Reviewing Clinical Trials: A Guide for the Ethics Committee

1 Reviewing Clinical Trials: A Guide for the Ethics Committee Editors Johan PE Karlberg and Marjorie A Speers Clinical Trials Centre, The University of Hong Kong Hong Kong SAR, PR China Association for the Accreditation of human Research Protection Programs, Inc. Washington, DC, USA iii Reviewing Clinical Trials: A Guide for the Ethics Committee Editors Johan PE Karlberg and Marjorie A Speers Clinical Trials Centre, The University of Hong Kong Hong Kong SAR, PR China Association for the Accreditation of human Research Protection Programs, Inc. Washington, DC, USA Reviewing Clinical Trials: A Guide for the Ethics Committee Printed in Hong Kong, PR China, March 2010 Publisher: Karlberg, Johan Petter Einar E-mail: Copyright 2010 Karlberg, Johan Petter Einar ISBN 978-988-19041-1-9 All rights reserved.

2 No part of this book may be reproduced or distributed in any form or by any means, or stored in a database or retrieval system, without prior written permission. 1 Table of Contents Table of Contents _____ 1 Preface _____ 5 Contributors _____ 7 Comments from the Contributors _____ 8 Terms of Use _____ 11 Abbreviations _____ 13 Chapter 1. Introduction _____ 15 Ethics and Bioethics _____ 15 Ethical Codes The Declaration of Helsinki _____ 15 Ethical Codes The ICH GCP Guideline _____ 16 Ethical Codes Ethics Committee _____ 17 No Universal Ethical Code for Ethics committees _____ 17 Ethics Committee Definition _____ 18 Clinical Trials in the Context of Biomedical Research _____ 19 Clinical Trials on Medicinal Products _____ 19 Low and High Risk Clinical Trials _____ 20 Sponsors of Clinical Trials_____ 22 Clinical Trial Players and Their Responsibilities _____ 23 Drug Regulatory Authority _____ 23 Sponsor _____ 24 Investigator _____ 24 Ethics Committee _____ 25 Trial Participant _____ 26 Clinical Trial Services Provider _____ 26 Site Supporting Organisation _____ 27 Data Safety and Monitoring Committee _____ 27 Chapter 2.

3 Features of Clinical Trials _____ 29 Objectives of Clinical Trials _____ 29 Clinical Trial Design _____ 30 The Importance of Clinical Trial Design _____ 30 Clinical Equipoise _____ 32 Superiority, Non-inferiority and Equivalence Clinical Trials _____ 32 Types of Clinical Trial Designs _____ 32 Adaptive Clinical Trial Design _____ 34 Controls of Clinical Trials _____ 35 Placebo Treatment _____ 36 Clinical Trial Outcome/Endpoint _____ 38 Defining Clinical Trial Outcome/Endpoint _____ 38 Primary and Secondary Outcome/Endpoint _____ 39 Surrogate or Clinical Outcome/Endpoint _____ 40 Disadvantages of Using Surrogate Outcome/Endpoint _____ 42 2 Example: Surrogate Outcome/Endpoint in the Cardiovascular Area _____ 42 Randomisation _____ 43 Blinding _____ 44 Sample Size _____ 46 Trial Phases _____ 47 Drug Development at Large _____ 47 The Basics of Trial Phases _____ 48 Phase 0 Trials _____ 50 human Pharmacology/Phase I Clinical Trials _____ 51 Risk Assessment/Management of human Pharmacology/Phase I Trials _____ 52 Therapeutic Exploratory/Phase II Clinical Trials _____ 53 Therapeutic Confirmatory/Phase III Clinical Trials _____ 54 Therapeutic Use/Phase IV Clinical Trials _____ 55 Multicentre Trials _____ 56 Uninterrupted Globalisation of Industry-Sponsored Clinical Trials _____ 58 Chapter 3.

4 Science, Ethics and Quality Assurance of Clinical Trials _____ 61 Research in Humans _____ 61 Essential Clinical Trial EC Review Topics _____ 62 human Research Protection Assurance _____ 63 Clinical Trials of Today Only One Standard _____ 63 Science of Clinical Trials _____ 64 Issues of Ethics of Clinical Trials _____ 65 Risk-Benefit Balance _____ 65 Scientific Evaluation of a Clinical Trial Protocol _____ 66 Informed Consent Process _____ 70 Secondary Analysis of Clinical Database _____ 74 Vulnerable Participants_____ 74 Privacy and Confidentiality _____ 75 Safety Monitoring _____ 75 Participant Recruitment Procedures _____ 77 Qualification of Investigator and Research Staff _____ 79 Financial Conflict of Interest_____ 80 Clinical Trial Insurance and Indemnity _____ 81 Essential Clinical Trial

5 Documents _____ 82 Clinical Trial Registration _____ 83 Dissemination of Trial Results _____ 84 Operation of an EC _____ 85 Issues of EC Procedures _____ 86 Local Laws and Institutional Guidelines _____ 86 Proportionate EC Review: Expedited/Full _____ 86 Acceptability of Trial _____ 87 Continuing Review _____ 88 Trial Amendments _____ 88 Adverse Event Reporting _____ 89 Unanticipated Problems _____ 90 Complaints _____ 90 Appeals _____ 90 3 Non-compliance _____ 91 Suspension or Termination of a Trial _____ 91 Quality Assurance of Clinical Trials _____ 92 Quality Assurance Guidance and Legal Enforcements _____ 92 Assurance at Large_____ 93 Pre- Clinical and Clinical Quality Assurance _____ 94 Monitoring of Site Performance _____ 96 human Research Protection Programme Accreditation _____ 97 The AAHRPP Accreditation Standards _____ 98 Organisation _____ 98 Ethics Committee _____ 100 Investigator and Staff _____ 102 Quality Assurance and Quality Control _____ 103 Chapter 4.

