RANDOMISED CONTROLLED CLINICAL TRIALS, Second Edition

Transcription

1 RANDOMISED CONTROLLED CLINICAL TRIALS, Second Edition

2 RANDOMISED CONTROLLED CLINICAL TRIALS, Second Edition Christopher J Bulpitt Division of Geriatric Medicine Royal Postgraduate Medical School Hammersmith HospitaI Du Cane Road London W12... " SPRINGER SCIENCE+BUSINESS MEDIA, LLC

3 Library of Congress Cataloging-in-Publication Data A C.I.P. Catalogue record for this book is available from the Library of Congress. ISBN ISBN (ebook) DOI / Copyright 1996 by Springer Science+Business Media New York Originally published by Kluwer Academic Publishers, New York in 1996 Softcover reprint of the hardcover lst edition 1996 AII rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means, mechanical, photo-copying, recording, or otherwise, without the prior written permission of the publisher, Springer Science+Business Media, LLC. Printed on acid-free paper.

4 CONTENTS Preface vii 1. Introduction 1 2. The history of controlled trials 7 3. Ethical considerations The objectives of a randomised controlled trial Different trial designs How many subjects are required for a trial? How to ensure that the results are free of bias Writing the protocol Recruitment of subjects Information to be collected during a trial The conduct of the trial - Good Clinical Practice Stopping rules for trials The variability and validity of results Analysis of the results, subgroup and meta-analysis The evaluation of subjective well-being and measurement of quality of life 301

5 16. The detection of adverse drug reactions Measurement of the benefit: risk comparison, cost-effectiveness and cost-utility Early trials on new drugs Failure to accept the results of randomised controlled trials The advantages and disadvantages of randomised controlled trials 379 References 387 Index 427

6 PREFACE Bradford Hill has defined a clinical trial as "A carefully and ethically designed experiment with the aim of answering some precisely framed question" [1]. This definition specifies a careful design and requires the provision of adequate controls. Random allocation of treatments to subjects is important to ensure that the treated and control groups are similar. Therefore this book is entitled Randomised Controlled Clinical Trials. We can define a randomised controlled trial by rewriting Bradford Hill's definition as follows, "A carefu77y and ethica77y designed experiment which includes the provision of adequate and appropriate controls by a process of randomisation, so that precisely framed questions can be answered." I am a firm advocate of Randomised Controlled Clinical Trials but intend to give a balanced view of the advantages and disadvantages of these ethical experiments. This book is directed primarily at the medical research worker, although certain chapters may find a wider application. When discussing a randomised controlled trial, it is neither practicable nor desirable to divorce theory from practice, however the first seven chapters concentrate mainly on theory, and the remainder focus on practice. The segment on trial design is followed by sections on writing the protocol, designing the forms, conducting the trial, and analysing the results. This book is meant to serve both as a reference manual and a practical guide to the design and performance of a trial. vii

7 Preface to the second edition After 13 years there are new areas to discuss and more recent trials to be included. Good Clinical Practice; evaluation of quality of life; measurement of the benefit risk comparison; determination of cost-effectiveness and cost utility; stopping rules for trials; meta analysis and subgroup analysis are all new sections. The references are expanded from 305 to 512 and include the recent advances in trial design, such as the n-of-1 trials and megatrials, and up-todate examples to illustrate the points made in the 20 chapters. viii

8 ACKNOWLEDGEMENTS I am deeply indebted to many persons who have provided invaluable assistance in the preparation of this second edition. Miss Alison Palmer kindly read and corrected the manuscript. My secretary, Miss Nicola Piggott, p'atiently processed and printed the several versions of the work. Nevertheless I remain responsible for any errors. ix