title: Stopping guidelines for an effectiveness trial: what should the protocol specify?
abstract: BACKGROUND
  Despite long-standing problems in decisions to stop clinical trials, stopping guidelines are often vague or unspecified in the trial protocol. Clear, well-conceived guidelines are especially important to assist the data monitoring committees for effectiveness trials.
  
  
  METHODS
  To specify better stopping guidelines in the protocol for such trials, the clinical investigators and trial statistician should carefully consider the following kinds of questions: 1. How should the relative importance of the treatment benefits and hazards be assessed? 2. For decisions to stop a trial for benefit: (a) What would be the minimum clinically important difference for the study population? (b) How should the probability that the benefit exceeds that difference be assessed? (c) When should the interim analyses include data from other trials? (d) Would the evidence meet state-of-the-art standards for treatment recommendations and practice guidelines? 3. Should less evidence be required to stop the trial for harm than for benefit? 4. When should conventional stopping guidelines for futility be used for comparative effectiveness trials?
  
  
  CONCLUSIONS
  Both clinical and statistical expertise are required to address such challenging questions for effectiveness trials. Their joint consideration by clinical investigators and statisticians is needed to define better stopping guidelines before starting the trial.
authors.affiliation: Center for Clinical Research and Evidence-Based Medicine, Department of Pediatrics, University of Texas Health Science Center at Houston, 6431 Fannin St, MSB 2.106, Houston, TX, 77030, USA. jon.e.tyson@uth.tmc.edu.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Tyson
authors.affiliation: Center for Clinical Research and Evidence-Based Medicine, Department of Pediatrics, University of Texas Health Science Center at Houston, 6431 Fannin St, MSB 2.106, Houston, TX, 77030, USA.
authors.forename: Claudia
authors.initials: C
authors.lastname: Pedroza
authors.affiliation: RTI International, Durham, NC, 27709, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Wallace
authors.affiliation: University of Rochester School of Medicine and Dentistry, Rochester, NY, 14627, USA.
authors.forename: Carl
authors.initials: C
authors.lastname: D'Angio
authors.affiliation: Department of Pediatrics, University of Iowa, Iowa City, IA, 52242, USA.
authors.forename: Edward F
authors.initials: EF
authors.lastname: Bell
authors.affiliation: Social, Statistical and Environmental Sciences Unit, RTI International, Durham, NC, 27709, USA.
authors.forename: Abhik
authors.initials: A
authors.lastname: Das
mesh_terms: D026661:Clinical Trials Data Monitoring Committees / Q000592:standards* / Q000706:statistics & numerical data; D002986:Clinical Trials as Topic / Q000592:standards* / Q000706:statistics & numerical data; D003627:Data Interpretation, Statistical; D057239:Early Termination of Clinical Trials / Q000592:standards* / Q000706:statistics & numerical data; D006801:Humans; D018447:Medical Futility; D061214:Patient Safety / Q000592:standards; D017410:Practice Guidelines as Topic / Q000592:standards*; D012107:Research Design / Q000592:standards* / Q000706:statistics & numerical data; D018570:Risk Assessment; D017211:Treatment Failure
keywords: Clinical trials; Data monitoring committees; Effectiveness trials; Futility; Stopping guidelines