A Guide to Clinical Drug Research PDF
Preview A Guide to Clinical Drug Research
A GUIDE TO CLINICAL DRUG RESEARCH A GUIDE TO CLINICAL DRUG RESEARCH edited by ADAM COHEN Professor of Clinical Pharmacology, University of Leiden, Leiden, The Netherlands and Director of the Centre for Human Drug Research, Leiden University Hospital, Leiden, The Netherlands and JOHN POSNER Clinical Pharmacologist Glaxo WeUcome PLC Beckenham, Kent, UK Springer-Science+Business Media, B.V. Library of Congress Cataloging-in-Publication Data A guide to clinical drug research I edited by Adam Cohen and John Posner p. cm. Includes index. 1. Drugs--Research. I. Cohen, Adam. II. Posner, John. IDNLM: 1. Clinical Trials--methods. 2. Research Design. aV771 G946 19951 RM301.27.G85 1995 615' . 19--dc20 DNLM/DLC for Library of Congress 95-8825 ISBN 978-94-015-8465-4 ISBN 978-94-015-8463-0 (eBook) DOI 10.1007/978-94-015-8463-0 Printed on acid-free paper All Rights Reserved © 1995 Springer Science+Business Media Dordrecht Originally published by K1uwer Academic Publishers in 1995. Softcover reprint ofthe hardcover 1st edition 1995 No part of the material protected by this copyright notice may be reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording or by any information storage and retrieval system, without written permission from the copyright owner. Contents Foreword by Prof. Dr. D.D. Breimer Vll List of contributors IX 1. Clinical research: From idea to publication 2. Facilities and equipment 11 3. What does the investigator need to know about the drug? 17 4. The first administration of a new active substance to humans 39 5. Planning and coordinating the study 57 6. The study protocol 65 7. Study design 75 8. Data management and statistical analysis 85 9. Ethical considerations 99 10. Aspects of study conduct III 11. Good clinical practice 127 12. Communicating clinical research 139 13. Clinical research in a developing country 157 14. Computers in clinical research 171 Index 199 v Foreword Clinical drug research forms the experimental basis for efficacy and safety assessment of new therapeutic agents in man. In other words, it allows us to obtain relevant information on how to effectively and safely use a drug in an individual patient. Clinical research is a of key importance for developing and validating new concepts in clinical pharmacology and therapeutics, using already existing and new biologically active agents. Increasingly, it is also conducted to compare different treatment regimens in order to reveal that one is superior to another. In recent years clinical drug research has advanced strongly with the availability of new pharmacokinetic, pharmacodynamic and clinical methods and sophisticated ethical and quality assurance standards, automated and on line data management. This has made such research much more efficient and informative. The quality of the information to be obtained depends on a clear definition of the question to be answered or hypothesis to be tested, a scientifically sound concept has to be translated into an appropriate study design, protocol and data evaluation. Dissemination of the information obtained using the appropriate channels should also be considered an important objective of any study. This book is a 'Guide to Clinical Drug Research' in the literal sense of the word. It provides the reader with relevant information about every aspect of drug research in man, from the initial research idea to the ultimate publication and with every step in between. Never before has such a comprehensive text with such attention to practical detail been put together. The Editors, who started their career working together at the clinical pharmacology department of the Well come Research Laboratories in Beckenham, are very experienced in clinical drug research and very knowledgeable about what is needed to perform such research to up-to-date ethical scientific and technical standards. They have managed to successfully involve a number of colleagues working in clinical pharmacology or other departments in the pharmaceutical industry. In addition, experts from other fields have written about important topics. This book is not only of great importance for scientists and other persons engaged in clinical drug research. Much of the principles and technical aspects discussed are relevant for any type of clinical research. The use of this knowledge in any clinical research project will undoubtedly lead to improved quality and relevance. Douwe D.Breimer, Ph.D. Professor of Pharmacology, Director of Research of the Leidenl Amsterdam Center for Drug Research, Leiden University VII List of contributors Nigel S. Baber, MB, BSc, FRCP, FFPM Jos Hennen, MSc Clinical Pharmacologist Project Leader Clinical Data Glaxo Wellcome PLC Management Systems Greenford Road CHDR Leiden Greenford, Middlesex UB6 ORE, UK Zernikedreef 10 Chapter 3 2333 CL Leiden, The Netherlands Chapter 14 Peter van Brummelen, MD, PhD Director of Clinical Pharmacology William P. Howlett, DTM&H, FRCP (I), F. Hoffmann-la Roche Ltd. PhD Grenzacherstrasse 124 Consultant Physician CH-4002 Basel, Switzerland Kilimanjaro Christian Medical Centre Chapter 12 Moshi, Tanzania Chapter 13 Douglas E. Busch, PhD Busch International Dossiers and Les Huson, PhD Strategies Medical Statistician 95 River Road Glaxo Wellcome PLC Topsfield, MA 01983, USA Wellcome Research Laboratories Chapter 12 Langley Court Beckenham, Kent BR3 3BS, UK Adam F. Cohen, MD, PhD Chapter 7 Professor of Clinical Pharmacology CHDR Leiden Gregor B. E. Jemec, MD Zernikedreef 10 Assistant Professor of Dermatology 2333 CL Leiden, The Netherlands