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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) 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 Chichester New York Weinheim Brisbane. Singapore Toronto 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) Copyright 0 1999 John Wiley & Sons Ltd, Baffins Lane, Chichester, West Sussex P019 IUD, England National 017274 937 77 International (+M)1 243 779777 e-mail (for orders and customer service enquiries): [email protected] Visit our Home Page on http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency, 90T ottenham Court Road, London W1P 9HE, UK, without the permission in writing of the Publisher Other Wiley Editorial Offices John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany Jacaranda Wiley Ltd, 33 Park Road, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons (Canada) Ltd, 22 Worcester Road, Rexdale, Ontario M9W 1L1, Canada 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 investigator 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 important 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 standards. (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