E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) Guidance for Industry U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) March 2018 Procedural OMB Control No. 0910-0843 Expiration Date 09/30/2020 See additional PRA statement in section 9 of this guidance. E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) Guidance for Industry Additional copies are available from: Office of Communications, Division of Drug Information Center for Drug Evaluation and Research Food and Drug Administration 10001 New Hampshire Ave., Hillandale Bldg., 4th Floor Silver Spring, MD 20993-0002 Phone: 885-543-3784 or 301-796-3400; Fax: 301-431-6353 Email: [email protected] http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and/or Office of Communication, Outreach and Development Center for Biologics Evaluation and Research Food and Drug Administration 10903 New Hampshire Ave., Bldg. 71, Room 3128 Silver Spring, MD 20993-0002 Phone: 800-835-4709 or 240-402-8010 Email: [email protected] http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) March 2018 Procedural Contains Nonbinding Recommendations TABLE OF CONTENTS INTRODUCTION ................................................................................................................ 1 l. GLOSSARY ..................................................................................................................... 3 2. THE PRINCIPLES OF ICH GCP ......................................................................... 11 3. INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE (IRB/IEC) ....................................................................................... 12 3.1 Responsibilities ........................................................................................................ 12 3.2 Composition, Functions, and Operations ........................................................... 13 3.3 Procedures ................................................................................................................. 14 3.4 Records ....................................................................................................................... 15 4. INVESTIGATOR ....................................................................................................... 15 4.l Investigator’s Qualifications and Agreements .................................................. 15 4.2 Adequate Resources ................................................................................................. 15 4.3 Medical Care of Trial Subjects ............................................................................. 16 4.4 Communication with IRB/IEC ............................................................................. 16 4.5 Compliance with Protocol ...................................................................................... 17 4.6 Investigational Product(s) ...................................................................................... 17 4.7 Randomization Procedures and Unblinding ..................................................... 18 4.8 Informed Consent of Trial Subjects .................................................................... 18 4.9 Records and Reports ............................................................................................... 22 4.10 Progress Reports ...................................................................................................... 23 4.11 Safety Reporting ..................................................................................................... 23 4.12 Premature Termination or Suspension of a Trial ........................................... 23 4.13 Final Report(s) by Investigator ............................................................................ 24 5. SPONSOR ..................................................................................................................... 24 5.0 Quality Management ............................................................................................... 24 5.l Quality Assurance and Quality Control ............................................................ 25 5.2 Contract Research Organization (CRO) ........................................................... 26 5.3 Medical Expertise ..................................................................................................... 26 5.4 Trial Design ............................................................................................................... 26 5.5 Trial Management, Data Handling, and Recordkeeping ............................... 27 i Contains Nonbinding Recommendations 5.6 Investigator Selection ............................................................................................... 28 5.7 Allocation of Responsibilities .................................................................................. 29 5.8 Compensation to Subjects and Investigators .................................................... 29 5.9 Financing .................................................................................................................... 30 5.10 Notification/Submission to Regulatory Authority(ies) ..................................... 30 5.11 Confirmation of Review by IRB/IEC ................................................................... 30 5.12 Information on Investigational Product(s) ........................................................ 30 5.13 Manufacturing, Packaging, Labeling, and Coding Investigational Product(s) ................................................................................................................... 31 5.14 Supplying and Handling Investigational Product(s) ....................................... 31 5.15 Record Access ............................................................................................................ 32 5.16 Safety Information ................................................................................................... 32 5.17 Adverse Drug Reaction Reporting ....................................................................... 33 5.18 Monitoring ................................................................................................................ 33 5.18.1 Purpose ............................................................................................................. 33 5.18.2 Selection and Qualifications of Monitors ...................................................... 33 5.18.3 Extent and Nature of Monitoring .................................................................. 33 5.18.4 Monitor's Responsibilities.............................................................................. 34 5.18.5 Monitoring Procedures ................................................................................. 36 5.18.6 Monitoring Report ......................................................................................... 36 5.18.7 Monitoring Plan .............................................................................................. 37 5.19 Audit ........................................................................................................................... 37 5.19.1 Purpose ........................................................................................................... 37 5.19.2 Selection and Qualification of Auditors ...................................................... 37 5.19.3 Auditing Procedures ...................................................................................... 37 5.20 Noncompliance ........................................................................................................... 38 5.21 Premature Termination or Suspension of a Trial ........................................... 38 5.22 Clinical Trial/Study Reports ................................................................................. 38 5.23 Multicenter Trials.................................................................................................... 38 6. CLINICAL TRIAL PROTOCOL AND PROTOCOL AMENDMENT(S) .... 39 6.l General Information ............................................................................................... 39 ii Contains Nonbinding Recommendations 6.2 Background Information ....................................................................................... 40 6.3 Trial Objectives and Purpose ............................................................................... 40 6.4 Trial Design ............................................................................................................... 40 6.5 Selection and Withdrawal of Subjects ................................................................. 41 6.6 Treatment of Subjects ............................................................................................. 41 6.7 Assessment of Efficacy .............................................................................................. 41 6.8 Assessment of Safety ................................................................................................. 41 6.9 Statistics ..................................................................................................................... 42 6.10