1,608 research outputs found
Software tools for implementing simulation studies in adaptive seamless designs : introducing R package ASD
No full textAdaptive designs for clinical trials have the potential to
improve the efficiency of clinical research by, for instance,
seamlessly combining different stages of a clinical development programme
Adaptive seamless clinical trials using early outcomes for treatment or subgroup selection : methods, simulation model and their implementation in R
No full textAdaptive seamless designs combine confirmatory testing, a domain of phase III trials, with features such as treatment or subgroup selection, typically associated with phase II trials. They promise to increase the efficiency of development programmes of new drugs, for example, in terms of sample size and/or development time. It is well acknowledged that adaptive designs are more involved from a logistical perspective and require more upfront planning, often in the form of extensive simulation studies, than conventional approaches. Here, we present a framework for adaptive treatment and subgroup selection using the same notation, which links the somewhat disparate literature on treatment selection on one side and on subgroup selection on the other. Furthermore, we introduce a flexible and efficient simulation model that serves both designs. As primary endpoints often take a long time to observe, interim analyses are frequently informed by early outcomes. Therefore, all methods presented accommodate interim analyses informed by either the primary outcome or an early outcome. The R package asd, previously developed to simulate designs with treatment selection, was extended to include subgroup selection (so‐called adaptive enrichment designs). Here, we describe the functionality of the R package asd and use it to present some worked‐up examples motivated by clinical trials in chronic obstructive pulmonary disease and oncology. The examples both illustrate various features of the R package and provide insights into the operating characteristics of adaptive seamless studies
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A comparison of methods for treatment selection in seamless phase II/III clinical trials incorporating information on short-term endpoints
No full textIn an adaptive seamless phase II/III clinical trial interim
analysis data are used for treatment selection, enabling resources to be focussed on comparison of more effective treatment(s) with a control. In this paper we compare two methods recently proposed to enable use of short-term endpoint data for decision-making at the interim analysis. The comparison focusses on the power and the probability of correctly identifying the most promising treatment. We show that the choice of method depends on how well short-term data predict the best treatment, which may be measured by the correlation between treatment effects on short-term and long-term endpoints
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An R package for implementing simulations for seamless phase II/III clinical trials using early outcomes for treatment selection
No full textAdaptive seamless phase II/III clinical trial designs allowing treatment selection at an interim analysis have gained much attention because of their potential benefits compared to more conventional drug development programmes with separate trials for individual phases. A scenario of particular interest is that in which the final outcome in the trial is based on long-term follow-up, but the interim analysis can only realistically be based on early (short-term) outcomes. A new software package (asd) for the statistical software R implements simulations for designs of this type, in addition to the simpler scenario where treatment selection is based on the definitive (final) outcome. The methodology is briefly described and two examples of proposed trial designs in progressive multiple sclerosis are provided, with R code to illustrate application of the methodology
Adaptive designs for confirmatory clinical trials with subgroup selection
No full textGrowing interest in stratified medicine is leading to increasing importance of subgroup analyses in confirmatory clinical trials. Conventionally, confirmatory clinical trials either focus on a subgroup identified in advance or assess subgroup effects once the trial is completed. The focus of this article is methodology for adaptive clinical trials that both identify whether a treatment is particularly effective in a predefined subgroup, potentially enabling alteration of recruitment, and assess the effectiveness in the subgroup and/or whole population. Methods for such adaptive trials are described and compared, and the logistical and regulatory issues associated with such approaches are discussed
The influence of flow discharge variations on the morphodynamics of a diffluence-confluence unit on a large river
No full textThis is the author accepted manuscript. The final version is freely available from Wiley via the DOI in this record.Bifurcations are key geomorphological nodes in anabranching and braided fluvial channels, controlling local bed morphology, the routing of sediment and water, and ultimately defining the stability of their associated diffluence–confluence unit. Recently, numerical modelling of bifurcations has focused on the relationship between flow conditions and the partitioning of sediment between the bifurcate channels. Herein, we report on field observations spanning September 2013 to July 2014 of the three-dimensional flow structure, bed morphological change and partitioning of both flow discharge and suspended sediment through a large diffluence–confluence unit on the Mekong River, Cambodia, across a range of flow stages (from 13 500 to 27 000 m3 s−1).
