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Good Clinical Practices Guilin, PRC Dr AJ van Zyl for Quality Assurance and Safety: Medicines Medicines Policy and Standards Health Technology and Pharmaceuticals.

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Presentation on theme: "Good Clinical Practices Guilin, PRC Dr AJ van Zyl for Quality Assurance and Safety: Medicines Medicines Policy and Standards Health Technology and Pharmaceuticals."— Presentation transcript:

1 Good Clinical Practices Guilin, PRC Dr AJ van Zyl for Quality Assurance and Safety: Medicines Medicines Policy and Standards Health Technology and Pharmaceuticals Cluster World Health Organization

2 Program Thursday: Presentation on guidelines: GCP, GLP, CRO Group sessions Clinical and bio-analytical Friday: Presentation on GMP Group sessions Presentation on GMP Group sessions

3 Outline of presentation Bio-equivalence studies Good Clinical Practices (GCP) Good Practices for Quality Control Laboratories (GPQCL) Good Laboratory Practices (GLP) Good Practices for Contract Research Organizations (GPCRO)

4 Guidelines GCP World Health Organization WHO Technical Report Series, No. 850, 1995, Annex 3 GLP UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) HANDBOOK GOOD LABORATORY PRACTICE (GLP) CRO DRAFT ADDITIONAL GUIDANCE FOR ORGANIZATIONS PERFORMING IN VIVO BIOEQUIVALENCE STUDIES[1][1] [1] The present working document QAS/05.120 always refers to in-vivo bioequivalence studies

5 Good Clinical Practices (GCP) 1.PROVISIONS AND PREREQUISITES FOR A CLINICAL TRIAL 1.1Justification for the trial 1.2Ethical principles 1.3Supporting data for the investigational product1.4 Investigator and site(s) of investigation 1.5Regulatory requirements 2.THE PROTOCOL 3.PROTECTION OF TRIAL SUBJECTS 3.1Declaration of Helsinki 3.2Ethics committee 3.3Informed consent 3.4Confidentiality

6 GCP 4.RESPONSIBILITIES OF THE INVESTIGATOR 4.1Medical care of trial subjects 4.2Qualifications 4.3Selection of trial subjects 4.4Compliance with the protocol 4.5Information for subjects and informed consent4.6The investigational product 4.7The trial site 4.8Notification of the trial or submission to the DRA4.9 Review by an ethics committee 4.10Serious adverse events or reactions 4.11Financing 4.12Monitoring, auditing and inspection 4.13Record-keeping and handling of data 4.14Handling of and accountability for pharmaceutical products for trial 4.15Termination of trial 4.16Final report 4.17Trials in which the investigator is the sponsor

7 GCP 5.RESPONSIBILITIES OF THE SPONSOR 5.1Selection of the Investigator(s) 5.2Delegation of responsibilities 5.3Compliance with the protocol and procedures5.4 Product information 5.5 Safety information 5.6Investigational product 5.7Trial management and handling of data 5.8Standard operating procedures 5.9Compensation for subjects and investigators5.10 Monitoring 5.11Quality assurance 5.12Study reports 5.13Handling of adverse events 5.14Termination of trial

8 GCP 6.RESPONSIBILITIES OF THE MONITOR 6.1Qualifications 6.2Assessment of the trial site 6.3Staff education and compliance 6.4Data management 6.5Case-report forms 6.6Investigational product 6.7Communication 6.8Notification of the trial or submission to the regulatory authority 6.9Reports 7.MONITORING OF SAFETY 7.1Handling and recording adverse events 7.2Reporting adverse events 8.RECORD-KEEPING AND HANDLING OF DATA 8.1Responsibilities of the investigator 8.2Responsibilities of the sponsor and the monitor 8.3Archiving of data

9 GCP 9.STATISTICS AND CALCULATIONS 9.1Experimental design 9.2Randomization and blinding 9.3Statistical analysis 10.HANDLING OF AND ACCOUNTABILITY FOR PHARMACEUTICAL PRODUCTS 10.1Supply and storage 10.2Investigational labelling and packaging 10.3Responsibilities of the investigator 10.4Responsibilities of the sponsor and the monitor 11.ROLE OF THE DRUG REGULATORY AUTHORITY 11.1General responsibilities 11.2On-site inspections 12.QUALITY ASSURANCE FOR THE CONDUCT OF A CLINICAL TRIAL )

10 Good Practices for Quality Control Laboratories (GPQCL) Part One. Management and infrastructure 1. Organization and management 2. Quality system 3. Control of documentation 4. Records 5. Data processing equipment 6. Personnel 7. Premises 8. Equipment, instruments and other devices Part Two. Materials and set-up of equipment, instruments and other devices 9. Specifications archive 10. Reagents 11. Reference materials 12. Calibration, validation and verification of equipment, instruments and other devices 13. Traceability

