FDA Draft Guidance for Industry on Statistical Approaches for Assessing Bioequivalence

Recommendation

27/28 June 2023
Heidelberg, Germany

Dissolution Testing
Development / Quality Control and in vivo Relevance

The U.S. Food and Drug Administration (FDA) has published a draft guidance for industry entitled "Statistical Approaches to Establishing Bioequivalence". When finalized, the new document will replace the previous version, which was issued in February 2001.

Background

The guidance provides recommendations to sponsors and applicants who intend to use equivalence criteria in analyzing in vivo or in vitro bioequivalence (BE) studies for

• Investigational new drugs (INDs),
• New drug applications (NDAs),
• Abbreviated new drug applications (ANDAs),
• Supplements to these applications.

The introduction states that the "guidance discusses statistical approaches for BE comparisons and focuses on how to use these approaches both generally and in specific situations."

Content

The 29-page document starts with an introduction, giving a general overview about the content of the new document and some background information on previous documents on this subject, in particular:

• Statistical Procedures for Bioequivalence Studies Using a Standard Two-Treatment Crossover Design (1992 guidance),
• Statistical Approaches to Establishing Bioequivalence (2001 guidance).

The following chapter on general considerations covers the following aspects:

• Study design;
• Data preparation;
• Statistical models.

After that, the following specific situations are described:

• In vitro bioequivalence and population bioequivalence;
• Statistical methods for narrow therapeutic index and highly variable drug products;
• Comparative clinical endpoint bioequivalence studies;
• Studies in multiple groups;
• Bioequivalence statistics for adhesion and irritation studies;
• Dose scale for bioequivalence assessment;
• Bioequivalence studies using multiple references.

The document also contains three appendices on the following aspects:

• Choice of specific replicated crossover designs;
• Rationale for logarithmic transformation of pharmacokinetic data;
• SAS program statements for average bioequivalence analysis of replicated crossover studies.

Download and Comments

The document can be downloaded on the FDA's website.

The document is being distributed for comment purposes only. Comments and suggestions regarding the new draft document should be submitted within 60 days after publication in the Federal Register (until 04 February 2023).