Drug Regulators, EMA (EMEA), Re-Publish Note for Guidance on the Investigation of Bioavailability and Bioequivalence
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To exert an optimal therapeutic action an active moiety should be delivered to its site of action in an effective concentration for the desired period. To allow reliable prediction of the therapeutic effect the performance of the dosage form containing the active substance should be well characterised. In the past, several therapeutic misadventures related to differences in bioavailability (e.g. digoxin, phenytoin, primidone) testify to the necessity of testing the performance of dosage forms in delivering the active substance to the systemic circulation and thereby to the site of action. Thus the bioavailability of an active substance from a pharmaceutical product should
be known and reproducible. This is especially the case if one product containing one certain active substance is to be used instead of its innovator product. In that case the product should show the same therapeutic effect in the clinical situation. It is generally cumbersome to assess this by clinical studies.
Comparison of therapeutic performances of two medicinal products containing the same active substance is a critical means of assessing the possibility of alternative use between the innovator and any essentially similar medicinal product. Assuming that in the same subject an essentially similar plasma concentration time course will result in essentially similar concentrations at the site of action and thus in an essentially similar effect, pharmacokinetic data instead of therapeutic results may be used to establish equivalence: bioequivalence. It is the objective of this guidance to define, for products with a systemic effect, when bioavailability or bioequivalence studies are necessary and to formulate requirements for their design, conduct, and evaluation. The possibility of using in vitro instead of in vivo studies with pharmacokinetic end points is also envisaged. This guideline should be read in conjunction with Directive 75-318/EEC, as amended, and other pertinent elements outlined in current and future EU and ICH guidelines and regulations especially those on:
• Pharmacokinetic Studies in Man
• Modified Release Oral and Transdermal Dosage Forms: Section I (Pharmacokinetic and Clinical Evaluation)
• Modified Release Oral and Transdermal Dosage Forms: Section II (Quality)
• Investigation of Chiral Active Substances.
• Fixed Combination Medicinal Products
• Clinical Requirements for Locally Applied, Locally Acting Products Containing Known Constituents.
• The Investigation of Drug Interactions
• Development Pharmaceutics
• Process Validation
• Manufacture of the Finished Dosage Form
• Validation of analytical procedures: Definitions and Terminology (ICH topic Q2A)
• Validation of analytical procedures: Methodology (ICH topic Q2B)
• Structure and Content of Clinical Study Reports (ICH topic E3)
• Good Clinical Practice: Consolidated Guideline (ICH topic E6)
• General Considerations for Clinical Trials (ICH topic E8)
• Statistical Principles for Clinical Trials (ICH topic E9)
• Choice of Control Group in Clinical Trials (ICH topic E10)
• Amendments to Commission Regulation on (EC) 542/95
• Common Technical Document (ICH topic M4)
For medicinal products not intended to be delivered into the general circulation the commonsystemic bioavailability approach cannot be applied. Under these conditions the (local) availability may be assessed, where necessary, by measurements quantitatively reflecting the presence of the active substance at the site of action using methods specially chosen for that combination of active substance and localisation (see section 5.1.8). In this case, as well as in others, alternative methods may be required such as studies using pharmacodynamic end points. Furthermore, where specific requirements for different types of products are needed, the appropriate exceptions are mentioned therein. This Note for Guidance does not explicitly apply to biological products.
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