Good Clinical Practices

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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
Cluster World Health Organization
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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

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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)

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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
STUDIES1 1 The present working document
QAS/05.120 always refers to in-vivo
bioequivalence studies
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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 Investiga
tor 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
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GCP
4. RESPONSIBILITIES OF THE INVESTIGATOR 4.1 Medi
cal 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 Monito
ring, auditing and inspection 4.13 Record-keepin
g 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
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GCP
5. RESPONSIBILITIES OF THE SPONSOR 5.1 Selecti
on 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 Invest
igational 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
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GCP
6. RESPONSIBILITIES OF THE MONITOR 6.1 Qualificat
ions 6.2 Assessment of the trial
site 6.3 Staff education and compliance 6.4 Dat
a management 6.5 Case-report forms 6.6 Investi
gational product 6.7 Communication 6.8 Notifica
tion 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
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GCP
9. STATISTICS AND CALCULATIONS 9.1 Experimental
design 9.2 Randomization and blinding 9.3 Stat
istical 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 )
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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
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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
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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 Doc
umentation 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)
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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
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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"
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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)

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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.
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Research Organizations

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

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Research Organizations

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

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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

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Research Organizations

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

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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

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Research Organizations

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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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.

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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

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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

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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.

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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.

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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

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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

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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

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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.

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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

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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.

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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

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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

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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

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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.

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Program

• Group sessions
• Clinical
• Bio-analytical

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Good Clinical Practices (GCP)

• Q