1. WHO Prequalification Programme June 2007 Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Hotel Bratislava 1 Malyshko Street Kyiv, Ukraine Date: 25 to 27 June 2007 Multisource (generic) products and Interchangeability

2. WHO Prequalification Programme June 2007 Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. WHO guidance: Evaluation of bioequivalence (in vivo pharmacokinetic) studies Experience from prequalification (PQ) programme Presenter: Drs. J. Welink Senior pharmacokineticist Medicines Evaluation Board, NL WHO adviser E-mail: j.welink@cbg-meb.nl

3. WHO Prequalification Programme June 2007 Guidance documents

4. WHO Prequalification Programme June 2007 Guidance documents http://mednet3.who.int/prequal/ * Note to applicants on the choice of comparator products for the prequalification project * Guideline on generics - Annex 7 (Multisource (generic) pharm. products: guidelines on registration requirements to establish interchangeability) - Annex 11 (Guidance on the selection of comparator pharm. products for equivalence assessment of interchangeable multisource (generic) products)

5. WHO Prequalification Programme June 2007 Comparability Same pharmaceutical form; bioequivalence study needed

6. WHO Prequalification Programme June 2007 Comparability Different pharmaceutical form; no registration on bioequivalence only

7. WHO Prequalification Programme June 2007 Comparability Nearly identical; no bioequivalence study needed

8. WHO Prequalification Programme June 2007 Comparability Bioequivalence Bioavailability Pharmaceutical equivalent Pharmaceutical alternatives

9. WHO Prequalification Programme June 2007 Bioequivalence ReferenceTest Pharmaceutical Equivalent Products Possible Differences Drug particle size,.. Excipients Manufacturing process Equipment Site of manufacture Batch size …. Documented Bioequivalence = Therapeutic Equivalence (Note: Generally, same dissolution specifications)

10. WHO Prequalification Programme June 2007 Bioequivalence Dissolution, solubility, and intestinal permeability are the three major factors that govern the rate and extent of absorption of a drug that is stable in the GI tract TIME (hours) Fluid volume pH hydrodynamics surface tension other….

11. WHO Prequalification Programme June 2007 Bioequivalence BIOEQUIVALENCE acceptance criteria: comparative rate and extent of absorption: 90% CI for the Test/Reference for C max and AUC within 80 – 125% pharmaceutical equivalence methods: in principle comparative pharmacokinetics; in specific cases pharmacodynamic, clinical or in vitro studies IR tablets and capsules considered the same pharmaceutical form

12. WHO Prequalification Programme June 2007 Bioequivalence ref. BRIDGING STUDIES clinical batchcomm.batchchanged batch scale up variations ref.test approval innovator approval generic acceptance variations innovator generic bioequiv.batchcomm. batchchanged batch test ref.test scale upvariations acceptance variations ref.

13. WHO Prequalification Programme June 2007 Assessment Assessment of products dossiers i.e. quality, specifications, pharmaceutical development, bioequivalence etc. –teams of professionals from national drug regulatory authorities (DRA): Canada, Denmark, Finland, France, Germany, Hungary, Spain, South-Africa, Sweden, The Netherlands, Switzerland, Tanzania, Zimbabwe... –Copenhagen assessment week Up to about 15 assessors together during one week at least every two months at UNICEF in Copenhagen

14. WHO Prequalification Programme June 2007 Assessment Expression of interest (EOI): HIV/AIDS medication Antimalarial and tuberculosis medicines Reproductive health

15. WHO Prequalification Programme June 2007 Assessment HIV/AIDS medication: Nucleoside Reverse Transcriptase Inhibitors –Zidovudine, Didanosine, Lamivudine, Abacavir, Stavudine, Tenofovir, etc. Non-nucleoside Reverse Transcriptase Inhibitors –Nevirapine, Efavirenz Protease Inhibitors –Amprenavir, Saquinavir, Ritonavir, Lopinavir, Nelfinavir, Indinavir Other Anti-infective drugs: Antibacterials, Antimycotics, Antiprotozoals, other Antivirals, Anti-cancer drugs

16. WHO Prequalification Programme June 2007 Assessment 2006: appr. 280 expressions of Interest were 34 files for solutions for injection requiring no BE study 222 files for tablets/capsules/oral suspensions requiring BE study 19 submissions for oral solutions about 80 products up to now have been found acceptable …… …… …….

17. WHO Prequalification Programme June 2007 Assessment

18. WHO Prequalification Programme June 2007 Assessment

19. WHO Prequalification Programme June 2007 Assessment

20. WHO Prequalification Programme June 2007 Assessment

21. WHO Prequalification Programme June 2007 Assessment Update June 2007: approx. 3 solutions for injections 399 expressions of interest (+ 119) approx. 13 oral solutions approx. 104 tablets/capsules

22. WHO Prequalification Programme June 2007 Assessment Update June 2007: approx. 75 accepted of the additional 119 submissions approx. 24 additional data requested approx. 5 rejected 12 innovator products

23. WHO Prequalification Programme June 2007 Assessment Update June 2007: 146 accepted of the total of 399 submissions 29 additional data requested 20 rejected 175 cancelled/withdrawn all prequalified PI are from innovator companies