Bispeberg Hospital Editor University of Copenhagen DK-2400 Copenhagen, Denmark Chapter 9 IX LIST OF CONTRIBUTORS Alfred H.J. van Meurs Patricia Sohl, MD Consultant Paediatrician Nyhavn 45-IFAL Kilimanjaro Christian Medical Centre DK-I051 Kopenhagen, Denmark Moshi, Tanzania Chapter 9 current address: Juliana Children's Hospital Jean Soul-Lawton Dr van Welylaan 2 Clinical Research Scientist 2566 ER The Hague, The Netherlands Glaxo Wellcome PLC Chapter 13 Wellcome Research Laboratories Langley Court Fiona Peachy, PhD Beckenham, Kent BR3 3BS, UK International Project Manager Chapter 11 Glaxo Wellcome PLC Wellcome Research Laboratories Steve Warrington, MA, MD, FRCP, Langley Court FFPM Beckenham, Kent BR3 3BS, UK Medical Director Chapter 8 Hammersmith Medicines Research Ltd., Ward E2 John Posner, BSc, PhD, FRCP, FFPM Central Middlesex Hospital Clinical Pharmacologist Acton Lane Glaxo Wellcome PLC London NWlO, UK Wellcome Research Laboratories Chapter 10 Langley Court Beckenham, Kent BR3 3BS, UK Editor x Clinical research: From idea to publication This book is about the practical aspects of performing clinical Introduction drug research starting from the conception of an idea through to publication of a completed piece of research in a peer reviewed scientific journal. In the last two or three decades it has become progressively more difficult to perform good clinical research. There are a number of reasons for this: The volume of scientific literature published is now so vast that it is easy to miss important pieces of research which might impact on the project of interest to you. As the cost of health care rises, concern about the cost-effect iveness of therapeutic agents and strategies has increased. It is no longer good enough to demonstrate that a new medi cation is relatively safe and effective; rather it is necessary to provide evidence that it is superior to another treatment or even that there is an advantage over not treating the patient at all. Concerns about protection of subjects in clinical trials and fears of scientific fraud have led to a situation in which the development and licensing of new medicines has become highly regulated. Good Clinical Practice (GCP) and Good Laboratory Practice (GLP) have certainly contributed to the quality of medical research but place an enormous burden on the clinical researcher both in terms of resources and sheer complexity. Great care must be taken to ensure that all the activities necessary to perform successful clinical research do not compromise patient care. There are times when ethical issues may arise in reconciling these two. The first medicines were given for diseases in which the patho physiology was fairly well understood and for which the indicators of therapeutic efficacy were clear. Thus, in 1948 a trial of streptomycin for the treatment of tuberculosis (generally considered to be the first controlled clinical trial) only required 109 patients to achieve its objectives. Nowadays, many in- 1 / CLINICAL RESEARCH: FROM IDEA TO PUBLICATION fections can be cured by drugs or prevented with vaccines, hypertension, thyroid disorders and even epilepsy can usually be controlled quite well. The endpoints are now much more dif ficult to achieve such as the reduction of secondary myocardial infarction or mortality by long term intervention with a part icular treatment strategy. The current therapeutic challenges are diseases like cancer, rheumatoid arthritis, Alzheimer's dementia, septic shock and multiple sclerosis. The pathophysiology of these conditions is often poorly understood and complex therapeutic strategies are often required. The scale of work involved in determining the efficacy of these strategies is much greater. The ISIS IV study, which investigated three different drugs alone and in combination for the treatment of myocardial infarction required almost 60,000 patients! The complexity of these studies demands a multidisciplinary approach. This has changed the clinical scientist from somebody who could work almost single-handed to a manager of a large group of people and considerable financial resources. Anyone wanting to start a new research project is obviously best advised to do this in an established environment with experience in all operational aspects of performing clinical drug research. However this is not always possible and individual researchers are faced with the unenviable task of discovering for themselves, expending a great deal of effort on reinventing the wheel. Just as a travel guide allows you to visit a town more effectively than by rediscovering all important sites by yourself, this guide should ensure a more rapid entry into the field of clinical research. The emphasis will be on drug research but the principles and most of the detail should be applicable to all types of clinical research. The generation It is not difficult to have good ideas for clinical research. Whilst of ideas still students or during the course of carrying out their clinical duties most doctors are curious about why they do what they do to patients or why a particular disease behaves as it does. Likewise, scientists working in a medical field will be inquisitive by nature and training. This curiosity, the wanting to know 'how' or 'why' is the basis of all ideas for research. Limiting and When you have an idea, write it down as soon as possible. Some focussing ideas people have fleeting ideas at unpredictable moments, while driving home from work or in the middle of the night. It pays to write them down in a rough format so that they won't be 2
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