Implementation of a Reference-Scaled Average Bioequivalence Approach for Highly Variable Generic Drug Products by the US Food and Drug Administration

Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to en...

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Bibliographic Details
Published in:The AAPS journal 2012-12, Vol.14 (4), p.915-924
Main Authors: Davit, Barbara M., Chen, Mei-Ling, Conner, Dale P., Haidar, Sam H., Kim, Stephanie, Lee, Christina H., Lionberger, Robert A., Makhlouf, Fairouz T., Nwakama, Patrick E., Patel, Devvrat T., Schuirmann, Donald J., Yu, Lawrence X.
Format: Article
Language:English
Subjects:
Biochemistry
Biomedical and Life Sciences
Biomedicine
Biotechnology
Drug Approval - methods
Drugs, Generic - pharmacokinetics
Drugs, Generic - standards
Humans
Pharmaceutical Preparations - metabolism
Pharmaceutical Preparations - standards
Pharmacology/Toxicology
Pharmacy
Review
Review Article
Therapeutic Equivalency
United States
United States Food and Drug Administration
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Summary:Highly variable (HV) drugs are defined as those for which within-subject variability (%CV) in bioequivalence (BE) measures is 30% or greater. Because of this high variability, studies designed to show whether generic HV drugs are bioequivalent to their corresponding HV reference drugs may need to enroll large numbers of subjects even when the products have no significant mean differences. To avoid unnecessary human testing, the US Food and Drug Administration’s Office of Generic Drugs developed a reference-scaled average bioequivalence (RSABE) approach, whereby the BE acceptance limits are scaled to the variability of the reference product. For an acceptable RSABE study, an HV generic drug product must meet the scaled BE limit and a point estimate constraint. The approach has been implemented successfully. To date, the RSABE approach has supported four full approvals and one tentative approval of HV generic drug products.
ISSN:1550-7416
1550-7416
DOI:10.1208/s12248-012-9406-x