WHO Expert Committee on Specifications for Pharmaceutical Preparations - WHO Technical Report Series, No. 863 - Thirty-fourth Report
(1996; 200 pages) View the PDF document
Table of Contents
View the document1. Introduction
Open this folder and view contents2. The international pharmacopoeia and related activities
View the document3. Simple test methodology
Open this folder and view contents4. Stability of dosage forms
Open this folder and view contents5. Good manufacturing practices for pharmaceutical products
Open this folder and view contents6. Legal and administrative aspects of the functioning of national drug regulatory authorities
Open this folder and view contents7. Quality assurance in the supply system
View the document8. Terminology
View the documentAcknowledgements
View the documentReferences
Open this folder and view contentsAnnex 1 - Guidelines for the graphic representation of chemical formulae
View the documentAnnex 2 - List of available International Chemical Reference Substances1
View the documentAnnex 3 - List of available International Infrared Reference Spectra
Open this folder and view contentsAnnex 4 - General recommendations for the preparation and use of infrared spectra in pharmaceutical analysis
Open this folder and view contentsAnnex 5 - Guidelines for stability testing of pharmaceutical products containing well established drug substances in conventional dosage forms
Open this folder and view contentsAnnex 6 - Good manufacturing practices: guidelines on the validation of manufacturing processes
Open this folder and view contentsAnnex 7 - Good manufacturing practices: supplementary guidelines for the manufacture of investigational pharmaceutical products for clinical trials in humans
Open this folder and view contentsAnnex 8 - Good manufacturing practices: supplementary guidelines for the manufacture of herbal medicinal products1
Close this folderAnnex 9 - Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability
View the documentIntroduction
View the documentGlossary
Open this folder and view contentsPart One. Regulatory assessment of interchangeable multisource pharmaceutical products
Close this folderPart Two. Equivalence studies needed for marketing authorization
View the document7. Documentation of equivalence for marketing authorization
View the document8. When equivalence studies are not necessary
Close this folder9. When equivalence studies are necessary and types of studies required
View the documentIn vivo studies
View the documentIn vitro studies
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 contentsAnnex 10 - Guidelines for implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International Commerce
Open this folder and view contentsAnnex 11 - Guidelines for the assessment of herbal medicines1,2
Open this folder and view contentsAnnex 12 - Guidelines on import procedures for pharmaceutical products
View the documentBack Cover
 
In vivo studies

For certain drugs and dosage forms, in vivo documentation of equivalence, through either a bioequivalence study, a comparative clinical pharmacodynamic study, or a comparative clinical trial, is regarded as especially important. Examples include:

(a) oral immediate-release pharmaceutical products with systemic action when one or more of the following criteria apply:


(i) indicated for serious conditions requiring assured therapeutic response;

(ii) narrow therapeutic window/safety margin; steep dose-response curve;

(iii) pharmacokinetics complicated by variable or incomplete absorption or absorption window, non-linear pharmacokinetics, presystemic elimination/high first-pass metabolism >70%;

(iv) unfavourable physicochemical properties, e.g. low solubility, instability, metastable modifications, poor permeability;

(v) documented evidence for bioavailability problems related either to the drug itself or to drugs of similar chemical structure or formulation;

(vi) high ratio of excipients to active ingredients;


(b) non-oral and non-parenteral pharmaceutical products designed to act by systemic absorption (e.g. transdermal patches, suppositories);

(c) sustained-release and other types of modified-release pharmaceutical products designed to act by systemic absorption;

(d) fixed combination products (4) with systemic action;

(e) non-solution pharmaceutical products for non-systemic use (oral, nasal, ocular, dermal, rectal, vaginal, etc.) and intended to act without systemic absorption. The concept of bioequivalence is then not applicable, and comparative clinical or pharmacodynamic studies are required to prove equivalence. This does not, however, exclude the potential need for drug concentration measurements in order to assess unintended partial absorption.


For the first four types of pharmaceutical products, plasma concentration measurements over time (bioequivalence) are normally sufficient proof of efficacy and safety. For the last type, as already pointed out, the bioequivalence concept is not applicable, and comparative clinical or pharmacodynamic studies are required to prove equivalence.

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