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REFERENCE GUIDE
Contents
The Clinical Research Network, together with the Coordinating Centre, are key parts of the National Institute for
Health Research.
The National Institute for Health research was established by the Department of Health to create a world-class
health research system within the NHS, as part of the government health research strategy. The networks
support and deliver high quality clinical research studies. The NIHR Clinical Research Network delivers research
to make patients, and the NHS, better.
Author of ICH Guidelines is: ICH (International Conference on Harmonisation of Technical Requirements for
Registration of Pharmaceuticals for Human Use)
Editor is: ICH Secretariat
Publisher is: ICH Secretariat, c/o IFPMA, 15 chemin Louis-Dunant,
PO Box 195, 1211 Geneva 20, Switzerland
We fund research support posts in the NHS, and provide training, so that
researchers have access to experienced front-line staff, who can carry out
the additional practical activities required by their study such as obtaining
patient consent for participation, carrying out extra tests, and collecting the
clinical data required for the research.
We provide funding to meet the costs of using facilities such as scanners and
x-rays that are needed in the course of the study, so that research activity
adds value to patient care.
We also provide practical help in identifying and recruiting patients onto
Portfolio studies, so that researchers can be confident of completing the study
on time, and on target.
The rights, safety and well-being of the trial subjects shall prevail over the
interests of science and society.
Each individual involved in conducting a trial shall be qualified by education,
training and experience to perform his tasks.
Clinical trials shall be scientifically sound and guided by ethical principles in all
their aspects.
The necessary procedures to secure the quality of every aspect of the trial
shall be complied with.
The available non-clinical and clinical information on an investigational
medicinal product shall be adequate to support the proposed clinical trial.
Clinical trials shall be conducted in accordance with the principles of the
Declaration of Helsinki.
The protocol shall provide for the definition of inclusion and exclusion of
subjects participating in a clinical trial, monitoring and publication policy.
The investigator and sponsor shall consider all relevant guidance with respect
to commencing and conducting a clinical trial.
All clinical information shall be recorded, handled and stored in such a way
that it can be accurately reported, interpreted and verified, while the
confidentiality of records of the trial subjects remains protected.
11.
12.
13.
14.
Before the trial is initiated, foreseeable risks and inconveniences have been
weighed against the anticipated benefit for the individual trial subject and
other present and future patients. A trial should be initiated and continued only
if the anticipated benefits justify the risks.
The medical care given to, and medical decisions made on behalf of, subjects
shall always be the responsibility of an appropriately qualified doctor or, when
appropriate, of a qualified dentist.
A trial shall be initiated only if an ethics committee and the licensing authority
comes to the conclusion that the anticipated therapeutic and public health
benefits justify the risks and may be continued only if compliance with this
requirement is permanently monitored.
The rights of each subject to physical and mental integrity, to privacy and to
the protection of the data concerning him in accordance with the Data
Protection Act 1998 are safeguarded.
Provision has been made for insurance or indemnity to cover the liability of
the investigator and sponsor, which may arise in relation to the clinical trial.
Details of the laws which govern clinical trials in the UK can be found on the MHRAs
website: https://www.gov.uk/guidance/good-clinical-practice-for-clinical-trials
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.9
2.10
2.11
2.12
2.13
The E6 Guideline for Good Clinical Practice can be found on the ICH website:
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/
good-clinical-practice.html
I. Basic Principles
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
2.
3.
4.
5.
6.
In the treatment of the sick person, the physician must be free to use a new
diagnostic and therapeutic measure, if in his or her judgement it offers hope of
saving life, re-establishing health or alleviating suffering.
The potential benefits, hazards and discomfort of a new method should be
weighed against the advantages of the best current diagnostic and
therapeutic methods.
In any medical study, every patient including those of a control group, if any
should be assured of the best proven diagnostic and therapeutic method.
This does not exclude the use of inert placebo in studies where no proven
diagnostic or therapeutic method exists.
The refusal of the patient to participate in a study must never interfere with the
physician-patient relationship.
If the physician considers it essential not to obtain informed consent, the
specific reasons for this proposal should be stated in the experimental
protocol for transmission to the independent committee (I,2).
The physician can combine medical research with professional care, the
objective being the acquisition of new medical knowledge, only to the extent
that medical research is justified by its potential diagnostic or therapeutic
value for the patient.
2.
3.
