FDA Bioequivalence Studies in US Based Bioanalytical Laboratories and Clinical Facilities

Greater than 80% of US prescriptions are for generics. Generic drugs provide similar clinical benefits as reference listed drugs (RLDs) and comply with FDA standards. They show “bioequivalence” to an RLD in pharmaceutical, therapeutic and biological, terms. This article gives recommendations to sponsors and/or applicants planning to include bioavailability (BA) and bioequivalence (BE) information for drug products in INDs and NDAs. BA and BE study approaches are designed in a way that the FDA can evaluate the safety and effectiveness of drug products. 

Both BA and BE studies in clinical research focus on the release of a drug substance from a drug product and its subsequent absorption into the systemic circulation. Demonstrating BE involves a more formal comparative analysis that uses specific references with specified criteria for comparisons and predetermined BE limits.

Preapproval changes

BE documentation can be useful during the IND period to compare (1) early and late clinical trial formulations; (2) Different formulations used in clinical trials and stability studies (3) Different clinical trial formulations and to-be-marketed drug products and (4) product strength equivalence, as appropriate. The sponsor can decide whether further in-vitro and/or in vivo studies are needed to determine the changes in components, composition, and manufacturing method.

Post-approval changes

Suppose there are significant changes in components, composition, manufacturing site, and/or method of manufacture after approval. In that case, the FDA recommends sponsors to demonstrate in vivo BE for the drug, both after and before the change in comparison to the product.

Study design

Bioequivalence analysis must usually be conducted in a crossover design, and it is necessary to consider intrasubject variability when determining the study sample size. If researchers use parallel structure, they should consider inter-subject variability.

BE considerations

A test product might fail to demonstrate bioequivalence if its rate and/or extent of absorption concerning the reference product is outside the acceptable higher or lower limits.

When sponsors do not demonstrate BE, they should confirm that the differences in rate and extent of absorption do not significantly affect the safety and efficacy based on available dose-response or concentration-response data. In the absence of this evidence, failure to demonstrate BE may suggest that the test product should be reformulated, or the method of manufacture for the test product should change, or additional safety or efficacy data may be needed for the test product.

Documentation of BE studies

Under FDA’s regulations, applicants must use the most accurate, sensitive, and reproducible method available to demonstrate BE data.

The methods include pharmacokinetic (PK) studies, in vitro tests predictive of human in vivo BA studies (in vitro-in vivo correlation), pharmacodynamic (PD) studies, studies with clinical benefit endpoints, and other in vitro studies


BE studies have allowed drug development companies to move forward and reduce the need for human studies. Due to this, patients can gain access to drugs that were not available earlier. BE studies have made generic drug availability faster, easier, and at an affordable price for patients.

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