title: Designs for clinical trials with time-to-event outcomes based on stopping guidelines for lack of benefit.
abstract: BACKGROUND
  The 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  The 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: MRC Clinical Trials, London NW1 2DA UK. pr@ctu.mrc.ac.uk
authors.forename: Patrick
authors.initials: P
authors.lastname: Royston
authors.forename: Friederike M-S
authors.initials: FM
authors.lastname: Barthel
authors.forename: Mahesh Kb
authors.initials: MK
authors.lastname: Parmar
authors.forename: Babak
authors.initials: B
authors.lastname: Choodari-Oskooei
authors.forename: Valerie
authors.initials: V
authors.lastname: Isham
mesh_terms: D000726:Androgen Antagonists / Q000627:therapeutic use; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D002986:Clinical Trials as Topic / Q000379:methods* / Q000706:statistics & numerical data; D003198:Computer Simulation; D003627:Data Interpretation, Statistical; D018572:Disease-Free Survival; D057239:Early Termination of Clinical Trials / Q000706:statistics & numerical data; D023381:Endpoint Determination; D006801:Humans; D008297:Male; D018447:Medical Futility; D015233:Models, Statistical; D017410:Practice Guidelines as Topic; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000401:mortality; D012107:Research Design / Q000706:statistics & numerical data; D018401:Sample Size; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal