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Bioequivalence Requirements in the European Union: Critical Discussion

  • Review Article
  • Theme: Facilitating Oral Product Development and Reducing Regulatory Burden through Novel Approaches to Assess Bioavailability/B
  • Published:
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Abstract

The aim of the present paper is to summarize the revised European Union (EU) Guideline on the Investigation of Bioequivalence and to discuss critically with respect to previous European requirements and present US Food and Drug Administration guidelines its more relevant novelties such as the following: in order to facilitate the development of generic medicinal products, the EU guideline includes the eligibility for Biopharmaceutics Classification System (BCS)-based biowaivers not only for BCS class I drugs but also for class III drugs with tighter requirements for dissolution and excipient composition. The permeability criterion of BCS classification has been substituted with human absorbability, as per the Biopharmaceutical Drug Disposition Classification System. The widening of the acceptance range for C max is possible only for highly variable reference products with an additional clinical justification. This scaled widening is carried out with a proportionality constant of 0.760 which is more conservative than the FDA approach and maintains the consumer risk at a 5% level when the intra-subject CV is close to 30%, due to the smooth transition between the scaled and the constant criteria. The guideline allows for the possibility of two-stage designs to obtain the necessary information on formulation differences and variability from interim analyses as a part of the pivotal bioequivalence study, instead of undertaking pilot studies. The guideline also specifies that the statistical analyses should be performed considering all factors as fixed, which has implications in the case of replicate designs.

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Authors and Affiliations

  1. Division of Pharmacology and Clinical Evaluation, General Subdirectorate for Human Use Medicines, Spanish Agency for Medicines and Health Care Products, C/Campezo 1, Edificio 8, Planta 2 A, 28022, Madrid, Spain

    Alfredo García-Arieta

  2. Division of Biopharmaceutics Evaluation, Bureau of Pharmaceutical Sciences, Therapeutic Products Directorate, Health Canada, Ottawa, Ontario, Canada

    John Gordon

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  1. Alfredo García-Arieta
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Correspondence to Alfredo García-Arieta.

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Guest Editors: James Polli, Jack Cook, Barbara Davit, and Paul Dickinson

This manuscript represents the personal opinion of the authors and does not necessarily represent the views or policy of the Spanish Agency for Medicines and Health Care Products or Health Canada.

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García-Arieta, A., Gordon, J. Bioequivalence Requirements in the European Union: Critical Discussion. AAPS J 14, 738–748 (2012). https://doi.org/10.1208/s12248-012-9382-1

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