11 GPQCL Part Three. Working procedures 14. Incoming sample 15. Analytical worksheet 16. Testing 17. Evaluation of test results 18. Retained samples Part Four. Safety in pharmaceutical control laboratories 19. General rules

12 Good Laboratory Practices (GLP) INTRODUCTION TO GLP AND ITS APPLICATION The history of GLP What is GLP? GOOD LABORATORY PRACTICE TRAINING INTRODUCTION THE FUNDAMENTAL POINTS OF GLP Resources Rules Characterization Documentation Quality assurance RESOURCES Facilities: buildings and equipment Personnel RULES FOR THE CONDUCT OF STUDIES General aspects The study plan or protocol Standard Operating Procedures (SOPs)

13 GLP CHARACTERIZATION6 The test item Test system DOCUMENTATION – RAW DATA AND DATA COLLECTION Carrying out procedures and recording observations Records and recording QUALITY ASSURANCE UNIT Protocol (or study plan) review SOP review Planning (Master schedule, inspection plan) Audits and inspections Quality assurance statement QAU inspections of suppliers and contractors The distribution and archiving of QAU files and reports

14 Guidelines This presentation will focus on guidelines for CROs, then GCP and GLP What 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"

15 Research Organizations Scope: Guidance to organizations involved in the conduct and analysis of in vivo bioequivalence (BE) studies Note: BE studies should be performed in compliance with: General regulatory requirements Good practices in the WHO bio- equivalence guideline, Good clinical practice (GCP) Good laboratory practices (GLP)

16 Research 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.

17 Research Organizations ORGANIZATION & MANAGEMENT COMPUTER SYSTEMS Hardware Software Data Management ARCHIVE FACILITIES PREMISES CLINICAL PHASE CLINICAL LABORATORY PERSONNEL QUALITY ASSURANCE

18 Research Organizations ETHICS COMMITTEE Informed Consent MONITORING INVESTIGATORS RECEIVING, STORAGE AND HANDLING OF INVESTIGATIONAL DRUG PRODUCTS CASE REPORT FORMS VOLUNTEERS, RECRUITMENT METHODS DIETING

19 Research Organizations SAFETY, ADVERSE EVENTS, ADVERSE EVENT REPORTING SAMPLE COLLECTION, STORAGE AND HANDLING OF BIOLOGICAL MATERIAL LABORATORY PHASE (BIOANALYTICAL DATA) DOCUMENTATION PHARMACOKINECTIC & STATISTICAL CALCULATIONS CLINICAL STUDY REPORT

20 Research Organizations Organization and management Legal requirements Organization chart Key positions, names, authorized Job descriptions and responsibilities List of signatures

21 Research Organizations Computer systems Hardware Sufficient Data entry and handling, calculations, reports Capacity and memory Access control Software Suitable program Written procedures: program, virus tests, archiving, back-ups

22 Research Organizations Software can manage: Word processing, Data entry, Databases, Graphics, Pharmacokinetics and Statistical programmes Computer systems validated

23 Research Organizations Data management: Includes transfer of the data from case report forms (CRF), analytical data for pharmacokinetic and statistical analysis and reporting SOPs designed to prevent errors Double entry of the data Data validation methodology (proof- reading, double data entry, electronic logical control) in writing Changes to data entered in database - authorized persons only - specified and documented

24 Research Organizations ARCHIVE FACILITIES Sufficient and appropriately secure storage space, fire proof, archiving trial-related documentation and product samples SOP for archiving. Access to areas restricted and controlled Archiving period - documentation including raw data - product samples retained - defined in the SOP

25 Research Organizations PREMISES Conditions to ensure (consideration) adequate safety for the subjects stage of development of the product potential risk involved Sufficient space (personnel and activities) Adequate facilities, including laboratories Clinical phase: Areas well organized, activities in logical order Entry restricted and controlled

26 Research 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 regularly Daily monitoring and all the alarm checks should be documented. Access to telephone, E-mail and facsimile facilities to ensure proper communication and necessary office equipment (printer, copy- machine) to perform the required activities

27 Research Organizations Clinical Phase Sufficient space Where appropriate, beds should be available (overnight stay/ type of trial/ investigational drug) Facilities for: changing and storing clothes Washing and toilets - easily accessible and appropriate

28 Research 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

29 Research organizations CLINICAL LABORATORY A qualified clinical laboratory for analysing the screening samples. As per protocol: Haematological tests, urine analysis and other tests Information about analytical methods used, a dated list of laboratory normal ranges and accreditation certificate of the laboratory, if available. Curriculum vitae of the responsible analyst Actual original results (including raw-data) of all the tests performed should be documented and should be included in the CRFs

30 Research organizations PERSONNEL Sufficient number of qualified personnel Key persons with appropriate responsibilities: Medical/Scientific director Principal investigator Quality assurance manager Technical manager Quality Control manager Quality assurance should be independent, reporting structure Contract workers allowed Current curriculum vitae and training records Appropriate qualifications and sufficient knowledge Records for training and assessment - GCP and GLP

