title: Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach.
abstract: BACKGROUND
  Non-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. These advantages however are not included in the classic frequentist approach of sample size calculation for non-inferiority trials. In contrast, the decision theory approach of sample size calculation does include these factors. The objective of this study is to compare the conceptual and practical aspects of the frequentist approach and decision theory approach of sample size calculation for non-inferiority trials, thereby demonstrating that the decision theory approach is more appropriate for sample size calculation of non-inferiority trials.
  
  
  METHODS
  The frequentist approach and decision theory approach of sample size calculation for non-inferiority trials are compared and applied to a case of a non-inferiority trial on individually tailored duration of elastic compression stocking therapy compared to two years elastic compression stocking therapy for the prevention of post thrombotic syndrome after deep vein thrombosis.
  
  
  RESULTS
  The two approaches differ substantially in conceptual background, analytical approach, and input requirements. The sample size calculated according to the frequentist approach yielded 788 patients, using a power of 80% and a one-sided significance level of 5%. The decision theory approach indicated that the optimal sample size was 500 patients, with a net value of €92 million.
  
  
  CONCLUSIONS
  This study demonstrates and explains the differences between the classic frequentist approach and the decision theory approach of sample size calculation for non-inferiority trials. We argue that the decision theory approach of sample size estimation is most suitable for sample size calculation of non-inferiority trials.
authors.affiliation: Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Centre, Maastricht, the Netherlands; Laboratory for Thrombosis and Hemostasis, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: A C
authors.initials: AC
authors.lastname: Bouman
authors.affiliation: Laboratory for Thrombosis and Hemostasis, Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: A J
authors.initials: AJ
authors.lastname: ten Cate-Hoek
authors.affiliation: Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: B L T
authors.initials: BL
authors.lastname: Ramaekers
authors.affiliation: Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA), Maastricht University Medical Centre, Maastricht, the Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Joore
mesh_terms: D002986:Clinical Trials as Topic / Q000379:methods*; D003662:Decision Theory; D006801:Humans; D009426:Netherlands / Q000453:epidemiology; D018401:Sample Size; D053828:Stockings, Compression; D020246:Venous Thrombosis / Q000191:economics / Q000453:epidemiology* / Q000628:therapy