Background
In the phase III PACIFIC study, durvalumab improved survival versus placebo in patients with unresectable stage III non-small-cell lung cancer (NSCLC) whose disease had not progressed ...after platinum-based concurrent chemoradiotherapy. The appraisal by the UK’s National Institute for Health and Care Excellence (NICE) included a cost-effectiveness analysis based on an early data readout from PACIFIC March 2018 data cut-off (DCO); median follow-up duration 25.2 months; range 0.2–43.1. Uncertainties regarding long-term survival outcomes with durvalumab led to some challenges in estimating the cost effectiveness of this therapy.
Objective
Here, we validate the survival extrapolations used in the original company base-case analysis by benchmarking them against updated survival data from the 4-year follow-up analysis of PACIFIC (i.e. approximately 4 years after the last patient was randomised; March 2020 DCO; median follow-up duration 34.2 months; range 0.2–64.9). Moreover, we update the original analysis with these more mature survival data to examine the consistency of key economic outputs with the original analysis.
Methods
The original analysis used a semi-Markov (state-transition) approach and was based on patients whose tumours expressed programmed cell death-ligand 1 on ≥ 1% of cells (to reflect the European licence for durvalumab). We benchmarked the survival extrapolations used in the original company base-case analysis against survival data from the 4-year follow-up of PACIFIC and updated the cost-effectiveness analysis with these more mature survival data. Early deaths avoided by the adoption of durvalumab into the UK Cancer Drugs Fund (CDF) in March 2019 were estimated using the 4-year follow-up survival data and an assumed uptake of 125 patients/year (lower estimate) and 367 patients/year (higher estimate).
Results
The original company base-case analysis had a good visual fit with the observed overall survival (OS) distribution for the durvalumab arm and accurately predicted the 48-month OS rate (predicted 55%; observed 55%); by comparison, the fit was less precise for the placebo arm, for which the analysis underestimated the 48-month OS rate (predicted 32%; observed 38%). In the updated company base-case analysis, durvalumab yielded 2.51 incremental quality-adjusted life-years (QALYs) (− 0.43 vs. the original company base-case analysis), corresponding to an incremental cost-effectiveness ratio of £22,665/QALY (+£3298 vs. the original analysis), which falls within the upper bound of NICE’s willingness-to-pay threshold (£30,000/QALY gained). We estimate that between 31 and 91 early patient deaths may have been avoided by the adoption of durvalumab into the CDF.
Conclusions
These findings reinforce the patient benefit observed with durvalumab in unresectable stage III NSCLC, support the routine use and cost effectiveness of this therapy, and demonstrate how appropriate modelling can inform the early adoption of therapies by payers to achieve patient benefit.
Plain Language Summary
Based on the results of a clinical trial, the European Medicines Agency approved durvalumab for the treatment of adults with a specific type of advanced lung cancer whose tumours cannot be removed surgically and whose disease has not progressed after chemotherapy and radiotherapy. The UK’s National Institute for Health and Care Excellence (NICE) invites companies to submit cost-effectiveness analyses to help with decision making about adopting new therapies. The company included an analysis based on early trial data that suggested durvalumab was cost effective compared with other previous treatments. As patients in the study at the time of the initial submission to NICE were only followed for approximately 2 years, the long-term survival benefit that could be achieved with durvalumab was uncertain. Therefore, NICE recommended durvalumab for use within the Cancer Drugs Fund (CDF) to allow patients to access the drug while more data were being collected. Here, we demonstrate that the original cost-effectiveness model accurately predicted the rates of long-term survival for patients receiving durvalumab and that durvalumab remains a cost-effective use of healthcare resources based on recently published data from the trial (which added approximately 2 further years of follow-up). Moreover, we estimate that adopting durvalumab into the CDF may have avoided 31–91 early patient deaths from lung cancer. These findings support NICE’s early decision to make durvalumab available within the CDF and the adoption of durvalumab for routine use within the UK national health service.
Objective.
To compare the overall survival (OS) of patients treated with 3 mg/kg ipilimumab versus alternative systemic therapies in pretreated unresectable stage III or IV melanoma patients.
