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
12. Clinical trials

For certain drugs and dosage forms (see example (e), p. 72) plasma concentration time-profile data are not suitable for use in assessing equivalence between two formulations. While pharmacodynamic studies can sometimes be an appropriate tool for establishing equivalence (see section 11), in other instances this type of study cannot be performed because of a lack of meaningful and measurable pharmacodynamic parameters; a comparative clinical trial must then be performed in order to demonstrate equivalence between two formulations. In such a clinical trial, the same statistical principles will apply as in bioequivalence studies. The number of patients to be included in the study will depend on the variability of the target parameters and the acceptance range, and is usually much higher than that required in bioequivalence studies.

The methodology to be used in establishing equivalence between pharmaceutical products by means of a clinical trial in patients in which there is a therapeutic end-point has not yet been discussed as extensively as that used in bioequivalence trials. However, the following are important and need to be defined in the protocol:

(a) The target parameters; these are usually relevant clinical end-points from which the intensity and the onset, if applicable and relevant, of the response can be derived.

(b) The size of the acceptance range; this must be defined on a case-by-case basis, taking into consideration the specific clinical conditions, for example the natural course of the disease, the efficacy of available treatments and the chosen target parameter. In contrast to bioequivalence studies (where a conventional acceptance range is used), the size of the acceptance range in clinical trials cannot be based on a general consensus on all the therapeutic classes and indications.

(c) The statistical method used; this is currently the confidence interval approach, the main concern being to rule out the possibility that the test product is inferior to the reference pharmaceutical product by more than the specified amount. A one-sided confidence interval (for efficacy and/or safety) may therefore be appropriate. The confidence intervals can be derived by either parametric or non-parametric methods.

Where appropriate, a placebo leg should be included in the design, and it is sometimes appropriate to include safety end-points in the final comparative assessments.

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