Studies in healthy volunteers or patients using pharmacodynamic measurements may be used for establishing equivalence between two pharmaceutical products. These studies may become necessary if quantitative analysis of the drug and/or metabolite(s) in plasma or urine cannot be made with sufficient accuracy and sensitivity. Furthermore, pharmacodynamic studies in humans are required if measurements of drug concentrations cannot be used as surrogate endpoints for the demonstration of efficacy and safety of the particular pharmaceutical product e.g., for topical products without an intended absorption of the drug into the systemic circulation.
If pharmacodynamic studies are to be used they must be performed as rigorously as bioequivalence studies, and the principles of GCP (see WHO Guideline for GCP for Trials on Pharmaceutical Products) must be followed.
The following requirements must be recognized when planning, conducting and assessing the results of a study intended to demonstrate equivalence by means of measuring pharmacodynamic drug responses.
X The response which is measured should be a pharmacological or therapeutic effect which is relevant to the claims of efficacy and/or safety.
X The methodology must be validated for precision, accuracy, reproducibility and specificity.
X Neither the test nor the reference product should produce a maximal response in the course of the study, since it may be impossible to distinguish differences between formulations given in doses which give maximum or near-maximum effects. Investigation of dose-response relationships may be a necessary part of the design.
X The response should be measured quantitatively under double blind conditions and be recordable in an instrument-produced or instrument-recorded fashion on a repetitive basis to provide a record of the pharmacodynamic events which are substitutes for plasma concentrations. In those instances where such measurements are not possible, recordings on visual analogue scales may be used. In other instances where the data are limited to qualitative (categorized) measurements appropriate special statistical analysis will be required.
X Non-responders should be excluded from the study by prior screening. The criteria by which responders versus non-responders are identified must be stated in the protocol.
X In instances where an important placebo effect can occur, comparison between pharmaceutical products can only be made by a priori consideration of the placebo effect in the study design. This may be achieved by adding a third phase with placebo treatment in the design of the study.
X The underlying pathology and natural history of the condition must be considered in the study design. There should be knowledge of the reproducibility of base-line conditions.
X A cross-over design can be used. Where this is not appropriate a parallel group study design should be chosen.
In studies in which continuous variables could be recorded, the time course of the intensity of the drug action can be described in the same way as in a study in which plasma concentrations were measured, and parameters can be derived which describe the area under the effect-time curve, the maximum response and the time when maximum response occurred.
The statistical considerations for the assessment of the outcome of the study are in principle, the same as outlined for the bioequivalence studies. However, a correction for the potential non-linearity of the relationship between the dose and the area under the effect-time curve should be performed on the basis of the outcome of the dose-ranging study as mentioned above. However, it should be noted that the conventional acceptance range as applied for bioequivalence assessment is not appropriate (too large) in most of the cases but should be defined on a case-by-case basis and described in the protocol.