Reviewing Clinical Trials: A Guide For The Ethics Committee

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Reviewing Clinical Trials:A Guide for the Ethics CommitteeEditorsJohan PE Karlberg and Marjorie A SpeersClinical Trials Centre, The University of Hong KongHong Kong SAR, PR ChinaAssociation for the Accreditation of Human ResearchProtection Programs, Inc.Washington, DC, USA

iiiReviewing Clinical Trials:A Guide for the Ethics CommitteeEditorsJohan PE Karlberg and Marjorie A SpeersClinical Trials Centre, The University of Hong KongHong Kong SAR, PR ChinaAssociation for the Accreditation of Human ResearchProtection Programs, Inc.Washington, DC, USA

Reviewing Clinical Trials: A Guide for the Ethics CommitteePrinted in Hong Kong, PR China, March 2010Publisher: Karlberg, Johan Petter EinarE-mail: editorialboard@ClinicalTrialMagnifier.comCopyright 2010 Karlberg, Johan Petter EinarISBN 978-988-19041-1-9All rights reserved. No part of this book may be reproduced or distributed inany form or by any means, or stored in a database or retrieval system, withoutprior written permission.

1Table of ContentsTable of Contents 1Preface 5Contributors 7Comments from the Contributors 8Terms of Use 11Abbreviations 13Chapter 1. Introduction 151.1 Ethics and Bioethics 15Ethical Codes – The Declaration of Helsinki 15Ethical Codes – The ICH GCP Guideline 16Ethical Codes – Ethics Committee 17No Universal Ethical Code for Ethics Committees 17Ethics Committee Definition 181.2 Clinical Trials in the Context of Biomedical Research 19Clinical Trials on Medicinal Products 19Low and High Risk Clinical Trials 20Sponsors of Clinical Trials 221.3 Clinical Trial Players and Their Responsibilities 23Drug Regulatory Authority 23Sponsor 24Investigator 24Ethics Committee 25Trial Participant 26Clinical Trial Services Provider 26Site Supporting Organisation 27Data Safety and Monitoring Committee 27Chapter 2. Features of Clinical Trials 292.1 Objectives of Clinical Trials 292.2 Clinical Trial Design 30The Importance of Clinical Trial Design 30Clinical Equipoise 32Superiority, Non-inferiority and Equivalence Clinical Trials 32Types of Clinical Trial Designs 32Adaptive Clinical Trial Design 342.3 Controls of Clinical Trials 35Placebo Treatment 362.4 Clinical Trial Outcome/Endpoint 38Defining Clinical Trial Outcome/Endpoint 38Primary and Secondary Outcome/Endpoint 39Surrogate or Clinical Outcome/Endpoint 40Disadvantages of Using Surrogate Outcome/Endpoint 42

2Example: Surrogate Outcome/Endpoint in the Cardiovascular Area 422.5 Randomisation 432.6 Blinding 442.7 Sample Size 462.8 Trial Phases 47Drug Development at Large 47The Basics of Trial Phases 48Phase 0 Trials 50Human Pharmacology/Phase I Clinical Trials 51Risk Assessment/Management of Human Pharmacology/Phase I Trials 52Therapeutic Exploratory/Phase II Clinical Trials 53Therapeutic Confirmatory/Phase III Clinical Trials 54Therapeutic Use/Phase IV Clinical Trials 552.9 Multicentre Trials 56Uninterrupted Globalisation of Industry-Sponsored Clinical Trials 58Chapter 3. Science, Ethics and Quality Assurance of Clinical Trials 613.1 Research in Humans 61Essential Clinical Trial EC Review Topics 62Human Research Protection Assurance 63Clinical Trials of Today – Only One Standard 633.2 Science of Clinical Trials 643.3 Issues of Ethics of Clinical Trials 65Risk-Benefit Balance 65Scientific Evaluation of a Clinical Trial Protocol 66Informed Consent Process 70Secondary Analysis of Clinical Database 74Vulnerable Participants 74Privacy and Confidentiality 75Safety Monitoring 75Participant Recruitment Procedures 77Qualification of Investigator and Research Staff 79Financial Conflict of Interest 80Clinical Trial Insurance and Indemnity 81Essential Clinical Trial Documents 82Clinical Trial Registration 83Dissemination of Trial Results 84Operation of an EC 853.4 Issues of EC Procedures 86Local Laws and Institutional Guidelines 86Proportionate EC Review: Expedited/Full 86Acceptability of Trial 87Continuing Review 88Trial Amendments 88Adverse Event Reporting 89Unanticipated Problems 90Complaints 90Appeals 90

