10th Anniversary of a Two-Stage Design in Bioequivalence. Why Has it Still Not Been Implemented?

PurposeIn 2010 the European Medicines Agency allowed a two-stage design in bioequivalence studies. However, in the public domain there are mainly articles describing the theoretical and statistical base for the application of the two-stage design. One of the reasons seems to be the lack of practical guidance for the Sponsors on when and how the two-stage design can be beneficial in bioequivalence studies.MethodsDifferent variants with positive and negative outcomes have been evaluated, including a pivotal study, pilot + pivotal study and two-stage study. The scientific perspective on the two-stage bioequivalence study has been confronted with the industrial one.ResultsKey information needed to conduct a bioequivalence study - such as in vitro data and pharmacokinetics - have been listed and organized into a decision scheme. Advantages and disadvantages of the two-stage design have been summarized.ConclusionThe use of the two-stage design in bioequivalence studies seems to be a beneficial alternative to the 2x2 crossover study. Basic information on the properties of the active substance and the characteristics of the drug form are needed to make an initial decision to carry out the two-stage study.