1. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 1 Quality of Bioequivalence Studies Evaluation of Quality and Interchangeability of Medicinal Products 10 – 14 September 2007 Dar Es Salaam, Tanzania Dr. Henrike Potthast; Temporary Advisor to WHO

2. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 2 Quality of Bioequivalence Studies  e.g. acc. to Directive 2001/20/EC: “The verification of compliance with the standards of good clinical practice and the need to subject data, information and documents to inspection in order to confirm that they have been properly generated, recorded and reported are essential in order to justify the involvement of human subjects in clinical trials.” FGCP & GLP Ffinding/definition of inspection triggers

3. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 3 Quality of Bioequivalence Studies  General Requirements  BE studies as a substitute for clinical and preclinical data  Quality of the BE study is of decisive importance for approval of the product

4. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 4 Quality of Bioequivalence Studies  Environmental triggers - examples  random selection acc. to annual inspection program  information from other regulatory authorities F type of product (e.g. particular narrow therap. range) F lack of previous inspections for product/applicant/location F……  general indication for inspection

5. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 5 Quality of Bioequivalence Studies  Early phase triggers - examples  history of (serious) problems for sponsor, CRO, sites, labs F involvement of clinical site/CRO/labs in many studies F business related issues (e.g. bankruptcy, mergers) F lack of audit certificates F…..  Still general indication without direct implication of trial data

6. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 6 Quality of Bioequivalence Studies  Evaluation phase triggers - examples  protocol gives incomplete/illogical information F numerous protocol violations F unsatisfactory explanation for protocol violations F data too clean/too messy F number of missing values/drop outs/nds….  Findings due to knowledge from literature and other studies; type of generic product already known

7. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 7 Quality of Bioequivalence Studies  Evaluation phase triggers – contd.  conflicting (PK-)results as compared to known data F insufficient documentation (clinic, analytics, statistics) F missing documentation F implausibility/inconsistency of clinical or analytical data (e.g. long half-life – short wash-out – no carry-over?!) Fdoubtful statistics or change in the analysis….

8. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 8 Quality of Bioequivalence Studies  Information exchange Fevaluation of triggers positive (negative – non serious/’formal’) negative – serious  request/list of questions  e.g. EMEA inspection data base since 2004

9. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 9 Quality of Bioequivalence Studies  Evaluation/Inspection based on source data/raw data e.g. Fprint-outs of chromatograms  signed CRFs  analytic protocols Ftime schedules Flist of providers …….

10. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 10 Quality of Bioequivalence Studies Data verification & QA issues  GCP compliance statement available?  audit/monitoring reports available?  protocol valid, i.e. signed (incl. amendments)?  was the protocol followed?  genuine study subjects/volunteers?  archiving of source/raw data?  violations of the protocol justified? ….

11. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 11 Quality of Bioequivalence Studies Data verification & QA issues ctd.  excluded subjects - traceable?  consistent trial results?  final responsibility of investigators (signing)?  source of investigative products?  batch information available?  handling of investigative products?

12. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 12 Quality of Bioequivalence Studies Data verification & QA issues ctd.  validation of bioanalytical method?  timing  validation characteristics  adherence to GLP  SOPs available……  calibrated equipment?  computer systems????  archiving of bioanalytical raw data

13. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 13 Quality of Bioequivalence Studies Data verification & QA issues ctd.  statistical plan adhered to?  transfer of analytical data to statistics  main pharmacokinetic characteristics  method of determination  nd values considered?  statistical outcome and conclusions consistent?  archiving of statistical raw data

14. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 14 Quality of Bioequivalence Studies Regulatory & ethical issues  independent ethics committee?  ethical approval based on appropriate documentation?  protocol  amendments  investigators brochure; SPC  subjects information informed consent  approval of competent authority in time?  subjects from vulnerable populations?  signing of subjects available?

15. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 15 Quality of Bioequivalence Studies Regulatory & ethical issues ctd.  insurance of subjects adequate?  adequately instructed personnel?  investigators  technicians  suppliers…..  safety evaluation assured throughout the trial?  retention samples sufficient?  storage of retention samples?

16. Federal Institute for Drugs and Medical Devices The BfArM is a Federal Institute within the portfolio of the Federal Ministry of Health 16 Quality of Bioequivalence Studies THANK YOU FOR YOUR ATTENTION