4.
n)
o)
p)
q)
r)
s)
t)
The E6 Guideline for Good Clinical Practice can be found on the ICH website:
http://www.ich.org/products/guidelines/efficacy/efficacy-single/article/
good-clinical-practice.html
8.1 Introduction
Essential Documents are those documents which individually and collectively permit
evaluation of the conduct of a trial and the quality of the data produced. These
documents serve to demonstrate the compliance of the investigator, sponsor and
monitor with the standards of Good Clinical Practice and with all applicable
regulatory requirements.
Essential Documents also serve a number of other important purposes. Filing
essential documents at the investigator/institution and sponsor sites in a timely
manner can greatly assist in the successful management of a trial by the
investigator, sponsor and monitor. These documents are also the ones which are
usually audited by the sponsors independent audit function and inspected by the
regulatory authority(ies) as part of the process to confirm the validity of the trial
conduct and the integrity of data collected.
The minimum list of essential documents which has been developed follows. The
various documents are grouped in three sections according to the stage of the trial
during which they will normally be generated: 1) before the clinical phase of the trial
commences, 2) during the clinical conduct of the trial, and 3) after completion or
termination of the trial. A description is given of the purpose of each document, and
whether it should be filed in either the investigator/institution or sponsor files, or both.
It is acceptable to combine some of the documents, provided the individual elements
are readily identifiable.
Trial master files should be established at the beginning of the trial, both at the
investigator/institutions site and at the sponsors office. A final close-out of a trial can
only be done when the monitor has reviewed both investigator/institution and
sponsor files and confirmed that all necessary documents are in the appropriate files.
Any or all of the documents addressed in this guideline may be subject to, and
should be available for, audit by the sponsors auditor and inspection by the
regulatory authority(ies).
10
Title of Document
8.2.1
INVESTIGATORS BROCHURE
8.2.2
8.2.3
8.2.4
8.2.5
8.2.6
Purpose
To document that relevant and current scientific
information about the investigational product has been
provided to the investigator
To document investigator and sponsor agreement to the
protocol/amendment(s) and CRF
Located In Files of
Instigator/
Sponsor
Institution
X
X
X
X
X
X
X
X
(where
required)
X
X
11
8.2.7
8.2.8
8.2.9
8.2.10
8.2.11
Located In Files of
Instigator/
Sponsor
Institution
X
X
Title of Document
Purpose
DATED, DOCUMENTED
APPROVAL/FAVOURABLE OPINION OF
INSTITUTIONAL REVIEW BOARD
(IRB) /INDEPENDENT ETHICS COMMITTEE
(IEC) OF THE FOLLOWING:
protocol and any amendments
CRF (if applicable)
informed consent form(s)
any other written information to be provided to
the subject(s)
advertisement for subject recruitment (if used)
subject compensation (if any)
any other documents given approval/ favourable
opinion
INSTITUTIONAL REVIEW
COARD/INDEPENDENT ETHICS COMMITTEE
COMPOSITION
REGULATORY AUTHORITY(IES)
AUTHORISATION/APPROVAL/NOTIFICATION
OF PROTOCOL (where required)
X
(where
required)
X
(where
required)
X
(where
required)
12
Title of Document
8.2.12
8.2.13
8.2.14
8.2.15
8.2.16
8.2.17
MEDICAL/LABORATORY/TECHNICAL
PROCEDURES/TESTS
certification or
accreditation or
established quality control and/or external
quality assessment or
other validation (where required)
SAMPLE OF LABEL(S) ATTACHED TO
INVESTIGATIONAL PRODUCT CONTAINER(S)
INSTRUCTIONS FOR HANDLING OF
INVESTIGATIONAL PRODUCT(S) AND TRIALRELATED MATERIALS (if not included in
protocol or Investigators Brochure)
SHIPPING RECORDS FOR INVESTIGATIONAL
PRODUCT(S) AND TRIAL-RELATED
MATERIALS
CERTIFICATE(S) OF ANALYSIS OF
INVESTIGATIONAL PRODUCT(S) SHIPPED
DECODING PROCEDURES FOR BLINDED
TRIALS
8.2.18
8.2.19
8.2.20
Purpose
To document competence of facility to perform required
test(s), and support reliability of results
Located In Files of
Instigator/
Sponsor
Institution
X
X
(where
required)
X
X
X
(third party if
applicable)
X
(third party if
applicable)
X
8.3.2
8.3.3
Purpose
To document that investigator is informed in a timely
