Background: Dual bronchodilation with a long-acting muscarinic antagonist (LAMA)/long-acting β 2 -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 (FEV 1 ), 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 FEV 1 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.
Technical Support Document 21 discusses trial-based, flexible relative survival models. The authors generalized flexible relative survival models to the network meta-analysis (NMA) setting while ...accounting for different treatment-effect specifications.
The authors compared the standard parametric model with mixture, mixture cure and nonmixture cure, piecewise, splines and fractional polynomial models. The optimal treatment-effect parametrization was defined in two steps. First, all models were run with treatment effects on all parameters and subsequently the optimal model was defined by removing uncertain treatment effects, for which the parameter was smaller than its standard deviation. The authors used a network in previously treated advanced non-small-cell lung cancer.
Flexible model-based NMAs impact fit and incremental mean survival and they increase corresponding uncertainty. Treatment-effect specification impacts incremental survival, reduces uncertainty and improves the fit statistic.
Extrapolation techniques already available for individual trials can now be used for NMAs to ensure that the most plausible extrapolations are being used for health technology assessment submissions.
Abstract Objective Indacaterol was evaluated versus placebo, formoterol, and salmeterol in randomized controlled trials. No direct comparisons, however, are available for indacaterol 150 μg with ...formoterol or indacaterol 300 μg with salmeterol. Indacaterol trial evidence was synthesized to provide coherent estimates of indacaterol 150 μg and indacaterol 300 μg relative to formoterol, salmeterol, and tiotropium. Methods Four randomized controlled trials were combined with Bayesian mixed treatment comparisons by using individual patient-level data. End points of interest were trough forced expiratory volume in 1 second (FEV1 ), St. George's Respiratory Questionnaire (SGRQ) total score and response (≥4 points), and Transition Dyspnea Index total score and response (≥1 point). Results Indacaterol 150 μg demonstrated a higher FEV1 than did formoterol at 12 weeks and 6 months (0.10 L difference; 95% credible interval CrI = 0.06–0.14), as did indacaterol 300 μg versus salmeterol (0.06 L difference at 12 weeks; CrI = 0.02–0.10; 0.06 L at 6 months; CrI = 0.02–0.11). Regarding SGRQ, indacaterol 150 μg demonstrated a comparable proportion of responders versus formoterol, as did indacaterol 300 μg versus salmeterol. In comparison to tiotropium, indacaterol 150 μg demonstrated a greater proportion of responders (odds ratio = 1.52 at 12 weeks; CrI 1.15–2.00). For Transition Dyspnea Index, indacaterol 150 μg and formoterol showed a similar response. Indacaterol 300 μg was more efficacious than salmeterol (odds ratio = 1.65 at 12 weeks; CrI 1.16–2.34). Overall, indacaterol 150 μg showed the greatest efficacy for SGRQ and indacaterol 300 μg for FEV1 and Transition Dyspnea Index. Conclusion Indacaterol is expected to be comparable to formoterol, salmeterol, and tiotropium, providing higher FEV1 than formoterol and salmeterol and greater improvement in the SGRQ total score than tiotropium. Indacaterol 150 μg provided comparable improvement in dyspnea, while indacaterol 300 μg demonstrated the greatest response overall.
Abstract This study evaluates the cost-effectiveness of OctaplasLG® (pharmaceutically licensed plasma for transfusion) versus fresh frozen plasma (FFP) in critically ill patients in the UK using a ...decision-analytic approach. Transfusion with OctaplasLG® resulted in 0.03 quality adjusted life years (QALYs) and 0.03 life years saved compared with FFP. The discounted cost per life year was £949 ($1504), and the discounted cost per QALY saved was £1030 ($1632) with OctaplasLG® in the UK. Based on a higher price of £70 ($111) for OctaplasLG® versus £28.42 ($45.04) for FFP, OctaplasLG® is considered to be cost-effective at a threshold of £30,000 ($47,548) per QALY.
