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
Open this folder and view contentsPart Three. Tests for equivalence
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
 

Appendix 3. Technical aspects of bioequivalence statistics

The pharmacokinetic characteristics to be tested, the test procedure and the norms to be maintained should be specified beforehand in the protocol. A post hoc change in the methods specified for the statistical evaluation is acceptable only if adherence to the protocol would preclude a meaningful evaluation and if such a change in procedure has been fully justified.

Concentration-dependent data such as AUC and Cmax should be log transformed before statistical analysis in order to satisfy the fundamental assumption underlying analysis of variance that effects in the model act in an additive rather than a multiplicative manner.

Acceptance ranges for main characteristics

AUC-ratio

The 90% confidence interval for this measure of relative bioavailability should lie within a bioequivalence range of 80-125%. If the therapeutic range is particularly narrow, the acceptance range may need to be reduced. A larger acceptance range may be acceptable if clinically appropriate.

Cmax-ratio

This measure of relative bioavailability is inherently more variable than, for example, the AUC-ratio, and a wider acceptance range may be appropriate. The range used should be justified, taking into account safety and efficacy considerations.

tmax-diff

Statistical evaluation of tmax, makes sense only if there is a clinically relevant claim for rapid release or action, or signs of a relation to adverse effects. The non-parametric 90% confidence interval for this measure of relative bioavailability should lie within a clinically relevant range.

 

to previous section
to next section
 
 
The WHO Essential Medicines and Health Products Information Portal was designed and is maintained by Human Info NGO. Last updated: August 29, 2014