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Conducting GCP-compliantClinical Research

Conducting GCP-Compliant Clinical Research. W. Bohaychuk and G. BallCopyright 1999 John Wiley & Sons, Ltd

ISBNs: 0-471-98824-3 (Hardback); 0-470-84626-7 (Electronic)

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Conducting CCP-compliantClinical Research

Wendy BohaychukandCraham BallGood Clinical Research Practices, UK and Canada

JOHNWILEY & SONSChichester New York Weinheim Brisbane. Singapore Toronto



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Copyright 0 999 John Wiley & Sons Ltd,Baffins Lane, Chichester,West Sussex P019 IUD, EnglandNational 0124379777International (+M)1243 779777e-mail (for orders and customer service enquiries):[email protected] our Home Page on http://www.wiley.co.ukor http://www.wiley.com

All Rights Reserved. No part of this publication may be reproduced, stored in aretrieval system, or transmitted, in any form or by any means, electronic, mechanical,photocopying, recording, scanning or otherwise, except under the terms of theCopyright Designs and Patents Act 1988 or under the terms of a licence issued by theCopyright Licensing Agency, 90Tottenham Court Road, London W1P 9HE,UK,without the permission in writing of the PublisherOthe r W iley Editorial OfficesJohn Wiley & Sons, Inc., 605 Third Avenue,New York, NY 10158-0012, USAWILEY-VCH Verlag GmbH, Pappelallee 3,D-69469 Weinheim, GermanyJacaranda Wiley Ltd, 33 Park Road, Milton,Queensland 4064, AustraliaJohn Wiley & Sons (Asia) Pte Ltd, Clementi Loop #02-01,Jin Xing Distripark, Singapore 129809John Wiley & Sons (Canada) Ltd, 22 Worcester Road,Rexdale, Ontario M9W 1L1,CanadaL i b r a y of Congress Cataloging-in-Publication Da t aBohaychuk, Wendy.

and Graham Ball.p. cm.Conducting GCP-compliant clinical research / by Wendy BohaychukIncludes 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 compliantclinical research.R853.C55B641999615'. 19 01 4~ 21 4c 21[615'. CIP

British Li br ay Cataloguing in Publ icat ion D ataA catalogue record for this book is available from the British Library

ISBN 0 471 98824 3Typeset in 11/13 Palatino by Acorn Bookwork, Salisbury, WiltsPrinted and bound in Great Britain by Biddles,Guildford, SurreyThis book is printed on acid-free paper responsibly manufactured from sustainableforestry, in which at least two rees are planted for each one used for paper production



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ContentsAbbreviationsIntroduction

ixxi

1. TheCurrentRules orConductingClinicalResearch 1Theasic Tenets of GCP.1

1.21.3

1.4

1.5

1.6

Checklist 1.1-1.General Systems and Proceduresfor Implementation of GCPThe General Regulatory Framework for GCPStandard Operating ProceduresChecklist 1.3-1. Suggestions for the Format andContents of SOPsChecklist 1.3-2. Topics for SOPs forSponsors/CROsChecklist 1.3-3. Topics for SOPs for nvestigatorsClinical Research AuditingChecklist 1.4-1. Types of Audits which may beUndertaken to Assess GCP ComplianceChecklist 1.4-2. Activities During InvestigatorSite AuditsRegulatory InspectionsChecklist 1.5-1. Conduct During RegulatoryInspections of Study SitesFraud. The Ultimate Non-Compliance n GCPChecklist 1.6-1. Possible Indications of FraudCASE STUDY ONE

