The FDA has issued two final guidances for industry on establishing bioequivalence, aimed at helping sponsors and applicants design and analyze bioequivalence (BE) studies more efficiently for generic and other drug products submitted under abbreviated new drug applications (ANDAs), NDAs, and INDs. The documents are part of FDA’s Drug Competition Action Plan, which seeks to improve the efficiency of generic drug development, review, and approval to expand access to lower-cost medicines.
The first guidance, “Bioequivalence Studies with Pharmacokinetic Endpoints for Drugs Submitted Under an ANDA,” provides recommendations to applicants on how to meet BE requirements in the Federal Food, Drug, and Cosmetic Act and FDA regulations for ANDA submissions. It is generally applicable to orally administered dosage forms and to non-oral products where systemic exposure measures are suitable for establishing BE, such as transdermal systems and certain rectal and nasal products. It also applies to BE studies conducted postapproval for changes to an already approved ANDA product. The final guidance aligns with ICH M13A on immediate-release solid oral dosage forms, clarifies recommendations on study population and design, and updates in vitro dissolution testing information. The guidance is available at:
FDA also encourages ANDA applicants to consult product-specific guidances (PSGs) when planning BE and other studies for proposed generics. These can be found at:
The second guidance, “Statistical Approaches to Establishing Bioequivalence,” provides recommendations for sponsors and applicants using equivalence criteria in analyzing in vivo or in vitro BE studies for INDs, NDAs, ANDAs, and related amendments and supplements. It discusses statistical approaches for BE comparisons, both in general and in specific scenarios. This final version updates and replaces the February 2001 guidance and finalizes the December 2022 draft. It adds clarifying information on estimands and intercurrent events, sample size determination, and outlier data; expands discussion of population bioequivalence and modified population bioequivalence (previously covered in PSGs); and provides additional detail on reference-scaled average BE methods for narrow therapeutic index and highly variable drugs (previously in the 2021 ANDA BE draft guidance). The guidance is available at:
FDA said the two guidances are intended to help applicants more effectively plan BE studies and apply equivalence criteria in their analyses, reducing duplicative work, regulatory delays, development costs, and process uncertainty for industry, while also decreasing review burden for the agency. By supporting a more efficient generic drug review process, FDA aims to help broaden access to safe, high-quality, effective generic medicines that can lower health care costs. More information on FDA’s broader effort can be found in its Drug Competition Action Plan:
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