Table Of ContentConducting GCP-Compliant Clinical Research. W. Bohaychuk and G. Ball
Copyright © 1999 John Wiley & Sons, Ltd
ISBNs: 0-471-98824-3 (Hardback); 0-470-84626-7 (Electronic)
Conducting GCP-compliant
Clinical Research
Conducting GCP-Compliant Clinical Research. W. Bohaychuk and G. Ball
Copyright © 1999 John Wiley & Sons, Ltd
ISBNs: 0-471-98824-3 (Hardback); 0-470-84626-7 (Electronic)
Conducting CCP-compliant
Clinical Research
Wendy Bohaychuk
and
Craham Ball
Good Clinical Research Practices, UK and Canada
JOHN WILEY & SONS
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Conducting GCP-Compliant Clinical Research. W. Bohaychuk and G. Ball
Copyright © 1999 John Wiley & Sons, Ltd
ISBNs: 0-471-98824-3 (Hardback); 0-470-84626-7 (Electronic)
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Libray of Congress Cataloging-in-Publication Data
Bohaychuk, Wendy.
Conducting GCP-compliant clinical research / by Wendy Bohaychuk
and Graham Ball.
p. cm.
Includes bibliographical references and index.
ISBN 0-471-98824-3 (alk. paper)
1. Clinical trials-Standards. 2. Drugs-Testing-Standards.
I. Ball, Graham. 11. Title. 111. Title: Conducting GCP compliant
clinical research.
R853C. 55B641 999
615'. 19014~21 4c21
98-54676 19011 [615'.
CIP
British Libray Cataloguing in Publication Data
A catalogue record for this book is available from the British Library
ISBN 0 471 98824 3
Typeset in 11/13 Palatino by Acorn Bookwork, Salisbury, Wilts
Printed and bound in Great Britain by Biddles,G uildford, Surrey
This book is printed on acid-free paper responsibly manufactured from sustainable
forestry, in which at least two trees are planted for each one used for paper production
Conducting GCP-Compliant Clinical Research. W. Bohaychuk and G. Ball
Copyright © 1999 John Wiley & Sons, Ltd
ISBNs: 0-471-98824-3 (Hardback); 0-470-84626-7 (Electronic)
Contents
Abbreviations ix
Introduction xi
1. TheC urrentR ulesf orC onductingC linicaRl esearch 1
B1a.1s ic The Tene2ts of GCP
Checklist 1.1-1. General Systems and Procedures
for Implementation of GCP 3
1.2 The General Regulatory Framework for GCP 4
1.3 Standard Operating Procedures 5
Checklist 1.3-1. Suggestions for the Format and
Contents of SOPs 8
Checklist 1.3-2. Topics for SOPs for
Sponsors/CROs 8
Checklist 1.3-3. Topics for SOPs forI nvestigators 9
1.4 Clinical Research Auditing 10
Checklist 1.4-1. Types of Audits which may be
Undertaken to Assess GCP Compliance 12
Checklist 1.4-2. Activities During Investigator
Site Audits 14
1.5 Regulatory Inspections 15
Checklist 1.5-1. Conduct During Regulatory
Inspections of Study Sites 17
1.6 Fraud. The Ultimate Non-Compliancei n GCP 17
Checklist 1.6-1. Possible Indications of Fraud 18
CASE STUDY ONE 19
2. Setting Up ClinicalS tudies 25
2.1 Protocols 26
vi Contents
2.2 CRFs and Other Data Collection Forms 29
Checklist 2.2-1. Information to be Collected
in CRFs 31
Checklist 2.2-2. Basic Design Features of CRFs 32
2.3 Investigator Brochures 33
2.4 Regulatory Requirements 36
Checklist 2.4-1. Items to be Submitted to
Regulatory Authorities 36
2.5 Selection of Investigators and Study Sites 37
Checklist 2.5-1. Items to Consider at Pre-Study
Assessment Visits 40
Checklist 2.5-2. Additional Considerations for
Assessment of Phase I Facilities 42
2.6 Qualifications of Clinical Research Personnel 42
2.7 Study Agreements 44
Checklist 2.7-1. Investigator Responsibilities 47
Checklist 2.7-2. Sponsor/CRO Responsibilities 49
Checklist 2.7-3. Items in Financial Agreements 50
2.8 Selection of CROs 50
Checklist 2.8-1. Items to Review in Selecting
CROs 51
Checklist 2.8-2. Contracts with CROs 52
2.9 Selecting Clinical Laboratories 52
Checklist 2.9-1. Selecting Clinical Laboratories 53
2.10 Initiation Visits 54
Checklist 2.10-1. Items to be Addressed at Study
Visits Initiation 56
Checklist 2.10-2. Items to be Provided to the
StudyB Sei tfeo re Stth ued y Be5g6i n s
STUDY CASE TWO 57
3. EthicCa lo nsiderations 65
3.1E thicsC ommittee/IRBR eview and Approval 66
