Presentation on theme: "Good Clinical Practices"— Presentation transcript:
1Good Clinical Practices Guilin, PRCDr AJ van ZylforQuality Assurance and Safety: MedicinesMedicines Policy and StandardsHealth Technology and Pharmaceuticals ClusterWorld Health Organization
2Program Thursday: Presentation on guidelines: GCP, GLP, CRO Group sessionsClinical and bio-analyticalFriday:Presentation on GMP
3Outline of presentation Bio-equivalence studiesGood Clinical Practices (GCP)Good Practices for Quality Control Laboratories (GPQCL)Good Laboratory Practices (GLP)Good Practices for Contract Research Organizations (GPCRO)
4Guidelines GCP GLP CRO World Health Organization WHO Technical Report Series, No. 850, 1995, Annex 3GLPUNDP/World Bank/WHOSpecial Programme for Research and Training in Tropical Diseases (TDR)HANDBOOK GOOD LABORATORY PRACTICE (GLP)CRODRAFT ADDITIONAL GUIDANCE FOR ORGANIZATIONS PERFORMING IN VIVO BIOEQUIVALENCE STUDIES The present working document QAS/ always refers to in-vivo bioequivalence studies
5Good Clinical Practices (GCP) 1. PROVISIONS AND PREREQUISITES FOR A CLINICAL TRIAL1.1 Justification for the trial1.2 Ethical principles1.3 Supporting data for the investigational product 1.4 Investigator and site(s) of investigation1.5 Regulatory requirements2. THE PROTOCOL3. PROTECTION OF TRIAL SUBJECTS3.1 Declaration of Helsinki3.2 Ethics committee3.3 Informed consent3.4 Confidentiality
6GCP 4. RESPONSIBILITIES OF THE INVESTIGATOR 4.1 Medical care of trial subjects4.2 Qualifications4.3 Selection of trial subjects4.4 Compliance with the protocol4.5 Information for subjects and informed consent 4.6 The investigational product4.7 The trial site4.8 Notification of the trial or submission to the DRA 4.9 Review by an ethics committee4.10 Serious adverse events or reactions4.11 Financing4.12 Monitoring, auditing and inspection4.13 Record-keeping and handling of data4.14 Handling of and accountability for pharmaceutical products for trial4.15 Termination of trial4.16 Final report4.17 Trials in which the investigator is the sponsor
7GCP 5. RESPONSIBILITIES OF THE SPONSOR 5.1 Selection of the Investigator(s)5.2 Delegation of responsibilities5.3 Compliance with the protocol and procedures 5.4 Product information5.5 Safety information5.6 Investigational product5.7 Trial management and handling of data5.8 Standard operating procedures5.9 Compensation for subjects and investigators 5.10 Monitoring5.11 Quality assurance5.12 Study reports5.13 Handling of adverse events5.14 Termination of trial
8GCP 6. RESPONSIBILITIES OF THE MONITOR 6.1 Qualifications 6.2 Assessment of the trial site6.3 Staff education and compliance6.4 Data management6.5 Case-report forms6.6 Investigational product6.7 Communication6.8 Notification of the trial or submission to the regulatory authority6.9 Reports7. MONITORING OF SAFETY7.1 Handling and recording adverse events7.2 Reporting adverse events8. RECORD-KEEPING AND HANDLING OF DATA8.1 Responsibilities of the investigator8.2 Responsibilities of the sponsor and the monitor8.3 Archiving of data
9GCP 9. STATISTICS AND CALCULATIONS 9.1 Experimental design 9.2 Randomization and blinding9.3 Statistical analysis10. HANDLING OF AND ACCOUNTABILITY FOR PHARMACEUTICAL PRODUCTS10.1 Supply and storage10.2 Investigational labelling and packaging10.3 Responsibilities of the investigator10.4 Responsibilities of the sponsor and the monitor11. ROLE OF THE DRUG REGULATORY AUTHORITY11.1 General responsibilities11.2 On-site inspections12. QUALITY ASSURANCE FOR THE CONDUCT OF A CLINICAL TRIAL )
10Good Practices for Quality Control Laboratories (GPQCL) Part One. Management and infrastructure1. Organization and management2. Quality system3. Control of documentation4. Records5. Data processing equipment6. Personnel7. Premises8. Equipment, instruments and other devicesPart Two. Materials and set-up of equipment, instruments and other devices9. Specifications archive10. Reagents11. Reference materials12. Calibration, validation and verification of equipment, instruments and other devices13. Traceability
11GPQCL Part Three. Working procedures 14. Incoming sample 15. Analytical worksheet16. Testing17. Evaluation of test results18. Retained samplesPart Four. Safety in pharmaceutical control laboratories19. General rules
12Good Laboratory Practices (GLP) INTRODUCTION TO GLP AND ITS APPLICATIONThe history of GLPWhat is GLP?GOOD LABORATORY PRACTICE TRAININGINTRODUCTIONTHE FUNDAMENTAL POINTS OF GLPResourcesRulesCharacterizationDocumentationQuality assuranceRESOURCESFacilities: buildings and equipmentPersonnelRULES FOR THE CONDUCT OF STUDIESGeneral aspectsThe study plan or protocolStandard Operating Procedures (SOPs)