...Methods.
A systematic literature search was performed to identify relevant randomized clinical trials. From these trials, Kaplan–Meier survival curves for each intervention were digitized and combined by means of a Bayesian network meta‐analysis (NMA) to compare different drug classes.
Results.
Of 38 trials identified, 15 formed one interlinked network by drug class to allow for an NMA. Ipilimumab, at a dose of 3 mg/kg, was associated with a greater mean OS time (18.8 months; 95% credible interval CrI, 15.5–23.0 months) than single‐agent chemotherapy (12.3 months; 95% CrI, 6.3–28.0 months), chemotherapy combinations (12.2 months; 95% CrI, 7.1–23.3 months), biochemotherapies (11.9 months; 95% CrI, 7.0–22.0 months), single‐agent immunotherapy (11.1 months; 95% CrI, 8.5–16.2 months), and immunotherapy combinations (14.1 months; 95% CrI, 9.0–23.8 months).
Conclusion.
Results of this NMA were in line with previous findings and suggest that OS with ipilimumab is expected to be greater than with alternative systemic therapies, alone or in combination, for the management of pretreated patients with unresectable stage III or IV melanoma.
摘要
目的： 比较易普利单抗3 mg/kg与替代全身疗法治疗经治不可切除III或IV期黑色素瘤患者的总生存期（OS）。
方法： 通过系统文献检索查找相关随机临床试验。从这些试验中，将每种药物干预的Kaplan‐Meier生存曲线数字化并通过Bayesian网络荟萃分析（NMA）结合用于比较不同的药物类别。
结果： 在检索到的38项研究中，15项通过药物类别形成一个互相关联的网络进而可用来进行NMA。与单药化疗12.3个月；95%可信区间（CrI），6.3 ~28.0个月、联合化疗（12.2个月；95% CrI，7.1 ~23.3个月）、生物化疗（11.9个月；95% CrI，7.0 ~22.0个月）和单药免疫疗法（11.1 个月；95% CrI，8.5 ~16.2个月）和联合免疫疗法（14.1个月；95% CrI，9.0 ~23.8个月）相比，易普利单抗3 mg/kg与更长的平均OS相关（18.8个月；95% CrI，15.5 ~23.0个月）。
结论： 该NMA结果与既往的研究结果相一致，并提示易普利单抗治疗经治不可切除III或IV期黑色素瘤患者的预期OS要长于替代全身疗法（单药或联合治疗）的OS。
The overall survival of patients treated with 3 mg/kg ipilimumab was compared with those given alternative systemic therapies in pretreated unresectable stage III or IV melanoma patients. The overall survival times seen with ipilimumab are expected to be greater than those with alternative systemic therapies.
To evaluate if previously found associations between low serum bilirubin concentration and kidney function decline is independent of hemoglobin and other key confounders. Clinical trial data from the ...SAVOR-TIMI 53 trial as well as the UK primary care electronic healthcare records, Clinical Practice Research Datalink (CPRD), were used to construct three cohorts of patients at risk of chronic kidney disease (CKD). The randomized clinical trial (RCT) cohort from the subset of SAVOR-TIMI 53 trial consisted of 10,555 type-2 diabetic patients with increased risk of cardiovascular disease. The two observational data cohorts from CPRD consisted of 71,104 newly diagnosed type-2 diabetes (CPRD-DM2) and 82,065 newly diagnosed hypertensive (CPRD-HT) patients without diabetes. Cohorts were stratified according to baseline circulating total bilirubin levels to determine association on the primary end point of a 30% reduction from baseline in estimated glomerular filtration rate (eGFR) and the secondary end point of albuminuria. The confounder adjusted hazard ratios of the subpopulation with lower than median bilirubin levels compared to above median bilirubin levels for the primary end point were 1.18 (1.02-1.37), 1.12 (1.05-1.19) and 1.09 (1.01-1.17), for the secondary end point were 1.26 (1.06-1.52), 1.11 (1.01-1.21) and 1.18 (1.01-1.39) for SAVOR-TIMI 53, CPRD-DM2, CPRD-HT, respectively. Our findings are consistent across all cohorts and endpoints: lower serum bilirubin levels are associated with a greater kidney function decline independent of hemoglobin and other key confounders. This suggests that increased monitoring of kidney health in patients with lower bilirubin levels may be considered, especially for diabetic patients.
