Textbook of Clinical Trials Textbook of Clinical Trials. Green 2004 John Wiley & Sons, Ltd ISBN: 0-471-98787-5 Textbook of Clinical Trials Edited by David Machin Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre, Singapore and UK Children’s Cancer Study Group, University of Leicester, UK. Simon Day Medicines and Healthcare products Regulatory Agency, London, UK Sylvan Green Arizona Cancer Centre, Tucson, Arizona, USA Section Editors Brian Everitt Institute of Psychiatry, London, UK Stephen George Department of Biostatistics and Informatics, Duke University Medical Centre, Durham, NC, USA Copyright 2004 John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex PO19 8SQ, England Telephone (+44) 1243 779777 Email (for orders and customer service enquiries): cs-books@wiley.uk Visit our Home Page on www.com or www.com All Rights Reserved. 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If professional advice or other expert assistance is required, the services of a competent professional should be sought. Other Wiley Editorial Offices John Wiley & Sons Inc., 111 River Street, Hoboken, NJ 07030, USA Jossey-Bass, 989 Market Street, San Francisco, CA 94103-1741, USA Wiley-VCH Verlag GmbH, Boschstr. 12, D-69469 Weinheim, Germany John Wiley & Sons Australia Ltd, 33 Park Road, Milton, Queensland 4064, Australia John Wiley & Sons (Asia) Pte Ltd, 2 Clementi Loop #02-01, Jin Xing Distripark, Singapore 129809 John Wiley & Sons Canada Ltd, 22 Worcester Road, Etobicoke, Ontario, Canada M9W 1L1 Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be available in electronic books. Library of Congress Cataloging-in-Publication Data Textbook of clinical trials / edited by David Machin . Includes bibliographical references and index.72 4–dc22 2003065147 British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library ISBN 0-471-98787-5 Typeset in 10/12pt Times by Laserwords Private Limited, Chennai, India Printed and bound in Great Britain by Antony Rowe Ltd, Chippenham, Wiltshire This book is printed on acid-free paper responsibly manufactured from sustainable forestry in which at least two trees are planted for each one used for paper production. 1 1 Brief History of Clinical Trials . Ederer 2 General Issues . 11 David Machin 3 Clinical Trials in Paediatrics . Karlberg 4 Clinical Trials Involving Older People . 55 Carol Jagger and Antony J. Arthur 5 Complementary Medicine . Leung CANCER 85 6 Breast Cancer . Smith and Aman U. Buzdar 7 Childhood Cancer . Murphy and Jonathan J. Shuster 8 Gastrointestinal Cancers . 117 Dan Sargent, Rich Goldberg and Paul Limburg 9 Haematologic Cancers . Schiffer and Stephen L. George vi CONTENTS 10 Melanoma . Liu and Vernon K. Sondak 11 Respiratory Cancers . 159 Kyungmann Kim CARDIOVASCULAR . 175 Lawrence Friedman and Eleanor Schron DENTISTRY AND MAXILLO-FACIAL . 191 13 Dentistry and Maxillo-facial . Wong, Colman McGrath and Edward C. 211 Luigi Naldi and Cosetta Minelli PSYCHIATRY . Everitt 16 Alzheimer’s Disease . Thal and Ronald G. Thomas 17 Anxiety Disorders . Katherine Shear and Philip W. Lavori 18 Cognitive Behaviour . 273 Nicholas Tarrier and Til Wykes 19 Depression . 297 Graham Dunn REPRODUCTIVE HEALTH . 315 Gilda Piaggio 21 Gynaecology and Infertility . 337 Siladitya Bhattacharya and Jill Mollison RESPIRATORY 357 22 Respiratory 359 Anders Källén Index . 401 Contributors TONY ARTHUR School of Nursing, Faculty of Medicine and Health Sciences, University of Nottingham, Queens Medical Centre, Nottingham NG7 2UH, UK, Email: tony.uk DONALD BERRY Department of Biostatistics, UTMD Anderson Cancer Centre, 1400 Holcombe Blvd, Box 447, Houston, TX 77030, USA, Email: dberry@odin. BHATTACHARYA Department of Obstetrics and Gynaecology, Aberdeen Maternity Hospital, Cronhill Road, Aberdeen AB25 2ZD, UK, Email: s.uk ARMAN BUZDAR Department of Breast Medical Oncology, The University of Texas, M. Anderson Cancer Centre, Texas, USA SIMON DAY Licensing Division, Medicines and Healthcare products Regulatory Agency, Room 13-205 Market Towers, 1 