title: Statistical issues in the design, conduct and analysis of two large safety studies.
abstract: The emergence, post approval, of serious medical events, which may be associated with the use of a particular drug or class of drugs, is an important public health and regulatory issue. The best method to address this issue is through a large, rigorously designed safety study. Therefore, it is important to elucidate the statistical issues involved in these large safety studies.
  
  
  
  Two such studies are PRECISION and EAGLES. PRECISION is the primary focus of this article. PRECISION is a non-inferiority design with a clinically relevant non-inferiority margin. Statistical issues in the design, conduct and analysis of PRECISION are discussed.
  
  
  
  Quantitative and clinical aspects of the selection of the composite primary endpoint, the determination and role of the non-inferiority margin in a large safety study and the intent-to-treat and modified intent-to-treat analyses in a non-inferiority safety study are shown. Protocol changes that were necessary during the conduct of PRECISION are discussed from a statistical perspective. Issues regarding the complex analysis and interpretation of the results of PRECISION are outlined. EAGLES is presented as a large, rigorously designed safety study when a non-inferiority margin was not able to be determined by a strong clinical/scientific method. In general, when a non-inferiority margin is not able to be determined, the width of the 95% confidence interval is a way to size the study and to assess the cost-benefit of relative trial size.
  
  
  
  A non-inferiority margin, when able to be determined by a strong scientific method, should be included in a large safety study. Although these studies could not be called "pragmatic," they are examples of best real-world designs to address safety and regulatory concerns.
authors.affiliation: Pfizer Inc.-Statistical Research, New York, NY, USA michael.gaffney@pfizer.com.
authors.forename: Michael
authors.initials: M
authors.lastname: Gaffney
mesh_terms: D035843:Biomedical Research / Q000706:statistics & numerical data*; D006801:Humans; D055553:Prescription Drugs / Q000592:standards*; D012107:Research Design / Q000706:statistics & numerical data*; D017751:Safety Management / Q000458:organization & administration*
chemical_list: D055553:Prescription Drugs
keywords: EAGLES; Large safety trial; PRECISION; informative censoring; intent-to-treat; modified intent-to-treat; non-inferiority margin