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 are listed below.
(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, nonlinear pharmacokinetics, presystemic elimination/high first-pass metabolism >70%;
(iv) unfavourable physicochemical properties, e.g., low solubility, instability, metastable modifications, poor permeability, etc.;
(v) documented evidence for bioavailability problems related to the drug or drugs of similar chemical structure or formulations;
(vi) where a high ratio of excipients to active ingredients exists.
(b) Non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (such as transdermal patches, suppositories, etc.).
(c) Sustained or otherwise modified release pharmaceutical products designed to act by systemic absorption.
(d) Fixed combination products (see WHO Technical Report Series No. 825, 1992) with systemic action.
(e) Non-solution pharmaceutical products which are for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc. application) and are intended to act without systemic absorption. In these cases, the bioequivalence concept is not suitable 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.
In cases (a) to (d) plasma concentration measurements over time (bioequivalence) are normally sufficient proof for efficacy and safety. In case (e) the bioequivalence concept is not suitable and comparative clinical or pharmacodynamic studies are required to prove equivalence.