Nine Elms Lane, London SW8 5NQ, UK, Email: simon.uk GRAHAM DUNN Biostatistics Group, School of Epidemiology and Health Sciences, Stopford Building, Oxford Road, Manchester M13 9PT, UK, Email: graham.uk, chartell@man.uk FRED EDERER The EMMES Corporation, 401 North Washington Street, Suite 700, Rockville, MD 20850, USA, Email: federer@emmes.com viii CONTRIBUTORS BRIAN EVERITT Box 20, Biostatistics Department, Institute of Psychiatry, Denmark Hill, London SE5 8AF, UK, Email: b.uk LARRY FRIEDMAN National Heart, Lung, and Blood Institute, Building 31, Room 5A03, Bethesda, MD 20892 2482, USA, Email: FriedmaL@hlbi.gov STEPHEN GEORGE Department of Biostatistics and Bioinformatics, Duke University Medical Centre, Durham, NC 27710, USA, Email: george001@mc.edu RICH GOLDBERG Medical Oncology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA, Email: goldberg.edu SYLVAN GREEN Arizona Cancer Centre, 1515 N Campbell Ave, PO Box 245024, Tucson, AZ 85724, USA, Email: sgreen@azcc.edu CAROL JAGGER Trent Institute for HSR, Department of Epidemiology and Public Health, University of Leicester, 22–28 Princess Road West, Leicester LE1 6TP, UK, Email: cxj@leicester.uk ANDERS KÄLLÉN AstraZeneca R&D, Lund, Sweden, Email: Anders.com JOHAN KARLBERG Clinical Trials Centre, Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, PR China, Email: jpekarl@hkucc.hk KYUNGMANN KIM Department of Biostatistics & Medical Informatics, University of Wisconsin, 600 Highland Avenue, Box 4675, Madison, WI 53792, USA, Email: kmkim@biostat.edu PHILIP LAVORI VACSPCC (151K), 795 Willow Road, Menlo Park, CA 94025 2539, USA, Email: Philip. LEUNG Department of Orthopaedics & Traumatology, The Chinese University of Hong Kong, Room 74026, 5th Floor, Clinical Sciences Building, Prince of Wales Hospital, Shatin, Hong Kong, Email: pingcleung@cuhk.hk PAUL LIMBURG Gastroenterology and Hepatology, Mayo Clinic, 200 1st Street SW, Rochester, MN 55905, USA, Email: limburg.edu CONTRIBUTORS ix P. LIU SWOG Statistical Centre, MP 557, Fred Hutchinson Cancer Research Centre, 1100 Fairview Avenue North, PO Box 19024, Seattle, WA 98109 1024, USA, Email: pyl@swog.org EDWARD LO Dental Public Health, Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Hong Kong, Email: edward-lo@hku.hk DAVID MACHIN Division of Clinical Trials and Epidemiological Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore, Email: ctedav@nccs.sg, david@machin-home.uk COLAMN MCGRATH Dental Public Health, Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Hong Kong, Email: mcgrath@hkucc.hk COSETTA MINELLI Medical Statistics Group, Department of Epidemiology and Public Health, University of Leicester, 22–28 Princess Road West, Leicester LE1 6TP, UK, Email: cm109@le.uk JILL MOLLISON Department of Public Health, University of Aberdeen, Polwarth Building, Foresterhill, Aberdeen AB25 2ZD, UK, Email: j. MURPHY Children’s Cancer Research Institute, The University of Texas Health Science Centre at San Antonio, 7703 Floyd Curl Drive, MC 7784, San Antonio, TX 78229-3900, USA, Email: murphysb@uthscsa.edu LUIGI NALDI Clinica Dermatologica, Ospedali Riuniti, L.go Barozzi 1, 24100 Bergamo, Italy, Email: luiginal@tin.it GILDA PIAGGIO Special Programme of Research, Development and Research Training in Human Reproduction, Department of Reproductive Health and Research, World Health Organisation, 1211 Geneva 27, Switzerland, Email: piaggiog@who.int DANIEL SARGENT Mayo Clinic, 200 First Street, SW, Kahler 1A, Rochester, MN 55905, USA, Email: sargent.edu CHARLES SCHIFFER Division of Oncology and Hematology/Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA. ELEANOR SCHRON National Heart, Lung, and Blood Institute, Bethesda, MD 20892 2482, USA, Email: schrone@nhlbi.edu x CONTRIBUTORS KATHERINE SHEAR Panic Anxiety and Traumatic Grief Program, Western Psychiatric Institute and Clinic, 3811 O’Hara Street, Pittsburgh, PA 15213, USA, Email: shearmk@msx.edu, corcorannl@msx.edu JON SHUSTER PO Box 100212, College of Medicine, University of Florida, Gainesville, FL 32610 