National Institute for Health and Care Excellence guidance (Technical Support Document 19) highlights a key challenge of state transition models (STMs) being their difficulty in achieving a ...satisfactory fit to the observed within-trial endpoints. Fitting poorly to data over the trial period can then have implications for long-term extrapolations. A novel estimation approach is defined in which the predicted overall survival (OS) and progression-free survival (PFS) extrapolations from an STM are optimized to provide closer estimates of the within-trial endpoints.
An STM was fitted to the SQUIRE trial data in non-small-cell lung cancer (obtained from Project Data Sphere). Two methods were used: a standard approach whereby the maximum likelihood was utilized for the individual transitions and the best-fitting parametric model selected based on AIC/BIC, and a novel approach in which parameters were optimized by minimizing the area between the STM-predicted OS and PFS curves and the corresponding OS and PFS Kaplan-Meier curves. Sensitivity analyses were conducted to assess uncertainty.
The novel approach resulted in closer estimations to the OS and PFS Kaplan-Meier for all combinations of parametric distributions analyzed compared with the standard approach. Though the uncertainty associated with the novel approach was slightly larger, it provided better estimates to the restricted mean survival time in 10 of the 12 parametric distributions analyzed.
A novel approach is defined which provides an alternative STM estimation method enabling improved fits to modeled endpoints, which can easily be extended to more complex model structures.
IntroductionIn patients with chronic obstructive pulmonary disease (COPD), the risk of certain cardiovascular (CV) events is increased by threefold to fivefold in the year following acute ...exacerbation of COPD (AECOPD), compared with a non-exacerbation period. While the effect of severe AECOPD is well established, the relationship of moderate exacerbation or prior exacerbation to elevated risk of CV events is less clear. We will conduct cohort studies in multiple countries to further characterise the association between AECOPD and CV events.Methods and analysisRetrospective longitudinal cohort studies will be conducted within routinely collected electronic healthcare records or claims databases. The study cohorts will include patients meeting inclusion criteria for COPD between 1 January 2014 and 31 December 2018. Moderate exacerbation is defined as an outpatient visit and/or medication dispensation/prescription for exacerbation; severe exacerbation is defined as hospitalisation for COPD. The primary outcomes of interest are the time to (1) first hospitalisation for a CV event (including acute coronary syndrome, heart failure, arrhythmias or cerebral ischaemia) since cohort entry or (2) death. Time-dependent Cox proportional hazards models will compare the hazard of a CV event between exposed periods following exacerbation (split into these periods: 1–7, 8–14, 15–30, 31–180 and 181–365 days) and the unexposed reference time period, adjusted on time-fixed and time-varying confounders.Ethics and disseminationStudies have been approved in Canada, Japan, the Netherlands, Spain and the UK, where an institutional review board is mandated. For each study, the results will be published in peer-reviewed journals.
Objective:
To assess the efficacy of fenofibrate and statin dual therapy versus a double or equivalent dose of statin monotherapy.
Methods:
A systematic literature search and meta-analysis was ...performed for publications before 1 January 2014 in MEDLINE, Embase, and BIOSIS Previews, among others.
Results:
The difference in percentage change from baseline was in favor of dual therapy versus a double dose of statin monotherapy for triglycerides (difference −20%; standard error SE 2.6%) and HDL-C (8.7%; SE 1.2%), but not for LDL-C (8.4%; SE 1.5%), non-HDL-C (2.8%; SE 1.1%), total cholesterol (4.5%; SE 1.0%) and apolipoprotein B (2.6%; SE 1.1%). For high intensity statins, the difference in percentage change from baseline was in favor of dual therapy versus equivalent statin monotherapy for triglycerides (−17%; SE 2.6%) and for HDL-C (8.7%; SE 1.9%). The difference in percentage change from baseline for LDL-C was 6% (SE 1.7%), implying a greater reduction in LDL-C with statin monotherapy. For moderate intensity statins, the difference in percentage change from baseline was in favor of dual therapy versus equivalent statin monotherapy for triglycerides (−24.2%; SE 1.2%) and HDL-C (8.2%; SE 0.9%). LDL-C decreased 2.2% (SE 1.4%) more with dual therapy.
