WHO inspections of Contract Research Organizations

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 acceptable2. Safety/efficacy part of dossier acceptable3. Manufacturing site (FPP, API) compliant with WHO norms and standards for GMP4. Study compliant with norms and standards for GCP (WHO) and GLP (GPNPCL, and OECD as appropriate)

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

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)

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

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)

CRO inspections- areas covered

ClinicalGeneral 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 trialBioanalyticalApparatuses/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

WHO CRO inspections

Findings?

Clinical

General organization

Transfer of responsibilities from sponsor to CRO not documentedUnclear procedure for assigning Subject ID (two subjects assigned the same ID on the Attendance Sheet Form!)No SOP for drug dispensingNo SOP for assigning study numbersNo site staff sample signature log for the studyOrganization chart not readily available, no version dateNo QC system to ensure accuracy and consistency in recording and document control

Clinical

The protocolWHO 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 investigatorsMethod and procedure of randomisation, randomisation schedule and how it was establishedMethod and timing of subject allocation to investigational groups

Clinical

The protocol, cont'dNot included:Information to volunteersProcedures for maintaining subject identification code listStatistical justification for the number of subjectsMethod for measuring blood pressure - sitting or supine? And if both, which value to use…Type of test tubes for blood samplingPK analysis; Method of calculating PK pararmeters, e.g. AUC, how to deal with deviations from planned sampling timesHow to evaluate the results, including statistics and how to handle withdrawals

Clinical

Protection of trial subjectsWHO GCP 3

Independence of EC questionableChairman had expanded his own authorisation (Chairman's approval invalid)Unclear whether study protocol, ICF and related documentation had been properly discussed at the EC meetingUnclear if one or two ICFsUnclear when EC convenedDiscrepancy 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

Clinical

Protection of trial subjects, cont'd

Screening before EC approvalNo 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 validatedNo measures to protect confidentiality of subjects

Clinical

Responsibilities of the InvestigatorWHO 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 subjectsDeviations 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 doneNa, K, Cl, bleeding time and ECG not required, however tests were done

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 beenVital signs recorded at absolute rather than relative timepoints contrary to protocolBlood sample drawn at times contrary to protocol – deviations not mentioned in the study reportIncomplete recording of vital signsOne subject's identity not verifiedDate of birth of subjects?Violations of incl/excl criteriaNo maintenance, calibration or log book for X-ray machineInvestigator CV not signed or dated – CV current?

Clinical

Responsibilities of the Sponsor/MonitorWHO 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

Clinical

Record-keeping and handling of dataWHO 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 subjectFor several subjects the "screening" and "follow up" ECGs appeared to have been recorded from different subjectsNo mention on ECG print outs of the identity of the equipment usedSome ECGs had no date of birth of subject

Doubts as to the authenticity of ECG documentation!

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 dataDiscrepancies 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 reportedInconsistencies in screening dates

Clinical

Record-keeping and handling of data, cont'd

Deliberate attempt to change subject codeDiscrepancies between source documents and study reportMethod/procedure of randomization not documentedNo record of subjects screenedSource documents not keptOriginal entry erased!Type of tubes and anticoagulant used not documentedCRF used was not specific to the study Errors on the CRFsLab ref ranges on CRF different from those reported by the labExpiry date of medications not recorded on CRFsAppearance of tablets incorrectly describedMissing: Lab data, ECG…Final study report not signed by the monitor

Clinical

Handling and accountability for pharmaceutical products

WHO GCP 10What 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?

Clinical

Quality Assurance for the conduct of a clinical trialWHO GCP 1 & 2

QA system in place at all (see above)?

No records of labels printedNo record of reconciliation procedureNo SOP for labelling/dispensing of empty vials and return of filled vials No SOP for further sample handling (centrifugation etc)No SOP for blood samplingNo SOP for sample transportNo SOP in the event of freezer break downNo SOP for handling of out-of-specification resultsNo record/minutes of a pre-study meetingSOPs from before 2001 not archived or available during the inspection

Bioanalytical

Apparatuses/Material/ReagentsOECD GLP 4

Pipettes not identified – no traceabilityInfrequent or no controls of balance (calibrated weights?)Storage temperature?No validation of time of freezer temp recordingRecord of freezer contents?Centrifuge maintenance?Expiry date for Vacutainers?Calculation of concentrations

Bioanalytical

SOPsOECD 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)

Bioanalytical

Performance of the studyOECD GLP 8

Matrix effects?Acceptance criteria for analytical runs not in accordance with study planChromatograms without unique study numberBioanalytical method used =method described in the study report?No or improper source documentsErrors in documentation re preparation of stock solutions, calibration and control samplesDiscrepancies between volumes prepared and volumes actually usedOrigin of blank plasma?

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?

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

Bioanalytical

Test and reference substancesOECD 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!

Bioanalytical

Storage and retention of records and materialsOECD 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.

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

PK and statistical analysisWHO 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

ReportingOECD GLP 2 & 9

Same or different stock solution for calibration/control samples?Concentrations <LOQ or LOD reported – SOP not followedSome zidovudine conc's were lamivudine conc'sDiscrepancy between conc on chromatogram and in study report Composition of buffer for sample preparation not in SOPNot specified in study protocol/report which results to useErrors in the bioanalytical reportRounding errors