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Randomized Clinical Trials
 Randomized Clinical Trials
Design, Practice and Reporting

David Machin
Medical Statistics Group, School of Health and Related Sciences,
University of Sheffield, UK
Children’s Cancer and Leukaemia Group,
University of Leicester, UK

Peter M Fayers
Department of Public Health, University of Aberdeen, UK
Faculty of Medicine, Norwegian University of Science and Technology,
Trondheim, Norway

A John Wiley & Sons, Ltd., Publication

This edition first published 2010, Ó 2010 John Wiley & Sons, Ltd
Wiley-Blackwell is an imprint of John Wiley & Sons, formed by the merger of Wiley’s global Scientific,
Technical and Medical business with Blackwell Publishing.
Registered office: John Wiley & Sons Ltd, The Atrium, Southern Gate, Chichester, West Sussex, PO19 8SQ, UK
Other Editorial Offices:
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111 River Street, Hoboken, NJ 07030-5774, USA
For details of our global editorial offices, for customer services and for information about how to apply for
permission to reuse the copyright material in this book please see our website at www.wiley.com/wiley-blackwell
The right of the author to be identified as the author of this work has been asserted in accordance with the
Copyright, Designs and Patents Act 1988.
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 the UK Copyright, Designs and Patents Act 1988, without the prior permission of the publisher.
Wiley also publishes its books in a variety of electronic formats. Some content that appears in print may not be
available in electronic books.
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and product names used in this book are trade names, service marks, trademarks or registered trademarks
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The contents of this work are intended to further general scientific research, understanding, and discussion only and
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damages arising herefrom.
Library of Congress Cataloging-in-Publication Data
Machin, David, 1939–
Randomized clinical trials : design, practice and reporting / David
Machin, Peter M Fayers.
p. ; cm.
Includes bibliographical references and index.
ISBN 978-0-471-49812-4 (pbk.)
1. Clinical trials. 2. Clinical trials—Statistical methods. I.
2. Fayers, Peter M. II. Title.
[DNLM: 1. Biomedical Research—methods. 2. Randomized Controlled
Trials as Topic—methods. 3. Data Interpretation, Statistical. 4.
Research Design. W 20.5 M149r 2010]
R853.C55M337 2010
610.720 4—dc22
2009054234
A catalogue record for this book is available from the British Library.
ISBN: 978-0-471-49812-4
Set in 10.5/12.5pt Minion by Integra Software Services Pvt. Ltd., Pondicherry, India
Printed in Singapore by Markono Print Media Pte Ltd.
First impression—2010
 Christine Machin
and
Tessa and Emma Fayers
 Contents

Preface xi

1 Introduction 1
1.1 Introduction 1
1.2 Some completed trials 2
1.3 Choice of design 9
1.4 Practical constraints 14
1.5 Influencing clinical practice 15
1.6 History 16
1.7 How trials arise 18
1.8 Ethical considerations 19
1.9 Regulatory requirements 20
1.10 Focus 20
1.11 Further reading 21

2 Design Features 23
2.1 Introduction 23
2.2 The research question 24
2.3 Patient selection 26
2.4 The consent process 28
2.5 Choice of interventions 29
2.6 Choice of design 31
2.7 Assigning the interventions 33
2.8 Making the assessments 34
2.9 Analysis and reporting 34
2.10 Technical details 37
2.11 Guidelines 38
2.12 Further reading 39

3 The Trial Protocol 41

3.1 Introduction 41
3.2 Protocol – abstract 43
3.3 Protocol – background 44
3.4 Protocol – research objectives 45
3.5 Protocol – design 48
3.6 Protocol – intervention details 49
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viii CONTENTS

3.7 Protocol – eligibility 52

3.8 Protocol – randomization 53
3.9 Protocol – assessment and data collection 56
3.10 Protocol – statistical considerations 58
3.11 Protocol – ethical issues 62
3.12 Protocol – organizational structure 64
3.13 Protocol – publication policy 65
3.14 Protocol – trial forms 66
3.15 Protocol – appendices 67
3.16 Regulatory requirements 68
3.17 Guidelines 69
3.18 Protocols 69

4 Measurement and Data Capture 71

4.1 Introduction 71
4.2 Measures and endpoints 72
4.3 Making the observations 79
4.4 Baseline measures 82
4.5 Types of measures 82
4.6 Data recording 84
4.7 Technical notes 92
4.8 Guidelines 93

5 Randomization 95
5.1 Introduction 95
5.2 Rationale 96
5.3 Mechanics 96
5.4 Application 105
5.5 Carrying out randomization 106
5.6 Documentation 109
5.7 Unacceptable methods 110
5.8 Software 110
5.9 Guidelines 111

