Guideline for good clinical practice E6(R2)

1 30 Churchill Place Canary Wharf London E14 5EU United Kingdom An agency of the European Union Telephone +44 (0)20 3660 6000 Facsimile +44 (0)20 3660 5555 Send a question via our website European Medicines Agency, 2015. Reproduction is authorised provided the source is acknowledged. 23 July 2015 1 EMA/CHMP/ICH/135/1995 2 Committee for Human Medicinal Products 3 Guideline for good clinical practice E6(R2) 4 Step 2b 5 Adopted by CHMP for release for consultation 23 July 2015 Start of public consultation 4 August 2015 End of consultation (deadline for comments) 3 February 2016 6 7 Comments should be provided using this template. The completed comments form should be sent to 8 9 Guideline for good clinical practice E6(R2) EMA/CHMP/ICH/135/1995 Page 2/75 Document History 10 11 First Codification History Date New Codification November 2005 E6 Approval by the CPMP under Step 3 and release for public consultation.

2 May 1995 E6 E6 Approval by the CPMP under Step 4 and released for information. July 1996 E6 Step 5 corrected version 12 E6 Approval by the CPMP of Post-Step 4 editorial corrections. July 2002 E6(R1) Current E6(R2) Addendum Step 2 version 13 Code History Date E6 Approval by the Steering Committee under Step 2 and release for public consultation. Integrated Addendum to ICH E6(R1) document. Changes are integrated directly into the following sections of the parental Guideline : Introduction, , , , , , , , , , , , , , , , , , , , , , , , 11 June 2015 14 Guideline for good clinical practice E6(R2) EMA/CHMP/ICH/135/1995 Page 3/75 Guideline for good clinical practice E6(R2) 15 Table of contents 16 Introduction .. 7 17 1. Glossary .. 8 18 Adverse Drug Reaction (ADR) .. 8 19 Adverse Event (AE) .. 8 20 Amendment (to the protocol) .. 8 21 Applicable regulatory requirement(s).

3 8 22 Approval (in relation to institutional review boards) .. 8 23 Audit .. 8 24 Audit certificate .. 8 25 Audit report .. 9 26 Audit trail .. 9 27 Blinding/masking .. 9 28 Case Report Form (CRF) .. 9 29 clinical trial/study .. 9 30 clinical trial/study report .. 9 31 Comparator (Product) .. 9 32 Compliance (in relation to trials) .. 10 33 Confidentiality .. 10 34 Contract .. 10 35 Coordinating committee .. 10 36 Coordinating investigator .. 10 37 Contract Research Organization (CRO) .. 10 38 Direct 10 39 Documentation .. 10 40 Essential documents .. 10 41 good clinical practice (GCP) .. 11 42 Independent Data-Monitoring Committee (IDMC) (data and safety monitoring 43 board, monitoring committee, data monitoring committee) .. 11 44 Impartial witness .. 11 45 Independent Ethics Committee (IEC) .. 11 46 Informed consent .. 11 47 Inspection.

4 11 48 Institution (medical) .. 11 49 Institutional Review Board (IRB).. 12 50 Interim clinical trial/study report .. 12 51 Investigational product .. 12 52 Investigator .. 12 53 Investigator / institution .. 12 54 Investigator's brochure .. 12 55 Legally acceptable representative .. 12 56 Monitoring .. 12 57 Guideline for good clinical practice E6(R2) EMA/CHMP/ICH/135/1995 Page 4/75 Monitoring report .. 13 58 Multicentre trial .. 13 59 Nonclinical study .. 13 60 Opinion (in relation to independent ethics committee) .. 13 61 Original medical 13 62 Protocol .. 13 63 Protocol amendment .. 13 64 Quality Assurance (QA) .. 13 65 Quality Control (QC) .. 13 66 Randomization .. 14 67 Regulatory authorities .. 14 68 Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (Serious ADR). 14 69 Source data .. 14 70 Source documents.

5 14 71 Sponsor .. 14 72 Sponsor-Investigator .. 14 73 Standard Operating Procedures (SOPs) .. 15 74 Subinvestigator .. 15 75 Subject/trial subject .. 15 76 Subject identification code .. 15 77 Trial site .. 15 78 Unexpected adverse drug reaction .. 15 79 Vulnerable subjects .. 15 80 Well-being (of the trial subjects) .. 16 81 2. The principles of ICH GCP .. 17 82 3. Institutional Review Board / Independent Ethics Committee (IRB/IEC)83 .. 19 84 Responsibilities .. 19 85 Composition, Functions and Operations .. 20 86 Procedures .. 21 87 Records .. 22 88 4. Investigator .. 23 89 Investigator's Qualifications and Agreements .. 23 90 Adequate Resources .. 23 91 Medical Care of Trial Subjects .. 24 92 Communication with IRB/IEC .. 24 93 Compliance with Protocol .. 25 94 Investigational Product(s) .. 26 95 Randomization Procedures and Unblinding .. 26 96 Informed Consent of Trial Subjects.

