Pharmaceutically equivalent multisource pharmaceutical products must be shown to be therapeutically equivalent to one another in order to be considered interchangeable. Several test methods are available for assessing equivalence, including:
• Comparative bioavailability (bioequivalence) studies in humans, in which the active drug substance or one or more metabolites is measured in an accessible biological fluid such as plasma, blood or urine.
• Comparative pharmacodynamic studies in humans.
• Comparative clinical trials.
• In vitro dissolution tests.
The applicability of each of these four methods is discussed in subsequent sections of these guidelines and special guidance is provided on assessing bioequivalence studies. Other methods have also been used to assess bioequivalence, e.g. bioequivalence studies in animals, but are not discussed here because they have not been accepted worldwide.
The acceptance of any test procedure in the documentation of the equivalence of two pharmaceutical products by a drug regulatory authority depends on many factors, including the characteristics of the active drug substance and the drug product, and the availability of the resources necessary for the conduct of a specific type of study. Where a drug produces meaningful concentrations in an accessible biological fluid, such as plasma, bioequivalence studies are preferred. Where a drug does not produce measurable concentrations in such a fluid, comparative clinical trials or pharmacodynamic studies may be necessary to document equivalence. In vitro testing, preferably based on a documented in vitro/in vivo correlation, may sometimes provide some indication of equivalence between two pharmaceutical products (see section 13).
Other criteria that indicate when equivalence studies are, or are not, necessary are discussed in sections 8 and 9 below.