Bioequivalence
Bioequivalence is defined in CFR 320.1 as:
The absence of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of drug action when administered at the same molar dose under similar conditions in an appropriately designed study.
As noted in the statutory definitions, both bioequivalence (BE) and product quality BA focus on the release of a drug substance from a drug product and subsequent absorption into the systemic circulation. As a result, FDA recommends that similar approaches to measuring bioavailability BA in an NDA generally be
followed in demonstrating BE for an NDA or an ANDA. Establishing product quality BA is a benchmarking effort with comparisons to an oral solution, oral suspension, or an intravenous formulation. In contrast, demonstrating bioequivalence (BE) is usually a more formal comparative test that uses specified criteria for comparisons and predetermined bioequivalence (BE) limits for such criteria.
1. NDAs/IND
BE documentation can be useful during the IND or NDA period to establish links between (1) early and late clinical trial formulations; (2) formulations used in clinical trial and stability studies, if different; (3) clinical trial formulations and to-be-marketed drug product; and (4) other comparisons, as appropriate. In each comparison, the new formulation or new method of manufacture is the test product and the prior formulation or method of manufacture is the reference product. US FDA recommend that the determination to redocument BE during the IND period be generally left to the judgment of the sponsor, who can wish to use the principles of relevant guidances ( Postapproval Changes, and III.D, in Vitro Studies) to determine when changes in components, composition, and/or method of manufacture suggest further in vitro and/or in vivo studies be performed.
A test product can fail to meet bioequivalence (BE) limits because the test product has higher or lower measures of rate and extent of absorption compared to the reference product or because the performance of the test or reference product is more variable. In some cases, nondocumentation of bioequivalence (BE) can arise because of inadequate numbers of subjects in the study relative to the magnitude of intrasubject variability, and not because of either high or low relative bioavailability BA of the test product. Adequate design and execution of a bioequivalence (BE) study will facilitate understanding of the causes of nondocumentation of bioequivalence (BE).
Where the test product generates plasma levels that are substantially above those of the reference product, the regulatory concern is not therapeutic failure, but the adequacy of the safety database from the test product. Where the test product has levels that are substantially below those of the reference product, the regulatory concern becomes therapeutic efficacy. When the variability of the test product rises, the regulatory concern relates to both safety and efficacy, because it may suggest that the test product does not perform as well as the reference product, and the test product may be too variable to be clinically useful.
Proper mapping of individual dose-response or concentration-response curves is useful in situations where the drug product has plasma levels that are either higher or lower than the reference product and are outside usual BE limits. In the absence of individual data, population dose-response or concentration-response data acquired over a range of doses, including doses above the recommended therapeutic doses, may be sufficient to demonstrate that the increase in plasma levels would not be accompanied by additional risk. Similarly, population dose- or concentration-response relationships observed over a lower range of doses, including doses below the recommended therapeutic doses, may be able to demonstrate that reduced levels of the test product compared to the reference product are associated with adequate efficacy. In either event, the burden is on the sponsor to demonstrate the adequacy of the clinical trial dose-response or concentrationresponse data to provide evidence of therapeutic equivalence. In the absence of this evidence, failure to document bioequivalence (BE) may suggest the product should be reformulated, the method of manufacture for the test product be changed, and/or the BE study be repeated.
2. ANDAs
Bioequivalence (BE) studies are a critical component of ANDA submissions. The purpose of these studies is to demonstrate BE between a pharmaceutically equivalent generic drug product and the corresponding reference listed drug (21 CFR 314.94 (a)(7)). Together with the determination of pharmaceutical equivalence, establishing BE allows a regulatory conclusion of therapeutic equivalence.
3. Postapproval Changes
In the presence of certain major changes in components, composition, and/or method of manufacture after approval, fda requires that in vivo BE be redemonstrated. For approved NDAs, FDA also recommend that the drug product after the change be compared to the drug product before the change. For approved ANDAs, fda also recommend that the drug product after the change be compared to the reference listed drug. Under section 506A(c)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. 356a(c)(2)(B)), postapproval changes requiring completion of studies in accordance with part 320 must be submitted in a supplement and approved by FDA before distributing a drug product made with the change.
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