Checklist 3.1-1. Review by Ethics
Committees/IRBs Before Clinical Studies Begin 72
Checklist 3.1-2. Review by Ethics
Committees/IRBs During and After Clinical
Studies 74
3.2 Documentation of SafeE thics
Committee/IRB Approval 75
Contents vii
Checklist 3.2-1. Documentation of Ethics
Committees/IRB Review and Approval 79
Checklist 3.2-2. Membership of Ethics
Committees/IRBs 79
Checklist 3.2-3. Working Procedures of Ethics
Committees/IRBs 80
3.3 Conduct of Informed Consent 81
Checklist 3.3-1. Principles for the Conduct
of Informed Consent 85
3.4 Information to be Provided to Study
Subjects in Clinical Studies 86
Checklist 3.4-1. Items for Informed Consent 88
CASE STUDY THREE 91
4. Monitoring and Safety Reporting 97
4.1 Monitoring 98
Checklist 4.1-1. The Major Objectiveso f
Monitoring Visits 102
Checklist 4.1-2. Management of CROs and
Clinical Laboratories During Studies 104
4.2 ProtocolV iolations and Protocol Amendments 105
Checklist 4.2-1. Contents of Protocol
Amendments 109
4.3 Reporting and RecordingS afetyE vents 109
Checklist 4.3-1. Adverse Event Terminology 115
Checklist 4.3-2. Items of Information to Include
on AE Pages in CRFs 117
CASE STUDY FOUR 117
5. Collecting Data with Integrity 127
5.1T heD ifferenceB etweenS ource Documents
and CRFs 128
5.2A ccess to Source Documents 130
5.3S ourceD ataV erification 133
Checklist 5.3-1. Initial Monitor Review and
Retrieval of CRFs at the Investigator Site 138
Checklist 5.3-2. Extent of Source Data
Verification 139
5.D4 ata Queries 141
Checklist 5.4-1. Initial Internal CRF Review 144
viii Contents
Gen 5e.r5a l InternaPl rDo ca1et4as s5 i ng
PS1r4toaG6ct iees d ntiuecr raealsl 5 .6
148 FIVE STUDY CASE
6. MMaSendt uaicdg ayitn igo ndDevices 159
6.1 Preparation of Study Medications/Devices 160
Checklist 6.1-1. General Labelling Requirements 163
6.2 Shipment of Study Medications/Devices 164
6.3 Control of Study Medications/Devices at
168 Study Sites
Checklist 6.3-1. Study Medications/Devices
Inventory 171
Checklist 6.3-2. Study Medications/Devices
Records Dispensing 171
6.4 Overall Accountability of Study
Medications/Devices 172
Checklist 6.4-1. Items to Consider for
Re-allocation of Study Medications/Device1s 7 7
6.5 Randomisation a1n7d7 Bl inding
Checklist 6.5-1. Information to Consider in
ReqRufae onsr dt so misaStico hne dules 181
6.6 Management of ClinicaLl aboratoryS amples1 82
Checklist 6.6-1. Study Site Personnel Briefing
for Management of Clinical Laboratory Samples 183
Checklist 6.6-2. Biological Sample Analysis
Forms Request 184
184 SIX STUDY CASE
7. FinalS tages in ClinicalS tudies 189
7.1 Closure of ClinicalS tudies 190
Checklist 7.1-1. Procedures at Study Closure
Visits 192
7.2F inaCl linicaRl eports 193
7.3 Archiving 194
Checklist 7.3-1. Typical Documents in
Sponsor/CRO Archives 195
Checklist 7.3-2. Typical Documents in
Investigator Archives 196
CASE STUDY 7 197
Reading List 202
Index 207
Conducting GCP-Compliant Clinical Research. W. Bohaychuk and G. Ball
Copyright © 1999 John Wiley & Sons, Ltd
ISBNs: 0-471-98824-3 (Hardback); 0-470-84626-7 (Electronic)
Abbreviations
ADR adverse drug reaction
AE adverse event
CIOMS Councilf or International Organizations of Medical
Sciences
CRA clinical research associate
CRF case report form (case record form)
CRO contract research organisation
CV curriculum vitae
DQF data query form
EMEA European Medicines Evaluation Agency
FDA Food and Drug Administration (USA)
GCP good clinical practice
GLP good laboratory practice
GMP good manufacturing practice
IB investigator brochure
ICH International Conference on Harmonisation
IRB Institutional Review Board
NCR no carbon/copying required
SAE serious adverse event
SOP standard operating procedure
WHO World Health Organization
Subject patient volunteer or healthy volunteer
Monitor person who monitors the study. Thet itle of this in-
dividualm ay dzj5er according to Sponsora nd/or CRO
preferencesa ndc ould be thec linical monitor, clinical
research associate (CM), medical director, etc.
