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G GOOD CLINICAL LABORATORY PRACTICE (GCLP)OOD C for
WHO Library
Cataloguing-in-Publication Data :
Good clinical laboratory practice (GCLP).
1.Clinical trials -
standards.
2.Clinical trials - methods.
3.Laboratories - organization
and administration.
4.Laboratories techniques and
procedures.
5.Ethics, Medical.
UNICEF/UNDP/WorldBank/WHO
Special Programme for Research and Training in Tropical Diseases.
ISBN 978 92 4 159785 2 (NLM
classification: QY 25)
1. PREFAC E
The regulatory environment in
which clinical trials are conducted continues to evolve. The changes are
generally focused on requiring more rigorous control within the organisations
performing clinical trials in order to ensure patient safety and the
reliability of data produced. The global acceptance of the ICH Guideline for
Good Clinical Practice (GCP) and the implementation of the European Union
Clinical Trials Directive (2001/20/EC) are two clear examples of such change.
While the EU Clinical Trials Directive and ICH GCP Guideline clearly specify roles
such as that of the Ethics Committee, the Sponsor and the Investigator to
name just a few, they only vaguely define the standards to be applied in the analysis
of samples from a clinical trial.
The EU Clinical Trial
Directive states that guidance documents may be issued to define the
requirements for various aspects of trials, but it is not clear at this time
whether these will include the analyses of trial samples. The most applicable
reference within ICH that indicate the standards required for the analysis of
samples are in sections 2.13 “Systems with procedures that assure the quality
of every aspect of the trial should be implemented”, and in section 8
“Essential Documents” parts 8.2.12 and 8.3.7.
This document is intended to
provide a framework for the analysis of samples from clinical trials on the
facilities, systems and procedures that should be present to assure the
reliability, quality and integrity of the work and results generated by their
contribution to a clinical trial.
2. SCOPE
It is recommended that the
framework outlined in this document be adopted by any organisation that
analyses samples generated by a clinical trial. The principles defined in
this framework are intended to be applied equally tothe analysis of a blood
sample for routine safety screening of volunteers (haematology/ biochemistry)
as to pharmacokinetics or even the process for the analysis of ECG traces. The
types of facilities undertaking analyses of clinical samples may include pharmaceutical
company laboratories, contract research organisations (CROs), central
laboratories, pharmacogenetic laboratories, hospital laboratories, clinics, Investigator
sites and specialized analytical services.
3. INTRODUCTION
Good Clinical Practice (GCP) is an international ethical and scientific quality
standard for designing, conducting, recording and reporting trials that
involve the participation of human subjects. Compliance with this standard
provides public assurance that the rights, safety and well-being of trial
subjects are protected, consistent with the principles that have their origin
in the Declaration of Helsinki (ICH GCP Guideline).
Good Laboratory Practice
(GLP) is intended to promote the
quality and validity of test data. It is a managerial concept covering the organizational
process and the conditions under which laboratory studies are planned, performed,
monitored, recorded and reported (OECD GLP Guideline).
Good Clinical Laboratory
Practice (GCLP) applies those principles
established under GLP for data generation used in regulatory submissions
relevant to the analysis of samples from a clinical trial. At the same time
it ensures that the objectives of the GCP principles are carried out. This
ensures the reliability and integrity of data generated by analytical
laboratories. It is recognized that a number of countries are already
applying the GCLP principles to the analysis of clinical trial samples.
Indeed it is possible within some of these countries for clinical
laboratories to be accredited by the National Monitoring Authority.
Some organizations and indeed
countries operate proficiency testing schemes to which laboratories
subscribe. While these ensure the integrity of the analytical process they
may not assure compliance with GCP.
This document is intended to
provide a unified framework for sample analysis to lend credibility to the
data generated and facilitate the acceptance of clinical data by regulatory
authorities from around the world. It is important to recognize that the
framework outlined in this document will be applied across a diverse set of
disciplines involved in the analysis of samples from clinical trials. It is
therefore important to understand that this framework should be interpreted
and applied to the work of those organisations that undertake such analyses
with the objective of assuring the quality of every aspect of the work that
they perform.
4. DEFINITIONS
Analytical Plan: a formal document describing all aspects of the
work to be performed by the trial facility.
Analytical Project Manager:
the individual responsible
for the overall conduct of the work defined by the analytical plan.
