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Individual Bioequivalence Revisited

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Abstract

For decades, the establishment of bioequivalence has generally relied on the comparison of population averages between the test and reference formulations. In the early 1990s, individual bioequivalence was proposed to ensure that an individual could be switched from the reference product to the test product with unchanged efficacy and safety.

Since 1997, the US Food and Drug Administration (FDA) has published three guidance documents on the proposed criterion and statistical methodology for the individual bioequivalence approach. From a scientific stand-point, the individual bioequivalence criterion appears to offer several advantages for some drug products compared with the average criterion. It allows comparison of intraindividual variances, scaling the bioequivalence criterion to the reference variability and detection of an important subject-by-formulation interaction if it exists. Based on these considerations, the FDA has recently recommended replicate study designs for modified release dosage forms and highly variable drug products. The new criterion also promotes inclusion of a heterogeneous population of volunteers in bioequivalence studies.

Despite all the advantages of the individual bioequivalence approach, questions remain on the optimal use of replicate study designs and the proposed criterion for evaluation of bioequivalence between formulations. In the finalised guidance documents, therefore, the FDA maintains the average bioequivalence criterion while allowing other criteria under certain circumstances. Collection and analysis of bioequivalence data from replicate study designs may permit further assessment and resolution of these questions.

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Acknowledgements

The authors would like to acknowledge Walter Hauck, Roger Williams, Terry Hyslop, as well as the US Food and Drug Administration Population and Individual Bioequivalence Working Group for their contributions to the discussions that formed the basis for this article. The current members of this working group are Mei-Ling Chen, Rabindra Patnaik (Co-chairs), Dale Conner, Lawrence Lesko, Stella Machado and Donald Schuirmann.

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Authors and Affiliations

  1. Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland, USA

    Mei-Ling Chen

  2. Office of Clinical Pharmacology and Biopharmaceutics, Office of Pharmaceutical Science, Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland, USA

    Lawrence J. Lesko

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  1. Mei-Ling Chen
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  2. Lawrence J. Lesko
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Correspondence to Lawrence J. Lesko.

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Chen, ML., Lesko, L.J. Individual Bioequivalence Revisited. Clin Pharmacokinet 40, 701–706 (2001). https://doi.org/10.2165/00003088-200140100-00001

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