2. Setting Up ClinicalStudies2.1 Protocols

345889

10121415171718192526



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vi Contents2.2

2.32.4

2.5

2.62.7

2.8

2.92.10

CRFs and Other Data Collection FormsChecklist 2.2-1. Information to be Collectedin CRFsChecklist 2.2-2. Basic Design Features of CRFsInvestigator BrochuresRegulatory RequirementsChecklist 2.4-1. Items to be Submitted toRegulatory AuthoritiesSelection of Investigators and Study SitesChecklist 2.5-1. Items to Consider at Pre-StudyAssessment VisitsChecklist 2.5-2. Additional Considerations forAssessment of Phase I FacilitiesQualifications of Clinical Research PersonnelStudy AgreementsChecklist 2.7-1. Investigator ResponsibilitiesChecklist 2.7-2. Sponsor/CRO ResponsibilitiesChecklist 2.7-3. Items in Financial AgreementsSelection of CROsChecklist 2.8-1. Items to Review in SelectingCROsChecklist 2.8-2. Contracts with CROsSelecting Clinical LaboratoriesChecklist 2.9-1. Selecting Clinical LaboratoriesInitiation Visits

2931323336363740424244474950505152525354

Checklist 2.10-1. Items to be Addressed at StudyInitiationts 56Checklist 2.10-2. Items to be Provided to theStudy Siteefore thetudy Begins6CASETUDY TWO 57

3. EthicalConsiderations3.1EthicsCommittee/IRBReview and Approval

Checklist 3.1-1. Review by EthicsCommittees/IRBs Before Clinical Studies BeginChecklist 3.1-2. Review by EthicsCommittees/IRBs During and After ClinicalStudiesCommittee/IRB Approval

3.2 Documentation of SafeEthics

656672

7475

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ContentsChecklist 3.2-1. Documentation of EthicsCommittees/IRB Review and ApprovalChecklist 3.2-2. Membership of EthicsCommittees/IRBsChecklist 3.2-3. Working Procedures of EthicsCommittees/IRBsChecklist 3.3-1. Principles for the Conductof Informed ConsentSubjects in Clinical StudiesChecklist 3.4-1. Items for Informed ConsentCASE STUDY THREE

3.3 Conduct of Informed Consent

3.4 Information to be Provided to Study

4. Monitoring and Safety Reporting4.1 Monitoring

Checklist 4.1-1. The Major ObjectivesofMonitoring VisitsChecklist 4.1-2. Management of CROs andClinical Laboratories During StudiesChecklist 4.2-1. Contents of ProtocolAmendmentsChecklist 4.3-1. Adverse Event TerminologyChecklist 4.3-2. Items of Information to Includeon AE Pages in CRFsCASE STUDY FOUR

4.2 ProtocolViolations and Protocol Amendments

4.3 Reporting and RecordingSafetyEvents

5. Collecting Data with Integrity5.1TheDifferenceBetweenSource Documents5.2Access to Source Documents5.3SourceDataVerification

and CRFs

Checklist 5.3-1. Initial Monitor Review andRetrieval of CRFs at the Investigator SiteChecklist 5.3-2. Extent of Source DataVerificationChecklist 5.4-1. Initial Internal CRF Review

5.4Data Queries

vii

79798081858688919798

102104105109109115117117127128130133138139141144

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6.16.26.3

6.4

6.5

6.6

viii Contents5.5eneral Internal Datarocessing455.6eneraltatisticalrocedures46

CASETUDY6. ManagingtudyedicationdDevices 159Preparation of Study Medications/Devices 160

Checklist 6.1-1. General Labelling Requirements 163Shipment of Study Medications/Devices 164Control of Study Medications/Devices atStudy SitesChecklist 6.3-1. Study Medications/DevicesInventoryChecklist 6.3-2. Study Medications/DevicesDispensingecords 171Overall Accountability of StudyMedications/DevicesChecklist 6.4-1. Items to Consider forRe-allocation of Study Medications/Devices77Randomisation and Blinding77Checklist 6.5-1. Information to Consider inRequestsorandomisationchedules 181Management of ClinicalLaboratorySamples182Checklist 6.6-1. Study Site Personnel Briefingfor Management of Clinical Laboratory Samples 183Checklist 6.6-2. Biological Sample AnalysisRequest 184CASETUDY