Analytical Report: a formal report which may be issued on completion
of the work as detailed in the analytical plan.
Analytical Results: a document(s) containing the results of the
analyses issued on completion of sample analysis.
Facility Records: records that confirm and support non-trial
activities essential to the reconstruction of the work performed. This may
include supporting data such as fridge/ freezer temperature records,
equipment service, maintenance and calibration records.
Investigator: the individual responsible for the conduct of the
clinical trial whose role is as defined by ICH GCP.
Quality Audit: a defined system, including personnel, which is
independent of trial conduct and is designed to assure trial facility
management of compliance with Good Clinical Laboratory Practice.
Raw Data: all original records and documentation, or
verified copies of these, generated by observations and activities during the
conduct of the work. They are necessary for the reconstruction and evaluation
of the reported results. For the purposes of this guideline, “source data”
(ICH GCP) and “raw data” are the same.
Sponsor: an individual, company, institution, or
organization that takes responsibility for the initiation, management, and/or
financing of a clinical trial.
Trial Facility: the persons, premises and facilities necessary for
conducting the work.
Trial Facility Management: the individual(s) within an organization performing
the analysis who is responsible for ensuring that the facility operates
according to Good Clinical Laboratory Practice.
Trial Material: any material from a clinical trial that is to be
analyzed; this may include, but is not limited to the following: samples,
specimens, data, results, ECG traces or x-ray plates.
Trial Protocol: the overall Study Protocol approved by the sponsor
which describes the entire activities which make up the study.
5. ORGAN IZATION AND PERSONNEL
5.1 Trial Facility Management Responsibilities
5.1.1 Trial facility management should ensure that the
principles of Good Clinical Laboratory Practice as defined in this document
are complied with in their facility.
5.1.2 At a minimum it should:
a) ensure that qualified
personnel, appropriate facilities, equipment, and materials are available;
b) maintain a record of the
qualifications, training, experience and job description for each individual
working within the trial facility;
c) ensure that personnel
clearly understand the functions they are to perform and, where necessary,
provide training for these functions;
d) ensure that health and
safety precautions within the trial facility are applied according to
national and/or international regulations;
e) ensure that appropriate
standard operating procedures are established and followed and an historical
file of all standard operating procedures is maintained;
f) ensure that there is a
quality audit programme with designated personnel;
g) ensure as and when
appropriate, a programme of quality control is operated within the trial
facility;
h) ensure an analytical plan
exists which defines the analyses to be performed by the facility. This
instruction maybe included as part of the trial protocol;
i) ensure that any amendments
to the analytical plan are agreed and documented;
j) maintain copies of all
trial protocols and analytical plans;
k) ensure that a sufficient
number of personnel are available for the timely and proper conduct of the
work;
l) for each trial designate
an individual with the appropriate qualifications,
training, and experience as
the Analytical Project Manager before the work is initiated in the trial
facility. If it is necessary to replace the Analytical Project Manager during
a trial, this should be documented;
m) ensure that an individual
or organisation is identified as having responsibility for the management of
the archives used for the retention of trial and facility records;
n) for any work
sub-contracted by the trial facility, trial facility management are
responsible to the sponsor for its conduct.
5.2 Analytical Project Manager Responsibilities
5.2.1 The Analytical Project Manager has the
responsibility for the overall conduct of the analyses performed by the trial
facility and for its report.
5.2.2 These responsibilities should include, but not be
limited to, the following functions:
a) agree to the analytical
plan by dated signature;
b) ensure the procedures
specified in the analytical plan are followed, and that authorisation for any
modification is obtained and documented together with the reasons for change;
c) ensure that all results of
the analyses are fully documented and recorded;
d) sign and date the
analytical report, if issued, to indicate acceptance of responsibility for
the validity of the results and to confirm compliance with Good Clinical
Laboratory Practice;
e) when analytical results
are issued the Analytical Project Manager should ensure that these results
are only issued under the dated signature of an authorized signatory.
f) ensure that after
completion of the analyses, the analytical plan, the analytical report and/or
analytical results, raw data and supporting documentation are archived and
retained.
5.3 Trial Staff Responsibilities
5.3.1 All staff working with trial materials should be
aware of those guidelines that apply to their work.
