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Annex 3: *Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability
Overview
Why is bioequivalence needed? What are the ways of demonstrating bioequivalence? When are bioequivalence studies needed/not needed
or may be waived by a regulatory agency?
Design of comparative bioavailability studies Bioequivalence standards (acceptance ranges) Some statistical considerations Other issues - selection of reference product, extended-release delivery systems, stereoisomers Critical parameters to look into when evaluating dossiers with respect to bioequivalence studies Some useful reference materials
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Bioequivalence studies are not needed when the multisource product is:
a) an aqueous solution for parenteral use b) a solution for oral use c) a gas d) a powder for reconstitution as a solution for oral or parenteral use e) an otic or ophthalmic solution f) a topical aqueous solution g) an inhalation product or nasal spray as an aqueous solution
For e, f and g, formulation of multisource product must be similar to reference product. Also, bioequivalence studies may be waived for compositionally similar strengths when one strength in a range has been studied.
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Bioequivalence studies are particularly needed for pharmaceutical products for systemic action such as:
a) Oral immediate release 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) complicated pharmacokinetics iv) unfavourable physicochemical properties, e.g., low solubility v) documented evidence for bioavailability problems related to the drug vi) where a high ratio of excipients to active ingredients exists b) Non-oral and non-parenteral, such as transdermal patches, suppositories c) Modified release d) Fixed combination
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Assay validation
specificity accuracy precision sensitivity stability
must cover before- and within-study phases calibration range must be appropriate
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Other issues
Selection of a reference product -should be a product for which the safety, efficacy and quality are well established, usually the innovators product Modified-release delivery systems -greater safety concern due to possibility of dose-dumping -may be more difficult to establish equivalence Stereoisomers -multisource product must have same proportion of enantiomers in the formulation -non-stereospecific assay usually adequate in determination of bioequivalence
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Some References
WHO bioequivalence guideline:
Marketing Authorization of Pharmaceutical Products with Special Reference to Multisource (Generic) Products. A Manual for a Drug Regulatory Authority (WHO)
Assay validation:
Conference report on analytical methods validation: Bioavailability, Bioequivalence and Pharmacokinetic Studies, Pharmaceutical Research Vol.9, No.4, 1992
Statistical method:
A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability, Schuirman DJ, J Pharmacokinet Biopharm, 1987, 15:657-680.
Drug characteristics:
American Hospital Formulary Service Drug Information Physicians Desk Reference
Comprehensive text:
Generics and Bioequivalence, Ed. A.J. Jackson, CRC Press, 1994
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Conclusion
Multisource products should meet the same standards of quality, safety and efficacy as the reference products AND must be interchangeable Bioequivalence to a reference product demonstrates safety and efficacy of the multisource product and is a good indicator of interchangeability
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