manner of relevant information as it becomes available
To document revisions of these trial related documents
that take effect during trial
14
Located In Files of
Instigator/
Sponsor
Institution
X
X
X
Title of Document
8.3.4
8.3.5
8.3.6
8.3.7
8.3.8
8.3.9
8.3.10
8.3.11
REGULATORY AUTHORITY(IES)
AUTHORISATIONS/APPROVALS/NOTIFICATIONS
WHERE REQUIRED FOR:
protocol amendment(s) and other documents
CURRICULUM VITAE FOR NEW
INVESTIGATOR(S) AND/OR SUBINVESTIGATOR(S)
UPDATES TO NORMAL VALUE(S)/RANGE(S)
FOR MEDICAL / LABORATORY/ TECHNICAL
PROCEDURE(S)/
TEST(S) INCLUDED IN THE PROTOCOL
UPDATES OF
MEDICAL/LABORATORY/TECHNICAL
PROCEDURES/TESTS
certification or
accreditation or
established quality control and/or external quality
assessment or
other validation (where required)
DOCUMENTATION OF INVESTIGATIONAL
PRODUCT(S) AND TRIAL-RELATED MATERIALS
SHIPMENT
CERTIFICATE(S) OF ANALYSIS FOR NEW
BATCHES OF INVESTIGATIONAL PRODUCTS
MONITORING VISIT REPORTS
RELEVANT COMMUNICATIONS OTHER THAN
SITE VISITS
Purpose
To document compliance with applicable regulatory
requirements
Located In Files of
Instigator/
Sponsor
Institution
X
X
(where
required)
(see 8.2.10)
X
(where
required)
(see 8.2.15)
(see 8.2.16)
To document site visits by, and findings of, the monitor
To document any agreements or significant
discussions regarding trial administration, protocol
violations, trial conduct, adverse event (AE) reporting
letters
meeting notes
15
X
X
Title of Document
8.3.12
8.3.13
SOURCE DOCUMENTS
8.3.14
8.3.15
8.3.16
NOTIFICATION BY ORIGINATING
INVESTIGATOR TO SPONSOR OF SERIOUS
ADVERSE EVENTS AND RELATED REPORTS
NOTIFICATION BY SPONSOR AND/OR
INVESTIGATOR, WHERE APPLICABLE, TO
REGULATORY AUTHORITY(IES) AND IRB(S)/
IEC(S) OF UNEXPECTED SERIOUS ADVERSE
DRUG REACTIONS AND OF OTHER SAFETY
INFORMATION
NOTIFICATION BY SPONSOR TO
INVESTIGATORS OF SAFETY INFORMATION
8.3.17
8.3.18
Purpose
To document that consent is obtained in accordance with
GCP and protocol and dated prior to participation of each
subject in trial. Also to document direct access
permission (see 8.2.3)
To document the existence of the subject and
substantiate integrity of trial data collected. To include
original documents related to the trial, to medical
treatment, and history of subject
To document that the investigator or authorised member
of the investigators staff confirms the observations
recorded
To document all changes/additions or corrections made
to CRF after initial data were recorded
Notification by originating investigator to sponsor of
serious adverse events and related reports in accordance
with 4.11
Notification by sponsor and/or investigator, where
applicable, to regulatory authorities and IRB(s)/IEC(s) of
unexpected serious adverse drug reactions in
accordance with 5.17 and 4.11.1 and of other safety
information in accordance with 5.16.2
Notification by sponsor to investigators of safety
information in accordance with 5.16.2
16
Located In Files of
Instigator/
Sponsor
Institution
X
X
(copy)
X
(original)
X
(copy)
X
X
(original)
X
X
(where
required)
Title of Document
8.3.19
8.3.20
8.3.21
8.3.22
8.3.23
INVESTIGATIONAL PRODUCTS
ACCOUNTABILITY AT THE SITE
SIGNATURE SHEET
8.3.24
8.3.25
Purpose
Interim or annual reports provided to IRB/IEC in
accordance with 4.10 and to authority(ies) in accordance
with 5.17.3
To document identification of subjects who entered pretrial screening
To document that investigator/institution keeps a
confidential list of names of all subjects allocated to trial
numbers on enrolling in the trial. Allows investigator/
institution to reveal identity of any subject
To document chronological enrolment of subjects by trial
number
To document that investigational product(s) have been
used according to the protocol
To document signatures and initials of all persons
authorised to make entries and/or corrections on CRFs
To document location and identification of retained
samples if assays need to be repeated
17
Located In Files of
Instigator/
Sponsor
Institution
X
X
(where
required)
X
X
(where
required)
X
X
X
Title of Document
8.4.1
INVESTIGATIONAL PRODUCT(S)
ACCOUNTABILITY AT SITE
8.4.2
DOCUMENTATION OF INVESTIGATIONAL
PRODUCT DESTRUCTION
8.4.3
8.4.4
8.4.5
8.4.6
8.4.7
8.4.8
Purpose
To document that the investigational product(s) have
been used according to the protocol. To documents the