Conclusions and implications of key findings:
When aiming to change HDL-C or triglycerides, dual therapy is to be preferred to doubling the statin dose; conversely, doubling the statin dose is to be preferred when aiming to reduce LDL-C. If the aim is both to change HDL-C or triglycerides and to reduce LDL-C, the importance of the three outcomes may need to be weighed depending on the intensity of the statin. Combining high intensity statin therapy with fenofibrate improves the effect on HDL-C and triglycerides, but lowers the effect on LDL-C. Combining a moderate intensity statin with fenofibrate improves the effect on HDL-C and triglycerides without reducing the effect on LDL-C. There is a need for long-term randomized clinical trials to compare dual therapy versus doubling the statin dose to assess the importance of improvement in HDL-C and triglycerides versus improvement in LDL-C in terms of cardiovascular outcomes. Further, the addition of ezetimibe to statin/fenofibrate therapy may be of interest.
This subanalysis compared the efficacy of betahistine plus piracetam dual therapy versus betahistine monotherapy using data from OSVaLD, a 3 month, open-label, observational study conducted in 2272 ...patients with peripheral vestibular vertigo. Of the 1898 patients included in the original efficacy population, 1076 were from countries where betahistine plus piracetam dual therapy was prescribed to >1 patient; 114 of these 1076 patients (11%) received the dual therapy and 567 (53%) were treated with betahistine monotherapy; these patients were selected for analysis.
Efficacy was assessed using the Dizziness Handicap Inventory (DHI) total and subscale scores. Propensity-score matching was used to correct potential differences in patient baseline characteristics between treatment groups. In addition, a subgroup analysis evaluated 103 patients treated with betahistine because of insufficient efficacy with their existing treatment.
In the propensity-score matched, total-population evaluation, improvements in the DHI total and subscale scores were numerically greater in the betahistine plus piracetam group (n = 88) versus the betahistine group (n = 89) (DHI total, −42.9 vs. −37.6, respectively; DHI physical, −12.1 vs. −10.4; DHI emotional, −13.5 vs. −13.2) and statistically significant for the DHI functional score (−17.3 vs. −14.0, respectively, p = 0.01). The percentage of patients with no impairment at final visit was 27% with betahistine and 47% with betahistine plus piracetam; odds ratio: 2.3, 95% confidence interval: 1.3-2.4 (p = 0.007). Similar results were obtained in the subgroup analyses for patients whose current vertigo treatment was insufficient. The overall incidence of adverse events was low and similar in both groups, and there were no discontinuations due to drug-related adverse events.
By using propensity-score matching, which controls for potential heterogeneity in patient baseline characteristics and small patient numbers, the results of this analysis suggest that combined betahistine and piracetam may be more effective than betahistine alone in patients with peripheral vestibular vertigo.
Abstract Objectives Many regulatory agencies require that manufacturers establish both efficacy and cost-effectiveness. The statistical analysis of the randomized, controlled trial (RCT) outcomes ...should be the same for both purposes. The question addressed by this article is the following: for survival outcomes, what is the relationship between the statistical analyses used to support inference and the statistical model used to support decision making based on cost-effectiveness analysis (CEA)? Methods We performed a review of CEAs alongside trials and CEAs based on a synthesis of RCT results, which were submitted to the National Institute for Health and Clinical Excellence (NICE) Technology Appraisal program and included survival outcomes. We recorded the summary statistics and the statistical models used in both efficacy and cost-effectiveness analyses as well as procedures for model diagnosis and selection. Results In no case was the statistical model for efficacy and CEA the same. For efficacy, relative risks or Cox regression was used. For CEA, the common practice was to fit a parametric model to the control arm, then to apply the hazard ratio from the efficacy analysis to predict the treatment arm. The proportional hazards assumption was seldom checked; the choice of model was seldom based on formal criteria, and uncertainty in model choice was seldom addressed and never propagated through the model. Conclusions Both inference and decisions based on CEAs should be based on the same statistical model. This article shows that for survival outcomes, this is not the case. In the interests of transparency, trial protocols should specify a common procedure for model choice for both purposes. Further, the sufficient statistics and the life tables for each arm should be reported to improve transparency and to facilitate secondary analyses of results of RCTs.
