Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System.

1. Multisource (generic) products Training Workshop on Dissolution, Pharmaceutical Product Interchangeability and Biopharmaceutical Classification System. Hotel Bratislava 1 Malyshko Street Kyiv, Ukraine Date: 25 to 27 June 2007

2. Multisource (generic) products WHO Guidelines for Registration Requirements to Establish Interchangeability Presenter: Dr Lembit Rägo Director and Coordinator, Quality Assurance and Safety: Medicines (QSM) Medicines Policy and Standards (PSM) World Health Organization Geneva, Switzerland E-mail: ragol@who.int

3. What are the problems with BE studies (I)? • BE studies in vivo – small scale clinical trials! • Lack of appropriate regulations • Lack of ethical review/ review capacity • Local industries may not have the experience and resources • Lack of regulatory capacity • Lack of financial resources • Lack of adequately trained human resources • Copying ICH GCP and other relevant documents from ICH regions alone does not solve the problems (regulations do not stand in vacuum…) • …

4. What are the problems (II)? • Complaints that no organizations that can carry out BE studies in vivo • Historically in Europe it was done by universities • CROs increasing in middle-income countries • Local CROs and branches of international CROs • Sever problems with CROs revealed by WHO inspections (in the framework of WHO prequalification programme) in some developing countries

5. WHO Definitions Related to in vivo BE Studies (I) • Contract Research organization (CRO):A scientific organization (commercial, academic or other) to which a sponsor may transfer some of its tasks and obligations. Any such transfer should be defined in writing. • Good Clinical Practice (GCP):A standard for clinical studies which encompasses the design, conduct, monitoring, termination, audit, analyses, reporting and documentation of the studies and which ensures that the studies are scientifically and ethically sound and that the clinical properties of the pharmaceutical product (diagnostic, therapeutic or prophylactic) under investigation are properly documented.

6. WHO Definitions Related to in vivo BE Studies (II) • Good Laboratory Practice (GLP)*: A quality system concerned with the organisational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported (OECD/WHO) *as applied to human bioanalysis studies

7. Handbook for Good Clinical Research Practice (GCP), World Health Organization 2005 • Structured as 14 principles, 115 pages • Serves as and adjunct to WHO's GCP from 1995, and subsequent ICH GCP • Contains CD version with all major reference documents as hyperlinks

8. Bioequivalence studies • Products to be prequalified usually multisource (generic) products • Therapeutic equivalence generally demonstrated by a bioequivalence study in CROs • Findings of deficient and discrepant bioequivalence data and non-compliance with norms and standards for GCP (WHO) and GLP (WHO GPNPCL, and OECD/WHO as appropriate)

9. What resources are available to assist proper conduct of BE studies from WHO (I)? • Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability (1) • Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms (2) • Additional guidance for organizations performing in vivo bioequivalence studies (3) • Guidance on the selection of comparator pharmaceutical products for equivalence

10. What resources are available to assist proper conduct of BE studies from WHO (II)? • Assessment of interchangeable multisource (generic) products (4) • "Note to applicants on the choice of comparator products for the prequalification project” (see WHO PQ web site - 5) • WHO Public Inspection reports of CROs (see PQ web site - 6) • Guidance for Ethics Committees (7) • WHO Training courses (see materials of previous courses on PQ web site) • … advise to manufacturers applying for prequalification

11. WHO Documents • The Expert Committee documents pass wide international consultation and are finally adopted by the Committee composed of outstanding inernational technical experts

12. WHO Technical Report Series, No. 937, 2006Annex 7 • Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. • Intended to provide recommendations to sponsors and national regulatory authorities on in vivo and vitro requirements to assure interchangeability of multisource medicinal products without compromising quality, safety and efficacy. • http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf

13. WHO Technical Report Series, No. 937, 2006, Annex 7 • Section 9: In vitro testing • Over the past three decades, dissolution testing has evolved into a powerful tool for characterizing the quality of oral pharmaceutical products. • The dissolution test … is now emerging as a surrogate equivalence test for certain categories of orally administered pharmaceutical products. • For these products (typically solid oral dosage forms containing APIs with suitable properties) a comparative in vitro dissolution profile similarity can be used to document equivalence of a multisource with a comparator product.

14. WHO Technical Report Series, No. 937, 2006Annex 7 • Section 9: In vitro testing • 9.1 In vitro testing and the Biopharmaceutical Classification System • 9.1.1 Biopharmaceutics classification system • High solubility • High permeability • 9.1.2 Determination of dissolution characteristics of multisource products in consideration of a biowaiver based on BCS • Very rapidly dissolving • Rapidly dissolving

15. WHO Technical Report Series, No. 937, 2006Annex 7 • Section 9: In vitro testing • 9.2 Qualification for a biowaiver based on BCS • 9.2.1 Dissolution criteria for biowaivers based on the BCS according to the properties of active pharmaceutical ingredients

16. 1 1.1

17. 1.2

18. Glossary

19. Glossary

20. Glossary

21. Glossary

22. Glossary

23. WHO Technical Report Series, No. 937, 2006Annex 8 • Proposal to waive in vivo bioequivalence requirements for WHO Model List of Essential Medicines immediate-release, solid oral dosage forms". • Intended to give national regulatory authorities information on orally administered APIs on WHO Model List of Essential Medicines whether biovaiwer can be granted for generic formulations. • http://www.who.int/medicines/publications/pharmprep/TRS_937.pdf

