Stopping clinical trials because of treatment ineffectiveness: a comparison of a futility design with a method of stochastic curtailment

This paper introduces a simple futility design that allows a comparative clinical trial to be stopped due to lack of effect at any of a series of planned interim analyses. Stopping due to apparent benefit is not permitted. The design is for use when any positive claim should be based on the maximum sample size, for example to allow subgroup analyses or the evaluation of safety or secondary efficacy responses. A final frequentist analysis can be performed that is valid for the type of design employed. Here the design is described and its properties are presented. Its advantages and disadvantages relative to the use of stochastic curtailment are discussed. Copyright (C) 2003 John Wiley Sons, Ltd.

Conditionally unbiased estimation in phase II/III clinical trials with early stopping for futility

Seamless phase II/III clinical trials combine traditional phases II and III into a single trial that is conducted in two stages, with stage 1 used to answer phase II objectives such as treatment selection and stage 2 used for the confirmatory analysis, which is a phase III objective. Although seamless phase II/III clinical trials are efficient because the confirmatory analysis includes phase II data from stage 1, inference can pose statistical challenges. In this paper, we consider point estimation following seamless phase II/III clinical trials in which stage 1 is used to select the most effective experimental treatment and to decide if, compared with a control, the trial should stop at stage 1 for futility. If the trial is not stopped, then the phase III confirmatory part of the trial involves evaluation of the selected most effective experimental treatment and the control. We have developed two new estimators for the treatment difference between these two treatments with the aim of reducing bias conditional on the treatment selection made and on the fact that the trial continues to stage 2. We have demonstrated the properties of these estimators using simulations

A simple two-stage design for quantitative responses with application to a study in diabetic neuropathic pain

Two-stage designs offer substantial advantages for early phase II studies. The interim analysis following the first stage allows the study to he stopped for futility, or more positively, it might lead to early progression to the trials needed for late phase H and phase III. If the study is to continue to its second stage, then there is an opportunity for a revision of the total sample size. Two-stage designs have been implemented widely in oncology studies in which there is a single treatment arm and patient responses are binary. In this paper the case of two-arm comparative studies in which responses are quantitative is considered. This setting is common in therapeutic areas other than oncology. It will be assumed that observations are normally distributed, but that there is some doubt concerning their standard deviation, motivating the need for sample size review. The work reported has been motivated by a study in diabetic neuropathic pain, and the development of the design for that trial is described in detail. Copyright (C) 2008 John Wiley & Sons, Ltd.

An investigation of the shortcomings of the CONSORT 2010 statement for the reporting of group sequential randomised controlled trials: a methodological systematic review

Background It can be argued that adaptive designs are underused in clinical research. We have explored concerns related to inadequate reporting of such trials, which may influence their uptake. Through a careful examination of the literature, we evaluated the standards of reporting of group sequential (GS) randomised controlled trials, one form of a confirmatory adaptive design. Methods We undertook a systematic review, by searching Ovid MEDLINE from the 1st January 2001 to 23rd September 2014, supplemented with trials from an audit study. We included parallel group, confirmatory, GS trials that were prospectively designed using a Frequentist approach. Eligible trials were examined for compliance in their reporting against the CONSORT 2010 checklist. In addition, as part of our evaluation, we developed a supplementary checklist to explicitly capture group sequential specific reporting aspects, and investigated how these are currently being reported. Results Of the 284 screened trials, 68(24%) were eligible. Most trials were published in “high impact” peer-reviewed journals. Examination of trials established that 46(68%) were stopped early, predominantly either for futility or efficacy. Suboptimal reporting compliance was found in general items relating to: access to full trials protocols; methods to generate randomisation list(s); details of randomisation concealment, and its implementation. Benchmarking against the supplementary checklist, GS aspects were largely inadequately reported. Only 3(7%) trials which stopped early reported use of statistical bias correction. Moreover, 52(76%) trials failed to disclose methods used to minimise the risk of operational bias, due to the knowledge or leakage of interim results. Occurrence of changes to trial methods and outcomes could not be determined in most trials, due to inaccessible protocols and amendments. Discussion and Conclusions There are issues with the reporting of GS trials, particularly those specific to the conduct of interim analyses. Suboptimal reporting of bias correction methods could potentially imply most GS trials stopping early are giving biased results of treatment effects. As a result, research consumers may question credibility of findings to change practice when trials are stopped early. These issues could be alleviated through a CONSORT extension. Assurance of scientific rigour through transparent adequate reporting is paramount to the credibility of findings from adaptive trials. Our systematic literature search was restricted to one database due to resource constraints.

The politics of slowness and the traps of modernity

This chapter re-evaluates the diachronic, evolutionist model that establishes the Second World War as a watershed between classical and modern cinemas, and ‘modernity’ as the political project of ‘slow cinema’. I will start by historicising the connection between cinematic speed and modernity, going on to survey the veritable obsession with the modern that continues to beset film studies despite the vagueness and contradictions inherent in the term. I will then attempt to clarify what is really at stake within the modern-classical debate by analysing two canonical examples of Japanese cinema, drawn from the geidomono genre (films on the lives of theatre actors), Kenji Mizoguchi’s Story of the Late Chrysanthemums (Zangiku monogatari, 1939) and Yasujiro Ozu’s Floating Weeds (Ukigusa, 1954), with a view to investigating the role of the long take or, conversely, classical editing, in the production or otherwise of a supposed ‘slow modernity’. By resorting to Ozu and Mizoguchi, I hope to demonstrate that the best narrative films in the world have always combined a ‘classical’ quest for perfection with the ‘modern’ doubt of its existence, hence the futility of classifying cinema in general according to an evolutionary and Eurocentric model based on the classical-modern binary. Rather than on a confusing politics of the modern, I will draw on Bazin’s prophetic insight of ‘impure cinema’, a concept he forged in defence of literary and theatrical screen adaptations. Anticipating by more than half a century the media convergence on which the near totality of our audiovisual experience is currently based, ‘impure cinema’ will give me the opportunity to focus on the confluence of film and theatre in these Mizoguchi and Ozu films as the site of a productive crisis where established genres dissolve into self-reflexive stasis, ambiguity of expression and the revelation of the reality of the film medium, all of which, I argue, are more reliable indicators of a film’s political programme than historical teleology. At the end of the journey, some answers may emerge to whether the combination of the long take and the long shot are sufficient to account for a film’s ‘slowness’ and whether ‘slow’ is indeed the best concept to signify resistance to the destructive pace of capitalism.