7. FinalStages in ClinicalStudies7.1 Closure of ClinicalStudiesChecklist 7.1-1. Procedures at Study ClosureVisits7.2FinalClinicalReports7.3 Archiving

Checklist 7.3-1. Typical Documents inSponsor/CRO ArchivesChecklist 7.3-2. Typical Documents inInvestigator ArchivesCASE STUDY 7

Reading ListIndex

189190192193194195196197202207

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Abbreviations

ADRAECIOMSCRACRFCROCVDQFEMEAFDAGCPGLPGMPIBICHIRBNCRSAESOPWHO

adverse drug reactionadverse eventCouncilfor International Organizations of MedicalSciencesclinical research associatecase report form (case record form)contract research organisationcurriculum vitaedata query formEuropean Medicines Evaluation AgencyFood and Drug Administration (USA)good clinical practicegood laboratory practicegood manufacturing practiceinvestigator brochureInternational Conference on HarmonisationInstitutional Review Boardno carbon/copying requiredserious adverse eventstandard operating procedureWorld Health Organization

Subject patient volunteer or healthy volunteerMonitor person who monitors the study. The itle of this in-dividualmay dzj5er according to Sponsorand/or CROpreferences nd ould be the linical monitor, clinicalresearch associate (CM), medical director, etc.



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Introduction

The overall aim of this work is to provide a reference bookwhich describes the general framework for conducting GCP-compliant clinical research, particularly pharmaceuticalindustry clinical research. Hopefully, it is written in simpleenough language so that it is readable to those who are new tothe business: however, we have also included many examplesfrom our years of practice to sustain the interest of a moreexperienced group. Pharmaceutical industry personnel (e.g.monitors, datamanagement personnel, statisticians, medicaladvisers, and study medication or device suppliers from bothsponsors and CROs) will find many helpful hints and examplesof how the situation can go awry. We also hope the book will beof value to new and experienced personnel at clinical study sitesincluding investigators, research nurses, study site co-ordinators,clinical laboratory staff and pharmacists. Members of ethicscommittees and IRBs should find this reference book useful toincrease their understanding of how clinical research operatesfrom the perspective of the pharmaceutical industry, andauditors and inspectors will especially find the book helpfulbecause of the numerous references to audit findings. Theremight be interest from an academic perspective as well.

First of all, we should make it clear that in our opinion there isno such thing as a fully GCP-compliantclinical study. It salmost impossible to achieve the ideal proclaimed in theexisting guidelines and regulations. However, this does notmeah we should not strive for the best standard possible. You



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xii introductionmust think beyond the minimum standard if you really want todo a good job and ensure the best quality possible. Slavishadherence to guidelines and regulations will not work: youmust be convinced of the basic logic, ethics and science behindGCP requirements. Going for the most expedient and cheapestroute will not only result in a poorer standard but it may alsocost lives.How much non-compliance should we tolerate? In 1996, wepublished a book on GCP compliance based on the findings ofour audit experience at 226 investigator study sites, involvingstudies conducted in 20 different countries, and audited by anindependent external audit team between 1991 and 1995. GCPcompliance wascompared for various factors and the datapatterns suggested some interesting trends. First, the overalllevel of GCP compliancewas generally poor across all investiga-tor study sites and far below the expectations of guidelines andregulations. (In many areas, the studies were possibly dangerousfor study subjects, in our opinion.) Second, there were no impor-tant differences in studies with regard to the year in which thestudy 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 periodis possibly too limited to draw conclusions on this point.)Third, there were no important differences in studies whichused a CRO (contract research organisation) compared to thosewhich did not. This appears to be because CROs simply followthe standards of the sponsor responsible for the conduct of thestudy rather than setting consistent and better standards them-selves. Fourth, some slight differences between phases ofstudies were observed, with better compliance in early phasestudies. However, this should not be surprising since a Phase Isingle-centre study with 20 subjects is much easier to controlthan a Phase I11 multicentre multinational study involvingseveral hundred study subjects. Fifth, there were some slightdifferences between therapeutic areas, but this was probablylinked to the standards of the sponsor or CRO managing thestudies. Sixth, overall, there were no basic overall differencesbetween levels of GCP ompliancen different countries.(However, a later analysis of selected items showed some indivi-dual differences between countries: for example, direct access to