13GLP CHARACTERIZATION6 The test item Test system DOCUMENTATION – RAW DATA AND DATA COLLECTIONCarrying out procedures and recording observationsRecords and recordingQUALITY ASSURANCE UNITProtocol (or study plan) reviewSOP reviewPlanning (Master schedule, inspection plan)Audits and inspectionsQuality assurance statementQAU inspections of suppliers and contractorsThe distribution and archiving of QAU files and reports
14GuidelinesThis presentation will focus on guidelines for CROs, then GCP and GLPWhat is a CRO:WHO: "any organization involved in the conduct or analysis of in vivo bioequivalence studies".Per ICH Tripartite Harmonized Guidelines: "a person or an organization (commercial, academic or other) contracted by the sponsor to perform one or more of a sponsor's trial-related duties and functions"
15Research Organizations Scope: Guidance to organizations involved in the conduct and analysis of in vivo bioequivalence (BE) studiesNote:BE studies should be performed in compliance with:General regulatory requirementsGood practices in the WHO bio- equivalence guideline,Good clinical practice (GCP)Good laboratory practices (GLP)
16Research Organizations Guideline provides information on:- organization and management;- study protocols;- clinical phase of a study;- bio-analytical phase of a study;- pharmacokinetic and statistical analysis;- study report.
18Research Organizations ETHICS COMMITTEEInformed ConsentMONITORINGINVESTIGATORSRECEIVING, STORAGE AND HANDLING OF INVESTIGATIONAL DRUG PRODUCTSCASE REPORT FORMSVOLUNTEERS, RECRUITMENT METHODSDIETING
19Research Organizations SAFETY, ADVERSE EVENTS, ADVERSE EVENT REPORTINGSAMPLE COLLECTION, STORAGE AND HANDLING OF BIOLOGICAL MATERIALLABORATORY PHASE (BIOANALYTICAL DATA)DOCUMENTATIONPHARMACOKINECTIC & STATISTICAL CALCULATIONSCLINICAL STUDY REPORT
20Research Organizations Organization and managementLegal requirementsOrganization chartKey positions, names, authorizedJob descriptions and responsibilitiesList of signatures
21Research Organizations Computer systemsHardwareSufficientData entry and handling, calculations, reportsCapacity and memoryAccess controlSoftwareSuitable programWritten procedures: program, virus tests, archiving, back-ups
22Research Organizations Software can manage:Word processing,Data entry,Databases,Graphics,Pharmacokinetics andStatistical programmesComputer systems validated
23Research Organizations Data management:Includes transfer of the data from case report forms (CRF), analytical data for pharmacokinetic and statistical analysis and reportingSOPs designed to prevent errorsDouble entry of the dataData validation methodology (proof-reading, double data entry, electronic logical control) in writingChanges to data entered in database- authorized persons only- specified and documented
24Research Organizations ARCHIVE FACILITIESSufficient and appropriately secure storage space, fire proof, archiving trial-related documentation and product samplesSOP for archiving.Access to areas restricted and controlledArchiving period- documentation including raw data- product samples retained- defined in the SOP
25Research Organizations PREMISESConditions to ensure (consideration)adequate safety for the subjectsstage of development of the productpotential risk involvedSufficient space (personnel and activities)Adequate facilities, including laboratoriesClinical phase:Areas well organized, activities in logical orderEntry restricted and controlled
26Research Organizations Laboratories with sufficient space to avoid mix-ups, contamination and cross-contamination, adequate, suitable storage space for samples, standards, solvents, reagents and records.Alarm system or adequate monitoring system to control the temperature of the critical stage areas.Automatic alarm system tested regularlyDaily monitoring and all the alarm checks should be documented.Access to telephone, and facsimile facilities to ensure proper communication and necessary office equipment (printer, copy-machine) to perform the required activities
27Research Organizations Clinical PhaseSufficient spaceWhere appropriate, beds should be available (overnight stay/ type of trial/ investigational drug)Facilities for:changing and storing clothesWashing and toilets - easily accessible and appropriate
28Research Organizations Other rooms or areas:Volunteer screening;"Clinic" for volunteers;Ancillary areas;Pharmaceutical operations (e.g. storage, repacking)Administration of investigational drug(s) and sample collection;Sample processing (e.g. plasma separation) and storage (freezer);Controlled storage areas for study materials, medication and documentation including CRFs;Preparation of standardized meals;Emergency or first-aid equipment and appropriate rescue medication for emergencies
