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Pharmaceutical Research

, Volume 32, Issue 1, pp 135–143 | Cite as

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

  • Meinolf Wonnemann
  • Cornelia Frömke
  • Armin Koch
Research Paper

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.

KEY WORDS

bioequivalence highly variable drug pharmacokinetic replicate design scaling 

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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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Meinolf Wonnemann
    • 1
    • 2
  • Cornelia Frömke
    • 1
    • 3
  • Armin Koch
    • 1
  1. 1.Institut für BiometrieMedizinische Hochschule HannoverHannoverGermany
  2. 2.Frankfurt a.MGermany
  3. 3.Institut für Biometrie, Epidemiologie und InformationsverarbeitungStiftung Tierärztliche Hochschule HannoverHannoverGermany

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