5.3.2 All staff are responsible for recording raw data
promptly and accurately and in compliance with these guidelines and are
responsible for the quality of their data.
5.3.3 All staff are responsible for following the
instructions given in the trial protocol, analytical plans and standard
operating procedures.
6. FACILITIES
6.1 Trial Facilities
6.1.1 The trial facility should be of suitable size, construction
and location to meet the requirements of the trial and minimize any
disturbances that might interfere with the validity of the trial.
6.1.2 The trial facility should have appropriately
designed areas of sufficient size for the type of work being performed and
provide an adequate degree of separation and security to assure the integrity
of trial samples at all times.
6.1.3 Suitable facilities should be available for the
preparation of trial supplies in order to ensure accurate preparation of such
materials.
6.1.4 There should be appropriate storage areas as
needed for samples and supplies. Storage areas should be separated as
appropriate to prevent contamination or mix up of trial samples or materials.
6.2 Archive Facilities
6.2.1 Where appropriate space should be provided for the
safe and secure archive storage and retrieval of data, reports, samples and
specimens.
6.2.2 If suitable facilities cannot be provided for the
storage of trial records alternative arrangements should be made. This could
include the use of third party contract archive facilities.
6.3 Waste Disposal
6.3.1 The handling and disposal of wastes generated
during the performance of a trial should be carried out in a manner that is
consistent with local regulatory requirements.
7. EQUIPMENT, MATERIALS and REAGENTS
7.1 Equipment
7.1.1 Equipment used in the analysis of trial material
and operation of the trial facility should be suitably located and of
appropriate design and adequate capacity.
7.1.2 Equipment used should be periodically inspected,
cleaned, maintained, and calibrated, as appropriate. Records of such
maintenance and any unscheduled maintenance or calibration should be
retained.
7.1.3 An equipment service schedule listing all relevant
equipment and the schedule of planned service and calibration activities
should be maintained.
7.1.4 Any equipment that is out of service for any
reason should be clearly identified as such.
7.1.5 Equipment users should be suitably qualified and
trained in the operation of the equipment.
7.1.6 In all cases equipment used should be demonstrably
fit for purpose.
7.2 Material
7.2.1 Materials used in the analysis of trial materials
should be demonstrably fit for purpose.
7.3 Reagents
7.3.1 Reagents should be suitably labeled and indicate
the identity, concentration, specific storage instructions and stability.
Stability information may include the preparation date and expiration date.
8. STANDARD OPERATING PROCEDURES (SOPS )
8.1 General
8.1.1 A trial facility should have documented standard
operating procedures approved by Trial Facility Management. These are
intended to ensure the quality and integrity of the work performed and the
data generated.
8.1.2 Standard operating procedures should be
periodically reviewed to ensure that they remain current and up to date.
8.1.3 A list of current standard operating procedures
which includes the version number should be maintained current and up to
date.
8.1.4 Staff within the trial facility should have
immediately available standard operating procedures relevant to the
activities being performed therein. Published textbooks, articles and manuals
may be used as supplements to these standard operating procedures provided
that these are also retained.
8.2 Application
8.2.1 Standard operating procedures should be available
for, but not be limited to, the following types of activities. The details
given under each heading are to be considered as illustrative examples.
a) Trial supplies
Supply, preparation,
labeling, handling, shipment and storage.
b) Equipment
Operation, maintenance,
cleaning, calibration of equipment.
c) Record keeping, reporting, storage, and
retrieval
Coding of trials, data
collection, preparation of reports, indexing systems, handling of data, the
use of computerized data systems and the operation of the archive.
d) Trial materials (where appropriate)
Storage, retrieval and chain
of custody of samples.
e) Preparation of trial
packs.
f) Procedures for receipt,
transfer, sampling, storage, identification and care of trial materials and
samples.
g) Procedures for the
analysis of trial samples.
h) Quality control procedures
The quality control
procedures operated by the trial facility to ensure the quality and accuracy
of results.
i) Quality audit procedures
Operation of quality audit
personnel in performing and reporting trial audits, inspections, and
analytical report reviews.
9 PLANNING
OF THE WORK
9.1 Analytical Plan
9.1.1 For each trial, a written analytical plan should
exist prior to initiation of the work and be available to the staff involved
in the work.
9.1.2 This plan should be agreed to by the dated
signature of the Analytical
Project Manager and Sponsor,
and as appropriate the Investigator.
