Guidelines and Tools available

1. Guidelines and Tools available TRS 937 and BTIF (Bioequivalence Trial Information Form) Dr. Barbara Sterzik, BfArM, Bonn

2. TRS 937 Basic information including the latest scientific and technical advice in: Technical Report Series (TRS) 937, 2006 Dr. Barbara Sterzik, BfArM, Bonn

3. TRS 937 Table of Content: • General policy • Quality control (specification and tests, International reference materials, National laboratories) • Quality assurance (GMP, Inspection, Distribution, Risk analysis, Stability) Dr. Barbara Sterzik, BfArM, Bonn

4. TRS 937 (Table of Content continue ) • Prequalification • Regulatory guidance on Interchangeability • Donation of medicines • Regulatory guidance on post-approval changes • Nomenclature and computerized systems • Summary and recommendations Dr. Barbara Sterzik, BfArM, Bonn

5. TRS 937 Dr. Barbara Sterzik, BfArM, Bonn

6. TRS 937 Annex 7 (TRS 937, 2006, p. 347 ff): Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability. Dr. Barbara Sterzik, BfArM, Bonn

7. TRS 937 TRS 937 includes revisions/updates: • Guidelines on registration requirements to establish interchangeability (annex 7) • Guidance on selection of comparator pharmaceutical drugs for equivalence assessment (revision of TRS 902, Annex 11) available on the web site Dr. Barbara Sterzik, BfArM, Bonn

8. TRS 937 • Proposal to waive in vivo bioequivalence requirements for the WHO Model List of Essential Medicines, immediate release, solid oral dosage forms (annex 8) available on the website • Additional guidelines for organizations performing in vivo bioequivalence studies (annex 9) Dr. Barbara Sterzik, BfArM, Bonn

9. TRS 937 – Annex 7 Multisource (generic) pharmaceutical products: Guidelines on registration requirements to establish interchangeability: • Recommendations for sponsors on the requirements for approval a generic product • Generic products should be used only after approval Dr. Barbara Sterzik, BfArM, Bonn

10. TRS 937 – Annex 7 • Regulatory authorities should require the documentation on: GMP quality control specifications pharmaceutical product interchangeability • applicable to orally administered drugs as well as to non-orally administered drugs (where systemic exposure measure are suitable e.g. certain rectal, nasal products) Dr. Barbara Sterzik, BfArM, Bonn

11. TRS 937 – Annex 7 • No need for equivalence studies:e.g.parenterally administered product in aqueous solution (same API in same molar concentration as comparator, similar excipients)orsolution for oral use equivalent gases Dr. Barbara Sterzik, BfArM, Bonn

12. TRS 937 – Annex 7 • Bioequivalence studies in human Justification (specific aim, problems, risk) Selection of investigators Study protocol • Study design 2-period, single dose, cross-over study in healthy alternative designs in special circumstances Dr. Barbara Sterzik, BfArM, Bonn

13. TRS 937 – Annex 7 • Subjects:Number:required sample size depends on variability either known through reasonable literature or by means of a pilot study considering: drop-outs and withdrawal Selection:healthy, mainly male, 18 – 55 y, Dr. Barbara Sterzik, BfArM, Bonn

14. TRS 937 – Annex 7 • Subjects:Verifying health of volunteers ( e. g. ECG, clinical blood chemistry, blood pressure etc.)Phenotyping of volunteers (possible side effects with “poor metabolisers” may cause drop-outs; variability reduction/explanation) Dr. Barbara Sterzik, BfArM, Bonn

15. TRS 937 – Annex 7 • Test product (identical to the projected commercial product; GMP; • Comparator productnormally the innovator product (quality, efficacy & safety well-assessed) Dr. Barbara Sterzik, BfArM, Bonn

16. TRS 937 – Annex 7 No innovator available: • Nationally authorized innovators • WHO comparator product (see list TRS 902) • ICH et al. innovator Dr. Barbara Sterzik, BfArM, Bonn

17. TRS 937 – Annex 7 • Study conduct selection of dose sampling times (before dosing, at least 1-2 points before Cmax, 2 points around, 3-4 points during elimination) sample fluids pk parameter metabolites Dr. Barbara Sterzik, BfArM, Bonn

18. TRS 937 – Annex 7 • Quantification of the API (and its metabolite/s)(GLP; methods should meet the requirements of specificity, sensitivity, accuracy, precision reproducibility) • Statistical analysis (should be specified in the protocol before data collection starts) Dr. Barbara Sterzik, BfArM, Bonn

19. TRS 937 – Annex 7 • Acceptance range(90% CI for AUC-ratio; Cmax-ratio of relative bioavailability should lie within the acceptance range 0.80 – 1.25) • Reporting of results Dr. Barbara Sterzik, BfArM, Bonn

20. TRS 937 – Annex 7 In vitro Testing For certain medicines and dosage forms , in vitro documentation of equivalencemay be appropriate (typically solid oral dosage forms) Dr. Barbara Sterzik, BfArM, Bonn

21. TRS 937 – Annex 7in vitro testing Dissolution test as a surrogate equivalence test Criteria for dissolution tests are described and are not those recommended in The International Pharmacopoeia for quality control. Dr. Barbara Sterzik, BfArM, Bonn

22. TRS 937 – Annex 7in vitro testing • Criteria Biopharmaceutics Classification System (BCS) is based on aqueous solubility and intestinal permeability of the drug substance. API is classified into four classes Dr. Barbara Sterzik, BfArM, Bonn

23. TRS 937 – Annex 7in vitro testing Class 1: high solubility, high permeability Class 2: low solubility, high permeability Class 3: high solubility, low permeability Class 4: low solubility, low permeability Dr. Barbara Sterzik, BfArM, Bonn

24. BTIF Bioequivalence Trial Information Form (BTIF) filled out by the applicant Important for assessors: Reference to the study documentation (ref. to pages, sections) should be given. Dr. Barbara Sterzik, BfArM, Bonn

25. BTIF Example of the structure of BTIF is presented. (see appendix) Dr. Barbara Sterzik, BfArM, Bonn