Bioequivalence studies: Regulatory Requirements on Conduct & Documentation of BE. Guidance & Experience.

1. Bioequivalence studies: Regulatory Requirements on Conduct & Documentation of BE. Guidance & Experience. Meeting on WHO Prequalification Programme on Priority Essential Medicines, WHO/EMRO 6-7 June 2007, Cairo, EGYPT Dr Lembit Rägo Coordinator Quality Assurance and Safety: Medicines (QSM) Medicines Policy and Standards(PSM) WHO Headquarters, Geneva, Switzerland ragol@who.int 1

2. History. One of the medicine's most celebrated clinical trials. Wood engraving from 1885 showing a young patient receiving an anti-rabies vaccine developed by Louis Pasteur. A physician administers the vaccine while Pasteur, a chemist, looks on.

3. What are the problems with BE studies (I)? • BE studies – 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)? • CROs increasing in middle-income developing countries • Local CROs and branches of international CROs • Recent sever problems with CROs revealed by WHO inspections (in the framework of WHO prequalification programme) in some developing countries

5. WHO Glossary • 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. • 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

6. 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

7. Bioequivalence studies • Products to be prequalified usually multisource (generic) products • Therapeutic equivalence generally demonstrated by 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)

8. 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 • 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) • WHO Training courses (see materials of previous courses on PQ web site) • … advise to manufacturers applying for prequalification

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

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19. What is WHO doing re ETHICS? • 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

20. 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

21. 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

22. 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

23. 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

24. 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

25. 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

26. 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!

27. 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

28. Record-keeping and handling of data (continued) • Deliberate attempt to change subject code • 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 • CRF (IPΦ) used was not specific to the study • 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 • …

29. 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!

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

31. What is WHO doing regarding Ethics? • 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. BSC based bio-waiver: a long way from concept to practice • 1995 FDA – SUPAC guidance • 1996 WHO – Interchangeability guideline - cautious and vague attitude • 1999 WHO – "Blue book" – cautious recognition of BCS potential, no change in reserved position • 2000 FDA – Guidance on BA and BE waiver based on BCS, deals with INDs/NDAs, ANDAs and post-approval changes • 2001 EU – Note for guidance on BA and BE – takes BCS into consideration • 2006 WHO – Interchangeability guideline and specific BCS guideline proposing the implementation of BCS approach

33. WHO Technical Report Series, No. 863, 1996 • Annex 9 • Multisource (generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability.

34. WHO Technical Report Series, No. 863, 1996 • Annex 9, Part III – Tests for equivalence • Section 13: In vitro dissolution • Comparative in vitro dissolution studies may be useful in the documentation of equivalence between two multisource pharmaceutical products. However because of the many limitations associated with the use of in vitro dissolution in the documentation of equivalence it is recommended in these guidelines that its application for this purpose should be kept to a minimum.

35. WHO Technical Report Series, No. 863, 1996 • Annex 9, Part III, Section 13: In vitro dissolution • In vitro dissolution testing … should be reserved for rapidly dissolving drug products. When the multisource test and reference products both dissolve with sufficient rapidity (e.g. >80% in 15 minutes) their in vivo equivalence may be presumed. Approval of multisource formulations by the use of comparative in vitro dissolution studies should be based on the generation of comparative dissolution profiles rather than single-point dissolution tests … Multiple dissolution test conditions and physiologically relevant media are recommended.

36. Chronology of BCS implementation • 1995 FDA – SUPAC guidance • 1996 WHO – Interchangeability guideline - cautious and vague attitude • 1999 WHO – "Blue book" – cautious recognition of BCS potential, no change in reserved position • 2000 FDA – Guidance on BA and BE waiver based on BCS, deals with INDs/NDAs, ANDAs and post-approval changes • 2001 EU – Note for guidance on BA and BE – takes BCS into consideration • 2006 WHO – Interchangeability guideline and specific BCS guideline proposing the implementation of BCS approach

37. 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

38. WHO Technical Report Series, No. 937, 2006Annex 7 • Section 9: In vitro testing • Over the past three decades, dissolution testing has evolved into a powerful tool for characterising 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.

39. 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

40. 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

41. 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

42. WHO Technical Report Series, No. 937, 2006Annex 8 WHO revisions to the criteria for BCS classification • High solubility: max 250ml at 37C over pH 1.2-6.8 • FDA - pH 1-7.5 • EMEA - pH 1-8, preferably 1, 4.6 and 6.8 • Highest strength (dose): according to Essential Medicines List (14th EML 2005) • Permeability: absorbed at least from 85% • FDA - 90% or more • EMEA – linear and complete absorption

43. WHO Technical Report Series, No. 937, 2006Annex 8 WHO extensions to the scope of application of biowaiver • Class I APIs classification criteria relaxed - both solubility and permeability • Class II weak acidic APIs eligible for biowaiver, if • soluble in 250 ml or less at pH 6.8 • rapid dissolution at pH 6.8 • similar dissolution profiles (f2) to comparator at pH 1.2, 4.5 and 6.8 • Class III APIs eligible for biowaiver, if very rapiddissolution

44. BCS according to WHO Solubility at pH 1-6.8 CLASS I Highly permeable Highly soluble (very rapid dissolution or profile comparison) Eligible CLASS II Highly permeable Poorly soluble Eligible only if the D:S at pH 6.8 is 250ml or lower* Absorbed >85% CLASS IV Poorly permeable Poorly soluble Not eligible CLASS III Poorly permeable Highly soluble Eligible if very rapidly dissolving

45. WHO Technical Report Series, No. 937, 2006Annex 8 • 3 Tables of APIs • non-complementary orally administered EML APIs • complementary EML APIs • newly /2005/ classified APIs • In case of incomplete data APIs classified conservatively ("worst case" approach) • Potential risks, indications (EML) and comments included to support risk assessment and decision making

46. WHO Technical Report Series, No. 937, 2006Annex 8

47. Conclusions • QUALITY first, only then BE • For many developing country manufacturers BE studies a "bottleneck" • Need to start implementing BSC based biowaiver in PQ Programme step-by-step • Need for additional guidance and training re BE and BSC/dissolution based biowaiver