Quality Assurance of Pharmaceuticals - A Compendium of Guidelines and Related Materials - Volume 1
(1997; 248 pages) [French] View the PDF document
Table of Contents
Open this folder and view contentsIntroduction
Open this folder and view contents1. National drug regulation
Close this folder2. Product assessment and registration
View the documentGuidelines for the assessment of herbal medicines1,2
Open this folder and view contentsStability of drug dosage forms1
Open this folder and view contentsGuidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms1
Close this folderMultisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability1
View the documentIntroduction
View the documentGlossary
Open this folder and view contentsPart One. Regulatory assessment of interchangeable multisource pharmaceutical products
Open this folder and view contentsPart Two. Equivalence studies needed for marketing authorization
Close this folderPart Three. Tests for equivalence
View the document10. Bioequivalence studies in humans
View the document11. Pharmacodynamic studies
View the document12. Clinical trials
View the document13. In vitro dissolution
View the documentPart Four. In vitro dissolution tests in product development and quality control
View the documentPart Five. Clinically important variations in bioavailability leading to non-approval of the product
View the documentPart Six. Studies needed to support new post-marketing manufacturing conditions
View the documentPart Seven. Choice of reference product
View the documentAuthors
View the documentReferences
View the documentAppendix 1. Examples of national requirements for in vivo equivalence studies for drugs included in the WHO Model List of Essential Drugs (Canada, Germany and the USA, December 1994)
View the documentAppendix 2. Explanation of symbols used in the design of bioequivalence studies in humans, and commonly used pharmacokinetic abbreviations
View the documentAppendix 3. Technical aspects of bioequivalence statistics
Open this folder and view contents3. Distribution
Open this folder and view contents4. The international pharmacopoeia and related activities
Open this folder and view contents5. Basic tests
Open this folder and view contents6. Laboratory services
Open this folder and view contents7. International trade in pharmaceuticals
Open this folder and view contents8. Counterfeit products
Open this folder and view contents9. Training
View the documentSelected WHO publications of related interest
View the documentBack cover
11. Pharmacodynamic studies

Pharmacodynamic measurements in healthy volunteers or patients may be used for establishing equivalence between two pharmaceutical products. This may be necessary if the drug and/or its metabolite(s) in plasma or urine cannot be determined quantitatively with sufficient accuracy and sensitivity. Furthermore, pharmacodynamic studies in humans are required if measurements of drug concentrations cannot be used as surrogate end-points for the demonstration of the efficacy and safety of the particular pharmaceutical product; this applies, for example, to topical products where it is not intended that the drug should be absorbed into the systemic circulation.

If pharmacodynamic studies are used, the conditions under which they are performed must be as rigorously controlled as those of bioequivalence studies, and the requirements of the guidelines for good clinical practice (GCP) for trials on pharmaceutical products (5) must be satisfied.

The following requirements must be taken into account in planning, conducting and assessing the results of a study intended to demonstrate equivalence by means of measurements of pharmacodynamic drug responses:

- the response measured should be a pharmacological or therapeutic effect relevant to the claims of efficacy and/or safety;

- the methodology must be validated for precision, accuracy, reproducibility and specificity;

- neither the test nor the reference product should produce a maximum response in the course of the study, since it may be impossible to distinguish differences between formulations given in doses that produce maximum or near-maximum effects; investigation of dose-response relationships may be a necessary part of the design;

- the response should be measured quantitatively under double-blind conditions and be recordable by means of a suitable instrument on a repetitive basis to provide a record of the pharmacodynamic events which are substitutes for plasma concentrations; where such measurements are not possible, recordings on visual analogue scales may be used, and where the data are limited to qualitative (categorized) measurements, appropriate special statistical analysis will be required;

- non-responders should be excluded from the study by prior screening, and the criteria whereby responders and non-responders are identified must be stated in the protocol;

- where an important placebo effect can occur, allowance for this effect should be made in the study design by including placebo treatment as a third phase in that design;

- the underlying pathology and natural history of the condition should be considered in the study design, and information on the reproducibility of baseline conditions should be available;

- where a cross-over design is not appropriate, a parallel group study design should be chosen.

In studies in which continuous variables can 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 are measured, and parameters can be derived which describe the area under the effect - time curve, the maximum response and the time when that response occurred.

The statistical methods for the assessment of the outcome of the study are, in principle, the same as those outlined for bioequivalence studies. However, a correction should be made for the potential non-linearity of the relationship between the dose and the area under the effect - time curve, based on the outcome of a dose-response study. However, it should be noted that the conventional acceptance range as applied for bioequivalence assessment is usually too large and therefore not appropriate; for this reason, it should be defined on a case-by-case basis and described in the protocol.

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