6 Trial Initiation 113

6.1 Introduction 113
6.2 Trial organization 114
6.3 Data collection and processing 121
6.4 Data monitoring 124
6.5 Ethical and regulatory requirements 127
6.6 Launching the trial 127
6.7 Trial registries 128
6.8 Guidelines 128

7 Trial Conduct 131

7.1 Introduction 131
7.2 Regular feedback 131
7.3 Publicity 134
7.4 Data monitoring committees 135
CONTENTS ix

7.5 Protocol modifications 139

7.6 Preparing the publication(s) 140
7.7 The next trial? 143
7.8 Protocols 143

8 Basics of Analysis 145

8.1 Introduction 145
8.2 Confidence intervals 146
8.3 Statistical tests 147
8.4 Examples of analysis 148
8.5 Other issues 171
8.6 Practice 175
8.7 Technical details 175

9 Trial Size 179

9.1 Introduction 179
9.2 Significance level and power 180
9.3 The fundamental equation 182
9.4 Specific situations 184
9.5 Practical considerations 190
9.6 Further topics 194
9.7 Other methods and software 196
9.8 Guideline 197

10 Reporting 199
10.1 Introduction 199
10.2 Publication guidelines 200
10.3 Responsibilities 204
10.4 Background 206
10.5 Methods 206
10.6 Findings 217
10.7 When things go wrong 226
10.8 Conclusions 227
10.9 Guidelines 227

11 Adaptations of the Basic Design 229

11.1 Introduction 229
11.2 Repeated measures 230
11.3 Cluster-randomized trials 236
11.4 Non-inferiority trials 244
11.5 Guidelines 249

12 Paired Designs 251

12.1 Cross-over trials 251
12.2 Split-mouth designs 264
12.3 Paired organs 269
x CONTENTS

13 More Than Two Interventions 275

13.1 Introduction 275
13.2 Unstructured comparisons 275
13.3 Comparisons with placebo (or standard) 279
13.4 Dose response designs 284
13.5 Factorial trials 289

14 Further Topics 297

14.1 Introduction 297
14.2 Adaptive approaches 298
14.3 Large simple trials 306
14.4 Bayesian methods 310
14.5 Zelen randomized-consent designs 315
14.6 Systematic overviews 318
14.7 Conclusion 322

Statistical Tables 323

Glossary 329
References 337
Index 349
 Preface

Clinical trials play a key role in developing strategies for healthcare, whether in the
development of a new drug or medical device, modifying existing approaches to better
effect, improving care in the community or, as at the time we write this preface,
vaccines for swine flu and many other situations. Many trials are conducted by
pharmaceutical and allied healthcare organizations, many by academic and charity-
supported research groups and many with support from multiple agencies. Trials vary
in size from those including tens of subjects to many thousands, and consume a
correspondingly wide range of resources – both financial and in terms of specialist
personnel required to conduct the trial.
Trials concerned with the later development of a new drug for a particular condition
will often be preceded by a long programme of laboratory, preclinical and early clinical
research, whereas other trials may arise more directly from clinical experience whether
in the hospital clinic, operating theatre or elsewhere.
It is not possible in a single text to cover the whole range of areas in which clinical
trials are conducted. Nor can we cover the plethora of clinical trial designs which are in
current use, the choice of which will crucially depend on the stage of the development.
Consequently, we have focused on the late stage of the process when, at least in many
situations, the relative efficacy of a new or test intervention is compared with a current
standard in a randomized comparative trial.
The context in which we are writing is for those directly concerned with patient care,
not because we wish to exclude from our readership those in the pharmaceutical and
allied industries, but rather to enable us to focus on issues which might not be so clear
for new investigators who wish to become involved with clinical trials research. In
general, these investigators will not come with the type of support available from
industry, either in monetary terms or with the ready and extensive clinical trials
expertise that industry has at hand. We believe, however, that even for those who
work on clinical trials in full collaboration with industry, a broad view of the whole
process will lead to a better understanding.
In this book we have tried to give an overview of the key issues to consider in
designing, conducting, analyzing and reporting clinical trials. We have used a parallel
two-group randomized design as a basis for this in Chapters 2–10. The subsequent
chapters extend this basic design to consider, for example, cross-over trials and trials
comparing more than two groups. A suggested first reading of the book is the
introductory Chapter 1, then Chapters 2–7, omitting Chapters 8 and 9 concerned
with the more statistical issues of analysis and trial size, and finally Chapter 10.
xii PREFACE

Many thanks are due to Simon Day who generously allowed us to copy freely from
his Dictionary for Clinical Trials in constructing the Glossary. Thanks are also due to
Nicky Cullum, University of York and Jane Nixon, Clinical Trials Research Unit,
University of Leeds who have allowed us to extensively quote from the PRESSURE
protocol funded by the NHS Health Technology Assessment Programme.

