Analysing adverse events by time ‐to‐event models: the CLEOPATRA study
When analysing primary and secondary endpoints in a clinical trial with patients suffering from a chronic disease, statistical models for time‐to‐event data are commonly used and accepted. This is in contrast to the analysis of data on adverse events where often only a table with observed frequencies and corresponding test statistics is reported. An example is the recently published CLEOPATRA study where a three‐drug regimen is compared with a two‐drug regimen in patients with HER2‐positive first‐line metastatic breast cancer. Here, as described earlier, primary and secondary endpoints (progression‐free and o...
Source: Pharmaceutical Statistics - June 15, 2016 Category: Statistics Authors: Tanja Proctor, Martin Schumacher Tags: Special Issue Paper Source Type: research
Survival trial design and monitoring using historical controls
In this paper, we propose a multistage group sequential procedure to design survival trials using historical controls. The formula for the number of events required for historical control trial designs is derived. Furthermore, a transformed information time is proposed for trial monitoring. An example is given to illustrate the application of the proposed methods to survival trial designs using historical controls. Copyright © 2016 John Wiley & Sons, Ltd. (Source: Pharmaceutical Statistics)
Source: Pharmaceutical Statistics - June 14, 2016 Category: Statistics Authors: Jianrong Wu, Xiaoping Xiong Tags: Main Paper Source Type: research
A modified varying ‐stage adaptive phase II/III clinical trial design
Conventionally, adaptive phase II/III clinical trials are carried out with a strict two‐stage design. Recently, a varying‐stage adaptive phase II/III clinical trial design has been developed. In this design, following the first stage, an intermediate stage can be adaptively added to obtain more data, so that a more informative decision can be made. Therefore, the number of further investigational stages is determined based upon data accumulated to the interim analysis. This design considers two plausible study endpoints, with one of them initially designated as the primary endpoint. Based on interim results, another en...
Source: Pharmaceutical Statistics - June 4, 2016 Category: Statistics Authors: Gaohong Dong, Marc Vandemeulebroecke Tags: Main Paper Source Type: research
Issue Information
Abstract
No abstract is available for this article. (Source: Pharmaceutical Statistics)
Source: Pharmaceutical Statistics - May 11, 2016 Category: Statistics Tags: Issue Information Source Type: research
Adaptive paediatric investigation plans, a small step to improve regulatory decision making in drug development for children?
Different arguments have been put forward why drug developers should commit themselves early for what they are planning to do for children. By EU regulation, paediatric investigation plans should be agreed on in early phases of drug development in adults. Here, extrapolation from adults to children is widely applied to reduce the burden and avoids unnecessary clinical trials in children, but early regulatory decisions on how far extrapolation can be used may be highly uncertain. Under special circumstances, the regulatory process should allow for adaptive paediatric investigation plans explicitly foreseeing a re‐evaluati...
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Peter Bauer, Franz König Tags: Viewpoint Source Type: research
Group sequential monitoring based on the weighted log‐rank test statistic with the Fleming–Harrington class of weights in cancer vaccine studies
In recent years, immunological science has evolved, and cancer vaccines are now approved and available for treating existing cancers. Because cancer vaccines require time to elicit an immune response, a delayed treatment effect is expected and is actually observed in drug approval studies. Accordingly, we propose the evaluation of survival endpoints by weighted log‐rank tests with the Fleming–Harrington class of weights. We consider group sequential monitoring, which allows early efficacy stopping, and determine a semiparametric information fraction for the Fleming–Harrington family of weights, which is necessary for...
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Takahiro Hasegawa Tags: Main Paper Source Type: research
Statistical methods for the analysis of adverse event data
(Source: Pharmaceutical Statistics)
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Meinhard Kieser Tags: Editorial Source Type: research
Analysing adverse events by time‐to‐event models: the CLEOPATRA study
When primary and secondary endpoints in a clinical trial with patients suffering from a chronic disease, statistical models for time‐to‐event data are commonly used and accepted. This is in contrast to the analysis of data on adverse events where often only a table with observed frequencies and corresponding test statistics is reported. An example is the recently published CLEOPATRA study where a three‐drug regimen is compared with a two‐drug regimen in patients with HER2‐positive first‐line metastatic breast cancer. Here, as described earlier, primary and secondary endpoints (progression‐free and overall sur...
