Abstract
Purpose
We investigated different evaluation strategies for bioequivalence trials with highly variable drugs on their resulting empirical type I error and empirical power. The classical ‘unscaled’ crossover design with average bioequivalence evaluation, the Add-on concept of the Japanese guideline, and the current ‘scaling’ approach of EMA were compared.
Methods
Simulation studies were performed based on the assumption of a single dose drug administration while changing the underlying intra-individual variability.
Results
Inclusion of Add-on subjects following the Japanese concept led to slight increases of the empirical α-error (≈7.5%). For the approach of EMA we noted an unexpected tremendous increase of the rejection rate at a geometric mean ratio of 1.25. Moreover, we detected error rates slightly above the pre-set limit of 5% even at the proposed ‘scaled’ bioequivalence limits.
Conclusions
With the classical ‘unscaled’ approach and the Japanese guideline concept the goal of reduced subject numbers in bioequivalence trials of HVDs cannot be achieved. On the other hand, widening the acceptance range comes at the price that quite a number of products will be accepted bioequivalent that had not been accepted in the past. A two-stage design with control of the global α therefore seems the better alternative.
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Abbreviations
- ANOVA:
-
Analysis of variances
- AUC:
-
Area under the curve
- BE:
-
Bioequivalence
- Cmax :
-
Maximum drug concentration
- CV:
-
Coefficient of variance
- CVANOVA :
-
Coefficient of variance calculated from the residual error in an ANOVA
- EMA:
-
European Medicines Agency
- FDA:
-
Food and Drug Administration
- GMR:
-
Geometric mean ratio
- HVD:
-
Highly variable drug
- k:
-
Regulatory constant of 0.760
- L:
-
Lower acceptance limit for bioequivalence
- Sw :
-
Residual error of an ANOVA calculation
- SWR :
-
Residual error of an ANOVA calculation of two Reference administrations in a partial replicate study design
- U:
-
Upper acceptance limit for bioequivalence
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Meinolf Wonnemann and Cornelia Frömke contributed equally to this project and should be considered co-first authors.
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Wonnemann, M., Frömke, C. & Koch, A. Inflation of the Type I Error: Investigations on Regulatory Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res 32, 135–143 (2015). https://doi.org/10.1007/s11095-014-1450-z
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DOI: https://doi.org/10.1007/s11095-014-1450-z