1. Malaysia, 2005-02-241 EVALUTION OF DOSSIERS IN WHO- PREQUALIFICATION PROJECT MULTISOURCE TB-DRUGS Evaluation of bioavailability/bioequivalence data Based, with some changes on a presentation by Anna-Karin Hamberg Medical products agency, Sweden Presented by Hans Kemmler Consultant to WHO (Clinical Reviewer, Swissmedic, Switzerland)

2. Malaysia, 2005-02-242 Why do we need Bioequivalence studies? No clinical studies have been performed in patients with the Generic Product to support its Efficacy and Safety. With data to support similar in vivo performance (= Bioequivalence) Efficacy and Safety data can be extrapolated from the Innovator Product to the Generic Product.

3. Malaysia, 2005-02-243 Overview Definition of some important Bioequivalence [BE] terms Key issues in the WHO Manual Annex 3 “Guidelines on Requirements to Establish Interchangeability” Major Deficiencies in BE-Studies identified within the WHO Procurement, Quality and Sourcing Project: Tuberculosis Drugs

4. Malaysia, 2005-02-244 Overview Comparison of WHO requirements with other (FDA and CPMP) Bioequivalence Guidelines A Note on Choice of Reference Products Present new WHO Template for Assessment of Bioequivalence data

5. Malaysia, 2005-02-245 Bioavailability “.. the extent and the rate at which a substance or its active moiety is delivered from a pharmaceutical form and becomes available in the general circulation.” Reference: intravenous administration = 100% bioavailability

6. Malaysia, 2005-02-246 Plasma concentration time profile C max T max AUC time concentration

7. Malaysia, 2005-02-247 Important Pharmacokinetic Parameters AUC: area under the concentration-time curve  measure of the extent of bioavailability C max : the observed maximum concentration of drug  measure of both the rate of absorption and the extent of bioavailability t max : the time after administration of drug at which C max is observed  measure of the rate of absorption

8. Malaysia, 2005-02-248 Bioavailability Absolute bioavailability (F): Relative bioavailability (F rel )

9. Malaysia, 2005-02-249 Bioavailability: Same Dose Absolute bioavailability (F): Relative bioavailability (F rel )

10. Malaysia, 2005-02-2410 Pharmaceutical Equivalents contain the same amount of the same active substance in the same dosage form meet the same or comparable standards intended to be administered by the same route Pharmaceutical equivalence by itself does not necessarily imply therapeutic equivalence

11. Malaysia, 2005-02-2411 Pharmaceutical Equivalents Possible Differences Drug particle size Excipients Manufacturing Equipment or Process Site of manufacture TestReference Could lead to differences in product performance in vivo  Possible Bioinequivalence

12. Malaysia, 2005-02-2412 Bioequivalence Two products are bioequivalent if they are pharmaceutically equivalent bioavailabilities (both rate and extent) after administration in the same molar dose are similar to such a degree that their effects can be expected to be essentially the same

13. Malaysia, 2005-02-2413 Therapeutic equivalence Two products are therapeutically equivalent if pharmaceutically equivalent their effects, with respect to both efficacy and safety, will be essentially the same as derived from appropriate studies –bioequivalence studies –pharmacodynamic studies –clinical studies –in vitro studies

14. Malaysia, 2005-02-2414 Interchangeable pharmaceutical products If a product is demonstrated to be therapeutically equivalent to a reference product, then the products are considered interchangeable.

15. Malaysia, 2005-02-2415 Bioanalytical Method Validation Quantitative determinations of drugs in biological samples, such as blood or plasma, play a significant role in evaluation and interpretation of bioequivalence data.

16. Malaysia, 2005-02-2416 Bioanalytical Method Validation Essential to use a well-characterised and fully validated analytical method to yield reliable results.

17. Malaysia, 2005-02-2417 Bioanalytical Method Validation Method Validation should include –Accuracy –Precision –Sensitivity –Specificity –Recovery –Stability

18. Malaysia, 2005-02-2418 Bioanalytical Method Validation Accuracy Closeness of determined value to the true value. The acceptance criteria is mean value  15% deviation from true value. At LOQ, 20% deviation is acceptable.

19. Malaysia, 2005-02-2419 Bioanalytical Method Validation Precision The closeness of replicate determinations of a sample by an assay. The acceptance criteria is  15% CV. At LOQ, 20% deviation is acceptable.

20. Malaysia, 2005-02-2420 Bioanalytical Method Validation Sensitivity The limit of quantitation (LOQ) is the lowest concentration which can be measured with acceptable accuracy and precision.

21. Malaysia, 2005-02-2421 Bioanalytical Method Validation Specificity (selectivity) Ability of the method to measure only what it is intended to measure in the presence of other components in the sample. Blank samples of the biological matrix should be tested for interfering peaks.

22. Malaysia, 2005-02-2422 Bioanalytical Method Validation Recovery The extraction efficiency of an analytical process, reported as a percentage of the known amount of an analyte carried through the sample extraction and processing steps of the method. Recovery does not have to be 100%, but the extent of recovery of an analyte and of the internal standard should be consistent.

23. Malaysia, 2005-02-2423 Bioanalytical Method Validation Stability Stability of the drug in the biological matrix during the collection process, the sample storage period and sample analysis, should be established.

24. Malaysia, 2005-02-2424 Bioanalytical Method Validation Useful references: FDA Guidance for Industry Bioanalytical Method Validation (May 2001) (http://www.fda.gov/cder/guidance/4252fnl.pdf) Published Workshop Reports Shah, V.P. et al, Pharmaceutical Research: 1992; 9:588-592 Shah, V.P. et al, Pharmaceutical Research: 2000; 17: 1551-1557