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Tanja Proctor, Martin Schumacher Tags: Special Issue Paper Source Type: research
Hyperbaric oxygen brain injury treatment (HOBIT) trial: a multifactor design with response adaptive randomization and longitudinal modeling
The goals of phase II clinical trials are to gain important information about the performance of novel treatments and decide whether to conduct a larger phase III trial. This can be complicated in cases when the phase II trial objective is to identify a novel treatment having several factors. Such multifactor treatment scenarios can be explored using fixed sample size trials. However, the alternative design could be response adaptive randomization with interim analyses and additionally, longitudinal modeling whereby more data could be used in the estimation process. This combined approach allows a quicker and more responsi...
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Byron J. Gajewski, Scott M. Berry, William G. Barsan, Robert Silbergleit, William J. Meurer, Renee Martin, Gaylan L. Rockswold Tags: Main Paper Source Type: research
Safety data from randomized controlled trials: applying models for recurrent events
Simple descriptive listings and inference statistics based on 2×2 tables are still the most common way of summarizing and reporting adverse events data from randomized controlled trials, although these methods do not account for differences in observation times between treatment groups. Using standard methods from survival analysis such as the Cox model or Kaplan–Meier estimates would overcome this problem but limit the analysis to the first safety‐related event of each subject. As an alternative, we discuss two models for recurrent events data—the Andersen–Gill and Prentice–Williams–Peterson model—regarding...
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Johannes Hengelbrock, Johanna Gillhaus, Sebastian Kloss, Friedhelm Leverkus Tags: Special Issue Paper Source Type: research
A modified varying‐stage adaptive phase II/III clinical trial design
Conventionally, adaptive phase II/III clinical trials are carried out with a strict two‐stage design. Recently, a varying‐stage adaptive phase II/III clinical trial design has been developed. In this design, following the first stage, an intermediate stage can be adaptively added to obtain more data, so that a more informative decision can be made. Therefore, the number of further investigational stages is determined based upon data accumulated to the interim analysis. This design considers two plausible study endpoints, with one of them initially designated as the primary endpoint. Based on interim results, another en...
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Gaohong Dong, Marc Vandemeulebroecke Tags: Main Paper Source Type: research
Comparing two treatments by decision theory
Decision theory is applied to the general problem of comparing two treatments in an experiment with subjects assigned to the treatments at random. The inferential agenda covers collection of evidence about superiority, non‐inferiority and average bioequivalence of the treatments. The proposed approach requires defining the terms ‘small’ and ‘large’ to qualify the magnitude of the treatment effect and specifying the losses (or loss functions) that quantify the consequences of the incorrect conclusions. We argue that any analysis that ignores these two inputs is deficient, and so is any ad hoc way of taking them in...
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Nicholas T. Longford Tags: Main Paper Source Type: research
Testing treatment effect in schizophrenia clinical trials with heavy patient dropout using latent class growth mixture models
This article is a U.S. Government work and is in the public domain in the USA. (Source: Pharmaceutical Statistics)
Source: Pharmaceutical Statistics - April 30, 2016 Category: Statistics Authors: Fanhui Kong, Yeh‐Fong Chen Tags: Main Paper Source Type: research
Estimands: discussion points from the PSI estimands and sensitivity expert group
ICH E9 Statistical Principles for Clinical Trials was issued in 1998. In October 2014, an addendum to ICH E9 was proposed relating to estimands and sensitivity analyses. In preparation for the release of the addendum, Statisticians in the Pharmaceutical Industry held a 1‐day expert group meeting in February 2015. Topics debated included definition, development, implementation, education and communication challenges associated with estimands and sensitivity analyses. The topic of estimands is an important and relatively new one in clinical development. A clear message from the meeting was that estimands bridge the gap bet...
Source: Pharmaceutical Statistics - March 21, 2016 Category: Statistics Authors: Alan Phillips, Juan Abellan‐Andres, Andersen Soren, Frank Bretz, Chrissie Fletcher, Lesley France, Andrew Garrett, Raymond Harris, Magnus Kjaer, Oliver Keene, David Morgan, Michael O'Kelly, James Roger Tags: Viewpoint Source Type: research
Decision‐making in early clinical drug development
This paper illustrates an approach to setting the decision framework for a study in early clinical drug development. It shows how the criteria for a go and a stop decision are calculated based on pre‐specified target and lower reference values. The framework can lead to a three‐outcome approach by including a consider zone; this could enable smaller studies to be performed in early development, with other information either external to or within the study used to reach a go or stop decision. In this way, Phase I/II trials can be geared towards providing actionable decision‐making rather than the traditional focus on ...
Source: Pharmaceutical Statistics - March 17, 2016 Category: Statistics Authors: Paul Frewer, Pat Mitchell, Claire Watkins, James Matcham Tags: Main Paper Source Type: research
