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: [email protected] Copyright © 2010 Karlberg, Johan Petter Einar ISBN 978-988-19041-1-9 All rights reserved. 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 1.1 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 1.2 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 1.3 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. Features of Clinical Trials _______________________________________ 29 2.1 Objectives of Clinical Trials ________________________________________________ 29 2.2 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 2.3 Controls of Clinical Trials __________________________________________________ 35 Placebo Treatment ____________________________________________________________________ 36 2.4 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 2.5 Randomisation ___________________________________________________________ 43 2.6 Blinding _________________________________________________________________ 44 2.7 Sample Size ______________________________________________________________ 46 2.8 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 2.9 Multicentre Trials ________________________________________________________ 56 Uninterrupted Globalisation of Industry-Sponsored Clinical Trials ___________________________ 58 Chapter 3. Science, Ethics and Quality Assurance of Clinical Trials ______________ 61 3.1 Research in Humans ______________________________________________________ 61 Essential Clinical Trial EC Review Topics _________________________________________________ 62 Human Research Protection Assurance __________________________________________________ 63 Clinical Trials of Today – Only One Standard ______________________________________________ 63 3.2 Science of Clinical Trials ___________________________________________________ 64 3.3 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 Documents ______________________________________________________ 82 Clinical Trial Registration ______________________________________________________________ 83 Dissemination of Trial Results __________________________________________________________ 84 Operation of an EC ____________________________________________________________________ 85 3.4 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 3.5 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 3.6 Human Research Protection Programme Accreditation