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

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

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)

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] The present working document QAS/05.120 always
refers to in-vivo bioequivalence studies

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

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 4.6The
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

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

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

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
TRIAL

CLINICAL

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

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

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)

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

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"

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 bioequivalence guideline,
Good clinical practice (GCP)
Good laboratory practices (GLP)

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.

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

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

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

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

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

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

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 (proofreading, double data entry, electronic
logical control) in writing
Changes to data entered in database
- authorized persons only
- specified and documented

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

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
order
Entry restricted and controlled

logical

Research Organizations
Laboratories with sufficient space to avoid mixups, 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, copymachine) to perform the required activities

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

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

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

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

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

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

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

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

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.

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

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

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.

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.

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

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

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

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.

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

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.

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

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

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

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.

Program
Group sessions
Clinical
Bio-analytical

Good Clinical Practices

(GCP)
Q