1. Hanoi, 2006-19-011 WORKSHOP ON PREQUALIFICATION OF ARV: BIOEQUIVALENCE Introduction to the Discussion of Bioequivalence Study Design and Conduct Presented by Hans Kemmler Consultant to WHO Swissmedic (Swiss drug regulatory authority)

2. Hanoi, 2006-19-012 Background: First Product to Market Innovator’s Product Quality Safety and efficacy –Based on extensive clinical trials –Expensive –Time consuming

3. Hanoi, 2006-19-013 Background: Other products with same medicinal ingredient Subsequent-entry products Generic products Multisource products How do these products gain marketing authorization?

4. Hanoi, 2006-19-014 Pharmaceutical equivalence Same amount of the same active pharmaceutical ingredient –Salts, esters Same dosage form –Comparable dosage forms –e.g., tablet vs. capsule Same route of administration Is pharmaceutical equivalence enough?

5. Hanoi, 2006-19-015 Sometimes pharmaceutical equivalence is enough Aqueous solutions –Intravenous solutions –Intramuscular, subcutaneous –Oral solutions –Otic or ophthalmic solutions –Topical preparations –Solutions for nasal administration Powders for reconstitution as solution Gases

6. Hanoi, 2006-19-016 Sometimes it is not enough Pharmaceutical equivalence by itself does not necessarily imply therapeutic equivalence Therapeutic equivalence: –Pharmaceutically equivalent –Same safety and efficacy profiles after administration of same dose

7. Hanoi, 2006-19-017 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

8. Hanoi, 2006-19-018 Additional data is required Oral immediate release products with systemic action –Generally required for solid oral dosage forms Critical use Narrow therapeutic range Bioavailability problems associated with the active ingredient Problematic polymorphism, excipient interaction, or sensitivity to manufacturing processes

9. Hanoi, 2006-19-019 Additional data is required Oral modified release products with systemic action Fixed dose combination products with systemic action –When at least one component requires study Non-oral / non-parental products with systemic action Non-solution products with non-systemic action

10. Hanoi, 2006-19-0110 Marketing authorization of multisource products Extensive clinical trials to demonstrate safety and efficacy –Interchangeability? Demonstration of equivalence to reference (comparator) product –Interchangeability –Therapeutic equivalence

11. Hanoi, 2006-19-0111 Marketing authorization through equivalence Suitable methods for assessing equivalence: –Comparative pharmacokinetic studies –Comparative pharmacodynamic studies –Comparative clinical trials –Comparative in vitro tests

12. Hanoi, 2006-19-0112 Comparative Pharmacokinetic Studies In vivo measurement of active ingredient “Some” relationship between concentration and safety/efficacy Product performance is the key Comparative bioavailability

13. Hanoi, 2006-19-0113 Bioavailability The rate and extent to 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

14. Hanoi, 2006-19-0114 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

15. Hanoi, 2006-19-0115 Plasma concentration time profile C max T max AUC time concentration

16. Hanoi, 2006-19-0116 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

17. Hanoi, 2006-19-0117 Therapeutic Equivalence Therapeutic equivalence: –Pharmaceutically equivalent –Same safety and efficacy profiles after administration of same dose: bioequivalent Interchangeability

18. Hanoi, 2006-19-0118 Comparative Pharmacodynamic Studies Not recommended when: –active ingredient is absorbed into the systemic circulation – pharmacokinetic study can be conducted Local action / no systemic absorption

19. Hanoi, 2006-19-0119 Comparative Clinical Studies Pharmacokinetic profile not possible Lack of suitable pharmacodynamic endpoint Typically insensitive

20. Hanoi, 2006-19-0120 Comparative in vitro Studies May be suitable in lieu of in vivo studies under certain circumstances Requirements for waiver to be discussed Currently no “biowaiver” (waiving the requirement for a bioequivalence study) in prequalification project except for additional strength

21. Hanoi, 2006-19-0121 When are bioequivalence studies employed? Multisource product vs. Innovative product Pre-approval changes –Bridging studies Post-approval changes Additional strengths of existing product

22. Hanoi, 2006-19-0122 Bioequivalence Studies: Basic Design Considerations Minimize variability not attributable to formulations Minimize bias REMEMBER: goal is to compare performance of the two products

23. Hanoi, 2006-19-0123 “Gold Standard” Study Design Single-dose, two-period, crossover Healthy volunteers Subjects receive each formulation once Adequate washout

24. Hanoi, 2006-19-0124 Multiple-dose Studies More relevant clinically? Less sensitive to formulation differences

25. Hanoi, 2006-19-0125 Multiple-dose Studies may be employed when: Drug is too potent/toxic for administration in healthy volunteers –Patients / no interruption of therapy Extended/modified release products –Accumulation using recommended dosing interval –In addition to single-dose studies

26. Hanoi, 2006-19-0126 Multiple-dose Studies may be employed when: Non-linear pharmacokinetics at steady-state (e.g., saturable metabolism) Assay not sufficiently sensitive for single-dose study

27. Hanoi, 2006-19-0127 Crossover vs. Parallel Designs Crossover design preferred –Intra-subject comparison –Lower variability –Generally fewer subjects required Parallel design may be useful –Drug with very long half-life –Crossover design not practical

28. Hanoi, 2006-19-0128 Parallel Design Considerations Ensure adequate number of subjects Adequate sample collection –Completion of Gastrointestinal transit / absorption process –72 hours normally sufficient

29. Hanoi, 2006-19-0129 Fasted vs. Fed Designs Fasted study design preferred –Minimize variability not attributable to formulation –Better able to detect formulation differences

30. Hanoi, 2006-19-0130 Fed Study Designs may be employed when: Significant gastrointestinal (GI) disturbance caused by fasted administration Product labeling restricts administration to fed state

31. Hanoi, 2006-19-0131 Fed Study Design Considerations Fed conditions depend on local diet and customs Dependent on reason for fed design –Avoiding GI disturbance Minimal meal to minimize impact –Required due to drug substance / dosage form Modified-release products

32. Hanoi, 2006-19-0132 Fed Study Design Considerations cont. –Required due to drug substance / dosage form Complicated pharmacokinetics Known effect of food on drug substance Fed conditions designed to promote maximal perturbation –High fat –High Calorie –Warm

33. Hanoi, 2006-19-0133 Replicate vs. non-replicate designs Standard approach –Non-replicated –Single administration of each product –Average bioequivalence

34. Hanoi, 2006-19-0134 Replicate Designs Typically four-period design –Each product administered twice Intra-subject variability Subject X formulation interaction Different approaches possible –Average bioequivalence –Individual bioequivalence

35. Hanoi, 2006-19-0135 Replicate Designs Advantages –More information available –Different approaches to assessment possible Disadvantages –Bigger commitment for volunteers –More administrations to healthy volunteers –More expensive to conduct

36. Hanoi, 2006-19-0136 Helpful Guidelines FDA - Guidance for Industry: “Bioavailability and Bioequivalence Studies for Orally Administered Drug Products – General Considerations” (Oct. 2000) Canadian Guidance for Industry: “Conduct and Analysis of Bioavailability and Bioequivalence Studies – Part A: Oral Dosage Formulations used for systemic effects.” (1992) EU “ Note for Guidance on the Investigation of Bioavailability and Bioequivalence ” –CPMP/EWP/QWP/1401/98 and related guidances and documents (www.emea.eu.int/pdfs/human/ewp ) Many other related guidances, consider current scientific discussion

37. Hanoi, 2006-19-0137 Discussion Questions Comments Opinions