Except for the cases listed in section 8, it is recommended in these guidelines that documentation of equivalence should be requested by registration authorities for multisource pharmaceutical products. In such documentation, the product should be compared with the reference pharmaceutical product. Studies must be carried out using the formulation intended for marketing (see also Part Seven).
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.
In vitro studies
For certain drugs and dosage forms (see also section 13), equivalence may be assessed by means of in vitro dissolution testing. This may be considered acceptable for example for:
(a) drugs for which in vivo studies (see above) are not required;
(b) different strengths of a multisource formulation, when the pharmaceutical products are manufactured by the same manufacturer at the same manufacturing site, and:
- the qualitative composition of the different strengths is essentially the same;
- the ratio of active ingredients to excipients for the different strengths is essentially the same or, for low strengths, the ratio between the excipients is the same;
- an appropriate equivalence study has been performed on at least one of the strengths of the formulation (usually the highest strength unless a lower strength is chosen for reasons of safety); and
- in the case of systemic availability, pharmacokinetics have been shown to be linear over the therapeutic dose range.
Although these guidelines are concerned primarily with the registration requirements for multisource pharmaceutical products, it should be noted that in vitro dissolution testing may also be suitable for use in confirming that product quality and performance characteristics have remained unchanged following minor changes in formulation or manufacture after approval (see Part Six).