FDA finalizes two guidances for industry on establishing bioequivalence
The US Food and Drug Administration (FDA) finalized two guidances on studies on 28 May to assist sponsors in establishing bioequivalence (BE) for new and generic drugs. One focuses on BE studies with pharmacokinetic (PK) endpoints, and the other on statistical methods for analyzing these studies.
“These guidances are intended to help applicants more effectively plan their BE studies and use equivalence criteria in analyzing these BE studies,” according to the FDA. “By providing clear information to applicants, these guidances will help generate savings by reducing duplicative efforts, regulatory delays, development costs, and process uncertainties for industry, as well as time spent by FDA assessing applications.”
The final guidance for industry on PK endpoints provides recommendations for applicants who intend to include BE information in abbreviated new drug applications (ANDAs), as well as in ANDA amendments and supplements. The guidance finalizes a draft version issued in August 2021 (RELATED: FDA refreshes bioequivalence guidance for generic drugs, Regulatory Focus 20 August 2021).
The guidance covers immediate-release and modified-release oral dosage forms. It is also applicable to non-orally administered drug products such as transdermal and certain rectal and nasal drug products. This guidance also covers the planning of BE studies intended to be conducted during the postapproval period for changes to a drug product approved under an ANDA.
Changes made from the draft to the final guidance include an update to align recommendations with those in the guidance for industry titled “M13A Bioequivalence for Immediate-Release Solid Oral Dosage Forms,” which was issued in October 2024, according to FDA. The final guidance also includes several clarifications regarding the study population and study design.
The update also includes revised information on in vitro dissolution testing. Additionally, the appendices related to statistical analysis for reference-scaled average BE concerning narrow therapeutic index (NTI) drugs and highly variable drugs have been removed, as this information has been integrated into the guidance for industry document titled “Statistical Approaches to Establishing Bioequivalence,” which was issued simultaneously. Furthermore, editorial changes have been made to improve clarity.
FDA finalizes guidance on statistical approaches
FDA also finalized a guidance on how to use statistical approaches in assessing in vivo or in vitro BE studies for investigational new drug applications (INDs), new drug applications (NDAs), ANDAs, and amendments and supplements to these applications. The document focuses on how to use these approaches both generally and in specific situations.
This guidance finalizes the draft guidance issued in December 2022 (RELATED: FDA updates statistical approaches for assessing bioequivalence, Regulatory Focus 2 December 2022).
This guidance offers recommendations on average BE and population BE, study design, logarithmic transformation, studies involving multiple groups, carryover effects, and outliers. It also addresses adaptive design and specific situations, such as NTI drugs and highly variable drugs. Additionally, it covers the management of missing data and intercurrent events.
The guidance states that “subjects may have missing data in the study for various reasons (e.g., subject’s refusal to continue in the study, attrition due to worsening of conditions or emergence of adverse events, subject’s failure to meet scheduled appointments for evaluation). Missing data is distinct from intercurrent events; however, both can introduce problems such as bias, misleading inference, loss of precision, and loss of power, any of which make it hard to interpret the trial outcome.”
According to an FDA notice, the changes from the draft to the final guidance include new information on estimands and intercurrent events, sample size determinations, and handling outlier data. The final guidance also provides additional details on statistical analysis for both population BE studies and modified population BE studies, which were previously included in product-specific guidelines. Furthermore, it includes more information on statistical analysis for reference-scaled average BE studies, particularly concerning NTI drugs and highly variable drugs.
FDA announcement; Guidance on pharmacokinetic studies; Notice on PK studies, Guidance on statistical approaches; Notice on statistical approaches