Historically, the standard of care for patients with unresectable, Stage III non–small cell lung cancer had been concurrent chemoradiotherapy. However, outcomes had been poor, with approximately 15% ...to 32% of patients alive at 5 years. In the placebo-controlled Phase III A PACIFIC trial, consolidation treatment with durvalumab after concurrent chemoradiotherapy significantly improved overall survival (OS) and progression-free survival in patients with unresectable, Stage III non–small cell lung cancer, establishing this regimen as a new standard of care in this setting. In the PACIFIC trial, crossover between treatment arms (durvalumab or placebo) was not permitted. However, after discontinuation from study treatment, patients from both arms of PACIFIC could switch to subsequent anticancer therapy, including durvalumab and other immunotherapies, which is known to influence standard intention-to-treat analysis of OS, potentially underestimating the effect of an experimental drug. Moreover, the introduction of immunotherapies has demonstrated marked improvements in the postprogression, metastatic non–small cell lung cancer setting.
To examine the influence of subsequent immunotherapy on OS in the PACIFIC trial.
Both a Rank Preserving Structural Failure Time Model (RPSFTM) and modified 2-stage method were used. RPSFTM assumes that a patient's survival time with no immunotherapy (counterfactual survival time) is equal to the observed time influenced by immunotherapy, multiplied by an acceleration factor, plus the time not influenced. The modified 2-stage method estimates the effect of immunotherapy by comparing postsubsequent-treatment-initiation survival times between patients with and without subsequent immunotherapy. In both models, OS was adjusted to reflect a hypothetical scenario in which no patients received subsequent immunotherapy. RPSFTM was also used for scenarios in which subsequent immunotherapy was received by increasing proportions of placebo patients but none of the durvalumab patients.
In the intention-to-treat analysis (3-year follow-up), durvalumab improved OS versus placebo (stratified hazard ratio = 0.69; 95% CI, 0.55–0.86). Overall, 10% and 27% of durvalumab and placebo patients, respectively, received subsequent immunotherapy. With subsequent immunotherapy removed from both arms, estimated hazard ratio was 0.66 (95% CI, 0.53–0.84) with RPSFTM and 0.68 (95% CI, 0.54–0.85) with the modified 2-stage method. With subsequent immunotherapy removed from the durvalumab arm only (RPSFTM), estimated hazard ratio increased as the proportion of placebo patients receiving subsequent immunotherapy increased, up to 0.75 (95% CI, 0.60–0.94) maximum (assuming all placebo patients with subsequent treatment received immunotherapy).
Results were consistent with the intention-to-treat analysis, supporting the conclusion that durvalumab after chemoradiotherapy provides substantial OS benefit in patients with Stage III, unresectable non–small cell lung cancer. ClinicalTrials.gov identifier: NCT02125461 (Curr Ther Res Clin Exp. 2021; 82:XXX–XXX)
ObjectiveTHALES demonstrated that ticagrelor plus aspirin reduced the risk of stroke or death but increased bleeding versus aspirin during the 30 days following a mild-to-moderate acute ...non-cardioembolic ischaemic stroke (AIS) or high-risk transient ischaemic attack (TIA). There are no cost-effectiveness analyses supporting this combination in Europe. To address this, a cost-effectiveness analysis was performed.MethodsCost-effectiveness was evaluated using a decision tree and Markov model with a short-term and long-term (30-year) horizon. Stroke, mortality, bleeding and EuroQol-5 Dimension (EQ-5D) data from THALES were used to estimate short-term outcomes. Model transitions were based on stroke severity (disabling stroke was defined as modified Rankin Scale >2). Healthcare resource utilisation and EQ-5D data beyond 30 days were based on SOCRATES, another trial in AIS/TIA that compared ticagrelor with aspirin. Long-term costs, survival and disutilities were based on published literature. Unit costs were derived from national databases and discounted at 3% annually from a Swedish healthcare perspective.ResultsOne-month treatment with ticagrelor plus aspirin resulted in 12 fewer strokes, 4 additional major bleeds and cost savings of €95 000 per 1000 patients versus aspirin from a Swedish healthcare perspective. This translated into increased quality-adjusted life-years (0.04) and reduced societal costs (−€1358) per patient over a lifetime horizon. Key drivers of cost-effectiveness were number of patients experiencing subsequent disabling stroke and degree of disability. Findings were robust over a range of input assumptions.ConclusionOne month of treatment with ticagrelor plus aspirin is likely to improve outcomes and reduce costs versus aspirin in mild-to-moderate AIS or high-risk TIA.Trial registration numberNCT03354429.
