setting.

Irbesartan

Microalbuminuria

Albuminuria

10.57187/smw.2006.11337

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Citations (7)