David Machin
Peter M Fayers
Leicester and Sheffield and Aberdeen and Trondheim
 CHAPTER 1

Introduction

A very large number of clinical trials have been conducted with human subjects in a wide
variety of contexts. Many of these have been concerned, for example, with improving (in
some way) the management of patients with disease and others the prevention of the
disease or the condition in the first place. The essence of a clinical trial is the comparison
of a standard strategy with an alternative (perhaps novel) intervention. The aim of this
chapter is to illustrate some of the wide variety of clinical trials that have been conducted
and to highlight some key features of their design, conduct and analysis.

1.1 Introduction
The aim of this book is to introduce those who are to become involved with randomized
clinical trials to the wide range of challenges that are faced by those who conduct such
trials. Our intended readership is therefore expected to range from health care profes-
sionals of all disciplines who are concerned with patient care to those more involved with
the non-clinical aspects such as the statistical design, data processing and subsequent
analysis of the results. We assume no prior knowledge of clinical trial processes and we
have attempted to explain the more statistical sections in as non-technical a way as
possible. In a first reading of this book, these sections could be omitted. Throughout the
book we stress the collaborative nature of clinical trials activity and would hope that
readers would consult their more experienced colleagues on aspects of our coverage.
The business of clinical trials is an ongoing process and, as we write, trials are
currently being designed, opened, conducted, closed, analyzed and reported. Results
are being filtered into current practice and the next trials planned. It is difficult to know
where to start in describing the key features of this process, as each stage interacts to
some extent with the others. For example, in designing a trial the investigators need to
be mindful of the eventual analysis to be undertaken as this governs (but it is only one
aspect) of how large a trial should be launched. Some of the steps are intellectually
challenging, for example, defining the key therapeutic question, while others may
perhaps appear more mundane, such as defining the data forms or the data entry
procedures. However, all steps (whether large or small, major or minor) underpin the
eventual successful outcome – the influence on clinical practice once the trial results are

Randomized Clinical Trials: Design, Practice and Reporting David Machin and Peter M Fayers
Ó 2010 John Wiley & Sons, Ltd
2 1 INTRODUCTION

available. Entire books have been written for many of these aspects we can only provide
an introduction to the process.
Numerous terms need to be introduced, including ‘clinical trial’ itself. As a conse-
quence we have included a Glossary of Terms, which is mainly extracted from Day (2007)
Dictionary of Clinical Trials. The Glossary defines clinical trial: any systematic study of the
effects of a treatment in human subjects. These definitions may not be exhaustive, in the
sense that ‘treatment’ used here may be substituted by, for example, ‘intervention’,
depending on the specific context of the clinical trial under consideration.
Clinical trials require a multidisciplinary approach in which all partners play a key
role at some stage of the trial process. Furthermore, this is the era of evidence-based
medicine (EBM), in which it is important to consider critically all the available
evidence about whether, for example, a treatment works before recommending it for
clinical practice. In this respect it is therefore vital that we can clearly see that a
proposed trial addresses a key question which will have a clinically meaningful out-
come, is well designed, conducted and reported and the results are persuasive enough
to change clinical practice if appropriate.
Despite perhaps having a professional interest in the science of clinical trials, every-
one has an additional vested interest as potential patients. How many of us have never
been to see a doctor, had a hospital admission or taken medication? All of us may be,
have been or certainly will be recipients of clinical trial results whether at pre-birth or
birth, childhood for vaccination and minor illness, as an adult for fertility, sports
injuries, minor and major non-life threatening or life-threatening illnesses and in old
age for care related to our mental or physical needs.

1.2 Some completed trials

As we have indicated, there are countless ongoing trials and many have been success-
fully conducted and reported. To give some indication of the range and diversity of
application, we describe a selection of clinical trials that have been conducted. Their
designs include some features that we will draw upon in later chapters.
The examples of successfully completed clinical trials illustrate a wide range of topics
investigated. These include patients with disease (breast cancer, colon cancer, eczema,
glaucoma, malaria and diabetes mellitus), those requiring coronary artery stents or hand
surgery, elderly residents of nursing homes, children with dental caries, healthy indivi-
duals and those requiring vaccinations. Although not included here, trials are also
conducted to evaluate different diagnostic procedures, different bed mattresses to reduce
the incidence of bed sores, different dressings for wounds of all types and fertility
regulation options for male and females of reproductive potential, for example.
These trials are often termed Phase III trials in contrast to Phase I and Phase II trials,
which are concerned with early stages of the (often pharmaceutical) development
process. Although the trials differ in aspects of their design, the majority have the
general structure of a two (or more) group parallel design in which eligible patients are
assigned to receive the alternative options (often treatments but more generally termed
interventions) and then at some later time assessed in a way which will be indicative of
(successful) outcome. The outcomes measured in these trials include: survival time,
1.2 SOME COMPLETED TRIALS 3

