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Randomised Clinical Trials
 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)
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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.
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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

Set in 10.5/12.5pt Minion by SPi Global, Pondicherry, India

10 9 8 7 6 5 4 3 2 1
 To
Lorna Christine Machin
Tessa and Emma Fayers
Isaac Xu-En and Kheng-Chuan Koh
 Contents

Preface xiii

Part I Basic Considerations 1

1 Introduction 3
1.1 Introduction 3
1.2 Some completed trials 4
1.3 Choice of design 13
1.4 Practical constraints 18
1.5 Influencing clinical practice 20
1.6 History 20
1.7 How do trials arise? 22
1.8 Ethical considerations 24
1.9 Regulatory requirements 24
1.10 Focus 25
1.11 Further reading 25

2 Design Features 27
2.1 Introduction 27
2.2 The research question 29
2.3 Patient selection 30
2.4 The consent process 32
2.5 Choice of interventions 33
2.6 Choice of design 35
2.7 Assigning the interventions 37
2.8 Making the assessments 38
2.9 Analysis and reporting 38
2.10 Technical details 42
2.11 Guidelines 43
2.12 Further reading 44

3 The Trial Protocol 45

3.1 Introduction 45
3.2 Abstract 47
viii CONTENTS

3.3 Background 49
3.4 Research objectives 49
3.5 Design 52
3.6 Intervention details 53
3.7 Eligibility 56
3.8 Randomisation 58
3.9 Assessment and data collection 61
3.10 Statistical considerations 63
3.11 Ethical issues 66
3.12 Organisational structure 69
3.13 Publication policy 69
3.14 Trial forms 70
3.15 Appendices 71
3.16 Regulatory requirements 72
3.17 Guidelines 74
3.18 Protocols 74

4 Measurement and Data Capture 77

4.1 Introduction 77
4.2 Types of measures 78
4.3 Measures and endpoints 80
4.4 Making the observations 91
4.5 Baseline measures 92
4.6 Data recording 93
4.7 Technical notes 101
4.8 Guidelines 101

5 Randomisation 103
5.1 Introduction 103
5.2 Rationale 104
5.3 Mechanics 104
5.4 Application 113
5.5 Carrying out randomisation 115
5.6 Documentation 119
5.7 Unacceptable methods 120
5.8 Guidelines 120

6 Trial Initiation 121

6.1 Introduction 121
6.2 Trial organisation 122
6.3 Data collection and processing 130
6.4 Internal data monitoring 132
6.5 Ethical and regulatory requirements 133
6.6 Launching the trial 134
6.7 Trial registries 134
6.8 Guidelines 135
CONTENTS ix

7 Trial Conduct and Completion 137

7.1 Introduction 137
7.2 Regular feedback 137
7.3 Publicity 141
7.4 Protocol modifications 142
7.5 Preparing the publication(s) 142
7.6 The next trial? 145
7.7 Protocol 146

8 Basics for Analysis 147

8.1 Introduction 147
8.2 The standard Normal distribution 148
8.3 Confidence intervals 149
8.4 Statistical tests 150
8.5 Examples of analysis 152
8.6 Regression methods 169
8.7 Other issues 179
8.8 Practice 182
8.9 Technical details 183

9 Trial Size 185

9.1 Introduction 185
9.2 Significance level and power 186
9.3 The fundamental equation 188
9.4 Specific situations 190
9.5 Practical considerations 198
9.6 Further topics 203
9.7 Guideline 206
9.8 Software 206

10 Data and Safety Monitoring 209

10.1 Introduction 209
10.2 The DSMB 211
10.3 Early reviews 214
10.4 Interim reviews 219
10.5 Protocols 228

11 Reporting 229
11.1 Introduction 229
11.2 Publication 230
11.3 Responsibilities 233
11.4 Background 235
11.5 Methods 236
11.6 Findings 248
x CONTENTS

11.7 When things go wrong 258

11.8 Conclusions 259
11.9 Guidelines 260

Part II Adaptions of the Basic Design 263

12 More Than Two Interventions 265

12.1 Introduction 265
12.2 Unstructured comparisons 266
12.3 Comparisons with placebo (or standard) 270
12.4 Dose–response designs 275
12.5 Factorial trials 280
12.6 Complex structure comparisons 289

13 Paired and Matched Designs 293

13.1 Matched-pair trials 293
13.2 Cross-over trials 305
13.3 Split-mouth designs 311
13.4 Guidelines 317

14 Repeated Measures Design 319

14.1 Introduction 319
14.2 Simplified analysis 322
14.3 Regression models 329
14.4 Auto-correlation 331
14.5 Accounting for auto-correlation 334
14.6 The design effect (DE) 338
14.7 Trial size 344
14.8 Practicalities 347
14.9 Reporting 350
14.10 Matched organs receiving the same intervention 354