6 Scenarios of Ethics Committee Review _____ 105 Introduction to Practical EC Review _____ 105 Risk-Benefit Balance Scenarios _____ 106 Informed Consent Process Scenarios _____ 109 Vulnerable Participants Scenarios _____ 114 Privacy and Confidentiality Scenarios _____ 117 Data Safety Monitoring Scenarios _____ 119 Participant Recruitment Procedures Scenarios _____ 120 Qualification of Investigator Scenarios _____ 124 Conflict of Interest Scenarios _____ 126 Clinical Trial Insurance and Indemnity Scenarios _____ 129 Essential Clinical Trial Documents Scenarios _____ 132 Clinical Trial Registration Scenarios _____ 133 Dissemination of Trial Results Scenarios _____ 135 Local Laws and Institutional Guidelines Scenarios _____ 136 Proportionate EC Review: Expedited/Full Scenarios _____ 137 Continuing Review Scenarios _____ 140 Acceptability of Trial Scenarios _____ 141 Trial Amendments Scenarios_____ 144 Adverse Event Reporting Scenarios _____ 145 Unanticipated Problems Scenarios _____ 147 Suspension or Termination of a Trial Scenarios _____ 150 Complaints Scenarios _____ 151 Appeals Scenarios _____ 152 Non-compliance Scenarios_____ 153 4 5 Preface The idea for this manual came from Pfizer in the US, which provided the Clinical Trials Centre at The University of Hong Kong, Hong Kong SAR, PR China with a nonbinding grant for its development.

7 The general project layout protocol was accepted by Pfizer in July 2009. Pfizer has not in any way interfered with the project, except for providing nonbinding comments to the final product. The entire text of this manual was written by Johan PE Karlberg. Marjorie A Speers provided considerable and essential comments on the contents and the first and subsequent drafts. A group of international human research protection experts mostly working in non-profit institutions or organisations see Contributors for details reviewed and provided important comments on the contents and final draft. It was solely created with the intention to promote human research protection of participants in Clinical trials. This manual will be translated into numerous languages and is provided free of charge as an electronic file over the Internet ( ) and offered in print for a fee.

8 The objective beyond this project is to establish educational activities, developed around the manual, and jointly organised with leading academic institutions worldwide. Marc B Wilenzick Chief Compliance Counsel, Pfizer R&D, New York, USA contacted Johan PE Karlberg in May 2009 and proposed the project for an Ethics Guide . The first question raised was: Why approach The University of Hong Kong and not a leading medical institution in the US or in Europe? The reply was: Because of the monthly newsletter that you produce, , the Clinical Trial Magnifier, ( ), which may be a valid reason, after all. The project has been a great challenge but also an honour. The final product fits well with the mission of the Clinical Trials Centre as one of the leading academic research organisations in Asia, in line with the mission of the Association for the Accreditation of human Research Protection Programs, Inc.

9 , Washington, DC, the sole non-profit human research accreditation organisation in the US. Once we agreed to consider the invitation, we arranged a phone conference with ten senior Pfizer global staff to discuss the overall objective of the project. It became clear that there was a large worldwide demand for educating Ethics Committee members on how to review Clinical trial protocols, especially in health care organisations outside the leading academic institutions in emerging Clinical trial locations, including Brazil, China, India and Russia, but also in other emerging regions such as Argentina, Bulgaria, Chile, Colombia, Croatia, the Czech Republic, Estonia, Hong Kong, Hungary, Latvia, Lithuania, Malaysia, Mexico, Peru, the Philippines, Poland, Romania, Russia, Serbia, Singapore, Slovakia, South Africa, South Korea, Taiwan, Thailand, Turkey and Ukraine.

10 In 2009 around 25% of all sites involved in industry-sponsored Clinical trials were located in emerging countries, corresponding to 12,500 sites annually or 50 Ethics Committee reviews of Clinical trials every working day. Although the publication is entitled Reviewing Clinical Trials: A Guide for the Ethics Committee , it was developed mindfully to be relevant and useful to all other categories of professionals entering the Clinical trial research area. We highly recommend anyone, whether a novice in the Clinical trials research area or experienced, wishing to learn more about the basic modern concepts of human research Ethics and Clinical trial research methodology to study this manual. The audience can equally be professionals acting as investigators, research nurses, research support staff, Ethics Committee 6 administrators, contract and budget development administrative staff, monitors, project managers, biostatisticians, Clinical data managers, regulators or inspectors.