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lntroduction xiiisource documents was achieved 100%of the time at US sites, butnot as frequently in other countries.) The only apparent impor-tant differences in levels of GCP compliance were between thedifferent sponsors (mostly pharmaceutical companies)managing the studies. The main conclusions reached fromanalysis of this audit database were that overall standards ofGCP compliance greatly needed improvement, and that stan-dards were only as good as the sponsor managing the studyregardless of where in the world the study wasbeing conducted.In theory, good research could be conducted anywhere providedit was managedproperly.

There is a desperate need to fill the educational gaps in ourunderstanding of GCP. Frankly, weare often appalled athow little those who are doing the job understand their respon-sibilities. CONDUCTINGCP-COMPLIANTLINICALRESEARCHIS A SERIOUS UNDERTAKING. The welfare ofcurrent study subjects and future patients is at stake and wemust never underestimate that the application of GCP requirescontinuous vigilance and care. We must get our prioritiesstraight first. Investigators complain that all this GCPsruining real science. The pharmaceutical industry complainsthat GCP requirements make drug development more expensiveand more time-consuming. Ethics committees and IRBscomplain (rightly) that they do not simply exist to take care ofthe pharmaceutical industry and anyway, who is educatingthemwith regard to thenew regulations and guidelines?Perhaps the smallest voice of objection has come from thehundreds of thousands of study participants, those for whomwe should be most concerned about achieving the right stan-dards. However, the latter situation is changing and theprotests of consumer groups, patient advocates, and those whomust pay for our healthcare, are probably most responsible forthe emergence of the many new guidelines and regulations inthe last 15-20 years. (In the United States, these changesoccurred much earlier.) The study subject obviously has themost to lose from non-compliance with GCP and we have triedhard to look at GCP from the point of view of what is best forthe study subject throughout this book.Many complain that GCP is a boring topic. We try toovercome this in training courses byproviding as manypractical

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xiv Introductionexamples as possible. In this book, we have also taken the sameapproach. At the end of each chapter, there is a case studydescribing all the serious findings of GCP non-compliance at aparticular study site. Further, throughout the book, there areanecdotes describing incidents which might help the readerunderstand certain points. All of these reports are based on trueevents, but the reader will understand that we have had to anon-ymize these as much as possible and must forgive us for a fewgeneralisations. Lists of requirements, which might be tedious ifthey are not relevant to a particular situation, have beenpresented in checklists so that they can be skipped in the firstreading and referenced at a later point. (These checklists are notexhaustive but they might provide a helpful starting point forpreparingtandard operating procedures.) We have alsoincluded our audit findings throughout the text to emphasizethe levels of non-compliance with certain requirements. As inde-pendent auditors, we are in a wonderful position to be able topresent the negative findings as openly as possible. Obviously,it would be difficult for sponsor and CRO personnel, and sitepersonnel, to publicly criticise their operations. We hopereaders will resist the temptation to dismiss negative findings.Criticism is not intended to be anti-industry or anti-research - tis intended to be pro-patients. After all, this is what GCP is allabout.