15 Non-Inferiority and Equivalence Trials 357

15.1 Introduction 357
15.2 Non-inferiority 358
15.3 Analysis 361
15.4 Trial size 366
15.5 Equivalence 370
15.6 Reporting 373
15.7 Practical Issues 373
15.8 Guidelines 373
CONTENTS xi

16 Cluster Designs 375

16.1 Design features 375
16.2 Procedures 376
16.3 Regression models 379
16.4 Intra-class correlation 380
16.5 Trial size 381
16.6 Analysis 386
16.7 Practicalities 388
16.8 Reporting 388
16.9 Further reading 389

17 Stepped Wedge Designs 391

17.1 Introduction 391
17.2 Notation 392
17.3 Basic structure 396
17.4 Randomisation 398
17.5 Cross-sectional design 398
17.6 Closed cohort design 408
17.7 Practicalities 413

Part III Further Topics 415

18 Genomic Targets 417

18.1 Introduction 417
18.2 Predictive markers 418
18.3 Enrichment design 420
18.4 Biomarker-Stratified Designs 422
18.5 Adaptive threshold designs 431

19 Feasibility and Pilot Studies 435

19.1 Introduction 435
19.2 Feasibility studies 436
19.3 External-pilot studies 437
19.4 Considerations across external-pilot and main trial 444
19.5 Internal-pilot studies 445
19.6 Other preliminary studies 447
19.7 Reporting 449

20 Further Topics 451

20.1 Introduction 451
20.2 Adaptive approaches 452
xii CONTENTS

20.3 Large simple trials 461

20.4 Bayesian methods 463
20.5 Interim analyses 467
20.6 Zelen randomised consent designs 472
20.7 Systematic overviews 476

Statistical Tables 483

Glossary 493
References 503
Index 523
 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, refin-
ing 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 devel-
opments 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 high-
lights 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 pla-
nning stages of the clinical trial which is planned. The chapter is included as there is
increasing recognition that perhaps a more structured approach is required at the pla-
nning stage of any proposed trial. The intention is to help avoid the conduct of clinical
trials which fail due to the basic assumptions made at the planning stage being
inappropriate.
This edition is divided into three sections: I Basic Considerations, II Adaptions of the
Basic Design and III Further Topics. As the title suggests, the first section is intended to
cover topics that are relevant to all randomised trials of whatever design and complex-
ity. Thus, it may be the key section for those who are new to clinical trials and an aide-
memoire for those more experienced in this area. For this purpose, it concentrates on
the parallel two-group controlled trial with a single outcome measure where patients are
randomised individually to one of the two interventions concerned.
The second section expands on the individually randomised design in several ways
by considering paired designs, repeated assessments of the (same) outcome measure
over time, more than two interventions and non-inferiority trials. It also includes cluster
trials, and stepped wedge designs in which groups rather than individuals are rando-
mised to the interventions concerned. The final section deals with genomic targets, fea-
sibility and pilot studies, and a final chapter on miscellaneous topics including adaptive
xiv PREFACE

designs, large simple trials and very small trials with new additions describing alpha
spending functions and the predictive probability test for use in interim analyses.
We are grateful to many colleagues, collaborators and numerous investigators who
have contributed directly or indirectly to this book over many years.
We thank Isaac Koh for the cover design and Leo Liu for his professional advice
on this.

David Machin
Peter M. Fayers
Bee Choo Tai
Leicester and Sheffield, Aberdeen, and Singapore

PS
As we read the proofs of this book, under lockdown conditions imposed by Covid-19,
results of successful randomised trials with respect to treatments for those who have con-
tracted the disease and protective vaccines against the pandemic have been published.
These include the use of dexamethasone as described by The RECOVERY Collaborative
Group (2020) and the Pfizer-BioNTech mega-sized vaccine trial against Covid-19 tested
by Polack, Thomas, Kitchin, et al. (2020). To overcome the challenges in conducting
clinical trials as a result of lockdown and the need to minimise face-to-face contact
due to the infectious nature of the coronavirus, the use of e-consent is briefly discussed
in Chapter 3.
 PART I

Basic Considerations
 CHAPTER 1

Introduction

A very large number of clinical trials with human subjects have been conducted in a
wide variety of contexts. Many of these have been concerned, for example, with improv-
ing (in some way) the management of patients with disease and others the prevention of
the disease or 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 randomised
clinical trials to the wide range of challenges that are faced by those who conduct such
trials. Thus, our intended readership is expected to range from healthcare professionals
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 anal-
ysis 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 cur-
rently being designed (particularly with respect to the coronavirus), opened, conducted,
closed, analysed, reported, results filtered into current practice and the next planned. To
describe the key features of this process, it is difficult to know where to start as each stage
interacts with each of the others to some extent. For example, in designing a trial the
investigators need to be mindful of the eventual analysis to be undertaken as this gov-
erns (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, whilst