29Research organizations CLINICAL LABORATORYA qualified clinical laboratory for analysing the screening samples.As per protocol: Haematological tests, urine analysis and other testsInformation about analytical methods used, a dated list of laboratory normal ranges and accreditation certificate of the laboratory, if available.Curriculum vitae of the responsible analystActual original results (including raw-data) of all the tests performed should be documented and should be included in the CRFs
30Research organizations PERSONNELSufficient number of qualified personnelKey persons with appropriate responsibilities:Medical/Scientific directorPrincipal investigatorQuality assurance managerTechnical managerQuality Control managerQuality assurance should be independent, reporting structureContract workers allowedCurrent curriculum vitae and training recordsAppropriate qualifications and sufficient knowledgeRecords for training and assessment - GCP and GLP
31Research organizations QUALITY ASSURANCEAppropriate quality assurance (QA) systemQA unit responsible for:Verifying all activities;Quality assurance systems, SOPs;Verifying data for reliability and traceability;Planning and performing self-inspections;Contract facilities - including auditing of such facilities.The CRO should allow the sponsor to monitor the studies and to perform audits of the clinical and analytical study and sites
32Research organizations ETHICS COMMITTEETrials approved beforehandIndependent from the promoter, the investigator, the CRODiscussions, recommendations and decisions in detailed minutes of the meetingSufficient time for reviewing protocols and ICFsInformed consentLanguage and a level understandableBoth orally and in writingGiven by the subject, documented, before startParticipation is voluntary, the right to withdraw without having to give a reasonCompensation paid pro rata temporisIf reasons given, included in the study recordsSubject access to information about insurance, and other procedures for compensation or treatment
33Research organizations MONITORINGNote: Monitoring is an essential part of the clinical trial.Qualified monitorEnsure compliance with the protocol, GCP, GLP and applicable ethical and regulatory requirementsCompletion of CRFs and verification of the accuracy of data obtainedPre- and post-study visit as well as a monitoring visit during the conduct of the trialWritten report after each site visitCRO: SOPs concerning the visit procedures, extent of source data verification, drug accountability and adherence to the protocol.Monitor: SOPs (with checklists)- initiation visit, routine monitoring visits and a closing visit
34Research organizations INVESTIGATORSPrincipal investigator: overall responsibility for the clinical conduct of the studyAppropriate qualifications, trained, experienceAt least one investigator practice medicine by lawResponsible for the integrity, health and welfare of the subjects during the trial, and the accurate documentation of all trial-related clinical data.Permanent employees or external investigators contracted and adequately trained
35Research organizations RECEIVING, STORAGE AND HANDLING OF INVESTIGATIONAL DRUG PRODUCTSRecords:for receipt, storage, handling and accountability of investigational and comparator products – all stages of the trial.Information about:the shipment, delivery, receipt, storage (including storage conditions), dispensing, administration, reconciliation, return and/or destructionProduct used:dosage form and strength, lot number, expiry date, and other coding that identifies the specific characteristics of the product tested.
36Research organizations RECEIVING, STORAGE AND HANDLING OF INVESTIGATIONAL DRUG PRODUCTSSamples in the original container retainedSuitable location within the CRO (pharmacy)Under appropriate storage conditionsIn a securely locked area accessible only to authorized personsRandomization and dispensing, including the labelling of drug products - SOP and recordsReconciliation verified by a second responsible person
37Research organizations CASE REPORT FORMSCase report forms (CRFs) to record data on each subjectProcedure for designing CRFsSample CRF should be appended to the protocol.Guarantee preservation, retention and retrieval of volunteer informationReflect the actual results obtained during the study and allow easy access to verification, audit and inspection of the data.Investigator's certification of the accuracy of CRFsErrors or omissions – clarified, corrected, dated and signed and explained
38Research organizations VOLUNTEERS, RECRUITMENT METHODSNote: Pool of healthy volunteers - medically tested and selected.Informed consent for any screening procedures required to determine eligibility for the study, in addition to informed consent for participation in the research portion of the study.Subject selection criteria (inclusion and exclusion criteria) and recruitment procedures should be described in the clinical trial protocol.