24. WHO Prequalification Programme June 2007 Assessment Summary of Submissions for Tuberculosis-Drugs 2-FDC (rifamp, isoniazid) Pyrazinamide Ethambutol Isoniazid 4-FDC (Rif, ison, pyraz, etham) Rifampicin 3-FDC 40 21 25 22 15 2

25. WHO Prequalification Programme June 2007 Assessment Pyrazinamide: (21 submissions, 2 prequalified, 3 rejected, 2 ongoing, 14 cancelled) For 14 products no BE study submitted For 3, BES were submitted, but major deficiencies in all aspects (reporting, reference product) Only 3 BE studies (for 4 products) acceptable -> 2e products prequalified

26. WHO Prequalification Programme June 2007 Assessment Summary of antimalarial drugs Mono –Artemether i.m. Inj. –Artemether oral –Artesunate oral 50mg –Artesunate oral 100 mg –Artesunate oral 200 mg –Artesunate rectal –Artesunate i.v. Inj. –Dihydroartemisinin oral –Amodiaquine 11 5 8 1 2 3 1 1 1 (N=34)

27. WHO Prequalification Programme June 2007 Assessment Summary of antimalarial drugs Artemisinin based combinations –Artesunate/ + Amodiaquine –Artesunate/ + Mefloquine –Artesunate + S/Pyrimethamin –Artesunate/ + Sulfamethoxypyrazin/P –Artemether/Lumefantrine –DHA/ + Piperaquine –Mono+ Combi 8 3 2 1 1 1 N=16 N=50

28. WHO Prequalification Programme June 2007 Assessment Summary of antimalarial drugs Mono+ Combi total submissions: Prequalified: Cancelled: “Active” : –(including rejected submissions with new data) All five prequalified products are “innovators” (clinical Phase III trials (controlled) done with the product itself, showing the products efficacy/safety directly; pharmacokinetic studies also present) N=50 5 19 26

29. WHO Prequalification Programme June 2007 Assessment Summary of antimalarial drugs

30. WHO Prequalification Programme June 2007 Deficiencies Overall: no bio-study submitted insufficient clinical data Test and Reference product outside the 90% confidence intervals Inadequate validation method of the bioanalysis no submission of dissolution test study design outliers GLP/GCP

31. WHO Prequalification Programme June 2007 Examples GLP/GCP:

32. WHO Prequalification Programme June 2007 Examples GLP/GCP:

33. WHO Prequalification Programme June 2007 Examples Exclusion of subjects: - number of subjects: 36 - used for statistical analysis: 35 - reason: low drug plasma levels in one subject calculated 90% CI: AUC 0-t 0.83 – 1.07 C max 0.82 – 1.04 Conclusion: Bioequivalent!

34. WHO Prequalification Programme June 2007 Examples Exclusion of subjects: - number of subjects: 36 - used for statistical analysis: 36 calculated 90% CI: AUC 0-t 0.76 – 1.03 C max 0.79 – 1.02 Conclusion: not bioequivalent!

35. WHO Prequalification Programme June 2007 Examples Study design: fed/fast

36. WHO Prequalification Programme June 2007 Examples fed/fast: Fasting: Fed:

37. WHO Prequalification Programme June 2007 Examples Blood sampling times: Adequate sampling times and period. - reliable estimation of Cmax - reliable estimation of extent of absorption (AUC) AUC 0-t / AUC inf > 80%

38. WHO Prequalification Programme June 2007 Examples Blood sampling times: Drug: literature reported t max 2 – 7 hours

39. WHO Prequalification Programme June 2007 Examples Blood sampling times:

40. WHO Prequalification Programme June 2007 Examples Analytical method: - LOQ: 10 ng/ml, sampling period 96 hours - AUC 0-t : 639 +/- 258 ng.h/ml; AUC inf : 1367 +/- 379 ng.h/ml - C max : 31 +/- 14 ng/ml

41. WHO Prequalification Programme June 2007 Examples Analytical method: Stability:

42. WHO Prequalification Programme June 2007 Examples Pharmacokinetic data:

43. WHO Prequalification Programme June 2007 Examples Statistical analysis: -Parent or metabolite? Parent normally to be used as representative for the rate of absorption. metabolite: 90% CI AUC and C max within 80 – 125% but parent..!

44. WHO Prequalification Programme June 2007 Examples Statistical analysis: - number of subjects: 24 - used for statistical analysis: 24 - non-parametric testing - reason: non normal distribution calculated 90% CI: AUC inf 0.98 – 1.23 C max 0.99 – 1.24 Conclusion: Bioequivalent!

45. WHO Prequalification Programme June 2007 Examples Statistical analysis:

46. WHO Prequalification Programme June 2007 Examples Statistical analysis: However, the presence of outliers should be explained. Without valid explanation, the following possibilities can not be discerned: - this is an effect specific for the reference capsule - this is an effect specific for the test capsule - this is an random effect, happening by chance, either in the test or reference capsule, or both.

47. WHO Prequalification Programme June 2007 Examples Statistical analysis: - number of subjects: 24 - used for statistical analysis: 24 - parametric testing !!!!!!!!!! - reason: detection of an outlier considered not acceptable calculated 90% CI: AUC 0-t 0.98 – 1.23 C max 1.01 – 1.38 Conclusion: Not bioequivalent! non parametric testing considered not acceptable!

48. WHO Prequalification Programme June 2007 End Thank you for your attention