Documentation of bioequivalence

1. Documentation of bioequivalence Drs. J. Welink Workshop on WHO prequalification requirements for reproductive health medicines, Jakarta, October 2009

2. http://apps.who.int/prequal/

3. Bioequivalence Bioequivalence: Two medicinal products are bioequivalents if they are pharmaceutical equivalents or alternatives and if their bioavailabilities (rate and extent) after administration in the same molar dose are similar to such degree that their effects, with respect to both efficacy and safety, will be essential the same.

4. Bioequivalence Pharmaceutical Equivalent Products Reference Test Possible Differences Drug particle size, .. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence

5. Bioequivalence pharmaceutical equivalence method: in principle comparative pharmacokinetics (AUC, Cmax) acceptance criteria: comparative rate and extent of absorption

6. Bioequivalence Different approach for establishing equivalence Standard: in vivo BE studies in vitro methods clinical studies PD studies ONLY IN EXCEPTIONAL CASE !!

7. Bioequivalence Cmax AUC Tmax Important PK parameters Cmax: the observed maximum concentration of a drug  measure of the rate of absorption AUC: area underthe concentration-time curve  measure of the extent of absorption tmax: time at which Cmax is observed  measure of the rate of absorption

8. Bioequivalence IR formulations Golden standard study design: single dose, two-period, crossover healthy volunteers Reference (comparator)/ Test (generic) 90% CI AUC and Cmax: 80 – 125%

9. Bioequivalence IR formulations Linear pharmacokinetics Non narrow therapeutic drug Non highly variable drug Decision based upon parent drug data Decision based upon plasma concentrations Stereochemistry not an issue Bioequivalence:

10. Bioequivalence IR formulations Dose- or time dependent pharmacokinetics Specific food recommendations Active metabolites Pro-drugs Enantiomers Special cases:

11. Bioequivalence IR formulations R T Other study designs.. Multiple dose studies Parallel design Replicate design

12. BE studies for modified release formulations MR dosage forms multiple unit formulations EC formulations single unit formulations

13. BE studies for modified release formulations Modified release (MR) oral dosage forms: Requested BE studies for enteric coated formulations: single dose, two-period, crossover, fed single dose, two-period, crossover, fasting pH! 90% CI AUC and Cmax: 80 – 125% 90% CI AUC and Cmax: 80 – 125% or not statistical significant different

14. BE studies for modified release formulations Modified release (MR) oral dosage forms: Requested BE studies for controlled release formulations: multiple dose, two-period, crossover, fasting single dose, two-period, crossover, fasting single dose, two-period, crossover, fed 90% CI AUC and Cmax: 80 – 125% 90% CI AUC and Cmax: 80 – 125% 90% CI AUC and Cmax: 80 – 125%; Cmin and PTF! • - dose dumping • - FDA guidance (Food effect bioavailability and fed bioequivalence studies; CDER, December 2002) - steady state conditions - EU, not FDA

15. Bioequivalence Most submitted bioequivalence studies are: Single dose studies. Fasted conditions. depends on drug substance! Crossover design. Non replicate.

16. Special case: biowaiver Different approach for establishing equivalence Standard: in vivo BE studies in vitro methods clinical studies PD studies

17. BCS low permeability high permeability high solubility HS/HP Class I HS/LP Class III low solubility LS/LP Class IV LS/HP Class II Biowaivers based on BCS

18. BCS 4 variables: Rapid (and similar) Dissolution High Solubility Candidates for Biowaivers Therapeutic Window High Permeability

19. WHO BCS-based biowaiver Active substances selected for biowaiving by WHO TB: • Levofloxacin • Ofloxacin • Ethambutol • Isoniazid • Pyrazinamide HIV/AIDS: • Lamivudine • Stavudine • Zidovudine

20. Biowaivers normally accepted in BE Immediate release (IR) oral dosage forms: Possible BE exemptions: • aqueous solution (incl. syrups, elixirs, but no suspensions) • gases • aqueous otic or opthalmic products (containing the same actives and excipients) • nebulizer inhalation products or nasal sprays (containing the same actives and excipients)

21. Biowaivers and dose proportionality Immediate release (IR) oral dosage forms: If a product concerns several strengths (EU): • Bioequivalence proven for one strength • Same manufacturer and manufacturing process • Linear pharmacokinetics • Same qualitative composition of different strengths (WHO) • Same ratio between active substance and excipients, or same excipients in case of low concentration active substance (less than 5%) • Similar dissolution profiles (WHO)

22. Comparator Comparator Introducing the comparator: * a pharmaceutical product with which the multi-source product is intended to be interchangeable in clinical practice. * the selection of the comparator product is usually made at the national level by the drug regulatory authority.

23. Choice of the comparator:

24. Comparator prequalification project List of acceptable reference products for the prequalification project for reproductive health List of acceptable reference products for the prequalification project for reproductive health

25. Comparator prequalification project Recommended comparator products: Reproductive Health medicines Comparator products should be obtained from a well regulated market with stringent regulatory authority i.e., from countries participating in the International Conference on Harmonization (ICH) Countries officially participating in ICH are the ICH members European Union, Japan and USA; and the ICH observers Canada and Switzerland.

26. Comparator prequalification project

27. Comparator prequalification project

28. Comparator prequalification project

29. Comparator prequalification project

30. http://apps.who.int/prequal/

34. BTIF

41. End Thank you for your attention