title: The role of the Data and Safety Monitoring Board in a clinical trial: the CRISIS study.
abstract: OBJECTIVE
  Randomized clinical trials are commonly overseen by a Data and Safety Monitoring Board comprised of experts in medicine, ethics, and biostatistics. Data and Safety Monitoring Board responsibilities include protocol approval, interim review of study enrollment, protocol compliance, safety, and efficacy data. Data and Safety Monitoring Board decisions can affect study design and conduct, as well as reported findings. Researchers must incorporate Data and Safety Monitoring Board oversight into the design, monitoring, and reporting of randomized trials.
  
  
  METHODS
  Case study, narrative review.
  
  
  METHODS
  The Data and Safety Monitoring Board's role during the comparative pediatric Critical Illness Stress-Induced Immune Suppression (CRISIS) Prevention Trial is described.
  
  
  RESULTS
  The National Institutes of Health-appointed CRISIS Data and Safety Monitoring Board was charged with monitoring sample size adequacy and feasibility, safety with respect to adverse events and 28-day mortality, and efficacy with respect to the primary nosocomial infection/sepsis outcome. The Federal Drug Administration also requested Data and Safety Monitoring Board interim review before opening CRISIS to children below 1 yr of age. The first interim analysis found higher 28-day mortality in one treatment arm. The Data and Safety Monitoring Board maintained trial closure to younger children and requested a second interim data review 6 months later. At this second meeting, mortality was no longer of concern, whereas a weak efficacy trend of lower infection/sepsis rates in one study arm emerged. As over 40% of total patients had been enrolled, the Data and Safety Monitoring Board elected to examine conditional power and unmask treatment arm identities. On finding somewhat greater efficacy in the placebo arm, the Data and Safety Monitoring Board recommended stopping CRISIS due to futility.
  
  
  CONCLUSIONS
  The design and operating procedures of a multicenter randomized trial must consider a pivotal Data and Safety Monitoring Board role. Maximum study design flexibility must be allowed, and investigators must be prepared for protocol modifications due to interim findings. The Data and Safety Monitoring Board must have sufficient clinical and statistical expertise to assess potential importance of interim treatment differences in the setting of multiple looks at accumulating data with numerous outcomes and subgroups.
authors: Division of Critical Care, Department of Pediatrics, University of Utah School of Medicine, Salt Lake City, UT, USA. rich.holubkov@hsc.utah.edu
authors: Richard
authors: R
authors: Holubkov
authors: T Charles
authors: TC
authors: Casper
authors: J Michael
authors: JM
authors: Dean
authors: K J S
authors: KJ
authors: Anand
authors: Jerry
authors: J
authors: Zimmerman
authors: Kathleen L
authors: KL
authors: Meert
authors: Christopher J L
authors: CJ
authors: Newth
authors: John
authors: J
authors: Berger
authors: Rick
authors: R
authors: Harrison
authors: Douglas F
authors: DF
authors: Willson
authors: Carol
authors: C
authors: Nicholson
mesh_terms: D000293:Adolescent; D035843:Biomedical Research / Q000592:standards; D002648:Child; D002675:Child, Preschool; D026661:Clinical Trials Data Monitoring Committees; D016638:Critical Illness; D003428:Cross Infection / Q000517:prevention & control; D057239:Early Termination of Clinical Trials; D005973:Glutamine / Q000627:therapeutic use; D006801:Humans; D007108:Immune Tolerance; D007223:Infant; D015278:Intensive Care Units, Pediatric; D018447:Medical Futility; D008787:Metoclopramide / Q000627:therapeutic use; D024382:Professional Role; D016032:Randomized Controlled Trials as Topic / Q000592:standards*; D012107:Research Design / Q000592:standards*; D012643:Selenium / Q000627:therapeutic use; D018805:Sepsis / Q000517:prevention & control; D013312:Stress, Physiological / Q000276:immunology; D013997:Time Factors; D015032:Zinc / Q000627:therapeutic use
chemical_list: D005973:Glutamine; D012643:Selenium; D015032:Zinc; D008787:Metoclopramide
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