Analysis of discharge and sediment load throughout the diffluence–confluence unit reveals that during the highest flows (Q = 27 000 m3 s−1), the downstream island complex is a net sink of sediment (losing 2600 ± 2000 kg s−1 between the diffluence and confluence), whereas during the rising limb (Q = 19 500 m3 s−1) and falling limb flows (Q = 13 500 m3 s−1) the sediment balance is in quasi-equilibrium. We show that the discharge asymmetry of the bifurcation varies with discharge and highlight that the influence of upstream curvature-induced water surface slope and bed morphological change may be first-order controls on bifurcation configuration. Comparison of our field data to existing bifurcation stability diagrams reveals that during lower (rising and falling limb) flow the bifurcation may be classified as unstable, yet transitions to a stable condition at high flows. However, over the long term (1959–2013) aerial imagery reveals the diffluence–confluence unit to be fairly stable. We propose, therefore, that the long-term stability of the bifurcation, as well as the larger channel planform and morphology of the diffluence–confluence unit, may be controlled by the dominant sediment transport regime of the system. © 2017 The Authors. Earth Surface Processes and Landforms published by John Wiley & Sons Ltd.Natural Environment Research Council. Grant Numbers: NE/JO21571/1, NE/JO21881/1, NE/JO21970/
Emulating Simulations of Cosmic Dawn for 21 cm Power Spectrum Constraints on Cosmology, Reionization, and X-Ray Heating
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Flexible selection of a single treatment incorporating short-term endpoint information in a phase II/III clinical trial
No full textSeamless phase II/III clinical trials in which an experimental treatment is selected at an interim analysis have been the focus of much recent research interest. Many of the methods proposed are based on the group sequential approach. This paper considers designs of this type in which the treatment selection can be based on short-term endpoint information for more patients than have primary endpoint data available. We show that in such a case, the familywise type I error rate may be inflated if previously proposed group sequential methods are used and the treatment selection rule is not specified in advance. A method is proposed to avoid this inflation by considering the treatment selection that maximises the conditional error given the data available at the interim analysis. A simulation study is reported that illustrates the type I error rate inflation and compares the power of the new approach with two other methods: a combination testing approach and a group sequential method that does not use the short-term endpoint data, both of which also strongly control the type I error rate. The new method is also illustrated through application to a study in Alzheimer's disease. © 2015 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd
Correction : A conditional error function approach for subgroup selection in adaptive clinical trials
No full textIt has recently come to our attention that some of the results presented in Table II in ’A conditional error function approach for subgroup selection in adaptive clinical trials’ (Statistics in Medicine 2012; 31:4309–4320) are not correct. An R software coding issue resulted in numerical errors in the reported results for the conditional error function approach (CEF) and for the combination test approach by Spiessens and Debois (CT-SD). We have corrected these errors in the following table. We also, for reasons of consistency with the CEF approach, now present type I error rates for the CT-SD approach based purely on rejection of the intersection hypothesis inline image rather than as previously on rejection of both intersection and one or the other of the elementary hypotheses inline image and inline image. It is now clear that type I error rates are controlled at the nominal 2.5% level for both approaches, and our previous assertion that the CEF methodology was uniformly, although only marginally, more powerful than the CT-SD methodology is no longer supported by the simulation results for the selected scenarios. Correction of coding errors produced such small changes to data presented in Figures 1–3 as to be indistinguishable from normal simulation error; updated data underlying these plots are available on request from the authors. We apologize for any inconvenience this error has caused
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Designing a seamless phase II/III clinical trial using early outcomes for treatment selection: an application in multiple sclerosis
No full textIn recent years adaptive seamless phase II/III designs (ASDs) allowing treatment or dose selection at an interim analysis have gained much attention because of their potential to save development costs and to shorten time-to-market of a new compound compared to conventional drug development programmes with separate trials for individual phases. In this paper, we describe an ASD with treatment selection based on early outcome data, specifically considering the situation where no final outcomes are observed at the time of the interim analysis. Bringing together combination tests for adaptive designs and the closure principle for multiple testing, control of the familywise type I error rate in the strong sense is achieved. Furthermore, a simulation model is proposed based on standardized test statistics that allows the generation of virtual trials for a variety of outcomes. We use this simulation model to investigate the actual type I error rate of the proposed testing procedure and find that the familywise type I error rate is controlled as expected. The method is often conservative, with the degree of conservatism depending on the correlation between early and late outcome, the true mean values of the early outcome in the different treatment groups and the selection rule. The investigations are motivated and illustrated by an application of the proposed design and simulation model to progressive multiple sclerosis. Copyright © 2011 John Wiley & Sons, Ltd
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