1. Quality of Bioequivalence Data Alfredo García - Arieta Training workshop: Training of BE assessors, Kiev, October 2009

2. 2 |2 | Annex 9 WHO Technical Report Series No. 937, 2006 The bioequivalence study provides indirect evidence of the efficacy and safety of a multisource drug product Often this will be the only evidence that the product is safe and efficacious It is therefore crucial that the bioequivalence study is performed in an appropriate manner Several guidance documents stress the importance of on-site inspections to verify compliance with standards of good clinical practice (GCP)” –Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. Geneva, World Health Organization, 1995 (WHO Technical Report Series, No. 850):97–137 –Directive 2001/20/EC of the European Parliament and the Council

3. Training workshop: Training of BE assessors, Kiev, October 2009 3 |3 | Annex 9 WHO Technical Report Series No. 937, 2006 It is vital that the CRO used by the sponsor to undertake the bioequivalence studies complies with WHO GCP and considers relevant elements from WHO good laboratory practice (GLP) and good practices for quality control laboratories to ensure integrity and traceability of data Bioequivalence studies should be performed in compliance with the general regulatory requirements and recommendations on good practices as specified in the WHO bioequivalence guidelines, good clinical practices and good laboratory practices guidelines

4. Training workshop: Training of BE assessors, Kiev, October 2009 4 |4 | Similarly, the Directive 2001/20 states “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.” –Directive 2001/20/EC of the European Parliament and the Council, “approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use”. Official Journal of the European Communities, 1 May 2001

5. Training workshop: Training of BE assessors, Kiev, October 2009 5 |5 | GCP 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.

6. Training workshop: Training of BE assessors, Kiev, October 2009 6 |6 | Sponsor An individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial When an investigator initiates and takes full responsibility for a trial, the investigator then also assumes the role of the sponsor

7. Training workshop: Training of BE assessors, Kiev, October 2009 7 |7 | Monitoring 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)

8. Training workshop: Training of BE assessors, Kiev, October 2009 8 |8 | Purpose of trial monitoring is to verify that The rights and well-being of human subjects are protected. The reported trial data are accurate, complete, and verifiable from source documents. The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with GCP, and with the applicable regulatory requirement(s).

9. Training workshop: Training of BE assessors, Kiev, October 2009 9 |9 | Monitor A person appointed by, and responsible to, the sponsor or CRO for the monitoring and reporting of progress of the trial and for verification of data.

10. Training workshop: Training of BE assessors, Kiev, October 2009 10 | Selection and Qualifications of Monitors Monitors should be appointed by the sponsor. Monitors should be appropriately trained, and should have the scientific and/or clinical knowledge needed to monitor the trial adequately A monitor’s qualification should be documented. 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 sponsor, SOPs, GCP, and the applicable regulatory requirement(s).

11. Training workshop: Training of BE assessors, Kiev, October 2009 11 | 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

12. Training workshop: Training of BE assessors, Kiev, October 2009 12 | Monitor’s Responsibilities 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 enrolling 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.

13. Training workshop: Training of BE assessors, Kiev, October 2009 13 | Monitor’s Responsibilities 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.

14. Training workshop: Training of BE assessors, Kiev, October 2009 14 | 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) It is independent of and separate from routine monitoring or quality control functions

15. Training workshop: Training of BE assessors, Kiev, October 2009 15 | Purpose of a sponsor’s audit The purpose of a sponsor's audit should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and the applicable regulatory requirements. It has to be performed by individuals, who are independent of the clinical trials / systems

16. Training workshop: Training of BE assessors, Kiev, October 2009 16 | Reasons for Regulatory Inspection Examples during the “Evaluation Phase” –Final report gives incomplete / illogical information –Insufficient documentation (clinic, analytics, statistics) –Numerous protocol violations –Unsatisfactory explanation for protocol violations –Data too clean / too messy –Number of missing values / drop-outs / discontinuations –Inconsistency with literature without any comment –Inconsistency with other studies already assessed –Implausibility / inconsistency of clinical or analytical data e.g. Drug with long half-life in a study with short wash-out and no carry-over! –Doubtful statistics or change in the analysis

17. Training workshop: Training of BE assessors, Kiev, October 2009 17 | Evaluation of source data / raw data Print-outs of chromatograms Signed “Case Report Forms” (CRFs) Analytic protocols Time schedules List of providers …

18. Training workshop: Training of BE assessors, Kiev, October 2009 18 | Data verification & QA issues GCP compliance statement available? Audit / monitoring reports available? Valid protocol, i.e. signed (incl. amendments)? Was the protocol followed? Genuine study subjects / volunteers? Archiving of source / raw data? Violations of the protocol justified? …

19. Training workshop: Training of BE assessors, Kiev, October 2009 19 | Data verification & QA issues Excluded subjects - traceable? Consistent trial results? Final responsibility of investigators (signing)? Source of investigative products? Batch information available? Handling of investigative products?

20. Training workshop: Training of BE assessors, Kiev, October 2009 20 | Data verification & QA issues Validation of bioanalytical method? –Timing –Validation characteristics –Adherence to GLP –SOPs available…… Calibrated equipment? Computer systems? Archiving of bioanalytical raw data

21. Training workshop: Training of BE assessors, Kiev, October 2009 21 | Data verification & QA issues Statistical plan adhered to? –Main pharmacokinetic characteristics –Method of determination –Transfer of analytical data to statistics –Values considered? Statistical outcome and conclusions consistent? Archiving of statistical raw data

22. Training workshop: Training of BE assessors, Kiev, October 2009 22 | 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? Signing of subjects available? Subjects from vulnerable populations?

23. Training workshop: Training of BE assessors, Kiev, October 2009 23 | Regulatory & ethical issues Safety evaluation assured throughout the trial? Insurance of subjects adequate? Adequately instructed personnel? –investigators –technicians –suppliers….. Retention samples sufficient? Storage of retention samples?

24. Training workshop: Training of BE assessors, Kiev, October 2009 24 | Quality of Bioequivalence Studies Example 1 (publ. data): Verapamil

25. Training workshop: Training of BE assessors, Kiev, October 2009 25 | Quality of Bioequivalence Studies Example 2 (publ. data): Verapamil

26. Training workshop: Training of BE assessors, Kiev, October 2009 26 | Quality of Bioequivalence Studies Example 2 (publ. data): Verapamil

27. Training workshop: Training of BE assessors, Kiev, October 2009 27 | Quality of Bioequivalence Studies Example 3 (publ. data): Verapamil

28. Training workshop: Training of BE assessors, Kiev, October 2009 28 | Quality of Bioequivalence Studies Example 3 (publ. data): Verapamil

29. Training workshop: Training of BE assessors, Kiev, October 2009 29 | Quality of Bioequivalence Studies Example 4 (publ. data): Glibenclamide

30. Training workshop: Training of BE assessors, Kiev, October 2009 30 | Quality of Bioequivalence Studies Example 4 (publ. data): Glibenclamide

31. Training workshop: Training of BE assessors, Kiev, October 2009 31 | Quality of Bioequivalence Studies Example 5 (publ. data): Glibenclamide

32. Training workshop: Training of BE assessors, Kiev, October 2009 32 | Quality of Bioequivalence Studies Example 5 (publ. data): Glibenclamide

33. Training workshop: Training of BE assessors, Kiev, October 2009 33 | Thank you very much for your attention!