Conducting GCP-Compliant Clinical Research. W. Bohaychuk and G. Ball
Copyright © 1999 John Wiley & Sons, Ltd
ISBNs: 0-471-98824-3 (Hardback); 0-470-84626-7 (Electronic)
Introduction
The overall aim of this work is to provide a reference book
which describes the general framework for conducting GCP-
compliant clinical research, particularly pharmaceutical
industry clinical research. Hopefully, it is written in simple
enough language so that it is readable to those who are new to
the business: however, we have also included many examples
from our years of practice to sustain the interest of a more
experienced group. Pharmaceutical industry personnel (e.g.
monitors, datam anagement personnel, statisticians, medical
advisers, and study medication or device suppliers from both
sponsors and CROs) will find many helpful hints and examples
of how the situation can go awry. We also hope the book will be
of value to new and experienced personnel at clinical study sites
including investigators, research nurses, study site co-ordinators,
clinical laboratory staff and pharmacists. Members of ethics
committees and IRBs should find this reference book useful to
increase their understanding of how clinical research operates
from the perspective of the pharmaceutical industry, and
auditors and inspectors will especially find the book helpful
because of the numerous references to audit findings. There
might be interest from an academic perspective as well.
First of all, we should make it clear that in our opinion there is
no such thing as a fully GCP-compliantc linical study. Iti s
almost impossible to achieve the ideal proclaimed in the
existing guidelines and regulations. However, this does not
meah we should not strive for the best standard possible. You
xii introduction
must think beyond the ’minimum standard’ if you really want to
do a good job and ensure the best quality possible. Slavish
adherence to guidelines and regulations will not work: you
must be convinced of the basic logic, ethics and science behind
GCP requirements. Going for the most expedient and cheapest
route will not only result in a poorer standard but it may also
cost lives.
How much non-compliance should we tolerate? In 1996, we
published a book on GCP compliance based on the findings of
our audit experience at 226 investigator study sites, involving
studies conducted in 20 different countries, and audited by an
independent external audit team between 1991 and 1995. GCP
compliance wasc ompared for various factors and the data
patterns suggested some interesting trends. First, the overall
level of GCP compliancew as generally poor across all investiga-
tor study sites and far below the expectations of guidelines and
regulations. (In many areas, the studies were possibly dangerous
for study subjects, in our opinion.) Second, there were no impor-
tant differences in studies with regard to the year in which the
study was conducted. Basically, all the new regulatory efforts,
particularly in Europe, did not show a positive effect on stan-
dards. (However, a survey over a five- to six-year time period
is possibly too limited to draw conclusions on this point.)
Third, there were no important differences in studies which
used a CRO (contract research organisation) compared to those
which did not. This appears to be because CROs simply follow
the standards of the sponsor responsible for the conduct of the
study rather than setting consistent and better standards them-
selves. Fourth, some slight differences between phases of
studies were observed, with better compliance in early phase
studies. However, this should not be surprising since a Phase I
single-centre study with 20 subjects is much easier to control
than a Phase I11 multicentre multinational study involving
several hundred study subjects. Fifth, there were some slight
differences between therapeutic areas, but this was probably
linked to the standards of the sponsor or CRO managing the
studies. Sixth, overall, there were no basic overall differences
between levels of GCPc ompliancei n different countries.
(However, a later analysis of selected items showed some indivi-
dual differences between countries: for example, direct access to
