1. Tanzania, 21-25 August 2006 Dr. Barbara Sterzik, BfArM, Bonn 1 Bioequivalence dossier requirements for the prequalification project WHO Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice and Bioequivalence with a Focus on Artemisinines

2. Tanzania, 21-25 August 2006 2Dr. Barbara Sterzik, BfArM, Bonn Dossier requirements general The product dossier should include information on: 1. Details of the product 1. Details of the product 2. Regulatory situation in other countries 2. Regulatory situation in other countries 3. Active pharmaceutical ingredient(s)- API 3. Active pharmaceutical ingredient(s)- API

3. Tanzania, 21-25 August 2006 3Dr. Barbara Sterzik, BfArM, Bonn Dossier requirements general (3. API continue) 3.1 Properties of the API(s) 3.2 Sites of manufacture 3.2 Sites of manufacture 3.3 Route of synthesis 3.3 Route of synthesis 3.4 Specification API described in a pharmacopoeia API not described in a pharmacopoeia API not described in a pharmacopoeia 3.5 Stability testing 3.5 Stability testing

4. Tanzania, 21-25 August 2006 4Dr. Barbara Sterzik, BfArM, Bonn Dossier requirements general 4. Finished product 4. Finished product 4.1 Formulation 4.1 Formulation 4.2 Sites of manufacture 4.2 Sites of manufacture 4.3 Manufacturing procedure 4.3 Manufacturing procedure 4.4 Specifications for excipients 4.4 Specifications for excipients 4.5 Specifications for finished product 4.5 Specifications for finished product 4.6 Container/closure system(s) and other packaging 4.6 Container/closure system(s) and other packaging

5. Tanzania, 21-25 August 2006 5Dr. Barbara Sterzik, BfArM, Bonn Dossier requirements general ( 4. Finished product continue ) 4.7 Stability testing 4.7 Stability testing 4.8 Container labeling 4.8 Container labeling 4.9 Product information 4.9 Product information 4.10 Patient information and package inserts 4.10 Patient information and package inserts 4.11 Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s) 4.11 Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s)

6. Tanzania, 21-25 August 2006 6Dr. Barbara Sterzik, BfArM, Bonn Dossier requirements general 5. Interchangeability 5.1 Bioequivalence study 5.2 Summary of pharmacology, toxicology* and efficacy of the product (expert reports) * not required anymore for artemisinines but for combinations

7. Tanzania, 21-25 August 2006 7Dr. Barbara Sterzik, BfArM, Bonn Basic guidelines In vivo Bioequivalence studies are clinical trials: in accordance with the guidelines on Good Clinical Practice Good Clinical Practice Good Manufacturing Practice Good Manufacturing Practice Good Laboratory Practice Good Laboratory Practice

8. Tanzania, 21-25 August 2006 8Dr. Barbara Sterzik, BfArM, Bonn Basic guidelines Additional guidance Additional guidance WHO TRS No. 937, 2006, Annex 9 WHO TRS No. 937, 2006, Annex 9 Guidelines for organizations performing in vivo bioequivalence studies. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Fortieth report. Geneva, World Health Organization

9. Tanzania, 21-25 August 2006 9Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence study report The Bioequivalence study report should include information on: Ethics, Investigators and administrative structure Ethics, Investigators and administrative structure Clinical phase of a study Clinical phase of a study Bioanalytical method of study Bioanalytical method of study Pharmacokinetic and statistical analysis Pharmacokinetic and statistical analysis Study protocol Study protocol

10. Tanzania, 21-25 August 2006 10Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence study report 1. Ethical principles : current version of the Declaration of Helsinki Ethic Committee (EC) should be independent Information about the EC e.g. members constitution of meetings discussions, recommendations, decisions of the EC should be documented Ethic Committee (EC) should be independent Information about the EC e.g. members constitution of meetings discussions, recommendations, decisions of the EC should be documented

11. Tanzania, 21-25 August 2006 11Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence study report All clinical trial protocols, screening consent and informed consent forms (ICFs) should be reviewed, amended and approved by the EC before the start any trial-related activities.

12. Tanzania, 21-25 August 2006 12Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence study report 2. Justification of the study design Specific aim, problems, risk, and benefit should be considered Specific aim, problems, risk, and benefit should be considered based on the knowledge of the pharmacokinetics, pharmacodynamics, therapeutics of the API. based on the knowledge of the pharmacokinetics, pharmacodynamics, therapeutics of the API. Information on the manufacturing procedure and used batch Information on the manufacturing procedure and used batch

13. Tanzania, 21-25 August 2006 13Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence study report 3. Selection of Investigators Expertise, qualifications, competence Expertise, qualifications, competence Before starting: agreement between investigator(s) and sponsor on protocol monitoring auditing SOP responsibilities (study related) Before starting: agreement between investigator(s) and sponsor on protocol monitoring auditing SOP responsibilities (study related)

14. Tanzania, 21-25 August 2006 14Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence study report Complete structure is presented: Table of Contents (see example on Cd Rom 2) Table of Contents (see example on Cd Rom 2) Bioequivalence Trial Information Form (BTIF) Bioequivalence Trial Information Form (BTIF)

15. Tanzania, 21-25 August 2006 15Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence dossier requirements particulars General study design: A two-period, single-dose, cross-over study in healthy volunteers. Alternatives Using the API at a lower strength in case of toxicity (PK should be proportional, no solubility problems) Using the API at a lower strength in case of toxicity (PK should be proportional, no solubility problems)

16. Tanzania, 21-25 August 2006 16Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence dossier requirements particulars single-dose, cross-over study in case of drugs with long elimination half-life (wash-out about 5 times terminal t 1/2, not more than 3-4 weeks) single-dose, cross-over study in case of drugs with long elimination half-life (wash-out about 5 times terminal t 1/2, not more than 3-4 weeks)or parallel design (example: amodiaquine) parallel design (example: amodiaquine)

17. Tanzania, 21-25 August 2006 17Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence dossier requirements particulars Multiple dose, cross-over study in patients in case of an too toxic and/or too potent drug without interrupting the therapy. Multiple dose, cross-over study in patients in case of an too toxic and/or too potent drug without interrupting the therapy.

18. Tanzania, 21-25 August 2006 18Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence dossier requirements particulars Fixed-dose combination products: Comparison with a) an existing combination b) separate active APIs (drug)

19. Tanzania, 21-25 August 2006 19Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence dossier requirements particulars ► Problem: no existing combination and no established therapeutic use of the individual APIs (Example: Artesunate/amodiaquine) ►Consequence: as there is no acceptable reference available, additionally clinical studies on efficacy and safety are necessary.

20. Tanzania, 21-25 August 2006 20Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence dossier requirements SPC and PIL EU – Guidelines - A guideline on Summary of Product Characteristics - Notice to applicants; Rev0, December 1999) - Guideline on the readability of the label and package leaflet of medicinal products for human use – Notice to applicants; Vol. IIA Rev3, September 1999 WHO – Guideline - SPC: according to the EU guideline http://mednet3.who.int/prequal/ http://mednet3.who.int/prequal/http://mednet3.who.int/prequal/

21. Tanzania, 21-25 August 2006 21Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence dossier requirements SPC and PIL The “generic” SPC + PIL = innovator SPC + PIL

22. Tanzania, 21-25 August 2006 22Dr. Barbara Sterzik, BfArM, Bonn Bioequivalence dossier requirements Thank you for your Thank you for your attention attention