1. WHO inspections of Contract Research Organizations

2. The prequalification project The prequalification project started in 2001 to assure medicinal products supplied for procurement meet WHO norms and standards (quality, safety, efficacy) (http://mednet3.who.int/prequal/) Requirements for prequalification: 1. Quality part of dossier acceptable 2. Safety/efficacy part of dossier acceptable 3. Manufacturing site (FPP, API) compliant with WHO norms and standards for GMP 4. Study compliant with norms and standards for GCP (WHO) and GLP (GPNPCL, and OECD as appropriate)http://mednet3.who.int/prequal/

3. 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) *as applied to human bioanalysis studies WHO Glossary

4. 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 as appropriate)

5. Reference documents... Guidelines for good clinical practice (GCP) for trials on pharmaceutical products. WHO Technical Report Series, No. 850, Annex 3, 1995. Multisource (generic) pharmaceutical products: guidelines on registration requirements to establish interchangeability. WHO Technical Report Series, No. 863, 1996. OECD Principles of good laboratory practice (GLP). [C(97)186/Final], 1997. Good practices for national pharmaceutical control laboratories. WHO Technical Report Series, No. 902, Annex 3, 2002

6. CRO inspections CRO inspections performed by WHO May- Nov 2004 Study-specific Team of 3 inspectors 6 CROs in India (all for HIV/AIDS products)

7. 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 Bioanalytical Apparatuses/materials/reagents, SOPs, performance of the study, test and reference products, storage and retention of records and materials, quality assurance PK analysis and statistics Reporting

8. WHO CRO inspections Findings?

9. Clinical 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 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

10. Clinical The protocol WHO GCP 1 & Appendix 2 Validity of screening tests? No CRFs designed for the study (raw data not transferred to CRFs) In some cases, several CRFs missing – only a few still available as archived 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

11. Clinical The protocol, cont'd Not included: Information to volunteers 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

12. Clinical Protection of trial subjects WHO GCP 3 Independence of EC questionable Chairman had expanded his own authorisation (Chairman's approval invalid) Unclear whether study protocol, ICF and related documentation had been properly discussed at the EC meeting Unclear if one or two ICFs Unclear when EC convened Discrepancy between EC approval form and the minutes of the corresponding meeting (who present/who absent) Some relevant EC documents (register page) could not be produced

13. Clinical Protection of trial subjects, cont'd Screening before EC approval No written consent before screening (e.g. lab tests) Freely given informed consent/valid written consent? One subject signed ICF with thumb print… ICF seriously lacking in information Professional terminology (Stevens-Johnsons syndrome, thrombocytopenia etc) Identification system (finger print matching) to ensure volunteers had not participated in another study within the last 3 months not validated No measures to protect confidentiality of subjects

14. Clinical Responsibilities of the Investigator WHO GCP 4 No protocol deviations according to the study report! However a number of deviations: Source of reference product unclear (US, UK or India?) Amount of meal/time for consumption only recorded for some subjects Deviations in some of the meal times (not mentioned in the study report) No anticoagulant in tubes contrary to protocol (or different anticoagulant) ESR and plasma cholesterol required but not done Na, K, Cl, bleeding time and ECG not required, however tests were done

15. Clinical Responsibilities of the Investigator, cont'd Deviations, cont'd; Protocol and ICF were supposed to be reviewed by EC but ICF appears not to have been Vital signs recorded at absolute rather than relative timepoints contrary to protocol Blood sample drawn at times contrary to protocol – deviations not mentioned in the study report Incomplete recording of vital signs One subject's identity not verified Date of birth of subjects? Violations of incl/excl criteria No maintenance, calibration or log book for X-ray machine Investigator CV not signed or dated – CV current?

16. Clinical Responsibilities of the Sponsor/Monitor WHO GCP 5 & 6 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

17. Clinical Record-keeping and handling of data WHO GCP 8 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 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!

