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Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailabilities, in terms of rate (Cmax and tmax ) and extent of absorption (area under the curve (AUC)), after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same.

Documentation of equivalence for marketing authorization

Multisource pharmaceutical products must be shown, either directly or indirectly, to be therapeutically equivalent to the comparator product if they are to be considered interchangeable. Suitable test methods to assess equivalence are: – comparative pharmacokinetic studies in humans, in which the API and/or its metabolite(s) are measured as a function of time in an accessible biological fluid such as blood, plasma, serum or urine to obtain pharmacokinetic measures, such as AUC and Cmax that reflect the systemic exposure; – comparative pharmacodynamic studies in humans; – comparative clinical trials; – comparative in vitro tests. The applicability of each of these four methods is discussed below. Detailed information is provided on conducting an assessment of equivalence studies using pharmacokinetic measurements and in vitro methods, which are currently the methods most often used to document equivalence for most orally administered pharmaceutical products for systemic exposure. Acceptance of any test procedure in the documentation of equivalence between two pharmaceutical products by an NRA depends on many factors, including the characteristics of the API and the pharmaceutical product. Where an API produces measurable concentrations in an accessible biological fluid, such as plasma, comparative pharmacokinetic studies can be performed. This type of study is considered to be the gold standard in equivalence testing; however, where appropriate, in vitro testing, e.g. BCS based biowaivers for immediate release

pharmaceutical products, can also assure equivalence between the multisource product and the comparator product (see sections 5 and 10). Where an API does not produce measurable concentrations in an accessible biological fluid and a BCS based biowaiver is not an option, comparative pharmacodynamics studies may be an alternative method for documenting equivalence. Further, in certain cases when it is not possible to assess equivalence through other methods, comparative clinical trials may be considered appropriate. The criteria that indicate when equivalence studies are necessary are discussed in sections 4 and 5 of these guidelines.

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