European Journal of Clinical Pharmacology

, Volume 74, Issue 5, pp 549–559 | Cite as

A comparison of group sequential and fixed sample size designs for bioequivalence trials with highly variable drugs

  • Sophie I. E. Knahl
  • Benjamin Lang
  • Frank Fleischer
  • Meinhard Kieser
Clinical Trial



A drug is defined as highly variable if its intra-individual coefficient of variation (CV) is greater than or equal to 30%. In such a case, bioequivalence may be assessed by means of methods that take the (high) variability into account. The Scaled Average Bioequivalence (SABE) approach is such a procedure and represents the recommendations of FDA. The aim of this investigation is to compare the performance characteristics of classical group sequential designs (GSD) and fixed design settings for three-period crossover bioequivalence studies with highly variable drugs, where the SABE procedure is utilized.


Monte Carlo simulations were performed to assess type I error rate, power, and average sample size for GSDs with Pocock’s and O’Brien-Fleming’s stopping rules and various timings of the interim analysis and for fixed design settings.


Based on our investigated scenarios, the GSDs show comparable properties with regard to power and type I error rate as compared to the corresponding fixed designs. However, due to an advantage in average sample size, the most appealing design is Pocock’s approach with interim analysis after 50% information fraction.


Due to their favorable performance characteristics, two-stage GSDs are an appealing alternative to fixed sample designs when assessing bioequivalence in highly variable drugs.


Bioequivalence Highly variable drugs Group sequential designs Two-stage designs 



The authors would like to thank the Editor and two anonymous reviewers for their helpful comments that helped us to improve the manuscript.

Author contribution

S.I.E.K., B.L., F.F., and M.K. wrote the manuscript; S.I.E.K., B.L., F.F., and M.K. designed the research; S.I.E.K. performed the research; S.I.E.K., B.L., F.F., and M.K. analyzed the results.

Supplementary material

228_2018_2415_MOESM1_ESM.docx (121 kb)
ESM 1 (DOCX 120 kb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Boehringer Ingelheim Pharma GmbH & Co. KGBiberachGermany
  2. 2.Institute of Medical Biometry and InformaticsUniversity of HeidelbergHeidelbergGermany

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