39Research organizations DIETINGMeals can significantly affect absorption of drugsFasting and meals should be standardized and adequately controlledArrange for standardized meals, snacks and drinks - protocol.Records should be maintained for timing, duration and amount of food and fluids consumed.
40Research organizations SAFETY, ADVERSE EVENTS, ADVERSE EVENT REPORTINGAppropriate study planning - evaluation of riskFirst-aid emergency equipment and appropriate rescue medicationAdequate facilities of the proper careInvestigator(s) responsible for:medical decisionsnotifying the relevant health authorities, the sponsor and, when applicable, the EC, without delay in the case of serious adverse events.Adverse event registration and reporting forms
41Research organizations SAMPLE COLLECTION, STORAGE AND HANDLING OF BIOLOGICAL MATERIALSamples (serum, plasma, or urine), sampling method, volume and number of samples - in the clinical trial protocol and the information provided to the volunteer.SOPs for the collection, preparation, transport and storage of samplesActual sampling times and deviations recorded.Labelling of samples clear - identification and traceability
42Research organizations SAMPLE COLLECTION, STORAGE AND HANDLING OF BIOLOGICAL MATERIALStorage conditions of samplesAll storage conditions (e.g. temperature in the freezer) protocol - controlled, monitored and recorded throughout the storage period and transportation.System failure.Storage and retrieval of samplesDuplicate or backup samples - stored and shipped separately.Local requirements for the handling and destruction
43Research organizations BIOANALYTICAL DATA (LABORATORY PHASE)Note: Same CRO or contracted to another laboratory or CROGLP to non-clinical safety studies - general principlesLaboratory with established quality assurance systemsAccredited laboratories should be used when possible.Premises and equipmentSufficient space and infrastructureUtilities such as water, air, gas and electricity - adequate, stable and uninterrupted.Equipment qualified and methods described validated.SOPs for the operation, use, calibration and preventive maintenance of equipment - records maintained.Equipment used should be identified - ensure traceability.
44Research organizations Validation requirements for the analytical method with SOPs for analytical method validation.Stability of the samples under the stated conditions and period of storageChemicals, reagents, solvents and solutions should be labelled to indicate identity, purity concentration (if appropriate), expiry date and specific storage instructions, information concerning source, preparation date and stability should be available.Quality assurance (QA)QA unit - independent from the person(s) responsible for analytical work and which should ensure that the analytical method in use is validated and current
45Research Organizations DOCUMENTATIONAll original analytical raw data (e.g. calculations, chromatograms, etc.) documentedTraceable to the sample number, equipment used, date and time of analysis and the name(s) of the technician(s).Each data point should be traceable to a specific sample, including sample number, time of collection of the sample, time of centrifugation, if applicable, time when the sample was placed in the freezer, time of sample analysis, etc, to be able to determine whether any aberrant results might have been due to sample mishandling.Coding techniques and methods to perform blinded analysis when relevant.
46Research Organizations PHARMACOKINETIC AND STATISTICAL CALCULATIONSCalculations should be made by qualified personsCalculation methods should be specified in the study protocol and data analysis should conform to the protocol requirements.Computerized systems can be used
47Research Organizations CLINICAL STUDY REPORTReflect the complete study procedures and results in an accurate manner.Well written and presentedAll deviations reportedNo discrepancies between the results in the report and the actual original (raw) dataComply with regulatory requirements as applicable and be in a standard format
48Research Organizations CLINICAL STUDY REPORTCover at least the items listed in the International Conference on Harmonization (ICH) guideline (Topic E3. Structure and Content of Clinical Study Report)Specifies the procedure for approval by the investigator and sponsor approved (signed and dated) by the responsible personsMonitoring report and audit report available before release of the final study report
49Research Organizations GCPWHO Technical Report Series, No. 850, 1995 (pp )GLPOECD Principles on Good Laboratory Practice (as revised in 1997). Organization for Economic Co-operation and Development. ENV/MC/CHEM(98) Jan, 1998International Conference on Harmonization (ICH) Guidelines. Tripartite Harmonized Guidelines on Good Clinical Practice, Step 4, May 1996.