3Non-compliance 91Suspension or Termination of a Trial 913.5 Quality Assurance of Clinical Trials 92Quality Assurance Guidance and Legal Enforcements 92Assurance at Large 93Pre-clinical and Clinical Quality Assurance 94Monitoring of Site Performance 963.6 Human Research Protection Programme Accreditation 973.7 The AAHRPP Accreditation Standards 98Organisation 98Ethics Committee 100Investigator and Staff 102Quality Assurance and Quality Control 103Chapter 4. Scenarios of Ethics Committee Review 1054.1 Introduction to Practical EC Review 105Risk-Benefit Balance – Scenarios 106Informed Consent Process – Scenarios 109Vulnerable Participants – Scenarios 114Privacy and Confidentiality – Scenarios 117Data Safety Monitoring – Scenarios 119Participant Recruitment Procedures – Scenarios 120Qualification of Investigator – Scenarios 124Conflict of Interest – Scenarios 126Clinical Trial Insurance and Indemnity – Scenarios 129Essential Clinical Trial Documents – Scenarios 132Clinical Trial Registration – Scenarios 133Dissemination of Trial Results – Scenarios 135Local Laws and Institutional Guidelines – Scenarios 136Proportionate EC Review: Expedited/Full – Scenarios 137Continuing Review – Scenarios 140Acceptability of Trial – Scenarios 141Trial Amendments – Scenarios 144Adverse Event Reporting – Scenarios 145Unanticipated Problems – Scenarios 147Suspension or Termination of a Trial – Scenarios 150Complaints – Scenarios 151Appeals – Scenarios 152Non-compliance – Scenarios 153

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5PrefaceThe idea for this manual came from Pfizer in the US, which provided the Clinical TrialsCentre at The University of Hong Kong, Hong Kong SAR, PR China with a nonbindinggrant for its development. The general project layout protocol was accepted by Pfizer inJuly 2009. Pfizer has not in any way interfered with the project, except for providingnonbinding comments to the final product.The entire text of this manual was written by Johan PE Karlberg. Marjorie A Speersprovided considerable and essential comments on the contents and the first andsubsequent drafts. A group of international human research protection experts mostlyworking in non-profit institutions or organisations – see Contributors for details –reviewed and provided important comments on the contents and final draft. It wassolely created with the intention to promote human research protection of participantsin clinical trials.This manual will be translated into numerous languages and is provided free of chargeas an electronic file over the Internet (http://www.ClinicalTrialMagnifier.com) andoffered in print for a fee. The objective beyond this project is to establish educationalactivities, developed around the manual, and jointly organised with leading academicinstitutions worldwide.Marc B Wilenzick – Chief Compliance Counsel, Pfizer R&D, New York, USA – contactedJohan PE Karlberg in May 2009 and proposed the project for an ethics guide. The firstquestion raised was: “Why approach The University of Hong Kong and not a leadingmedical institution in the US or in Europe?” The reply was: “Because of the monthlynewsletter that you produce, i.e., the Clinical Trial m), which may be a valid reason, after all. Theproject has been a great challenge but also an honour. The final product fits well withthe mission of the Clinical Trials Centre as one of the leading academic researchorganisations in Asia, in line with the mission of the Association for the Accreditation ofHuman Research Protection Programs, Inc., Washington, DC, the sole non-profit humanresearch accreditation organisation in the US.Once we agreed to consider the invitation, we arranged a phone conference with tensenior Pfizer global staff to discuss the overall objective of the project. It became clearthat there was a large worldwide demand for educating ethics committee members onhow to review clinical trial protocols, especially in health care organisations outside theleading 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. In 2009around 25% of all sites involved in industry-sponsored clinical trials were located inemerging countries, corresponding to 12,500 sites annually – or 50 ethics committeereviews of clinical trials every working day.Although the publication is entitled Reviewing Clinical Trials: A Guide for the EthicsCommittee, it was developed mindfully to be relevant and useful to all other categoriesof professionals entering the clinical trial research area. We highly recommend anyone,whether a novice in the clinical trials research area or experienced, wishing to learnmore about the basic modern concepts of human research ethics and clinical trialresearch methodology to study this manual. The audience can equally be professionalsacting as investigators, research nurses, research support staff, ethics committee

