Why are bioavailability / bioequivalence studies necessary?

1. Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data which are submitted to regulatory authorities Why are bioavailability / bioequivalence studies necessary? An Introduction to Bioequivalence Studies Presented by: Hans Kemmler, Consultant to WHO Accra, 5.Nov. 2008

2. Background:First Product to Market • Innovator’s Product • Quality • Safety and efficacy • Based on extensive clinical trials • Expensive • Time consuming

3. Background:Other products with same medicinal ingredient • Subsequent-entry products • Generic products • Multisource products • How do these products gain marketing authorization?

4. 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. 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. 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. Pharmaceutical Equivalents Test Reference Possible Differences • Drug particle size • Excipients • Manufacturing Equipment or Process • Site of manufacture Could lead to differences in product performance in vivo

8. 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. 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. 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. Marketing authorization through equivalence • Suitable methods for assessing equivalence: • Comparative pharmacokinetic studies • Comparative pharmacodynamic studies • Comparative clinical trials • Comparative in vitro tests

12. Comparative Pharmacokinetic Studies • In vivo measurement of active ingredient • “Some” relationship between concentration and safety/efficacy • Product performance is the key • Comparative bioavailability

13. 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. Important Pharmacokinetic Parameters • AUC: area under the concentration-time curve  measure of the extent of bioavailability • Cmax: the observed maximum concentration of drug  measure of both the rate of absorption and the extent of bioavailability • tmax: the time after administration of drug at which Cmax is observed  measure of the rate of absorption

15. Plasma concentration time profile concentration Cmax AUC time Tmax

16. 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. Bioavailability • Absolute bioavailability (F): • Relative bioavailability (Frel)

18. Bioavailability: Same Dose • Absolute bioavailability (F): • Relative bioavailability (Frel)

19. Therapeutic Equivalence • Therapeutic equivalence: • Pharmaceutically equivalent • Same safety and efficacy profiles after administration of same dose: bioequivalent • Interchangeability

20. Comparative Pharmacodynamic Studies • Not recommended when: • active ingredient is absorbed into the systemic circulation • pharmacokinetic study can be conducted • Local action / no systemic absorption

21. Comparative Clinical Studies • Pharmacokinetic profile not possible • Lack of suitable pharmacodynamic endpoint • Typically insensitive

22. Comparative in vitro Studies • May be suitable in lieu of in vivo studies under certain circumstances • Requirements for waiver to be discussed

23. When are bioequivalence studies employed? • Multisource product vs. Innovative product • Pre-approval changes • Bridging studies • Post-approval changes • Additional strengths of existing product

24. Bioequivalence Studies:Basic Design Considerations • Minimize variability not attributable to formulations • Minimize bias • REMEMBER: goal is to compare performance of the two products

25. “Gold Standard” Study Design • Single-dose, two-period, crossover • Healthy volunteers • Subjects receive each formulation once • Adequate washout

26. Multiple-dose Studies • More relevant clinically? • Less sensitive to formulation differences

27. 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

28. 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

29. 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

30. Parallel Design Considerations • Ensure adequate number of subjects • Adequate sample collection • Completion of Gastrointestinal transit / absorption process • 72 hours normally sufficient

31. Fasted vs. Fed Designs • Fasted study design preferred • Minimize variability not attributable to formulation • Better able to detect formulation differences

32. Fed Study Designs may be employed when: • Significant gastrointestinal (GI) disturbance caused by fasted administration • Product labeling restricts administration to fed state

33. 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 • Complicated pharmacokinetics • Known effect of food on drug substance

34. Fed Study Design Considerations cont. • Fed conditions designed to promote maximal perturbation • High fat • High Calorie • Warm

35. Replicate vs. non-replicate designs • Standard approach • Non-replicated • Single administration of each product • Average bioequivalence

36. Replicate Designs • Typically four-period design • Each product administered twice • Intra-subject variability • Subject X formulation interaction • Different approaches possible • Average bioequivalence • Individual bioequivalence

37. 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

38. Discussion • Questions • Comments • Opinions