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Reference Datasets for Studies in a Replicate Design Intended for Average Bioequivalence with Expanding Limits

Abstract

In order to help companies qualify and validate the software used to evaluate bioequivalence trials in a replicate design intended for average bioequivalence with expanding limits, this work aims to define datasets with known results. This paper releases 30 reference datasets into the public domain along with proposed consensus results. A proposal is made for results that should be used as validation targets. The datasets were evaluated by seven different software packages according to methods proposed by the European Medicines Agency. For the estimation of CVwR and Method A, all software packages produced results that are in agreement across all datasets. Due to different approximations of the degrees of freedom, slight differences were observed in two software packages for Method B in highly incomplete datasets. All software packages were suitable for the estimation of CVwR and Method A. For Method B, different methods for approximating the denominator degrees of freedom could lead to slight differences, which eventually could lead to contrary decisions in very rare borderline cases.

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Acknowledgments

We would like to thank Mahmoud Teaima (Cairo University, Faculty of Pharmacy) for testing an earlier version of the R package replicateBE and four reviewers whose comments substantially improved this article.

Contributors

The concept was developed by HS, DL, MT, and AS. HS (replicateBE, Phoenix), DL, MT (SAS), MG (Stata, SPSS, JMP), and AS (STATISTICA) were responsible for analyses with the respective software packages. HS drafted the manuscript and all authors revised the manuscript critically for intellectual content and approved the final version.

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Correspondence to Helmut Schütz.

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HS received a “named license” of Phoenix from Certara. DL, MT, MG, AS, and AF have no competing interests to declare.

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Schütz, H., Labes, D., Tomashevskiy, M. et al. Reference Datasets for Studies in a Replicate Design Intended for Average Bioequivalence with Expanding Limits. AAPS J 22, 44 (2020). https://doi.org/10.1208/s12248-020-0427-6

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KEY WORDS

  • average bioequivalence with expanding limits
  • black box software validation
  • replicate designs
  • reference scaling