0212, USA, Email: jshuster@biostat.edu TERRY SMITH UTMD Anderson Cancer Centre, 1400 Holcombe Blvd, Box 447, Houston, TX 77030, USA, Email: tsmith@odin. SONDAK University of Michigan Medical Centre, Division of Surgical Oncology, 1500 E Medical Centre Drive, 3306 Cancer/Geriatrics Ctr Box 0932, Ann Arbor, MI 48109 0932, USA, Email: vsondak@umich.edu NICHOLAS TARRIER University of Manchester, Academic Division of Clinical Psychology Education & Research Building, Wythenshawe Hospital, Southmoor Road, Manchester M23 9LT, UK, Email: ntarrier@man.uk LEON THAL Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive, San Diego, CA 92037, USA, Email: lthal@ucsd.edu RONALD THOMAS Department of Family and Preventative Medicine, and Neurosciences, UCSD 9500 Gilman Drive, La Jolla, CA 92039 0645, USA, Email: rgthomas@ucsd. WONG Dental Public Health, Faculty of Dentistry, The University of Hong Kong, 34 Hospital Road, Hong Kong, Email: mcmwong@hkucc.hk TIL WYKES Department of Psychiatry, De Crespigny Park, London SE5 8AF, UK, Email: t.uk Preface This Textbook of Clinical Trials is not a textbook needed from the concept stage, through design, of clinical trials in the traditional sense. Rather, it conduct, monitoring and reporting. catalogues in part both the impact of clinical tri- Some of the developments impacting on clini- als – particularly the randomised controlled trial cal trials have been truly statistical in nature, for –on the practice of medicine and allied fields example Cox’s proportional hazards model, while and on the developments and practice of medical others such as the intention-to-treat (ITT) princi- statistics. The latter has evolved in many ways ple are – in some sense – based more on expe- through the direct needs of clinical trials and the rience. Other important statistical developments consequent interaction of statistical and clinical have not depended on technical advancement, disciplines. The impact of the results from clin- but rather on conceptual advancement, such as ical trials, particularly the randomised controlled the now standard practice of reporting confidence trial, on the practice of clinical medicine and intervals rather then relying solely on p-values at the interpretation stage. Of major importance other areas of health care has been profound. In over this same time period has been the expansion particular, they have provided the essential under- in data processing capabilities and the range of pinning to evidence-based practice in many disci- analytical possibilities only made possible by the plines and are one of the key components for reg- tremendous development in computing power. ulatory approval of new therapeutic approaches However, despite many advances, the majority throughout the world. of randomised controlled trials remain simple in Probably the single most important contribu- design – most often a comparison between two tion to the science of comparative clinical trials randomised groups. was the recognition, more than 50 years ago, that On the medical side there have been many patients should be allocated to the options under changes including new diseases that raise consideration at random. This was the founda- new issues. Thus, as we write, SARS has tion for the science of clinical trial research and emerged: the final extent of the epidemic placed the medical statistician at the centre of the is unknown, diagnosis is problematical and process. Although the medical statistician may be no specific treatment is available. In more at the centre, he or she is by no means alone. established diseases there have been major Indeed the very nature of clinical trial research is advances in the types of treatment available, be multidisciplinary so that a ‘team’ effort is always they in surgical technique, cancer chemotherapy xii PREFACE or psychotropic drugs. Advances in medical the outcome cosmetic then a more conservative and associated technologies are not confined approach to treatment options would be justified.
