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10th Anniversary of a Two-Stage Design in Bioequivalence. Why Has it Still Not Been Implemented?
Michał Kaza1, Alexander Sokolovskyi2, Piotr J Rudzki3
1Pharmacokinetics Department, Łukasiewicz Research Network - Pharmaceutical Research Institute, 8 Rydygiera Str., 01-793, Warsaw, Poland. michal.kaza@gmail.com.
Purpose:
In 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.
Methods:
Different 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.
Results:
Key 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.
Conclusion:
The use of the two-stage design in bioequivalence studies seems to be a beneficial alternative to the 2 × 2 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.
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