The estimations of bioavailability discussed above are based on plasma and/or urine levels of the drug and/or its biotransformation products. It is understood in these calculations that these concentrations relate in some manner to the pharmacologic or clinical response of the drug. Ideally, therefore, it is desirable to measure bioavailability as a function of pharmacologic or clinical effect. In order to do so, a specific and discriminating test is needed. Some quantitative endpoint must be available which measures the efficacy or quantitates the drug effect. For example, lowering of blood sugar by an antidiabetic agent, lowering of blood pressure by a hypotensive agent, weight loss produces by an anorexic agent, etc., would be appropriate measures. Less reliable measures, such as psychologic rating score and a physician's opinion of efficacy, cannot be of great value in these studies.
Before any comparative bioavailability testing is performed using pharmacologic or clinical response, a satisfactory dose-response curve should be obtained on one of the formulations to be included in the study. The success of the application of the dose-response curve should be established on one of the formulations to be included in the study. The success of the application of this dose-response curve depends on two factors. First, the curve should be steep, indicating that significant changes in pharmacologic response occur with a small change in the dose, and second, the dose contained in the formulations should be such that the response lies between 20% and 80% of maximum response to assure linear measurements. Responses falling beyond these ranges are more difficult to quantify.
Few studies have reported the use of dose-response curves in bioavailability measurements, but the idea is certainly attractive and relevant to drug therapy.
Studies in healthy volunteers or patients using PD 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, PD 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 PD studies are to be used they must be performed as rigorously as bioequivalence studies, and the principles of good clinical practice (GCP) (see WHO Guidelines 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 PD drug responses:
1. The response that is being measured should be a pharmacologic or therapeutic effect that is relevant to the claims of efficacy and/or safety.
2. The methodology must be validated for precision, accuracy, reproducibility, specificity, and ruggedness.
3. 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 that give maximum or near-maximum effects. Investigation of dose-response relationships may be a necessary part of the design.
4. The response should be measured quantitatively under double blind conditions and be recorded in an instrument-produced or instrument-recorded fashion on a repetitive basis to provide a record of the PD events that 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.
5. Nonresponders should be excluded from the study through prior screening. The criteria by which responders versus nonresponders are identified must be stated in the protocol.
6. 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.
7. The underlying pathology and natural history of the condition must be considered in the study design. There should be knowledge of the reproducibility of baseline conditions.
8. A crossover design may 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 nonlinearity 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.
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