10th Anniversary of a Two-Stage Design in Bioequivalence. Why Has it Still Not Been Implemented?
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PERSPECTIVE
10th Anniversary of a Two-Stage Design in Bioequivalence. Why Has it Still Not Been Implemented? Michał Kaza 1
&
Alexander Sokolovskyi 2 & Piotr J. Rudzki 1
Received: 8 April 2020 / Accepted: 2 July 2020 / Published online: 13 July 2020 # The Author(s) 2020
ABSTRACT 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.
KEY WORDS Two-stage design . sequential design . bioequivalence . pharmacokinetics . in vitro dissolution
* Michał Kaza [email protected]
1
Pharmacokinetics Department, Łukasiewicz Research Network Pharmaceutical Research Institute, 8 Rydygiera Str., 01-793 Warsaw, Poland
2
Farmak JSC, Clinical Trial Department, 63 Kyrylivska Street, Kyiv, Ukraine
INTRODUCTION We have had more than 2200 results of bioequivalence studies in the last 32 years [1]. Since 2010, the European Medicines Agency (EMA) has allowed a two-stage design in bioequivalence studies [2]. A two-stage design is one of the alternative designs, group-sequential and adaptive designs, that have been considered for clinical use since the 1970s [3]. The alternative approach to a clinical trial design, accepted by FDA [4], EMA [5] and Health Canada [6], is widely used in innovative research due to significantly higher savings and no unnecessary exposure of people to drugs. It seems that this approach may also be convenient for bioequivalence studies. In accordance with the EMA guideline [2], the number of participants can be expanded if bioequivalence has not been demonstrated in the first group of subjects. The results for the initial and the second group are combined for the final assessment. However, the decision to conduct the two-stage clinical trial must be made before the study begins. And this requires an answer to the following question: when the twostage model is better than the standard cross-over design. There are actually more articles describing the the
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