title: An insight into the properties of a two-stage design in bioequivalence studies.
abstract: OBJECTIVE
  Unveil the properties of a two-stage design (TSD) for bioequivalence (BE) studies.
  
  
  METHODS
  A TSD with an upper sample size limit (UL) is described and analyzed under different conditions using Monte Carlo simulations. TSD was split into three branches: A, B1, and B2. The first stage included branches A and B1, while stage two referred to branch B2. Sample size re-estimation at B2 relies on the observed GMR and variability of stage 1. The properties studied were % BE acceptance, % uses and % efficiency of each branch, as well as the reason of BE failure.
  
  
  RESULTS
  No inflation of type I error was observed. Each TSD branch exhibits different performance. Stage two exhibits the greatest % BE acceptances when highly variable drugs are assessed with a low starting number of subjects (N₁) or when formulations differ significantly. Branch A is more frequently used when variability is low, drug products are similar, and a large N₁ is included. BE assessment at branch A is very efficient.
  
  
  CONCLUSIONS
  The overall acceptance profile of TSD resembles the typical pattern observed in single-stage studies, but it is actually different. Inclusion of a UL is necessary to avoid inflation of type I error.
authors.affiliation: Laboratory of Biopharmaceutics-Pharmacokinetics Faculty of Pharmacy, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece. vkaralis@pharm.uoa.gr
authors.forename: Vangelis
authors.initials: V
authors.lastname: Karalis
authors.forename: Panos
authors.initials: P
authors.lastname: Macheras
mesh_terms: D019540:Area Under Curve; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D009010:Monte Carlo Method; D018401:Sample Size; D013810:Therapeutic Equivalency