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Abstract
backgroundThe pace of novel medical treatments and approaches to therapy has accelerated in recent years. Unfortunately, many potential therapeutic advances do not fulfil their promise when subjected to randomized controlled trials. It is therefore highly desirable to speed up the process of evaluating new treatment options, particularly in phase II and phase III trials. To help realize such an aim, in 2003, Royston and colleagues proposed a class of multi-arm, two-stage trial designs intended to eliminate poorly performing contenders at a first stage (point in time). Only treatments showing a predefined degree of advantage against a control treatment were allowed through to a second stage. Arms that survived the first-stage comparison on an intermediate outcome measure entered a second stage of patient accrual, culminating in comparisons against control on the definitive outcome measure. The intermediate outcome is typically on the causal pathway to the definitive outcome (i.e. the features that cause an intermediate event also tend to cause a definitive event), an example in cancer being progression-free and overall survival. Although the 2003 paper alluded to multi-arm trials, most of the essential design features concerned only two-arm trials. Here, we extend the two-arm designs to allow an arbitrary number of stages, thereby increasing flexibility by building in several 'looks' at the accumulating data. Such trials can terminate at any of the intermediate stages or the final stage.MethodsWe describe the trial design and the mathematics required to obtain the timing of the 'looks' and the overall significance level and power of the design. We support our results by extensive simulation studies. As an example, we discuss the design of the STAMPEDE trial in prostate cancer.ResultsThe mathematical results on significance level and power are confirmed by the computer simulations. Our approach compares favourably with methodology based on beta spending functions and on monitoring only a primary outcome measure for lack of benefit of the new treatment.ConclusionsThe new designs are practical and are supported by theory. They hold considerable promise for speeding up the evaluation of new treatments in phase II and III trials.
Highlights
The ongoing developments in molecular sciences have increased our understanding of many serious diseases, including cancer, HIV and heart disease, resulting in many potential new therapies
Our approach compares favourably with methodology based on beta spending functions and on monitoring only a primary outcome measure for lack of benefit of the new treatment
The hazard ratio under H1 was fixed at 0.75. Derived from the former according to the methods i described in section 2, with Ni = j=1 nj
Summary
The ongoing developments in molecular sciences have increased our understanding of many serious diseases, including cancer, HIV and heart disease, resulting in many potential new therapies. There are Several methodologies have been proposed in the past to deal with stopping for futility or lack of benefit, including conditional power and spending functions. Assumptions are made about the distribution of trial data yet to be seen, given the data so far. At certain points during the trial, the conditional power is computed, the aim being to quantify the chance of a statistically significant final result given the data available so far. The calculations may be carried out under different assumptions about the data that could be seen if the trial were continued [2]. Treatment effects of different magnitudes might be investigated under the alternative hypothesis of a non-null treatment effect
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