9.1.3 The analytical plan may form part of the
contractual agreement with the Sponsor or be contained within the trial
protocol.
9.1.4 The analytical plan should be retained as part of
the records for the trial.
9.1.5 All changes, modifications, or revisions to the
agreed analytical plan should be documented, including justification(s).
Agreement by the Analytical Project Manager and Sponsor should be indicated
by dated signatures. Copies of all such amendments should be maintained with the
original analytical plan.
9.2 Content of the Analytical Plan
9.2.1 The analytical plan should be sufficiently detailed
to provide clear instruction to those undertaking the work and contain, but
not be limited to, the following information:
Identification of the work
a) A descriptive title.
b) A statement that indicates
the nature and purpose of the work.
c) A unique identifier that
will link the work within the analytical plan to the trial protocol while
retaining the chain of custody and identity of all trial samples.
Information Concerning the
Sponsor and the Trial Facility
d) Name and address of the
Sponsor.
e) Name and address of the
Investigator.
f) Name and address of the
Trial Facility.
g) Name of the Analytical
Project Manager.
Dates
h) The date of agreement to
the analytical plan by signature of the Analytical Project Manager and the
Sponsor.
i) The proposed starting and
completion dates for the work. Analytical Process
j) The methods to be used
during the analysis of trial materials. Reference
to published analytical
methods may also be made. This should include detailed information on the
analytical design, methods, materials and conditions, type and frequency of
analysis, measurements, observations and examinations to be performed.
k) The preparation and
shipment of materials such as sample kits to be used in the collection of
trial materials must be covered by an analytical plan. A separate plan for
the preparation of trial packs could be produced or such logistics could Be
included in the analytical plan.
l) The type and number of
trial materials to be received by the trial facility.
m) The method and condition
under which trial materials are transported from one location to another.
n) For “blinded” or “coded”
trials the conditions of blinding and the unblinding procedures to be
followed.
Records
o) A list of the records to
be retained and their location on completion of the work.
p) Method of reporting
results.
Quality Audit
q) The quality audit to be
performed to assure the quality and integrity of the data generated and the
accuracy of its reporting.
10. SUB-CONTRACTING
10.1 No analytical or other study related work should
be subcontracted without the prior approval of the sponsor.
10.2 When work is sub-contracted by the trial facility, trial
facility management are responsible to the sponsor for the conduct of this
work.
10.3 Prior to placement of sub-contracted work,
assurance should be obtained to confirm the subcontractor will work in
accordance with Good Clinical Laboratory Practice and any trial requirements.
10.4 The contract for sub-contracted work (agreement,
protocol or analytical plan) should clearly spell out the detail of the
analyses and the retention of trial data.
11. TRIAL MATERIALS
11.1 Receipt
11.1.1 Procedures for the receipt, handling, storage,
retrieval and management of trial materials should be designed to prevent
mix-ups and maintain their integrity. Trial materials should be adequately
identified at all times.
11.1.2 Trial materials should be checked on receipt to
confirm their identification. Records of identity, source, date of arrival,
and condition on arrival should be maintained.
11.2 Chain of Custody
11.2.1 Facilities and procedures should be designed and
operated to maintain trial materials identification and traceability at all
times.
11.2.2 Records should be maintained to allow the
reconstruction of the chain of custody of trial materials received and to
allow the retrospective evaluation of material storage.
11.2.3 Trial material storage areas should be monitored
where controlled conditions are required to maintain the integrity of trial
materials. Contingency plans that define the actions to be taken in the case
of failure of such equipment should be in place. Such plans should ensure the
integrity of the stored trial materials.
11.3 Logistics
11.3.1 When a trial facility prepares sample kits or
materials used for the collection of trial samples, the systems used for the
preparation, distribution, sample collection and return of such materials to
the trial facility must be documented and the systems and procedures used,
validated.
11.3.2 Details of the logistics required on a given trial
should be documented in the analytical plan or similar document approved by
the Sponsor and Analytical Project Manager.
11.3.3 The type of material required, the type and design
of the package, the timing and means of distribution both from the trial
facility to the Investigator site and return, the checks performed and
storage requirements should be detailed in the above document.
11.3.4 The processes involved in these logistics should
be subject to quality control procedures to confirm conformance of practice
with defined requirements.
