(1996; 200 pages)
In vivo studies
For certain drugs and dosage forms, in vivo documentation of equivalence, through either a bioequivalence study, a comparative clinical pharmacodynamic study, or a comparative clinical trial, is regarded as especially important. Examples include:
(a) oral immediate-release pharmaceutical products with systemic action when one or more of the following criteria apply:
(i) indicated for serious conditions requiring assured therapeutic response;
(ii) narrow therapeutic window/safety margin; steep dose-response curve;
(iii) pharmacokinetics complicated by variable or incomplete absorption or absorption window, non-linear pharmacokinetics, presystemic elimination/high first-pass metabolism >70%;
(iv) unfavourable physicochemical properties, e.g. low solubility, instability, metastable modifications, poor permeability;
(v) documented evidence for bioavailability problems related either to the drug itself or to drugs of similar chemical structure or formulation;
(vi) high ratio of excipients to active ingredients;
(b) non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (e.g. transdermal patches, suppositories);
(c) sustained-release and other types of modified-release pharmaceutical products designed to act by systemic absorption;
(d) fixed combination products (4) with systemic action;
(e) non-solution pharmaceutical products for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc.) and intended to act without systemic absorption. The concept of bioequivalence is then not applicable, and comparative clinical or pharmacodynamic studies are required to prove equivalence. This does not, however, exclude the potential need for drug concentration measurements in order to assess unintended partial absorption.
For the first four types of pharmaceutical products, plasma concentration measurements over time (bioequivalence) are normally sufficient proof of efficacy and safety. For the last type, as already pointed out, the bioequivalence concept is not applicable, and comparative clinical or pharmacodynamic studies are required to prove equivalence.