Bioequivalence and Bioavailability Forum

García-Arieta A, Gordon J. Bioequivalence Requirements in the European Union: Critical Discussion. AAPS J. 2012;14(4):738–48. doi:10.1208/s12248-012-9382-1

For the first time, this guideline acknowledges the possibility of a two-stage design to show BE. In this instance, the following should be noted:

1. The first stage is an interim analysis and the second stage is the analysis of the full data set. The second data set cannot be analysed separately.
   
2. In order to preserve the overall type I error, the significance level needs to be adjusted to obtain a coverage probability higher than 90%. Therefore, it is not acceptable to perform a 90% CI at the interim analysis and a 95% confidence interval in the final analysis with the full data set.
   
3. The plan to spend alpha must be pre-defined in the protocol. The same or a different amount of alpha can be spent in each analysis. If the same alpha is spent in both stages, the Bonferroni rule (95% confidence interval in both analyses) is too conservative and 94.12% confidence interval can be used. It is also possible to distribute the alpha differently, and as an extreme case, it is acceptable to plan no alpha expenditure in the interim analysis when it is designed to obtain information on formulation differences and intra-subject variability and 90% CI are not estimated at the interim stage.
   
4. A term for the stage should be included in the ANOVA model. However, the guideline does not clarify what the consequence should be if it is statistically significant. In principle, the data sets of both stages could not be combined.

Although the guideline is not explicit, even if the final sample size is going to be decided based on the intra-subject variability estimated in the interim analysis, a proposal for a final sample size must be included in the protocol so that a significant number of subjects (e.g., 12) is added to the interim sample size to avoid looking twice at almost identical samples. This proposed final sample size should be recruited even if the estimation obtained from the interim analysis is lower than the one pre-defined in the protocol in order to maintain the consumer risk.