1. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 1 |1 | Prequalification programme: Priority essential medicines Training Workshop for evaluators from National Medicines Regulatory Authorities in the East African Community: Evaluation of quality and interchangeability of medicinal products. Dar Es Salaam United Republic of Tanzania 10 – 14 September 2007

2. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 2 |2 | Training Workshop on Evaluation of quality and interchangeability of medicinal products. Complicated issues regarding bioequivalence Presenter: Drs. J. Welink Senior pharmacokineticist Medicines Evaluation Board, NL WHO adviser E-mail: j.welink@cbg-meb.nl

3. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 3 |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. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 4 |4 | Bioequivalence – single dose minimize variability not attributable to formulations Basic design considerations: goal: compare performance 2 formulations minimize bias

5. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 5 |5 | Bioequivalence – single dose single dose, two-period, crossover Golden standard study design: Reference (comparator)/ Test (generic) healthy volunteers

6. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 6 |6 | Bioequivalence – standard situation Bioequivalence: Linear pharmacokinetics Non narrow therapeutic drug Non highly variable drugDecision based upon parent drug data Stereochemistry not an issue Decision based upon plasma concentrations

7. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 7 |7 | Bioequivalence-non linear pharmacokinetics select the strength with the largest sensitivity to detect differences in the two products Goal: compare performance 2 formulations

8. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 8 |8 | Bioequivalence-non linear pharmacokinetics Linear PK: R T RT

9. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 9 |9 | Bioequivalence-non linear pharmacokinetics AUC/Cmax increase less than dose proportional exception: solubility !

10. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 10 | Bioequivalence-non linear pharmacokinetics AUC/Cmax increase more than dose proportional

11. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 11 | Bioequivalence-narrow therapeutic drugs ‘Critical dose drugs’ –Small changes in dose may cause Serious therapeutic failure Serious adverse events –Individual dose-titration needed (TDM) Narrow Therapeutic Index Drugs

12. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 12 | Bioequivalence-narrow therapeutic drug Acceptance range for bioequivalence testing The 90%-CI should lie within the range of 0.8-1.25 AUC-ratio C max -ratio In cases of NTI drugs the acceptance range may need to be tightened (0.9 – 1.11)

13. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 13 | Bioequivalence-narrow therapeutic drug NTI drugs – Does a 90%-CI = 0.8-1.25 assure clinical interchangeability? Probably not! If the BE study is repeated 10 times then 9 times out of 10 the average ratio would fall within 0.8-1.25 It does NOT mean that all the individuals will fall within the acceptance range

14. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 14 | Bioequivalence-narrow therapeutic drug Bioequivalence in healthy volunteers does not always assure therapeutic equivalence –A high intra-individual variation in patients may lead to…  Bioinequivalence  Difference in efficacy  Need for dose-adjustments when switching Food interaction –may be an additional problem..

15. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 15 | Bioequivalence-narrow therapeutic drug BE studies in (relevant) patients –Less feasible –Ethical considerations Options: Narrowing the BE acceptance range –90%-CI = 0.9-1.11 Additional requirements (ad hoc) –Steady-State studies (serial C through ?) –Fed/fasted state

16. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 16 | Bioequivalence-narrow therapeutic drug The EU position The current BE guideline does not specifically address NTI drugs Narrowing of BE acceptance range allowed

17. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 17 | Bioequivalence-narrow therapeutic drug The Canadian position:

18. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 18 | Bioequivalence-narrow therapeutic drug Canadian guidance for NTI drugs AUC: 90%-CI within 0.9-1.12 C max : 90%-CI within 0.8-1.25 Studies in both fasted and fed state Steady-state studies on a case-by-case basis –C min : 90%-CI within 0.8-1.25

19. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 19 | Bioequivalence – highly variable drugs

20. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 20 | Bioequivalence – highly variable drugs Highly variable drugs What are HVD? HVD drugs and products How to establish BE HVD

21. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 21 | Bioequivalence – highly variable drugs What are HVD? HVD are medicinal products which show high inter occasional variability: CV > 30% Occasion 1Occasion 2 Not the ANOVA CV!

22. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 22 | Bioequivalence – highly variable drugs HVD drugs and products High Variable Drug High variability caused by intrinsic intra- indiviudual variability in the pharmacokinetic response of the active compound High Variable Product High variability caused by intra indiviudual variability in the pharmacokinetic caused by formulation effects

23. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 23 | Bioequivalence – highly variable drugs How to establish HVD Problem: Difficult to establish bioequivalence with normal acceptance criteria (90 % CI) 45% CV=15% CV=30% N=88 subjects

24. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 24 | Bioequivalence-highly variable drugs Multiple dose (steady-state) studies Increase number of subjects Replicate design to determine intra-individual variability Scaling (not considered) –proposal to scale the average BE criterion Widen goal post - 80-125 for both AUC and C max –AUC - widen/narrow acceptance limits according to clinical considerations (not HVD) –C max - same as AUC, but wider for HVD (75-133) How to establish HVD

25. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 25 | Bioequivalence – metabolite Bioequivalence based on the metabolite Parent = pro-drug Analytical difficulties –too low concentration –unstable in matrix Short elimination half-life parent drug Metabolite contributes to the activity Pharmacokinetics non-linear (parent + metab.) Reasons:

26. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 26 | Bioequivalence – metabolite FORMATION RATE-LIMITED METABOLISM (IV) (FRL) ELIMINATION RATE-LIMITED METABOLISM (IV) (ERL)

27. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 27 | Bioequivalence – metabolite Metabolite data can only be used if the Applicant presents convincing, state-of-the art arguments that measurements of the parent compound are unreliable. Further considerations (1): Cmax of the metabolite is less sensitive to differences in the rate of absorption than Cmax of the parent drug. when the rate of absorption is considered of clinical importance, bioequivalence should, if possible, be determined for Cmax of the parent compound, if necessary at a higher dose.

28. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 28 | Bioequivalence – metabolite Metabolite is more reflective of metabolite formation, distribution and elimination. Further considerations (2): Measurement inactive metabolite can be rarily justified. When using metabolite data as a substitute for parent drug concentrations, the applicant should present data supporting the view that the parent drug exposure will be reflected by metabolite exposure dose. Bioequivalence based upon confidence interval approach.

29. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 29 | Bioequivalence – metabolite TRANDOLAPRILTRANDOLAPRILAT From Lenfant et al, J Cardiovasc Pharmacol 1994, 23 Example:

30. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 30 | Bioequivalence – stereochemistry

31. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 31 | Bioequivalence-stereochemistry WHO: - enantiomers different pharmacological/ metabolic profile - systemic availability non-linear Stereoselective assay EMEA: Not, in case of - R and T contain same single enantiomer - R and T contain racemate and show linear PK FDA: - enantiomers exhibit different PD - enantiomers exhibit different PK - primary efficacy/safety resides with minor enantiomer - non-linear absorption

32. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 32 | Bioequivalence – urine data Use of urine data in BE: only in exceptional case blood/plasma concentrations too low drug eliminated unchanged in urine absorption phase not good covered

33. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 33 | Bioequivalence – urine data Use of urine data in BE: input of data….

34. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 34 | Bioequivalence-urine data i.v. input: dAe/dt: Clr: Clin. Pharm; 3th ed. - take care of sampling!!!

35. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 35 | Bioequivalence-urine data Rmax (max. Ae/dt) Ae (=Cu x V) 2 main parameters for BE TmaxRmaxAe Treatment 0.53± 1.0246 ± 71151 ± 210SD Test ±mean 0.49 ± 1.0155 ± 68190 ± 201SD Reference ±mean to 36h cumulative urinary excretion from time zero Ae(0-36h) Rmax maximal rate of urine excretion Tmaxtime of maximal urinary excretion Rmax 0-36 AetTes vsReference 107%115 Ratio of least square means 92 – 122% 124% – 061 90% CI 41%37%CVANOVA

36. Evaluation of quality and interchangeability of medicinal products - EAC/EC/WHO Training workshop / 10-14 September 2007 36 | End