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Inflation of the Type I Error: Investigations on Regulatory Recommendations for Bioequivalence of Highly Variable Drugs

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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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Authors and Affiliations

  1. Institut für Biometrie, Medizinische Hochschule Hannover, OE 8410, 30625, Hannover, Germany

    Meinolf Wonnemann, Cornelia Frömke & Armin Koch

  2. Mainkurstrasse 18, 60385, Frankfurt a.M, Germany

    Meinolf Wonnemann

  3. Institut für Biometrie, Epidemiologie und Informationsverarbeitung, Stiftung Tierärztliche Hochschule Hannover, Bünteweg 2, 30559, Hannover, Germany

    Cornelia Frömke

Authors
  1. Meinolf Wonnemann
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  2. Cornelia Frömke
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  3. Armin Koch
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Corresponding author

Correspondence to Meinolf Wonnemann.

Additional information

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

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