title: Comparison of futility monitoring guidelines using completed phase III oncology trials.
abstract: BACKGROUND
  Futility (inefficacy) interim monitoring is an important component in the conduct of phase III clinical trials, especially in life-threatening diseases. Desirable futility monitoring guidelines allow timely stopping if the new therapy is harmful or if it is unlikely to demonstrate to be sufficiently effective if the trial were to continue to its final analysis. There are a number of analytical approaches that are used to construct futility monitoring boundaries. The most common approaches are based on conditional power, sequential testing of the alternative hypothesis, or sequential confidence intervals. The resulting futility boundaries vary considerably with respect to the level of evidence required for recommending stopping the study.
  
  
  OBJECTIVE
  We evaluate the performance of commonly used methods using event histories from completed phase III clinical trials of the Radiation Therapy Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group.
  
  
  METHODS
  We considered published superiority phase III trials with survival endpoints initiated after 1990. There are 52 studies available for this analysis from different disease sites. Total sample size and maximum number of events (statistical information) for each study were calculated using protocol-specified effect size, type I and type II error rates. In addition to the common futility approaches, we considered a recently proposed linear inefficacy boundary approach with an early harm look followed by several lack-of-efficacy analyses. For each futility approach, interim test statistics were generated for three schedules with different analysis frequency, and early stopping was recommended if the interim result crossed a futility stopping boundary. For trials not demonstrating superiority, the impact of each rule is summarized as savings on sample size, study duration, and information time scales.
  
  
  RESULTS
  For negative studies, our results show that the futility approaches based on testing the alternative hypothesis and repeated confidence interval rules yielded less savings (compared to the other two rules). These boundaries are too conservative, especially during the first half of the study (<50% of information). The conditional power rules are too aggressive during the second half of the study (>50% of information) and may stop a trial even when there is a clinically meaningful treatment effect. The linear inefficacy boundary with three or more interim analyses provided the best results. For positive studies, we demonstrated that none of the futility rules would have stopped the trials.
  
  
  CONCLUSIONS
  The linear inefficacy boundary futility approach is attractive from statistical, clinical, and logistical standpoints in clinical trials evaluating new anti-cancer agents.
authors: 1 Statistics and Data Management Center, NRG Oncology, Philadelphia, PA, USA.|2 Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors: Qiang
authors: Q
authors: Zhang
authors: 3 Biometric Research Program, National Cancer Institute, Bethesda, MD, USA.
authors: Boris
authors: B
authors: Freidlin
authors: 3 Biometric Research Program, National Cancer Institute, Bethesda, MD, USA.
authors: Edward L
authors: EL
authors: Korn
authors: 4 Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, NC, USA.
authors: Susan
authors: S
authors: Halabi
authors: 5 Division of Biomedical Statistics and Informatics, Alliance Statistics and Data Center, Mayo Clinic, Rochester, MN, USA.
authors: Sumithra
authors: S
authors: Mandrekar
authors: 1 Statistics and Data Management Center, NRG Oncology, Philadelphia, PA, USA.|6 Department of Public Health Sciences, University of Chicago, Chicago, IL, USA.
authors: James J
authors: JJ
authors: Dignam
mesh_terms: D026661:Clinical Trials Data Monitoring Committees; D017326:Clinical Trials, Phase III as Topic; D006801:Humans; D018447:Medical Futility; D009369:Neoplasms / Q000628:therapy*; D012107:Research Design
keywords: Futility monitoring; clinical trials; conditional power; linear inefficacy boundary; oncology; repeated confidence intervals; testing alternative hypothesis