Example 1.1 Recovery of gastrointestinal function after elective colonic

resection

Lobo, Bostock, Neal, et al. (2002) describe a randomized trial in which 20 patients
with colonic cancer either received postoperative intravenous fluids in accordance
with current hospital standard practice (S) or according to a restricted intake
regimen (R). A primary endpoint measure in each patient was the solid-phase
gastric emptying time on the fourth postoperative day. The observed difference
between the median emptying times was shorter with R by 56 minutes with 95%
confidence interval (CI) from 12 to 132 minutes. The trial also included pre-
operative and postoperative (days 1, 2, 4 and 6) measures of the concentrations of
serum albumin, haemoglobin and blood urea in a repeated measures design.
Key features include:

 Design: randomized comparison of a standard and test, single centre participa-

tion, unblinded assessment;
 Endpoint: gastric emptying time;
 Size: 21 patients following colonic resection;
 Analysis: Mann–Whitney-U test* for comparing two medians;
 Conclusion: The restricted group had shorter delays in returning to gastro-
intestinal function.
*This can also be referred to as the Wilcoxon Rank-Sum Test.

Example 1.2 Azathioprine for the treatment of atopic eczema

Meggitt, Gray and Reynolds (2006) randomized 63 patients with moderate-to

severe eczema to receive either azathioprine or placebo in a double-blind for-
mulation to ascertain the relative reduction in disease activity determined by the
six-area six-sign atopic dermatitis (SASSAD) score between the groups. They
reported a 5.4 unit advantage with azathioprine. In this trial patients were
randomized, using a minimization procedure, in the ratio of 2 to 1 in favour of
azathioprine in order to ‘. . . encourage recruitment, to reduce the numbers
receiving pharmacologically inactive systemic treatment, and to increase the
likelihood of identifying infrequent adverse events’.
Key features include:

 Design: single centre, randomized double-blind, placebo-controlled, 2 : 1

allocation ratio using minimization;
 Endpoint: SASSAD;
 Size: 63 patients with moderate-to-severe atopic eczema;
 Analysis: comparison of mean group regression slopes over a 12-week period;
 Conclusion: azathioprine produces a clinically relevant improvement.
4 1 INTRODUCTION

Example 1.3 Anacetrapib and blood pressure

Krishna, Anderson, Bergman, et al. (2007) describe a randomized placebo (P)

controlled, 2-period cross-over trial of anacetrapib (A) in 22 healthy volunteers. Half
of the individuals were randomized to receive the sequence AP (i.e. A in Period I of the
trial followed by P in Period II) and half PA. The primary endpoint recorded was the
blood pressure on day 10 of Period I and of Period II. The healthy individuals and
investigators were blinded to the order in which the trial medication was administered.
The authors state: ‘A one-sided test was applied, since another molecule in this class
was found to increase blood pressure . . .’. They reported a difference in mean systolic
blood pressure between A and P as 0.6 mm Hg (90% CI -1.54 to 2.74, p-value ¼ 0.634)
and concluded that: ‘. . ., anacetrapib seems not to increase blood pressure, . . .’.
Key features include:

 Design: single centre, randomized placebo controlled, 2-period cross-over trial;

 Size: 22 healthy volunteers;
 Endpoint: ambulatory blood pressure;
 Analysis: comparison of means using analysis of variance;
 Conclusion: anacetrapib seems not to increase blood pressure.

Example 1.4 Topical medication and argon laser trabeculoplasty

for glaucoma

The Glaucoma Laser Trial Research Group (1995) recruited 271 subjects with
newly diagnosed primary-angle glaucoma. One eye of each patient was randomly
assigned to argon laser trabeculoplasty (LT) or to a stepped medication (TM) as
initial treatment. They treated 261 eyes with LT first followed by TM and the same
number with TM first then LT. They found that measures of visual field status for
eyes treated by LT-MT were slightly better than those treated by MT-LT. The
authors state: ‘Statistical significance was attained for only some of the differences,
and the clinical implications of such small differences are not known.’
Key features include:

 Design: multicentre, paired design, compares alternative schedules for admin-

istering two procedures – the schedule was randomized to one eye with the
other eye receiving the alternative;
 Endpoint: visual field status;
 Size: 271 patients with primary open-angle glaucoma;
 Analysis: comparison of means at particular time points following initiation of
treatment using the paired t-test;
 Conclusion: eyes treated with laser trabeculoplasty first were judged to have
slightly more improvement and slightly less deterioration.
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