31 Research organizations QUALITY ASSURANCE Appropriate quality assurance (QA) system QA 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

32 Research organizations ETHICS COMMITTEE Trials approved beforehand Independent from the promoter, the investigator, the CRO Discussions, recommendations and decisions in detailed minutes of the meeting Sufficient time for reviewing protocols and ICFs Informed consent Language and a level understandable Both orally and in writing Given by the subject, documented, before start Participation is voluntary, the right to withdraw without having to give a reason Compensation paid pro rata temporis If reasons given, included in the study records Subject access to information about insurance, and other procedures for compensation or treatment

33 Research organizations MONITORING Note: Monitoring is an essential part of the clinical trial. Qualified monitor Ensure compliance with the protocol, GCP, GLP and applicable ethical and regulatory requirements Completion of CRFs and verification of the accuracy of data obtained Pre- and post-study visit as well as a monitoring visit during the conduct of the trial Written report after each site visit CRO: 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

34 Research organizations INVESTIGATORS Principal investigator: overall responsibility for the clinical conduct of the study Appropriate qualifications, trained, experience At least one investigator practice medicine by law Responsible 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

35 Research organizations RECEIVING, STORAGE AND HANDLING OF INVESTIGATIONAL DRUG PRODUCTS Records: 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 destruction Product used: dosage form and strength, lot number, expiry date, and other coding that identifies the specific characteristics of the product tested.

36 Research organizations RECEIVING, STORAGE AND HANDLING OF INVESTIGATIONAL DRUG PRODUCTS Samples in the original container retained Suitable location within the CRO (pharmacy) Under appropriate storage conditions In a securely locked area accessible only to authorized persons Randomization and dispensing, including the labelling of drug products - SOP and records Reconciliation verified by a second responsible person

37 Research organizations CASE REPORT FORMS Case report forms (CRFs) to record data on each subject Procedure for designing CRFs Sample CRF should be appended to the protocol. Guarantee preservation, retention and retrieval of volunteer information Reflect 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 CRFs Errors or omissions – clarified, corrected, dated and signed and explained

38 Research organizations VOLUNTEERS, RECRUITMENT METHODS Note: 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.

39 Research organizations DIETING Meals can significantly affect absorption of drugs Fasting and meals should be standardized and adequately controlled Arrange for standardized meals, snacks and drinks - protocol. Records should be maintained for timing, duration and amount of food and fluids consumed.

40 Research organizations SAFETY, ADVERSE EVENTS, ADVERSE EVENT REPORTING Appropriate study planning - evaluation of risk First-aid emergency equipment and appropriate rescue medication Adequate facilities of the proper care Investigator(s) responsible for: medical decisions notifying 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

41 Research organizations SAMPLE COLLECTION, STORAGE AND HANDLING OF BIOLOGICAL MATERIAL Samples (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 samples Actual sampling times and deviations recorded. Labelling of samples clear - identification and traceability

42 Research organizations SAMPLE COLLECTION, STORAGE AND HANDLING OF BIOLOGICAL MATERIAL Storage conditions of samples All 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 samples Duplicate or backup samples - stored and shipped separately. Local requirements for the handling and destruction

43 Research organizations BIOANALYTICAL DATA (LABORATORY PHASE) Note: Same CRO or contracted to another laboratory or CRO GLP to non-clinical safety studies - general principles Laboratory with established quality assurance systems Accredited laboratories should be used when possible. Premises and equipment Sufficient space and infrastructure Utilities 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.

44 Research organizations Validation requirements for the analytical method with SOPs for analytical method validation. Stability of the samples under the stated conditions and period of storage Chemicals, 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

45 Research Organizations DOCUMENTATION All original analytical raw data (e.g. calculations, chromatograms, etc.) documented Traceable 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.

46 Research Organizations PHARMACOKINETIC AND STATISTICAL CALCULATIONS Calculations should be made by qualified persons Calculation methods should be specified in the study protocol and data analysis should conform to the protocol requirements. Computerized systems can be used

47 Research Organizations CLINICAL STUDY REPORT Reflect the complete study procedures and results in an accurate manner. Well written and presented All deviations reported No discrepancies between the results in the report and the actual original (raw) data Comply with regulatory requirements as applicable and be in a standard format

48 Research Organizations CLINICAL STUDY REPORT Cover 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 persons Monitoring report and audit report available before release of the final study report

49 Research Organizations GCP WHO Technical Report Series, No. 850, 1995 (pp. 97-137) GLP OECD Principles on Good Laboratory Practice (as revised in 1997). Organization for Economic Co-operation and Development. ENV/MC/CHEM(98)17. 26.Jan, 1998 International Conference on Harmonization (ICH) Guidelines. Tripartite Harmonized Guidelines on Good Clinical Practice, Step 4, May 1996.

50 Program Group sessions Clinical Bio-analytical

51 Good Clinical Practices (GCP) Q


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