final accounting of investigational product(s) received at
the site, dispensed to subjects, returned by the subjects,
and returned to sponsor
To document destruction of unused investigational
products by sponsor or at site
18
Located In Files of
Instigator/
Sponsor
Institution
X
X
X
(if
destroyed
at site)
X
X
X
X
X
X
(if
applicable)
19
ASR
ATMP
BRC
BRU
CA
CC
CCF
CF
CFR
CI (i)
CI (ii)
CPMS
CRA
CRF (i)
CRF (ii)
CRN
CRO
CSAG
CSG
CSP
20
CTA (i)
CTA (ii)
CTA (iii)
CTA (iv)
CTAAC
CTIMP
CTU
Delegation
of Duties log
DH
DPA
DQ
DSMB
DSUR
ECMC
eCRF
Eligibility
EMA
EPAP
eTMF
EU
EudraCT
FDA
Feasibility
GAfREC
GCP
GLP
GMP
GTAC
HEI
HFEA
HRA
HRA
Approval
HRC
HSE
HTA
HTA
IB
ICF
ICH-GCP
IDMC
IMP
Indemnity
Investigator
IRAS
IRB
IRMER
ISF
ISRCTN
LCRN
LPMS
MCA
mCIA
mCTA
MfHU (CT)
MHRA
mNCA
Monitor
MRC
Multi Centre
Study
ND
NHS
NICE
NIHR
NIHR CRN
NIMP (or
non-IMP)
NK
NOCRI
Nonsubstantial
amendments
NRES
ODP
PI
PIC
PIS
PPIE (or
PPI)
QA
QC
QLQ
R&D
Medicines for Human Use (Clinical Trials) Regulations: SI 2004:1031 and subsequent
amendments 2006:1928, 2006:2984 ,2008:941, 2009:1164 and 2010:1882 are the UK
Statutory Instruments translating EU directives 2001/20/EC and 2005/28/EC into UK
law, laying down the legal requirements for conducting CTIMPs in the UK
Medicines and Healthcare products Regulatory Agency: The UK Competent Authority
(CA) and licensing authority for medicines and medical devices. It replaced both the
Medical Devices Agency (MDA) and the Medicines Control Agency (MCA) in April 2003
model Non-Commercial Agreement: for clinical research studies; standard template for
the UK (use is not obligatory)
The person designated by the sponsor to perform site visits and conduct the monitoring
process; eg check whether there are any deviations from the protocol and that all source
data was transferred into the Case Report Forms correctly
Medical Research Council
A study conducted according to a single protocol but carried out at more than one site
and by more than one investigator; one CI oversees several local PIs
Not done (in CRFs)
National Health Service
National Institute for health and Clinical Excellence: develop evidence-based guidelines
on the most effective ways to diagnose, treat and prevent disease and ill health
National Institute for Health Research: established by Department of Health for England
in 2006 to provide the framework through which DH will position, manage and maintain
the research, research staff and infrastructure of the NHS in England as a virtual
national research facility
National Institute for Health Research Clinical Research Network
Non-Investigational Medicinal Product: product used alongside IMP but not directly
under investigation in the research study, e.g. a challenge agent
Not known (in CRFs)
National Office for Clinical Research Infrastructure
Changes to the details of a study that have no significant implications for the subjects,
the conduct, the management or the scientific value of the study (sometimes referred to
as administrative amendments).
National Research Ethics Service: umbrella organisation responsible for all REC across
the UK (replaced COREC in 2007)
Open Data Platform: an online, open platform which provides secure access to collated
study and recruitment data
Principal Investigator: The lead person at a single site designated as taking
responsibility within the research team for the conduct of the study
Participant Identification Centre: NHS or other organisation which only identifies
participants from a database etc, but recruitment/receiving consent and study conduct
are managed elsewhere
Participant or Patient Information Sheet: An information leaflet given to those who have
been invited to participate in a research study. The sheet is designed to provide the
potential participant with sufficient information to allow that person to make an informed
decision on whether or not they want to take part
Patient and Public Involvement and Engagement
Quality Assurance
Quality Control
Quality of Life Questionnaire
Research and Development: often name of Department within NHS hospitals giving
permission to conduct projects on those facilities with patients/staff
23
RCT
RDS
REC
Research
Passport
RfPB
RGF
SAE
SAR
Screening
SDV
SI (i)
SI (ii)
Site
SIV
SLA
SMO
SmPC
SOP
Substantial
Amendment
SUSAR
TMF
UKCRC
WHO
WMA
24