Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System.

1. Multisource (generic) products and Interchangeability Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Hotel Bratislava 1 Malyshko Street Kyiv, Ukraine Date: 25 to 27 June 2007

2. Multisource (generic) products and Interchangeability Options for Establishing Bioequivalence according to New WHO Guidance Presenter: Vinod P. Shah, Ph. D. FIP Scientific Secretary North Potomac, MD 20878, USA E-mail: dr.vpshah@comcast.net

3. Regulatory Authority Mission “Assure that SAFE and EFFECTIVE drugs are marketed in the country and are available to the people” VPShah-Ukraine-07

4. Bioavailability and Bioequivalence • BA and BE are generally required for approvals of comparator and multisource drug products. • BE based on blood level determination of Cmax and AUC has become the most commonly used and successful biomarker for safety and efficacy of the drug product. • BE products can be substituted for each other without any adjustment in dose or other additional therapeutic monitoring. VPShah-Ukraine-07

5. Outline • Definitions • Documentation of Bioequivalence • Study design • Biowaiver • Conclusion VPShah-Ukraine-07

6. Bioequivalence Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailabilities, in terms of peak (Cmax and Tmax) and total exposure (area under the curve (AUC)) after administration of the same molar dose under the same conditions, are similar as to such a degree that their effects can be expected to be essentially the same. Ref: WHO Technical report series, No. 937, 2006. Annex 7. VPShah-Ukraine-07

7. Bioequivalence • What is Bioequivalence? • Comparison of two products with respect to rate and extent of drug availability. • Why do Bioequivalence? • For product approval and to use as a substitute for brand name product (interchangeability) • When do you do Bioequivalence? • To establish BE between clinical batch and to-be-marketed batch • To compare BA between the comparator and multisource products VPShah-Ukraine-07

8. Multisource Pharmaceutical Product • Therapeutic equivalence of a multisource product can be assured when the multisource product is both pharmaceutically equivalent / alternative and bioequivalent. • Concept of interchangeability includes the equivalence of the dosage form as well as for the indications and instructions for use. TE = PE + BE VPShah-Ukraine-07

9. Biowaiver The term biowaiver is applied to a regulatory drug approval process when the dossier (application) is approved based on evidence of equivalence other than through in vivo equivalence testing. VPShah-Ukraine-07

10. Equivalence Test A test that determines the equivalence between the multisource product and the comparator product using in vivo and/or in vitro approaches. VPShah-Ukraine-07

11. Pharmaceutical Equivalence • Products are pharmaceutically equivalent if they contain - the same molar amount of the same API, - the same dosage form, - if they meet comparable standards, and - are intended to be administered by the same route. • Pharmaceutical equivalent does not necessarily imply therapeutic equivalence, as differences in the excipients and/or the manufacturing process and some other variables can lead to differences in product performance. VPShah-Ukraine-07

12. Approaches to Determine Bioequivalence • Comparative pharmacokinetic studies in humans - API and/or its metabolite measurement in biological fluid such as blood, plasma, serum or urine to obtain PK measures such as AUC and Cmax. • Comparative PD studies in humans • Comparative clinical trials and • Comparative in vitro tests VPShah-Ukraine-07

13. When Equivalence Studies are Not Necessary • Parenteral preparations – aqueous solutions • Solutions for oral use • Powders for reconstitution as a solution • Gases • Otic or ophthalmic products prepared as aqueous solutions • Topical products prepared as solutions • Aqueous solutions for nebulizer inhalation or nasal sprays VPShah-Ukraine-07

14. When Equivalence Studies are Necessary • Oral Immediate Release products • Critical use medicines • Narrow therapeutic range drug products • Documented BA or BE problems related to API • Scientific evidence suggesting polymorphs of API, excipients, and/or process affecting BA • Non-oral, non-parenteral products designed to act systemically • Oral Modified Release products • Fixed-combination products with systemic absorption where at least one of the API requires an in vivo study VPShah-Ukraine-07