Abstract Objective The goal of this study was to examine the cost-effectiveness of fulvestrant 500 mg for the treatment of first progression or recurrence of advanced breast cancer in postmenopausal ...patients compared with generic nonsteroidal aromatase inhibitors (anastrozole and letrozole) in the United Kingdom. Methods A cost-utility model based on a time-in-state approach was used. Clinical effectiveness estimates used in the model were derived from a network meta-analysis for overall survival and serious adverse events. Overall survival was extrapolated by using a Weibull distribution, and progression-free survival (PFS) estimates were derived from a simultaneous network meta-analysis and extrapolation of PFS curves by using the log-normal distribution. Data on resource use, costs, and utilities were based on various sources, including expert opinion and published data. To explore uncertainty, 1-way and probability sensitivity analyses were conducted. The study was conducted from the perspective of the UK National Health Service, and costs are reported in 2010/2011 British pounds. Results The base case incremental cost-effectiveness ratio (ICER) for fulvestrant 500 mg versus letrozole was £34,528, with incremental costs of £14,383 and an incremental quality-adjusted life-year (QALY) of 0.417. Extended dominance occurred for anastrozole because the ICER for anastrozole versus letrozole was higher than the ICER for fulvestrant 500 mg versus anastrozole. Based on the probability sensitivity analyses, the probability that fulvestrant 500 mg was the most cost-effective treatment option was 3%, 20%, and 53% at a willingness-to-pay threshold of £20,000, £30,000, and £40,000 per QALY, respectively. According to the 1-way sensitivity analyses, the PFS estimates were the key drivers of the model results. Conclusions Although fulvestrant 500 mg was found not to be a cost-effective option at a standard UK threshold of £20,000 to £30,000 per QALY, it may be relevant to apply a higher threshold due to the poor prognosis of patients with advanced breast cancer and the limited number of hormonal treatment options available for this stage of treatment. Certain subgroups may also benefit from fulvestrant as a treatment option; however, limited data are currently available to identify these subgroups.
In this article, the optimal selection and allocation of time points in repeated measures experiments is considered. D‐optimal cohort designs are computed numerically for the first‐ and second‐degree ...polynomial models with random intercept, random slope, and first‐order autoregressive serial correlations. Because the optimal designs are locally optimal, it is proposed to use a maximin criterion. It is shown that, for a large class of symmetric designs, the smallest relative efficiency over the model parameter space is substantial.
Stakeholders in healthcare are increasingly turning to real world evidence (RWE) to inform their decisions, alongside evidence from randomized controlled trials. RWE is generated by analysing data ...gathered from routine clinical practice, and can be used across the product lifecycle, providing insights into areas including disease epidemiology, treatment effectiveness and safety, and health economic value and impact. Recently, the US Food and Drug Administration and the European Medicines Agency have stated their ambition for greater use of RWE to support applications for new indications, and are now consulting with their stakeholders to formalize standards and expected methods for generating RWE.
Pharmaceutical companies are responding to the increasing demands for RWE by developing standards and processes for each stage of the evidence generation pathway. Some conventions are already in place for assuring quality, whereas other processes are specific to the research question and data sources available. As evidence generation increasingly becomes a core role of medical affairs divisions in large pharmaceutical companies, standards of rigour will continue to evolve and improve. Senior pharmaceutical leaders can drive this change by making RWE a core element of their corporate strategy, providing top-level direction on how their respective companies should approach RWE for maximum quality.
Here, we describe the current and future areas of RWE application within the pharmaceutical industry, necessary access to data to generate RWE, and the challenges in communicating RWE. Supporting and building on viewpoints from industry and publicly funded research, our perspective is that at each stage of RWE generation, quality will be critical to the impact that RWE has on healthcare decision-makers; not only where RWE is an established and evolving tool, but also in new areas that have the potential to disrupt and to improve drug development pathways.
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