24. 2

25. 3.1

26. 3.2

27. 4

28. 5

29. 6.1

30. 6.2

31. What is WHO doing re ETHICS? 7 • Operational Guidelines for Ethics Committees that Review Biomedical Research (TDR/PRD/ETHICS/2000.1) • http://www.who.int/tdr/publications/publications/pdf/ethics.pdf • Surveying and Evaluating Ethical Review Practices: a complementary guideline to the Operational Guidelines for Ethics Committees that Review Biomedical Research (PUB: TDR/PRD/ETHICS/2002.1) • http://www.who.int/tdr/publications/publications/pdf/ethics2.pdf

32. CRO inspections - areas covered Clinical:General organization, the protocol, protection of trial subjects, responsibilities of the investigator, responsibilities of the sponsor/monitor, record-keeping and handling of data, handling and accountability for pharmaceutical products, quality assurance for the conduct of a clinical trial Bio-analytical:Apparatuses/material/reagents, SOPs, performance of the study, test and reference items, storage and retention of records and materials, quality assurance PK analysis and statistics Reporting

33. Examples of findings • Based on CRO inspections performed by WHO • Inspections study-specific • Team of 3 inspectors (2 WHO team + national inspector as observer) • Based on 6 CROs inspected

34. Findings. General organization. • Transfer of responsibilities from sponsor to CRO not documented • Unclear procedure for assigning Subject ID (two subjects assigned the same ID on the Attendance Sheet Form!) • No SOP for drug dispensing • No SOP for assigning study numbers • No trial site staff sample signature log for the study • Organization chart not readily available, no version date • No QC system to ensure accuracy and consistency in recording and document control

35. Findings. The protocol (II) • Validity of screening tests? • No CRFs designed for the study (raw data not transferred to CRFs) • Not included: • Name and address of sponsor • Description of trial site and information on investigators • Method and procedure of randomisation, randomisation schedule and how it was established • Method and timing of subject allocation to investigational groups

36. Findings. The Protocol, cont. (III) Not included: • Information to volunteers (informed consent) • Procedures for maintaining subject identification code list • Statistical justification for the number of subjects • Method for measuring blood pressure - sitting or supine? And if both, which value to use… • Type of test tubes for blood sampling • PK analysis; Method of calculating PK pararmeters, e.g. AUC, how to deal with deviations from planned sampling times • How to evaluate the results, including statistics and how to handle withdrawals

37. Responsibilities of the Sponsor/Monitor • No monitors appointed by the sponsor. No monitoring/audit reports available. • No evidence of assessment of the trial site (labs, equipment, staff, facilities) • Audits performed by the sponsor, but scheduled after the report was issued and no audits' reports available • Issues with certificate of insurance subscribed by the CRO

38. Record-keeping and handling of data • No study or protocol number on ECGs to link them to the study. • Of 95 ECGs copied by inspectors, 43 appeared to have been recorded from one subject, 21 from a second subject and 11 from a third subject (i.e. in total 75 ECGs from 3 persons!). • For several subjects the "screening" and "follow up" ECGs appeared to have been recorded from different subjects • No mention on ECG print outs of the identity of the equipment used • Some ECGs had no date of birth of subject • Doubts as to the authenticity of ECG documentation!

39. Record-keeping and handling of data (continued) • No mention of name, batch no or expiry date of the in vitro diagnostic serology test kit in source doc's or lab data • Discrepancies between Attendance Sheet Forms and CRF Screening pages (screening visit dates) • Discrepancies between Volunteer Card and CRF (smoking/alcohol) • Unclear dosing time • Identical (actual) blood sampling times for two subjects! • Recordings of actual sampling times - same handwriting, however initials of phlebotomists different at different sampling times! • Deviations from planned blood sampling times not reported • Inconsistencies in screening dates

40. Record-keeping and handling of data (continued) • Discrepancies between source documents and study report • Method/procedure of randomization not documented • No record of subjects screened • Source documents not kept • Original entry erased! • Type of tubes and anticoagulant used not documented • Errors on the CRFs • Expiry date of medications not recorded on CRFs • Appearance of tablets incorrectly described • Missing: Lab data, ECG… • Final study report not signed by the monitor • …

41. Bioanalytical. Test and reference items • Batch numbers of reference substances used not documented – were the batches used, those for which CAs were available? • Not possible to verify purity of reference substances used!

42. Reporting.(OECD GLP 2 & 9) • Some zidovudine conc's were lamivudine conc's • Discrepancy between concentration on chromatogram and in study report • Same or different stock solution for calibration/control samples? • Composition of buffer for sample preparation not in SOP • Errors in the bioanalytical report • Rounding errors

43. Conclusions • QUALITY first, only then BE has any meaning • If consistent quality can not be assured this has to be achieved first! • For many developing country manufacturers in vivo BE studies are a "bottleneck" • Need for additional guidance and training regarding BE and BSC/dissolution based biowaiver implementation