title: Challenges in the design and analysis of non-inferiority trials: a case study.
abstract: BACKGROUND
  The literature on the design, conduct, and analysis of non-inferiority trials is continuously evolving. Several design issues continue to be researched including the choice of active control, choice of non-inferiority margin, and optimal analytic approaches. To date, there has been relatively little in the literature documenting actual experiences with implementing available methodology for non-inferiority trials.
  
  
  OBJECTIVE
  This article serves as a case study and highlights some of the challenges encountered in the design of a Phase III non-inferiority trial in status epilepticus that is being conducted under a Food and Drug Administration Investigational New Drug Application (IND).
  
  
  METHODS
  The IND application was put on clinical hold by the Food Drug and Administration due to concerns with the design. Specifically, support for the active control, non-inferiority margin, and overall interpretability of trial results were questioned, and a recommendation was made to consider a superiority design. The authors describe their interactions with the Food Drug and Administration and their application of available methods and approaches to address these concerns.
  
  
  RESULTS
  The investigators' response to the clinical hold provided detailed information to support the conduct of a non-inferiority trial. The study team received Food Drug and Administration approval to initiate the trial in October 2008. The trial enrollment began in June 2009 and is being conducted by roughly 800 paramedic units in over 40 Emergency Medicine Service systems across the United States.
  
  
  CONCLUSIONS
  There is still a great deal of methodological research needed to fully understand the application and impact of the non-inferiority trial design.
  
  
  CONCLUSIONS
  It is evident that non-inferiority trials have an important place in clinical trial design and analysis. These trials may be the only way and only opportunity to answer certain questions; so, they must be designed and conducted with rigor. This case study is an attempt to share our experiences in implementation.
authors.affiliation: Division of Biostatistics and Epidemiology, Medical University of South Carolina, Charleston, SC 29425-8150, USA. durkalsv@musc.edu
authors.forename: Valerie
authors.initials: V
authors.lastname: Durkalski
authors.forename: Robert
authors.initials: R
authors.lastname: Silbergleit
authors.forename: Daniel
authors.initials: D
authors.lastname: Lowenstein
mesh_terms: D000488:Allied Health Personnel; D000927:Anticonvulsants / Q000627:therapeutic use*; D017326:Clinical Trials, Phase III as Topic / Q000379:methods*; D003627:Data Interpretation, Statistical; D004632:Emergency Medical Services; D004635:Emergency Medicine; D006801:Humans; D017387:Investigational New Drug Application; D019982:Organizational Case Studies; D010919:Placebos; D012107:Research Design; D013226:Status Epilepticus / Q000188:drug therapy*; D014481:United States; D014486:United States Food and Drug Administration
chemical_list: D000927:Anticonvulsants; D010919:Placebos