This USA chapter presents a comprehensive review of the foundational scientific principles and recent advances in the field of bioequivalence as it relates to regulatory assessment and approval of generic drugs. Since the initial edition of the book (Barbara M Davit and Dale P Connor. In: Bioequivalence Requirements in Various Global Jurisdictions, Chapter 2, pp. 269–305. AAPS Advances in the Pharmaceutical Sciences Series 28, Isadore Kanfer, Editor, Springer International Publishing, AG, Switzerland, 2018. ISBN 978-3-319-68077-4), new International Council for Harmonization (ICH) guidelines and revised FDA guidance have been released. Specifically, the FDA published its revised Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application (August 2021) (refers as 2021 FDA guidance thereafter). Subsequently, the ICH published its draft M13A Bioequivalence for Immediate-Release (IR) Solid Oral Dosage Forms (refers as M13A guidance thereafter) in 2023. An in-depth coverage of recent regulatory and scientific developments reflected in these updated guidelines is provided in this chapter. Notable revisions in the 2021 FDA guidance include elucidation on the reference listed drug (RLD) and reference standard (RS) in the Orange Book, expanded considerations for study populations regarding sex and age, modified recommendations for assessing formulation proportional similarity for modified-release (MR) drug products, the inclusion of sections addressing alternative routes of administration (e.g., products administered via a nasogastric tube or a gastric tube, orally disintegrating tablets, sublingual and transdermal products), appendices on reference scaled average BE analyses and handling of outliers, and the removal of sections related to orally administered locally acting drugs. The ICH M13A guidance introduces a risk-based approach for study design and meal type selection in BE study(ies) for IR drug products. Additionally, it expands recommendations for accepting multiple comparator products from different regions in a single bioequivalence (BE) trial. Among other notable updates, noteworthy additions also include a section on pH dependency for drugs with pH-dependent solubility as well as clarification on exceptional cases where exclusion of data due to non-measurable concentrations or very low concentrations is justifiable. Moreover, this chapter underscores the growing role of modeling and simulation approaches in BE assessment, showcasing their utility in complementing conventional methods for BE demonstration. In addition, the chapter highlights the adoption of a totality of evidence approach for establishing BE, particularly in the context of complex generic drug products. This approach reflects a shift towards more holistic evaluation methodologies, leveraging new technologies and scientific concepts. Ultimately, these updates collectively contribute to advancing regulatory standards and ensuring the safety and efficacy of generic drugs that are marketed in the U.S.

The United States of America

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发表日期：

2025年

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Rong Wang,
Partha Roy,
Bing V. Li

摘要

This USA chapter presents a comprehensive review of the foundational scientific principles and recent advances in the field of bioequivalence as it relates to regulatory assessment and approval of generic drugs. Since the initial edition of the book (Barbara M Davit and Dale P Connor. In: Bioequivalence Requirements in Various Global Jurisdictions, Chapter 2, pp. 269–305. AAPS Advances in the Pharmaceutical Sciences Series 28, Isadore Kanfer, Editor, Springer International Publishing, AG, Switzerland, 2018. ISBN 978-3-319-68077-4), new International Council for Harmonization (ICH) guidelines and revised FDA guidance have been released. Specifically, the FDA published its revised Guidance for Industry: Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an Abbreviated New Drug Application (August 2021) (refers as 2021 FDA guidance thereafter). Subsequently, the ICH published its draft M13A Bioequivalence for Immediate-Release (IR) Solid Oral Dosage Forms (refers as M13A guidance thereafter) in 2023. An in-depth coverage of recent regulatory and scientific developments reflected in these updated guidelines is provided in this chapter. Notable revisions in the 2021 FDA guidance include elucidation on the reference listed drug (RLD) and reference standard (RS) in the Orange Book, expanded considerations for study populations regarding sex and age, modified recommendations for assessing formulation proportional similarity for modified-release (MR) drug products, the inclusion of sections addressing alternative routes of administration (e.g., products administered via a nasogastric tube or a gastric tube, orally disintegrating tablets, sublingual and transdermal products), appendices on reference scaled average BE analyses and handling of outliers, and the removal of sections related to orally administered locally acting drugs. The ICH M13A guidance introduces a risk-based approach for study design and meal type selection in BE study(ies) for IR drug products. Additionally, it expands recommendations for accepting multiple comparator products from different regions in a single bioequivalence (BE) trial. Among other notable updates, noteworthy additions also include a section on pH dependency for drugs with pH-dependent solubility as well as clarification on exceptional cases where exclusion of data due to non-measurable concentrations or very low concentrations is justifiable. Moreover, this chapter underscores the growing role of modeling and simulation approaches in BE assessment, showcasing their utility in complementing conventional methods for BE demonstration. In addition, the chapter highlights the adoption of a totality of evidence approach for establishing BE, particularly in the context of complex generic drug products. This approach reflects a shift towards more holistic evaluation methodologies, leveraging new technologies and scientific concepts. Ultimately, these updates collectively contribute to advancing regulatory standards and ensuring the safety and efficacy of generic drugs that are marketed in the U.S.