Randomised Clinical Trials
Design, Practice and Reporting
Second Edition
David Machin
Leicester Cancer Research Centre
University of Leicester, Leicester, UK
Medical Statistics Group, School of Health and Related Research
University of Sheffield, Sheffield, UK
Peter M. Fayers
Institute of Applied Health
University of Aberdeen, Scotland, UK
Bee Choo Tai
Saw Swee Hock School of Public Health
National University of Singapore and National University Health System Singapore
Singapore, Singapore
This edition first published 2021, © 2021 John Wiley & Sons Ltd
Edition History John Wiley & Sons, Ltd (1e, 2010)
All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, except as permitted by law. Advice on how to obtain permission to reuse material from this title is available at http://www.wiley.com/go/permissions.
The right of David Machin, Peter M. Fayers, and Bee Choo Tai to be identified as the authors of this work has been asserted in accordance with law.
Registered Office(s) John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
Editorial Office 9600 Garsington Road, Oxford, OX4 2DQ, UK
For details of our global editorial offices, customer services, and more information about Wiley products visit us at www.wiley.com.
Wiley also publishes its books in a variety of electronic formats and by print‐on‐demand. Some content that appears in standard print versions of this book may not be available in other formats.
Limit of Liability/Disclaimer of Warranty The contents of this work are intended to further general scientific research, understanding, and discussion only and are not intended and should not be relied upon as recommending or promoting scientific method, diagnosis, or treatment by physicians for any particular patient. In view of ongoing research, equipment modifications, changes in governmental regulations, and the constant flow of information relating to the use of medicines, equipment, and devices, the reader is urged to review and evaluate the information provided in the package insert or instructions for each medicine, equipment, or device for, among other things, any changes in the instructions or indication of usage and for added warnings and precautions. While the publisher and authors have used their best efforts in preparing this work, they make no representations or warranties with respect to the accuracy or completeness of the contents of this work and specifically disclaim all warranties, including without limitation any implied warranties of merchantability or fitness for a particular purpose. No warranty may be created or extended by sales representatives, written sales materials or promotional statements for this work. The fact that an organization, website, or product is referred to in this work as a citation and/or potential source of further information does not mean that the publisher and authors endorse the information or services the organization, website, or product may provide or recommendations it may make. This work is sold with the understanding that the publisher is not engaged in rendering professional services. The advice and strategies contained herein may not be suitable for your situation. You should consult with a specialist where appropriate. Further, readers should be aware that websites listed in this work may have changed or disappeared between when this work was written and when it is read. Neither the publisher nor authors shall be liable for any loss of profit or any other commercial damages, including but not limited to special, incidental, consequential, or other damages.
Library of Congress Cataloging‐in‐Publication Data
Names: Machin, David, 1939- author. | Fayers, Peter M., author. | Tai, Bee Choo, author.
Title: Randomized clinical trials : design, practice and reporting / David Machin, Peter M. Fayers, Bee Choo Tai.
Description: Second edition. | Hoboken, NJ : Wiley-Blackwell, 2021. | Includes bibliographical references and index.
Identifiers: LCCN 2020044539 (print) | LCCN 2020044540 (ebook) | ISBN 9781119524649 (paperback) | ISBN 9781119524656 (adobe pdf) | ISBN 9781119524670 (epub)
Subjects: MESH: Randomized Controlled Trials as Topic–methods | Biomedical Research–methods | Research Design | Data Interpretation, Statistical
Classification: LCC R853.C55 (print) | LCC R853.C55 (ebook) | NLM W 20.55.C5 | DDC 610.72/4–dc23
LC record available at https://lccn.loc.gov/2020044539 LC ebook record available at https://lccn.loc.gov/2020044540
Cover Design: Wiley
Cover Image: © Kenishirotie/Shutterstock
To
Lorna Christine Machin
Tessa and Emma Fayers
Isaac Xu‐En and Kheng‐Chuan Koh
Preface
It is now more than 10 years since the first edition of this book was published. In the intervening years, while many things have remained unchanged, there have also been many new developments over the period. This second edition refreshes the first, refining some of the sections to better explain their contents and, at the same time, replacing some examples with more current illustrations. To reflect the changes, we have created new chapters by splitting and then expanding old chapters. Thus, we now include full chapters on data and safety monitoring including interim analyses of accumulating data, cluster designs, repeated measures, and noninferiority designs as there has been a rapid increase in the use of such trial designs along with some methodological developments and improvements in statistical software available for analysis. In addition, we have included entirely new chapters on stepped wedge designs, genomic targets and, feasibility and pilot studies. The chapter on stepped wedge designs reflects the growing importance of such complex intervention designs while that on genomic targets highlights the research focus directed towards more individualised medicine. In contrast, the new chapter concerned with feasibility and pilot studies brings us back to the early planning stages of the clinical trial which is planned. The chapter is included as there is increasing recognition that perhaps