1. Assessment of Interchangeable Multisource Medicines Quality of BE Data Dr. Henrike Potthast (h.potthast@bfarm.de) Training workshop: Assessment of Interchangeable Multisource Medicines, Kenya, August 2009

2. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 2 |2 | Quality of Bioequivalence Studies Citation from 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.” GCP & GLP Ffinding/definition of inspection triggers

3. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 3 |3 | Quality of Bioequivalence Studies General Requirements FBE studies as a substitute for clinical and preclinical data  Quality of the BE study is of decisive importance for approval of the product

4. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 4 |4 | Quality of Bioequivalence Studies Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety and well-being of trials subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical trial data are credible.

5. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 5 |5 | Quality of Bioequivalence Studies Basic Responsibility - Sponsor An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial.

6. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 6 |6 | Quality of Bioequivalence Studies Montoring The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

7. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 7 |7 | Quality of Bioequivalence Studies Purpose The purposes of trial monitoring are to verify that: a)The rights and well-beeing of human subjects are protected. b)The reported trial data are accurate, complete, and verifiable from source documents. c)The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

8. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 8 |8 | Quality of Bioequivalence Studies Selection and Qualifications of Monitors a)Monitors should be appointed by the sponsor. b)Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitors qualification should be documented. c)Monitors should be thoroughly familiar with the investigational product(s), the protocol, written informed consent form and any other written information to be provided to subjects, the sponsoris SOPs, GCP, and the applicable regulatory requirement(s).

9. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 9 |9 | Quality of Bioequivalence Studies Monitor´s Responsibilities Acting as the main line of communication. Verifying that the investigator has adequate qualifications and resources. Verifying complete track of the investigational product(s). Verifying that the investigator follows the approved protocol and all approved amendment(s). Verifying that written informed consent was obtained before each subject´s participation in the trial.

10. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 10 | Quality of Bioequivalence Studies Monitor´s Responsibilities ctd. Ensuring that the investigator receives the current Investigator´s Brochure, all documents, and all trial supplies needed. Ensuring that the investigator and the investigator´s trial staff are adequately informed. Verifying that the investigator is enroling only eligible subjects. Reporting the subject recruitment rate. Verifying that source documents and other trial records are accurate, complete, kept up-to-date and maintained.

11. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 11 | Quality of Bioequivalence Studies Monitor´s Responsibilities ctd. Verifying that the investigator provides all the required reports. Checking the accuracy and completeness of the CRF entries. Informing the investigator of any CRF entry error, omission, or illegibility. Determining whether all adverse events (AEs) are appropriately reported. Communicating deviations from the protocol, SOPs, GCP, and the applicable regulatory requirements.

12. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 12 | Quality of Bioequivalence Studies Audit A systematic and independent examination of trial related activities and documents to determine whether the evaluated trial related activities were conducted, and the data were recorded, analyzed and accurately reported according to the protocol, sponsor´s standard operating procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).

13. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 13 | Quality of Bioequivalence Studies Audit The purpose of a sponsor´s audit, which is independent of and separate from routine monitoring or quality control functions, should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements. Done by individuals, who are independent of the clinical trials/systems.

14. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 14 | Quality of Bioequivalence Studies Reg. project-related inspections Evaluation phase – 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

15. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 15 | Quality of Bioequivalence Studies Reg. inspections… Evaluation phase – ctd. Fconflicting (PK-)results as compared to known data without any comment 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….

16. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 16 | Quality of Bioequivalence Studies Reg. inspections… Evaluation of source data/raw data e.g. Fprint-outs of chromatograms  signed CRFs  analytic protocols Ftime schedules Flist of providers …….

17. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 17 | Quality of Bioequivalence Studies Reg. 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? ….

18. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 18 | Quality of Bioequivalence Studies Reg. 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?

19. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 19 | Quality of Bioequivalence Studies Reg. 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

20. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 20 | Quality of Bioequivalence Studies Reg. 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

21. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 21 | Quality of Bioequivalence Studies Reg. 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? e.g.  signing of subjects available?

22. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 22 | Quality of Bioequivalence Studies Reg. 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?

23. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 23 | Quality of Bioequivalence Studies Example 1 (publ. data): Verapamil

24. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 24 | Quality of Bioequivalence Studies Example 2 (publ. data): Verapamil

25. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 25 | Quality of Bioequivalence Studies Example 2 (publ. data): Verapamil

26. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 26 | Quality of Bioequivalence Studies Example 3 (publ. data): Verapamil

27. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 27 | Quality of Bioequivalence Studies Example 3 (publ. data): Verapamil

28. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 28 | Quality of Bioequivalence Studies Example 4 (publ. data): Glibenclamide

29. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 29 | Quality of Bioequivalence Studies Example 4 (publ. data): Glibenclamide

30. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 30 | Quality of Bioequivalence Studies Example 5 (publ. data): Glibenclamide

31. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 31 | Quality of Bioequivalence Studies Example 5 (publ. data): Glibenclamide

32. Assessment of Interchangeable Multisource Medicines, Kenya, August 2009 32 | Quality of Bioequivalence Studies THANK YOU FOR YOUR ATTENTION