6 27 97 Records and Reports .. 30 98 Progress Reports .. 31 99 Safety Reporting .. 32 100 Premature Termination or Suspension of a 32 101 Guideline for good clinical practice E6(R2) EMA/CHMP/ICH/135/1995 Page 5/75 Final Report(s) by Investigator .. 33 102 5. Sponsor .. 34 103 Quality management .. 34 104 Quality assurance and quality control .. 35 105 Contract Research Organization (CRO) .. 36 106 Medical expertise .. 36 107 Trial 36 108 Trial management, data handling, and record keeping .. 37 109 Investigator 39 110 Allocation of responsibilities .. 39 111 Compensation to subjects and investigators .. 39 112 Financing .. 40 113 Notification/submission to regulatory authority(ies) .. 40 114 Confirmation of review by IRB/IEC .. 40 115 The sponsor should obtain from the investigator/institution: .. 40 116 Information on investigational product(s).

7 41 117 Manufacturing, packaging, labelling, and coding investigational product(s) .. 41 118 Supplying and handling investigational product(s) .. 42 119 Record access .. 43 120 Safety information .. 43 121 Adverse drug reaction reporting .. 43 122 Monitoring .. 44 123 Audit .. 47 124 Noncompliance .. 48 125 Premature termination or suspension of a trial .. 48 126 clinical trial/study reports .. 48 127 Multicentre trials .. 49 128 6. clinical trial protocol and protocol amendment(s) .. 50 129 General Information .. 50 130 Background Information .. 50 131 Trial objectives and purpose .. 51 132 Trial 51 133 Selection and withdrawal of 52 134 Treatment of 53 135 Assessment of Efficacy .. 53 136 Assessment of Safety .. 53 137 Statistics .. 54 138 Direct access to source data/documents .. 54 139 Quality control and quality assurance .. 54 140 Ethics.

8 54 141 Data handling and record 55 142 Financing and insurance .. 55 143 Publication policy .. 55 144 Supplements .. 55 145 Guideline for good clinical practice E6(R2) EMA/CHMP/ICH/135/1995 Page 6/75 7. Investigator s brochure .. 56 146 56 147 General considerations .. 56 148 Contents of the investigator s brochure .. 57 149 Appendix 1: .. 61 150 Appendix 2: .. 62 151 8. Essential documents for the conduct of a clinical trial .. 63 152 63 153 Before the clinical phase of the trial commences .. 64 154 During the clinical Conduct of the Trial .. 68 155 After Completion or Termination of the Trial .. 74 156 157 158 Guideline for good clinical practice E6(R2) EMA/CHMP/ICH/135/1995 Page 7/75 Introduction 159 good clinical practice (GCP) is an international ethical and scientific quality standard for 160 designing, conducting, recording and reporting trials that involve the participation of human subjects.

9 161 Compliance with this standard provides public assurance that the rights, safety and well-being of trial 162 subjects are protected, consistent with the principles that have their origin in the Declaration of 163 Helsinki, and that the clinical trial data are credible. 164 The objective of this ICH GCP Guideline is to provide a unified standard for the European Union (EU), 165 Japan and the United States to facilitate the mutual acceptance of clinical data by the regulatory 166 authorities in these jurisdictions. 167 The Guideline was developed with consideration of the current good clinical practices of the European 168 Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries and 169 the World Health Organization (WHO). 170 This Guideline should be followed when generating clinical trial data that are intended to be 171 submitted to regulatory authorities.

10 172 The principles established in this Guideline may also be applied to other clinical investigations that may 173 have an impact on the safety and well-being of human subjects. 174 ADDENDUM 175 Since the development of the ICH GCP Guideline , the scale, complexity, and cost of clinical trials have 176 increased. Evolutions in technology and risk management processes offer new opportunities to 177 increase efficiency and focus on relevant activities. This Guideline has been amended to encourage 178 implementation of improved and more efficient approaches to clinical trial design, conduct, oversight, 179 recording and reporting while continuing to ensure human subject protection and data integrity. 180 Standards regarding electronic records and essential documents intended to increase clinical trial 181 quality and efficiency have also been updated. 182 This ICH GCP Guideline addendum provides a unified standard for the European Union (EU), Japan, the 183 United States, Canada and Switzerland to facilitate the mutual acceptance of clinical data by the 184 regulatory authorities in these jurisdictions.