The authors suggest that this problem seems to be caused by the use of a simplified formula that implies that the sample size is equal in either sequences or groups. ( 1, 2) have identified that the software Kinetica (version 5.0.10, Thermo Fisher Scientific 2007) provides incorrect 90% confidence intervals for the ratio of test/reference where the groups are imbalanced in two-sequence two-period crossover designs ( 1) and parallel designs ( 2). Therefore, bioequivalence studies should be reanalyzed by regulatory agencies to confirm the submitted results. However, the error may be relevant if the sample size is small and the imbalance is large. According to our data, the error is minor if the imbalance between groups is small. 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. 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. 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.
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