15. In Vivo Studies • In vivo documentation of equivalence through either - Comparative Pharmacokinetic study - Comparative Pharmacodynamic study - Comparative Clinical trial • In vivo documentation of equivalence is needed when there is a risk that possible differences in bioavailability may result in therapeutic inequivalence. VPShah-Ukraine-07

16. Choice of Comparator Product • Nationally authorized innovator • WHO Comparator product • ICH et al. innovator product • Well selected comparator product VPShah-Ukraine-07

17. Pharmacokinetic Study - Pilot Study • Generally performed in a smaller number of subjects - To validate analytical methodology - To assess variability - To optimize sample collection time intervals, • In case of modified release dosage form • To determine the lag time and • To assure that there is no dose dumping. VPShah-Ukraine-07

18. Pharmacokinetic Bioequivalence Study • Crossover study design (T and R products) in 24-36 subjects • Average BE based on 2 products, 2 period, 2 sequence • Study protocol with adequate washout period, 12 to 18 samples (3 or more terminal half lives) • Sample analysis (Bioanalytical method validation) • PK analysis – Cmax and AUC • Log transformed AUC and Cmax data analyzed by ANOVA • 90% Confidence Interval on geometric mean ratio of T and R product, must be within BE limits of 80-125% VPShah-Ukraine-07

19. IR and MR Products • Products marketed as • single strength • multiple strengths • Do all strengths need to be studied for BE? • BE study need to be carried out for only highest strength • Lower strength(s) can get biowaiver based on • dose proportional formulations and • dissolution profile comparison (similarity factor f2) VPShah-Ukraine-07

20. Modified Release Products Bioequelence Studies • Single dose study is considered more sensitive in assessing the drug product quality – release of the drug substance from the drug product into circulation • A multiple-dose study for MR dosage form is not generally recommended Study Requirements: • A single dose fasting study comparing highest strength of multisource and comparator (T and R) products • A single dose food-effect study comparing highest strength of multisource and comparator (T and R) products VPShah-Ukraine-07

21. Bioequivalence Study • How long should you collect blood samples in BE study? • In general for 3 or more terminal half lives • For long half life drugs for 72 hours • What should be measured in BE studies - Parent drug and/or metabolites? • In most cases parent drug only. • What should be measured in BE studies - Enantiomers or racemic mixtures? • In most BE studies racemic mixture (racemates) only. VPShah-Ukraine-07

22. Bioequivalence Study Why do they fail? • Bioinequivalent products • Not sufficient subjects/power (Highly variable drugs) • Highly variable formulations • Problems with bioanalytical method • Problem with multiple parameter measurements • Outliers VPShah-Ukraine-07

23. Pharmacodynamic Studies • PD measures are more variable than PK measures – more subjects needed • PD measures are subject to placebo effect • Response measured should be phrmacological or therapeutic effect relevant to efficacy and/or safety • Methodology must be validated for precision, accuracy, reproducibility and specificity VPShah-Ukraine-07

24. Clinical Trials • When PK or PD studies can not be performed, clinical trials has to be performed to demonstrate equivalence between multisource and comparator formulations. - Clinical trial requires large number of subjects - Methodology for establishing equivalence has not yet evolved extensively as for PK BE trials - The same statistical principles of confidence interval approach should be used (as for PK studies). VPShah-Ukraine-07

25. In Vitro Methods • BCS approach for biowaivers • Biowaivers for lower strength(s) preparations* based on dose-proportionality of formulations • Immediate release formulations • Extended release formulations – beads in a capsule • Extended release tablets • All requiring dissolution profile comparison * Requires BE study on highest strength VPShah-Ukraine-07

26. World Health Organization Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability WHO Technical Report Series, No. 937, 2006 Annex 7, Pages 347-390 VPShah-Ukraine-07

27. Thank You