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Index

Adverse drug reaction 115Adverse events (AEs) 35, 75,93-4,

96monitoring 103relationship to medication/

devices16reporting and recording 109-17

deficiencies 24, 124-5in CRF 117,140

severe and serious113severity 116-17terminology 115-17see also Serious adverse events

(SAEs)Agreements 44-50Archiving94-7

deficiencies 234, 62, 95, 122, 153-investigator documents 196-7sponsor/CROdocuments195-6

4,188

Association for the BritishPharmaceutical Industry (ABPI)46-7

Auditing,lO-15,31activities during investigator site

audits 14-15case study 148GCPcompliance 12-14

Clinical development plan 36Clinical laboratories

contracts 53management 1065monitoring 53reports 62-3responsibilities3selection 5 2 4

(Ilinical reports 189-90case study 197-8discrepancies 198-201final93monitoring 51current rules 1-24personnel qualifications 4 2 4results, integrity and

Clinical research

reproducibility 3Clinical studiesclosurevisits 190-2

final clinical reports 193final stages 189-206information provision 89prematurely terminatedor

suspended 190-1start-up meeting, objectives 55see also Setting up clinical studies

Compensation 46Confidentiality 46agreement 45-6

information 46names 132

Consent forms 65, 71,814, 13940



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208 IndexConsent forms (contd)

deficiencies 149-50drafting requirements 86-91items to be included 88-91non-compliance 82-5see also Informed consentclinical laboratories 53CROs 52AE recording 117,140amendments 30contents 29data contents 128-30data entry 129data verification 133deficiencies 21,60,94,95,96,120,

130,151, 1568,186design 21, 30, 32-3, 60, 94, 120,

151,186function 27information to be collected 31-2language 30monitoring 101-2, 138-9photocopies 125preparation 27,30purpose 128-9review 142, 1 4 4 5safety issues 110contracts 52deficiencies 51items to review in selecting 51-2management 50-2,104-5selection 50-2see also Sponsor/CROs

Contracts 44-50

CRFS 29-33

CROs

Curriculum vitae (CV) 38, 43Dataclarification 142-3Data collection 2,27, 127-58

forms 29-33monitoring 127verificationprocess 127-8

Data conventions 145-6Data corrections 125Datadeficiencies 6 3 4Data errors 141,148, 198

Data processing 145-6discrepancies 142personnel 141

Data queries 141-5Data query form 143, 198Data eview 142-3Dataverification 133, 142-3Declaration of Helsinki 65Documentation 20

deficiencies 22,24,43, 62ethics committee/IRB approvalmedication/devices 159

75-81

Equipment, monitoring 104Errors and fraud 17-18Ethical considerations 25,65-96Ethics committee/IRB

case study 91approval 65-6

documentation 75-81local approval 70local committee 68

commercial 69conflict of interest 77independence 69membership 76-80review 20,66-75

before clinical studies begindeficiencies 92,118,149, 185disapproval 69-70documentation 75-81during and after clinical studies

7 2 4

71, 7 P 5follow-~p 71non-compliance 67-72proposals for changes and other

recommendations 71-2vulnerable populations 77

working procedures 78-81European Medicines EvaluationExternal reviewers 27

Agency EMEA) 5

Facilities, monitoring 104FDA 5



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Index 209language 36preparation 34regulatoryrequirements33-6requirements 33-6

Investigator-initiated investigations176

Investigator signatures, datedeficiencies 64

Investigators, standard operatingprocedures (SOPS) 9-10

Investigators 27as monitors 101assessment 43medication/devices involvementqualifications3responsibilities2,47-9selection 3742deficiencies 58-9review 58-9

176

IRB

Filing, deficiencies 23-4, 62, 95, 122,Financial agreements46,50Fraud 2,17-24

1534,188

and errors 17-18case study 19confidentiality 17-18possible indications 18-19report 18

GCPauditing 12-14basic tenets 2 4general regulatory framework 4-5guideline 106implementation 34

Guidelines 4, 106Human rights protection 2Information sheets

deficiencies 92-3drafting requirements 8G91items to be included 88-91deficiencies 20-1, 59, 92-3, 119,information to be provided to

study subjects 86-91non-compliance2principles for conducting 85-6procedures 13940see also Consent formsInitiation process 26

Initiation reports, deficiencies 55, 61Initiation visits 54-7Inspection 2, 5,15-17

