good clinical practices guilin, prc dr aj van zyl for quality assurance and safety: medicines...

Good Clinical Practices

Guilin, PRCDr AJ van Zyl

for Quality Assurance and Safety: Medicines

Medicines Policy and StandardsHealth Technology and Pharmaceuticals Cluster

World Health Organization

ProgramProgram• 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 presentationOutline 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)

GuidelinesGuidelines

GCPWorld Health Organization

WHO Technical Report Series, No. 850, 1995, Annex 3

GLPUNDP/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[1]

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

Good Clinical Practices Good Clinical Practices (GCP)(GCP)

1. PROVISIONS AND PREREQUISITES FOR A CLINICAL TRIAL1.1 Justification for the trial1.2 Ethical principles1.3 Supporting data for the investigational product1.4Investigator and site(s) of investigation1.5 Regulatory requirements

2. THE PROTOCOL

3. PROTECTION OF TRIAL SUBJECTS3.1 Declaration of Helsinki3.2 Ethics committee

3.3 Informed consent3.4 Confidentiality

GCPGCP 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 4.6The investigational product4.7 The trial site4.8 Notification of the trial or submission to the DRA 4.9Review 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

GCPGCP

5. RESPONSIBILITIES OF THE SPONSOR5.1 Selection of the Investigator(s)5.2 Delegation of responsibilities 5.3 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 5.10Monitoring5.11 Quality assurance5.12 Study reports5.13 Handling of adverse events5.14 Termination of trial

GCPGCP6. RESPONSIBILITIES OF THE MONITOR

6.1 Qualifications6.2 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 Reports

7. MONITORING OF SAFETY 7.1 Handling and recording adverse events7.2 Reporting adverse events

8. RECORD-KEEPING AND HANDLING OF DATA8.1 Responsibilities of the investigator8.2 Responsibilities of the sponsor and the monitor8.3 Archiving of data

GCPGCP9. STATISTICS AND CALCULATIONS

9.1 Experimental design9.2 Randomization and blinding9.3 Statistical analysis

10. HANDLING OF AND ACCOUNTABILITY FOR PHARMACEUTICAL PRODUCTS 10.1 Supply and storage10.2 Investigational labelling and packaging 10.3 Responsibilities of the investigator10.4 Responsibilities of the sponsor and the monitor

11. ROLE OF THE DRUG REGULATORY AUTHORITY11.1 General responsibilities11.2 On-site inspections

12. QUALITY ASSURANCE FOR THE CONDUCT OF A CLINICAL

TRIAL )

Good Practices for Quality Good Practices for Quality Control Laboratories Control Laboratories

(GPQCL)(GPQCL)Part One. Management and infrastructure

1. Organization and management2. Quality system3. Control of documentation4. Records5. Data processing equipment6. Personnel7. Premises8. Equipment, instruments and other devices

Part Two. Materials and set-up of equipment, instruments and other devices

9. Specifications archive10. Reagents11. Reference materials12. Calibration, validation and verification of equipment,

instruments and other devices13. Traceability

GPQCLGPQCL

Part Three. Working procedures

14. Incoming sample15. Analytical worksheet16. Testing17. Evaluation of test results18. Retained samples

Part Four. Safety in pharmaceutical control laboratories19. General rules

Good Laboratory Practices Good Laboratory Practices (GLP)(GLP)

INTRODUCTION TO GLP AND ITS APPLICATIONThe history of GLP What is GLP?

GOOD LABORATORY PRACTICE TRAININGINTRODUCTIONTHE FUNDAMENTAL POINTS OF GLPResourcesRulesCharacterizationDocumentationQuality assurance

RESOURCESFacilities: buildings and equipmentPersonnelRULES FOR THE CONDUCT OF STUDIESGeneral aspectsThe study plan or protocolStandard Operating Procedures (SOPs)

GLPGLP

CHARACTERIZATION6

The test itemTest system

DOCUMENTATION – RAW DATA AND DATA COLLECTIONCarrying out procedures and recording observationsRecords and recording

QUALITY 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

GuidelinesGuidelines

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 OrganizationsResearch 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)


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.


• ORGANIZATION & MANAGEMENT• COMPUTER SYSTEMS

HardwareSoftwareData Management

• ARCHIVE FACILITIES• PREMISES• CLINICAL PHASE• CLINICAL LABORATORY• PERSONNEL• QUALITY ASSURANCE


• ETHICS COMMITTEEInformed Consent

• MONITORING• INVESTIGATORS• RECEIVING, STORAGE AND HANDLING

OF INVESTIGATIONAL DRUG PRODUCTS• CASE REPORT FORMS• VOLUNTEERS, RECRUITMENT METHODS• DIETING


• 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


Organization and management

• Legal requirements

• Organization chart

•Key positions, names,

authorized

• Job descriptions and

responsibilities

• List of signatures


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


Software can manage:

• Word processing,

• Data entry,

• Databases,

• Graphics,

• Pharmacokinetics and

• Statistical programmes

• Computer systems validated


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


ARCHIVE FACILITIESSufficient 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


PREMISES

• Conditions to ensure (consideration)adequate safety for the subjectsstage of development of the productpotential risk involved

• Sufficient space (personnel and activities)

• Adequate facilities, including laboratories

• Clinical phase: Areas well organized, activities in logical orderEntry restricted and controlled

Research OrganizationsResearch 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


Clinical Phase

• Sufficient space• Where appropriate, beds should be

available (overnight stay/ type of trial/ investigational drug)

• Facilities for:changing and storing clothesWashing and toilets - easily accessible and appropriate

Research OrganizationsResearch OrganizationsOther 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 Research organizationsorganizations

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


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


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


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


MONITORINGNote: 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


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


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.


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


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


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.


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.


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 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


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


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


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.


• 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 OrganizationsResearch OrganizationsDOCUMENTATION• 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.


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


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


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


• GCPWHO Technical Report Series, No. 850, 1995 (pp.

97-137)

• GLPOECD 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.

ProgramProgram• Group sessions

•Clinical

•Bio-analytical

Good Clinical Practices Good Clinical Practices (GCP)(GCP)

• Q

good clinical practices guilin, prc dr aj van zyl for quality assurance and safety: medicines...

Documents

clinical trial slide

termination of trial

trial management

sponsor slide

handling of data

trial site

archiving of data slide

selection of trial subjects