1. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 1 WHO Training Workshop on Pharmaceutical Quality, Good Manufacturing Practice & Bioequivalence Quality of BE Studies Kiev, October 3-7, 2005 Dr. H. Potthast (h.potthast@bfarm.de)

2. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 2 Regulations  ICH-GCP guideline (CPMP/ICH/135/95)  Guide to GMP incl. Annex 13  WHO documents  EU “Note for Guidance on the Investigation of Bioavailability and Bioequivalence” CPMP/EWP/QWP/1401/98, related guidances and others

3. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 3 Legal Basis  acc. to e.g. 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.”  finding/definition of inspection triggers

4. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 4 Assessment Process  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

5. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 5 Inspection Triggers  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

6. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 6 Inspection Triggers  Early phase triggers - examples  history of (serious) problems for sponsor, CRO, sites, labs Finvolvement of clinical site/CRO/labs in many studies Fbusiness related issues (e.g. bankruptcy, mergers) F lack of audit certificates F…..  Still general indication without direct implication of trial data

7. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 7 Inspection Triggers  Evaluation phase triggers - examples  protocol gives incomplete/illogical information Fnumerous protocol violations Funsatisfactory explanation for protocol violations F data too clean/too messy Fnumber of missing values/drop outs/nds….  Findings due to knowledge from literature and other studies; type of generic product already known

8. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 8 Inspection Triggers  Evaluation phase triggers – contd.  conflicting (PK-)results as compared to known data Finsufficient documentation (clinic, analytics, statistics) Fmissing 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….

9. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 9 Inspection Triggers  Information exchange Fevaluation of triggers positive (negative – non serious/’formal’) negative – serious  request/list of questions  EMEA inspection data base since 2004

10. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 10 Inspections  Evaluation/Inspection based on source data/raw data e.g. Fprint outs of chromatograms  signed CRFs  analytic protocols Ftime schedules Flist of providers …….

11. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 11 Inspections 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?

12. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 12 Inspections 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?

13. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 13 Inspections 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

14. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 14 Inspections 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

15. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 15 Inspections 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?

16. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 16 Inspections 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?

17. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 17 Inspections FINDINGS  …  ….  …

18. Bundesinstitut für Arzneimittel und Medizinprodukte Pt WHO-consultant 18 Inspections A Matter of TRUST!