18. Clinical Record-keeping and handling of data, cont'd 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

19. Clinical Record-keeping and handling of data, cont'd 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 used was not specific to the study Errors on the CRFs Lab ref ranges on CRF different from those reported by the lab 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

20. Clinical Handling and accountability for pharmaceutical products WHO GCP 10 What was given? How much was given? Treatment sequence? Cross-over? Labelling? Dispensing or dosing? Confusion between the two! Dispensing not documented. SOP? Dispensing dates? Drug unused? Drug destroyed? Storage?

21. Clinical Quality Assurance for the conduct of a clinical trial WHO GCP 1 & 2 QA system in place at all (see above)? No records of labels printed No record of reconciliation procedure No SOP for labelling/dispensing of empty vials and return of filled vials No SOP for further sample handling (centrifugation etc) No SOP for blood sampling No SOP for sample transport No SOP in the event of freezer break down No SOP for handling of out-of-specification results No record/minutes of a pre-study meeting SOPs from before 2001 not archived or available during the inspection

22. Bioanalytical Apparatuses/Material/Reagents OECD GLP 4 Pipettes not identified – no traceability Infrequent or no controls of balance (calibrated weights?) Storage temperature? No validation of time of freezer temp recording Record of freezer contents? Centrifuge maintenance? Expiry date for Vacutainers? Calculation of concentrations

23. Bioanalytical SOPs OECD GLP 1 & 7 Type of C18 cartridges used (solid phase extraction) not described in the method SOP and not reported in the study report Only one SOP ("Calculation and reporting of bioanalytical data") for the bioanalytical part of BE trials SOPs from before 2001 not archived or available during the inspection (most of the ones for the study in question)

24. Bioanalytical Performance of the study OECD GLP 8 Matrix effects? Acceptance criteria for analytical runs not in accordance with study plan Chromatograms without unique study number Bioanalytical method used =method described in the study report? No or improper source documents Errors in documentation re preparation of stock solutions, calibration and control samples Discrepancies between volumes prepared and volumes actually used Origin of blank plasma?

25. Bioanalytical Performance of the study, cont'd Identical chromatograms with different identities Integration reports of identical chromatograms showed different peak areas, even though peak integration parameters were identical Identical chromatograms had different peak areas but the same area percent Inconsistencies noted between visual appearances of peaks and the area in the integration reports Long term stability of plasma samples? Authenticity of chromatograms and peak areas?

26. Bioanalytical Performance of the study, cont'd Interferences at retention time of lamivudine – concentrations still used and reported Discrepancies between concentrations printed on chromatograms and reported, and those recalculated by the inspectors from the calibration curve parameters – method failed validation acceptance criteria

27. Bioanalytical Test and reference substances OECD GLP 5 & 6 Batch numbers of reference substances used not documented – were the batches used, those for which CoAs were available? Not possible to verify purity of reference substances!

28. Bioanalytical Storage and retention of records and materials OECD GLP 10 Only uncertified copies of chromatograms at the CRO (original chromatograms reportedly sent to sponsor) Documents relating to chromatographic analysis of samples not available during the inspection.

29. Bioanalytical Quality assurance OECD GLP 1 & 2 The number and critical nature of the deviations from OECD GLP (below) highlight the lack of or insufficiency of the Quality Assurance system implemented by the CRO

30. PK and statistical analysis WHO GCP 9 Method of calculating AUC not specified in the study report AUC stated as calculated up to 8 hs when in fact it was up to last conc, 24 hs PK and statistical calculations

31. Reporting OECD GLP 2 & 9 Same or different stock solution for calibration/control samples? Concentrations <LOQ or LOD reported – SOP not followed Some zidovudine conc's were lamivudine conc's Discrepancy between conc on chromatogram and in study report Composition of buffer for sample preparation not in SOP Not specified in study protocol/report which results to use Errors in the bioanalytical report Rounding errors