Informedconsent 81-6149-50,185-6

items to be addressed 56report 16study sites17

Insuranceagreements 46Insuranceprovisions 74Investigator agreement 45Investigator brochures

confidentiality 35currency 34-5deficiencies 21-2, 34, 35, 121

Labelling 1624,168deficiencies21requirements 93

Medication/devices 159-88accountability160,172-7blindingprocedures 160,177-82case study 184-5compliance with use 170control and control deficiencies 23,

62,954,121-2,152-3,159-60,168-72,187-8destruction 173-4dispensing records 171-2distribution 161documentation 159environmentalconditions 168-9,informationprovision 89inventory 168,171,172investigator involvement176monitoring 034,165,167-9,172packaging 162-3preparation 1604randomisation 160,170,177-82

173



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210 IndexMedication/devices (contd)

re-allocation 174,177recall 174-5records 140replacement66requisition 161returned supplies 170security 168self-administration 170shipment 23,164-7storage 23use outside limitations of approvedsee also LabellingMonitoring 98-105aims 97clinical laboratories 53data collection127data queries 141-5deficiencies 22-3,61-2,95,101-2,equipment 104investigators role 101Medication/devices 1034, 165,

167-9,172number of study sites handled

100-1reports 22,51responsibilities 22review 99,138-9sample collection104sourcedocuments103staff04tasks to be undertaken 1 024visits 98-9

protocol 175-6

CRFS01-2,138-9

121, 152,187follow up 100

dates 140objectives 1024reports 100

case study 57Multicentre studies 55

Non-complianceconsent orms 82-5ethics committee/IRB review

67-72

informedconsent 82safety reporting 110withregulations 5

Personneldata processing 141qualifications 4 2 4study sites 43

sponsor/CRO 4 3 4Phase I facilities, assessment 42Placebo1Pre-study assessment visits 3840

items to be considered 40-1Pre-study report, deficiencies61Protocols6-9,45,86

amendments 29,60,71,97-8,105-9

contents09deficiencies 119-20

approval 27-9deficiencies19

deficiencies 21, 22, 59-60, 934 ,

distribution 28language 28preparation 26-7regulatory equirements27review 27-9role of 26versions 29,67violations 97-8,105-9

119-20,150-1,186

Questionnaires7Randomisation codebreak envelopesRegulations 4-5

62conformitywith 2non-compliance with 5

Regulatory affairs department 36Regulatory authoritiesinspection. See Inspection

items to be submitted 36-7Regulatory requirements review/Responsibilities agreement 45Risks/benefits, information

approval 3 6 7

provision 90



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Safety data, case study 117-18Safety events31,71

non-compliance 110reporting and recording 109-17

Safety information 112deficiencies 61observation and recording 98under-reporting 110

Safety summaries 112Sample analysis request forms 183,Sample collection

184kits 182monitoring 104Samples 1824handling 183management issues 183 4

Serious adverse events (SAEs) 75,reporting discrepancies 125-6

Setting up clinical studies 25-64deficiencies 21-2,61, 94-5, 121,

934,110-11,115-17

151-2,186-7Source data

deficiencies 24,95,122-6,154-8,188

verification 13341, 143,148Source documents

access 130-2datacontents 128-30dataentry 129deficiencies 63, 1234, 129-30,

1334,154-8monitoring 103purpose 128-9personnel qualifications 4 3 4responsibilities 25-6,45,49-50standard operating procedures

Sponsor/CROs

(SOPS) 8-9Staff monitoring 104Standard operating procedures

(SOPS) 5-10,86,133deficiencies19-20,58,92, 118, 149,format and contents 8pre-studyrequirements 26sponsor/CROs 8-9topics for investigators 9-10topics for sponsor/CROs 8-9

Standards setting and checking 2Statisticalanalysis147Statistical procedures 146-7Statistical report 147Statistical review, case study 148Sfudy co-ordinators 82Study sites

185

items to be provided to 56-7personnel 43pre-study assessment visits 40-1responsibilities 99selection 3742 , 66

Visual analogue scale (VAS) 148, 157

