Best Practice for … Clinical Monitoring (eBook)

1 An Introduction to Medicine andClinical Research 12
1.1 PRECLINICAL RESEARCH 14
1.2 CLINICAL RESEARCH 15
1.2.1 THE FUNDAMENTAL ELEMENTSOF A CLINICAL TRIAL 16
1.2.2 THE DIFFERENT PARTIES INVOLVED 19
1.2.3 PHASE I 21
1.2.4 PHASE II 22
1.2.5 PHASE III 23
1.2.6 PHASE IV 23
1.2.7 REGULATIONS GUIDING CLINICALRESEARCH 24
1.2.7.1 History 24
1.2.7.2 DeclaraQon of Helsinki 28
1.2.7.3 ICH-GCP 28
1.2.7.4 European legislaQon 30
1.2.7.5 Food & Drug AdministraQon
1.2.7.6 WHO 32
1.2.7.7 Other regulaQons 32
2 What Makes a GoodMonitor? 38
2.1 CHARACTERISTICS 38
2.2 RELATIONSHIP WITH THE INVESTIGATOR 39
2.3 TOOLS OF A MONITOR 40
3 Key Documents in ClinicalTrials / Documents to Know 46
3.1 PROTOCOL 46
3.2 INFORMED CONSENT FORM 48
3.3 CRF 50
3.4 INVESTIGATOR BROCHURE 52
3.5 SOURCE DOCUMENTS 53
4 Investigator Selection 56
4.1 SOURCES 57
4.2 COLD CALL 57
4.3 CONFIDENTIALITY 58
5 How to Prepare a Visit 62
6 Pre-Study Visit 66
6.1 WHAT TO CHECK 66
6.2 HOW TO CHECK 68
6.3 PROTOCOL READINESS 68
6.4 WHAT TO DO AFTER A VISIT 69
6.4.1 FOLLOW-UP LETTER 69
6.4.2 DOCUMENTATION 69
7 The Initiation Visit 76
7.1 TRAINING 76
7.2 HOW TO ... 77
7.3 WHAT TO DO AFTER AN INITIATION VISIT 78
7.3.1 FOLLOW-UP LETTER 78
7.3.2 DOCUMENTATION 79
8 Monitoring Visits 84
8.1 SOURCE DATA VERIFICATION 85
8.1.1 ELECTRONIC CRF 86
8.1.2 PAPER CRF 86
8.2 INVESTIGATIONAL MEDICINAL PRODUCT 87
8.2.1 DEFINITIONS 87
8.2.1.1 Inves7ga7onal medicinal product 87
8.2.1.2 Medical device 87
8.2.1.3 Accessory 88
8.2.1.4 AcYve implantable medical device 88
8.2.1.5 In vitro diagnosYc devices (IVD): 88
8.2.2 IMPORT AND EXPORT 88
8.2.3 IMP DISTRIBUTION 89
8.2.4 TRACKING OF IMP: SHIPMENTS 90
8.2.5 RETURN OF USED/UNUSED IMP 91
8.2.6 TRANSFER 91
8.2.7 CERTIFICATE OF ANALYSIS 91
8.2.8 INVESTIGATIONAL PRODUCT 91
8.2.9 LABELING 92
8.2.10 SITE INVENTORY & PATIENT ACCOUNTABILITY FORM
8.2.11 STORAGE CONDITIONS 93
8.2.12 IMP DESTRUCTION 94
8.3 FILING 94
8.4 SITE MANAGEMENT 95
8.5 RECRUITMENT ISSUES 96
8.5.1 THE RIGHT PROTOCOL 96
8.5.2 SELECTION AND SUPPORT OF STUDY SITES 96
8.5.3 HOW TO HELP SITES? 99
8.5.4 KEEPING TRACK 100
8.6 SAFETY 102
8.6.1 ADVERSE EVENT (AE) 102
8.6.2 ADVERSE DRUG REACTION (ADR) 104
8.6.3 SERIOUS ADVERSE EVENT (SAE) 105
8.6.4 SUSPECTED UNEXPECTED SERIOUSADVERSE REACTION (SUSAR) 106
8.6.5 NOTIFICATION TO EC AND THEAUTHORITIES (EUROPEAN LEGISLATION) 107
8.7 REPORTING BY THE MONITORS 108
8.8 WHAT TO DO AFTER A MONITORING VISIT 109
8.8.1 FOLLOW-UP LETTER 109
9 The Close-Out Visit 114
9.1 WHAT TO DO AFTER A CLOSE-OUT VISIT 115
9.1.1 FOLLOW-UP LETTER 115
9.1.2 DOCUMENTATION 117
10 Audits & Inspections
10.1 HOW TO PREPARE 121
10.2 DURING AN AUDIT OR INSPECTION 121
10.3 AFTER AN AUDIT 123
11 Reporting & Archiving
11.1 COMMUNICATION REPORTS 128
11.1.1 EXTERNAL 128
11.1.2 INTERNAL 129
11.2 SAFETY REPORTING 129
11.2.1 CIOMS REPORTS 129
11.2.2 LINE LISTINGS 129
11.2.3 ANNUAL SAFETY REPORT 130
11.2.4 CLINICAL STUDY REPORT 130
11.3 GOOD DOCUMENTATION 132
11.4 ARCHIVING 133
Appendix1 Answers to Self Study 136
Appendix2 List of Abbreviaions 140
Appendix3 Index 144

3 Key Documents in Clinical Trials / Documents to Know

In this chapter you will learn:
• What informaKon is crucial to know?
• Where can I find this informaKon?
• What are good study documents?

3.1 PROTOCOL

According to ICH-GCP 1.44 a protocol is: “A document that describes the objecnve(s), design, methodology, stansncal consideranons, and organizan- on of a trial. The protocol usually also gives the background and ranonale for the trial, but these could be provided in other protocol referenced documents.” For a clinical monitor the protocol is his basic manual. In the protocol the clinical study is explained in detail in several secnons. These secnons are quite standardized from protocol to protocol, since they are outlined by the Internanonal Conference of Harmonizanon. In general the following secnons are used: General Informanon, Background Informanon, Trial Objecnves and Purpose, Trial Design, Selecnon and Withdrawal of Subjects, Treatment of Subjects, Assessment of Efficacy, Assessment of Safety, Stansncs, Direct Access to Source Data/Documents, Quality Control and Quality Assurance, Ethics, Data Handling and Record Keeping, Financing and Insurance, Publicanon Policy, Supplements (annexes).

You have to read and understand the protocol thoroughly, as you will have discussions with the invesngator later on. Furthermore, youwill need to train or oversee the training of the site personnel on the study treatments, so during the ininanon phase of the trial youwill need to be an expert on the protocol. Of course your company also has the obliganon (ICH-GCP secnon 5.18.2) to train you on the protocol and especially on the indicanon, the conduct of the trial and the relevant stansncal consideranons.