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

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 GLP CRO 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] The present working document QAS/ always refers to in-vivo bioequivalence studies

5. Good Clinical Practices (GCP)
1. PROVISIONS AND PREREQUISITES FOR A CLINICAL TRIAL
1.1 Justification for the trial
1.2 Ethical principles
1.3 Supporting data for the investigational product 1.4 Investigator and site(s) of investigation
1.5 Regulatory requirements
2. THE PROTOCOL
3. PROTECTION OF TRIAL SUBJECTS
3.1 Declaration of Helsinki
3.2 Ethics committee
3.3 Informed consent
3.4 Confidentiality

6. GCP 4. RESPONSIBILITIES OF THE INVESTIGATOR
4.1 Medical care of trial subjects
4.2 Qualifications
4.3 Selection of trial subjects
4.4 Compliance with the protocol
4.5 Information for subjects and informed consent 4.6 The investigational product
4.7 The trial site
4.8 Notification of the trial or submission to the DRA 4.9 Review by an ethics committee
4.10 Serious adverse events or reactions
4.11 Financing
4.12 Monitoring, auditing and inspection
4.13 Record-keeping and handling of data
4.14 Handling of and accountability for pharmaceutical products for trial
4.15 Termination of trial
4.16 Final report
4.17 Trials in which the investigator is the sponsor

7. GCP 5. RESPONSIBILITIES OF THE SPONSOR
5.1 Selection of the Investigator(s)
5.2 Delegation of responsibilities
5.3 Compliance with the protocol and procedures 5.4 Product information
5.5 Safety information
5.6 Investigational product
5.7 Trial management and handling of data
5.8 Standard operating procedures
5.9 Compensation for subjects and investigators 5.10 Monitoring
5.11 Quality assurance
5.12 Study reports
5.13 Handling of adverse events
5.14 Termination of trial

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

9. GCP 9. STATISTICS AND CALCULATIONS 9.1 Experimental design
9.2 Randomization and blinding
9.3 Statistical analysis
10. HANDLING OF AND ACCOUNTABILITY FOR PHARMACEUTICAL PRODUCTS
10.1 Supply and storage
10.2 Investigational labelling and packaging
10.3 Responsibilities of the investigator
10.4 Responsibilities of the sponsor and the monitor
11. ROLE OF THE DRUG REGULATORY AUTHORITY
11.1 General responsibilities
11.2 On-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, 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 )
GLP
OECD Principles on Good Laboratory Practice (as revised in 1997). Organization for Economic Co-operation and Development. ENV/MC/CHEM(98) 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