12. CONDUCT
OF THE WORK
12.1 General
12.1.1 The work should be conducted in accordance with
the Trial Protocol and the analytical plan.
12.1.2 All data generated during the conduct of the
analytical phase should be recorded directly, promptly, accurately, and
legibly. These entries should be signed or initialled and dated.
12.1.3 Any change in the data should be made so as not to
obscure the previous entry, and should indicate the reason for the change and
should be identified by date and signed or initialled by the individual
making the change.
12.2 Computer systems
12.2.1 Computerized systems should meet the general
requirements for equipment as described in this document. Due to the nature
of computerized systems and their key role in operations, further
requirements apply to their use. In all cases computer systems should be
appropriately validated and maintained and be demonstrably fit for purpose.
12.2.2 Computerized systems used to receive, capture,
process or report data should be acquired, developed, tested, released, used,
maintained and retrieved according to established guidelines or laws. These
may include the OECD Monograph “The application of GLP Principles to
computerized systems” the FDA 21CFR Part 11: Electronic Records, Electronic Signatures,
Rule and the FDA Guideline for the use of computer systems in the conduct of
clinical trials.
12.2.3 Procedures that address the security and operation
of the computer systems should exist. These should include the maintenance of
a data audit trail, the date/time and individual responsible for the
collection of the data, system change control procedures, maintenance and
system security procedures that ensure the integrity of trial data.
12.2.4 Access to computer systems should be restricted to
authorized personnel.
12.2.5 If data is retained electronically means should
exist to ensure the data held can always be retrieved.
12.3 Method
validation
12.3.1 The selection of instrument platforms and
analytical methodologies should take into account current regulatory
standards and sponsor expectations, where appropriate.
12.3.2 Each analytical method used in the analysis of
trial materials should be appropriately documented, validated, controlled and
approved. Changes to a method should be controlled and validated and result
in the issue of a further version of the method.
12.3.3 Each analytical method should be appropriately
validated to establish and demonstrate its fitness for purpose.
12.3.4 Records to demonstrate the validity and
suitability of such methods within the trial facility should be retained.
12.3.5 Analytical platforms/methods should not be changed
during the course of a trial, without prior consultation and agreement with
the Sponsor. Such changes must be controlled, documented and appropriately
authorized and may result in the need for further method validation.
12.4 Processing trial materials
12.4.1 Trial material should be analysed and reported
within a time frame
consistent with patient
safety issues and trial protocol, analytical plan, standard operating
procedure and any contractual requirements.
Repeat analysis
12.4.2 The laboratory should have documented procedures
governing rules for repeat analysis consistent with pharmaceutical industry
standards. These may be included within the analytical plan.
12.4.3 Specific rules covering the performance of repeat
analysis may also be covered in the trial protocol or analytical plan.
Safety
12.4.4 Laboratory procedures should take account of local
legislation and standard practice in addressing the safe handling of
hazardous substances and trial materials.
13. REPORTING
RESULTS
13.1 General
13.1.1 There are two basic types of report that might be
produced when reporting results from analytical work.
1) Analytical Report: a formal report which may be issued on
completion of the work detailed in the analytical plan.
2) Analytical Results: a document(s) containing just the results which is
usually issued rapidly on completion of sample analysis on a given day.
13.1.2 The analytical plan should indicate the type of
reporting mechanism to be followed and the timeline for issuance of any such
documents.
13.1.3 The decision as to the type of document produced
should be agreed upon by the Sponsor and Analytical Project Manager and, when
appropriate, the Investigator.
Issue of reports
13.1.4 All results should be subject to a quality control
review to ensure the accuracy of the information produced.
13.1.5 Copies of analytical reports or analytical results
should be provided to the Sponsor and Investigator, as appropriate.
13.1.6 A copy of all issued analytical reports and
analytical results should be retained by the trial facility.
13.2 Analytical Report
13.2.1 The analytical report should be signed and dated
by the Analytical Project Manager to indicate acceptance of responsibility
for the validity of the data reported. The extent of compliance with these
principles should be indicated.