6administrators, contract and budget development administrative staff, monitors, projectmanagers, biostatisticians, clinical data managers, regulators or inspectors.We must stress that nothing in this manual overrules local laws, regulations andguidance. It was developed to provide an overall, theoretical background of clinicaltrials following the general principles spelt out in the Declaration of Helsinki and theICH GCP E6 Guideline. The final chapter includes about 50 ethics committee scenarioscovering most ethical areas in human research. Many of those scenarios have beenutilised in educational activities for ethics committee members and have provenexceptionally helpful in translating theory into practice, especially for novice clinicaltrial research professionals.Our gratitude goes to the advisors for their valuable comments and positive criticism onthe final version of this manual, and to Mr. Marc B Wilenzick at Pfizer R&D, for acting asthe sponsor’s representative, and also as the catalyst for the project. All contributorswho participated as individuals do not represent the institution, organisation orcompany where they are employed.While all the advisors agreed with overall content of this Guide, some occasionallydisagreed with specific content. Each advisor reserves the right to make suchdifferences of opinion public at any time.March 2010Hong Kong SAR, PR China and Washington, DC, USAJohan PE Karlberg and Marjorie A Speers

7ContributorsEditorsJohan PE Karlberg, MD, PhD, BSc, Professor, Director, Clinical Trials Centre, Li Ka ShingFaculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR ChinaMarjorie A Speers, PhD, President, CEO, Association for the Accreditation of HumanResearch Protection Programs, Inc., Washington, DC, USAAuthorJohan PE Karlberg, MD, PhD, BSc, Professor, Director, Clinical Trials Centre, Li Ka ShingFaculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR ChinaInternational AdvisorsMark Barnes, JD, LLM, Attorney, Senior Advisor to the Provost for Research Affairs andChief Research Compliance Officer for Harvard University, School of Law and the Schoolof Public Health, Harvard University, Boston, Massachusetts, USAAmes Dhai, MBChB, FCOG, LLM, Professor, Director, Steve Biko Centre for Bioethics,University of the Witwatersrand, Johannesburg, South AfricaDavid G Forster, JD, MA, CIP, Vice President, Office of Compliance, Western InstitutionalReview Board, Olympia, Washington, USAEdwin C Hui, MD, PhD, Professor, Director, Medical Ethics Unit, Li Ka Shing Faculty ofMedicine, The University of Hong Kong, Hong Kong SAR, PR ChinaJuntra Karbwang, MD, DTM&H, PhD, Special Programme for Research and Training inTropical Diseases (TDR), World Health Organization, Geneva, SwitzerlandBoleslav L Lichterman, MD, PhD, Senior Researcher, Centre for the History of Medicine,Russian Academy of Medical Sciences, Moscow, RussiaUlf Malmqvist, MD, PhD, Head, Clinical Research and Trial Centre, Lund UniversityHospital, Lund, SwedenCarlo Petrini, PhD, Senior Researcher, Responsible for the Bioethics Unit, Office of thePresident, National Institute of Health, Rome, ItalyMildred Z Solomon, EdD, Associate Clinical Professor of Medical Ethics, HarvardMedical School, and Vice President, Education Development Center, Inc., Newton,Massachusetts, USAJohn R Williams, PhD, Adjunct Professor, Department of Medicine, University of Ottawa,Ottawa, CanadaProject Sponsor ContactMarc B Wilenzick, Chief Compliance Counsel, Pfizer R&D, New York, New York, USA

8Comments from the ContributorsWhat is your background/experience within clinical research, human researchethics, research design, Good Clinical Practice (GCP) and quality assurance?Is this Manual a better choice over other books covering research ethics and/orgood clinical practice?Mark Barnes - Harvard University, USA“For many years, I have advised academic medical centers, medical schools andpharmaceutical and medical device companies on issues related

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 . Clinical Equipoise_ 32 Superiority, Non-inferiority and

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