Background:
Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) fixed-dose combination (FDC) is an established treatment strategy for chronic ...obstructive pulmonary disease (COPD). The relative efficacy and safety of glycopyrrolate/formoterol fumarate metered dose inhaler (GFF MDI 18/9.6 μg) in patients with moderate-to-very severe COPD, compared with other licensed LAMA/LABA FDCs, was investigated using an integrated Bayesian network meta-analysis (NMA).
Methods:
A systematic literature review and subsequent screening process identified randomized controlled trials of ⩾10 weeks’ duration that enrolled patients aged ⩾40 years with moderate-to-very severe COPD and included at least one LAMA/LABA FDC or open LAMA + LABA treatment arm. NMAs were conducted for outcomes including change from baseline in forced expiratory volume in 1 s (FEV1), St George’s Respiratory Questionnaire (SGRQ), and transition dyspnea index (TDI) parameters, annualized rate of exacerbations, use of rescue medication, adverse events, and all-cause withdrawals. Meta-regression and sensitivity analyses accounted for heterogeneity across studies.
Results:
In total, 29 studies including 34,617 patients contributed to the NMA for efficacy or safety outcomes at week 24 or exacerbations. For all LAMA/LABA FDCs with data available, significantly greater improvements in FEV1 trough, peak, and area under the curve (AUC)0–4, SGRQ total score and TDI focal score at week 24, and annualized rate of moderate-to-severe exacerbations, were observed versus placebo. Where indirect comparisons were possible, differences between GFF MDI and other LAMA/LABA FDCs were small relative to established margins of clinical relevance, and not statistically significant. The safety and tolerability profile of GFF MDI was consistent with other LAMA/LABA FDCs and placebo. The results of the meta-regression were generally similar to the base case.
Conclusions:
GFF MDI demonstrated comparable efficacy and safety outcomes to other LAMA/LABA FDCs. Personalization of treatment choice within the class on the basis of other factors such as patient preference may be appropriate.
IntroductionRandomised controlled trials (RCTs) may use surrogate endpoints as substitutes and predictors of patient-relevant/participant-relevant final outcomes (eg, survival, health-related quality ...of life). Translation of effects measured on a surrogate endpoint into health benefits for patients/participants is dependent on the validity of the surrogate; hence, more accurate and transparent reporting on surrogate endpoints is needed to limit misleading interpretation of trial findings. However, there is currently no explicit guidance for the reporting of such trials. Therefore, we aim to develop extensions to the SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) and CONSORT (Consolidated Standards of Reporting Trials) reporting guidelines to improve the design and completeness of reporting of RCTs and their protocols using a surrogate endpoint as a primary outcome.Methods and analysisThe project will have four phases: phase 1 (literature reviews) to identify candidate reporting items to be rated in a Delphi study; phase 2 (Delphi study) to rate the importance of items identified in phase 1 and receive suggestions for additional items; phase 3 (consensus meeting) to agree on final set of items for inclusion in the extensions and phase 4 (knowledge translation) to engage stakeholders and disseminate the project outputs through various strategies including peer-reviewed publications. Patient and public involvement will be embedded into all project phases.Ethics and disseminationThe study has received ethical approval from the University of Glasgow College of Medical, Veterinary and Life Sciences Ethics Committee (project no: 200210051). The findings will be published in open-access peer-reviewed publications and presented in conferences, meetings and relevant forums.
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