13.3 Content of the Analytical Report
An analytical report should
contain, but not be limited to, the following:
a) Identification of the
analytical work by a descriptive title and identification number;
b) The clinical trial number;
c) Name and address of the
Sponsor;
d) Name and address of the
Investigator(s);
e) Name and address of any
trial facilities and any investigator sites involved; including identity of
any Investigators;
f) Name and address of the
Analytical Project Manager;
g) The start and completion
dates of the laboratory work;
h) A Quality Audit Certificate;
i) Description of methods and
materials used including data manipulation techniques and any statistical
methods used;
j) Presentation of the
results;
k) All information and data
required by the analytical plan;
l) The location(s) where the
analytical plan, any specimens required to be retained, data and the final
analytical report are to be stored.
13.3.1 Corrections or additions to a final analytical
report once issued should be in the form of an amendment. Amendments should
clearly state the reasons for corrections or additions and should be
authorized by the dated signature of the Analytical Project Manager.
13.4 Analytical results
13.4.1 Analytical results should be appropriately and
accurately reported. Such reports should include but not necessarily be
limited to the following:
a) Identification of the
analytical work by unique identification number.
b) The clinical trial number.
c) Identity of the Sponsor.
d) Identity of the trial
facilities and the Investigator to whom the results are directed.
e) Name of the Analytical
Project Manager.
f) Presentation of the
results.
13.4.2 The analytical results should be issued under the
dated signature of an authorized signatory.
13.4.3 Analytical results may be reissued when
corrections or additions are required. In such circumstances the amended
document must clearly
indicate that the results
have been amended and the reason for any such change.
14. QUALITY CONTROL
14.1 The trial facility should maintain appropriate quality control
procedures to ensure the quality and accuracy of all aspects of the work
performed and reported.
14.2 Where appropriate, test facilities should
subscribe to membership of
external
accreditation/performance/proficiency schemes to demonstrate the competency
of the work performed.
15. QUALITY
AUDIT
15.1 Independent auditing of the trial facility should
be conducted to assure compliance with the trial protocol, analytical plan,
standard operating procedures and these principles.
15.2 Facilities, systems, equipment, methods, quality
control procedures,
personnel, reports and
documentation should be audited at intervals following a prearranged
programme.
15.3 Audits should be conducted by a competent person(s) designated
by trial facility management. This person(s) should be independent of the
work being audited. Independent audits by external experts may also be
utilized.
15.4 All audit results should be recorded. Reports of
the audits should contain all the observations made during the audit and,
where applicable, any corrective actions.
15.5 Analytical Project Managers and Trial Facility
management should respond to these audit reports in a timely manner.
15.6 Any corrective actions indicated should be tracked
to ensure appropriate implementation.
15.7 On the satisfactory completion of an audit, an
audit certificate should be produced, which identifies the activities
audited, and an indication of the compliance of those activities with this
guideline.
16. STORAGE
AND RETENTION OF RECORDS
16.1 The following should be retained for the period
specified by the appropriate authorities or as defined by the trial protocol:
a) The analytical plan, data,
samples/specimens (where appropriate), analytical results and if issued the
final analytical report;
b) Records of all audits
performed by the quality audit function;
c) Records of the
qualifications, training, experience and job descriptions of personnel;
d) Records and reports of the
maintenance and calibration of equipment;
e) The historical file of
standard operating procedures including the index,
plus any operating manuals
used as part of an SOP;
f) The records and results of
all the quality control tests performed to confirm the accuracy of the work.
16.2 Samples and specimens should be retained as required by GCP but only
as long as the quality of the preparation permits evaluation.
16.3 Trial materials should be retained in such a way as to ensure
the integrity and accessibility to the material retained.
16.4 If a trial facility does not have appropriate facilities for the
storage of such materials in the manner defined the use of commercial
contract archive facilities should be used.
16.5 If a trial facility goes out of business and has no legal
successor, the archive material should be transferred to a suitable archive
designated by the sponsor of the trial.
17. CONFIDENTIALITY
17.1 Procedures for the handling of trial materials,
collection of data and
reporting of results should
be designed to maintain subject confidentiality and study blinding/coding
arrangements within the requirements of Good Clinical Practice, Declaration
of Helsinki and the trial protocol.
17.2 The Sponsor should be informed of any event, either accidental
or arising as a result of an investigation, which may compromise study
blinding.
17.3 Procedures should assure that a sponsor’s proprietary
information is not disclosed to anyone other than authorized individuals.
/TDR.09.978-924-1597852
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Sunday, 15 June 2014
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