On the Incorrect Statistical Calculations of the Kinetica Software Package in Imbalanced Designs.

This regulatory note supports the previous findings that suggest that the software package Kinetica, up to version 5.0.10, provides incorrect results for the 90% confidence intervals for the ratio test/reference where the groups are imbalanced in 2 × 2 crossover designs and parallel designs. The incorrect calculation results from using the simplified formula that is shown as an example in the Canadian guideline for a balanced dataset, but which provides an erroneous point estimate and confidence interval width in cases of imbalanced designs. Importantly, this software is rarely used for regulatory submissions in the European Union according to the search conducted in the Spanish Agency for Medicines and Health Care Products. According to our data, the error is minor if the imbalance between groups is small. However, the error may be relevant if the sample size is small and the imbalance is large. Therefore, bioequivalence studies should be reanalyzed by regulatory agencies to confirm the submitted results.