Randomised Clinical Trials: Design, Practice and Reporting, Second Edition. David Machin, Peter M. Fayers, and Bee Choo Tai.
© 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.
4 1 INTRODUCTION

others may perhaps appear more mundane, such as defining the data forms or the data
entry procedures but all steps (whether large or small: major or minor) underpin the
eventual successful outcome – the influence on clinical practice once the trial results
are available. For many of these aspects of the process, whole books have been written.
We can only provide an introduction to these.
Numerous terms including ‘clinical trial’ itself need to be introduced. As a conse-
quence, we have included a Glossary of Terms, which is mainly extracted from Day
(2007) Dictionary of Clinical Trials. Thus, the Glossary defines: clinical trial: any sys-
tematic 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, ‘Evidence-Based Medicine’ (EBM)
requires that 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 one can clearly see that a proposed trial addresses
a key question which will have a clinically meaningful outcome, is well designed, con-
ducted and reported, and the results are persuasive enough to change clinical practice if
appropriate.
Despite perhaps not having a professional interest in the science of clinical trials,
everyone has a vested interest in them as potential patients requiring care. 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
during prebirth, at birth or in 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 also draw upon as examples in later chapters.

Example 1.1 Small parallel two-group design – gastrointestinal function

Lobo, Bostock, Neal, et al. (2002) describe a randomised 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 reg-
imen (R). A primary endpoint measure in each patient was the solid-phase gastric
1.2 SOME COMPLETED TRIALS 5

Example 1.1 (Continued)

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 preoperative and
postoperative (days 0, 1, 3 and 5) measures of the concentrations of serum
albumin, haemoglobin and blood urea in a repeated measures design.

Key features include the following:

• Design: Randomised comparison of a standard and test, single-centre participation,

unblinded assessment,
• Endpoint: Gastric emptying time,
• Size: 21 patients following colonic resection,
• Analysis: Mann–Whitney U-test1 for comparing two medians,
• Conclusion: The restricted intake group had shorter delays in returning to gastrointestinal
function.

1
This can also be referred to as the Wilcoxon rank-sum test.

Example 1.2 Parallel two-group design – hepatitis B

Levie, Gjorup, Skinhøj and Stoffel (2002) compared a 2-dose regimen of recom-
binant hepatitis B vaccine including the immune stimulant AS04 with the standard
3-dose regimen of HbsAg in healthy adults. The rationale behind testing a 2-dose
regimen was that fewer injections would improve compliance.

Key features include the following:

• Design: Two centres, open-label randomised two-group comparison,

• Endpoint: Seroprotection rate,
• Size: 340 healthy adults aged between 15 and 40 years,
• Analysis: Fisher’s exact test,
• Conclusion: The 2-dose regimen compared favourably with the standard.
6 1 INTRODUCTION

Example 1.3 Unstructured three-group design – newly diagnosed type 2

diabetes

The randomised trial of Weng, Li, Xu, et al. (2008) compared, in newly diagnosed
patients with type 2 diabetes, three treatments: multiple daily insulin injections
(MDI), continuous subcutaneous insulin infusion (CSII) and oral hypoglycaemic
agent (OHA).
Key features include the following:

• Design: Nine centres, randomised three-group comparison,

• Endpoint: Time of glycaemic remission,
• Size: 410 newly diagnosed patients with type 2 diabetes,
• Analysis: Cox proportional-hazards regression model,
• Conclusion: Early intensive therapy has favourable outcomes on recovery and mainte-
nance of β-cell function and protracted glycaemic remission compared to OHA.

Example 1.4 Small dose–response design – pain prevention following

hand surgery

Stevinson, Devaraj, Fountain-Barber, et al. (2003) conducted a randomised dou-

ble-blind, placebo-controlled trial to compare placebo with homoeopathic arnica
6C and arnica 30C to determine the degree of pain prevention in patients with
carpel tunnel syndrome undergoing elective surgery for their condition. Pain
was assessed postoperatively with the short-form McGill Pain Questionnaire
(SF-MPQ) at four days. A total of 64 patients were randomised to the three groups
resulting in median scores of 16.0 (range 0–69), 10.5 (0–76) and 15.0 (0–82) for the
respective groups. From these results, the authors suggest that homoeopathic
arnica has no advantage over placebo in reducing levels of postoperative pain.

Key features include the following:

• Design: Single-centre, randomised double-blind, placebo-controlled, three-group dose

response,
• Endpoint: Pain using the SF-MPQ,
• Size: 64 patients undergoing hand surgery for carpal tunnel syndrome,
• Analysis: Kruskal–Wallis test,
• Conclusion: Irrespective of dose homoeopathic arnica has no advantage over placebo.
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