Clinical Trials

275 Pages·1983·8.29 MB·English

by  Stuart J. Pocock(auth.)

CLINICAL TRIALS
A Practical Approach
CLINICAL TRIALS
A Practical Approach
STUA RT J. POCOCK
Professor ofM edical Statistics and Director of Clinical Trials Research Group
London School of Hygiene and Tropical Medicine
University of London
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ISBN 978 0 471 90155 6 (HB)

Typeset in Times New Roman by Eta Services Ltd, Beccles, Suffolk
Printed and bound in Great Britain by TJ International Ltd, Padstow, Cornwall
To
Peter Armitage and Marvin Zelen
with gratitude.
Contents
Preface XI
1. Introduction: The Rationale of Clinical Trials 1
1.1 Types of clinical trial. 1
1.2 Controlled clinical trials and the scientific method . 4
1.3 An example of a clinical trial for primary breast cancer 7
2. The Historical Development of Clinical Trials 14
2.1 Clinical trials before 1950 . 14
2.2 Clinical trials since 1950 18
2.3 Cancer chemotherapy in the United States 21
2.4 Treatment of acute myocardial infarction. 24
2.5 The pharmaceutical industry 26
3. Organization and Planning. 28
3.1 The protocol 28
3.2 Administration, staff and finance 31
3.3 Selection of patients . 35
3.4 Treatment schedules . 38
3.5 Evaluation of patient response 41
4. The Justification for Randomized Controlled Trials. 50
4.1 Problems with uncontrolled trials 51
4.2 Problems with historical controls 54
4.3 Problems with concurrent non-randomized controls 60
4.4 Is randomization feasible? . 63
5. Methods of Randomization. 66
5.1 Patient registration . 66
5.2 Preparing the randomization list . 73
5.3 Stratified randomization 80
5.4 Unequal randomization. 87
Vll
Vlll
6. Blinding and Placebos . 90
6.1 The justification for double-blind trials 90
6.2 The conduct of double-blind trials 93
6.3 When is blinding feasible? . 97
7. Ethical Issues . 100
7.1 Medical progress and individual patient care. 100
7.2 Informed patient consent 105
8. Crossover Trials . 110
8.1 Within-patient comparisons 110
8.2 The two-period crossover design . 112
8.3 The analysis and interpretation of crossover trials . 114
8.4 Multi-period crossover designs 119
9. The Size of a Clinical Trial 123
9.1 Statistical methods for determining trial size . 123
9.2 The realistic assessment of trial size. 130
9.3 The inadequacy of small trials 133
9.4 Multi-centre trials. 134
9.5 The number of treatments and factorial designs. 138
10. Monitoring Trial Progress . . 142
10.1 Reasons for monitoring. 142
10.2 Interim analyses . 143
10.3 Repeated significance testing: group sequential designs 147
10.4 Continuous sequential designs 155
11. Forms and Data Management. 160
11.1 Form design 160
11.2 Data management. 166
11.3 The use of computers 168
12. Protocol Deviations . 176
12.1 Ineligible patients . 176
12.2 Non-compliance and incomplete evaluation 179
12.3 Inclusion of withdrawals in analysis. 182
13. Basic Principles of Statistical Analysis . 187
13.1 Describing the data . . 188
13.2 Significance tests . 197
13.3 Estimation and confidence limits. 206
lX
14. Further Aspects of Data Analysis 211
14.1 Prognostic factors. . . . 211
14.2 The analysis of survival data 221
14.3 Multiplicity of data . . . 228
15. Publication and Interpretation of Findings. 234
15.1 Trial reports and their critical evaluation . 234
15.2 An excess of false-positives. . 239
15.3 Combining evidence and overall strategy 242
References 248
Index 257
Preface
There is an ever-increasing number of treatment innovations which require
proper investigation to see if they are of genuine benefit to patients. The
randomized controlled clinical trial has become widely regarded as the principal
method for obtaining a reliable evaluation of treatment effect on patients. The
purpose of this book is to explain in practical terms the basic principles of
clinical trials. Particular emphasis is given to their scientific rationale, including
the relevance of statistical methods, though ethical and organizational issues are
also discussed in some detail.
My intention has been to present the methodology of clinical trials in a style
which is comprehensible to a wide audience. I hope the book proves to be
especially useful to clinicians and others who are involved in conducting trials
and it would be particularly gratifying if this text encouraged more clinicians to
undertake or collaborate in properly designed trials to resolve relevant
therapeutic issues.
Pharmaceutical companies have a fundamental role in the organization of
trials for drug therapy. I have tried to give a balanced view of their activities in
this area and hope that my approach to clinical trials is conducive to
maintaining high standards of research in the clinical testing of new drugs.
However, I wish to emphasize that randomized controlled trials should also be
applied to assessing other (non-drug) aspects of therapy and patient
management.
The practice of medicine poses a need to interpret wisely the published
findings from clinical trials. Accordingly, the medical profession at large and
others concerned with the treatment and management of patients may benefit
from an increased understanding of how clinical trials are (and should be)
conducted.
The proper use of statistical methods is important at the planning stage of a
clinical trial as well as in the analysis and interpretation of results. I also
recognize that many clinicians and others without mathematical training
experience some difficulty in understanding statistical concepts. Hence, I have
used a straightforward non-mathematical approach in describing those statistical
issues that I consider of relevance to the practice of clinical trials. In particular,
XI
xii
I would like to think that the basic principles of statistical analysis described
in chapter 13 may be of more general interest beyond clinical trials. Indeed,
some readers who are unfamiliar with statistical terms may find it instructive
to begin with this chapter.
My own experience in teaching undergraduate medical students has en
couraged me to believe that the introduction of clinical trials and related
statistical ideas is a useful aspect of preclinical education. Accordingly, my
approach to such courses is reflected in much of this book.
As a medical statistician I believe that clinical trials require a successful
collaboration of clinical, organizational and statistical skills. I feel that my
profession needs to strive harder to achieve effective communication of our
ideas to non-statistical colleagues and I would be delighted if this book could
persuade other statisticians towards a commonsense and less theoretical
approach to medical research. In this respect, students of biostatistics may find
this book a useful antidote to their more mathematical courses!
Lastly, my policy has been always to introduce each concept via actual
examples of clinical trials. In this way, the reader should experience the reality
of clinical trials, not as an abstract collection of methods, but as a practical
contribution to furthering medical knowledge.
I greatly appreciate the contributions of Sheila Gore and Austin Heady who
read the book in draft and made many suggestions for improvement. I am also
grateful to Tom Meade and Simon Thompson for their helpful comments on
the draft. I am indebted to Peter Armitage for first stimulating the publishers to
realize the need for such a book. I wish to express sincere thanks to Yvonne
Ayton for typing the manuscript and to other colleagues for their invaluable
support. Lastly, this whole project was made easier by the help and encourage
ment of my wife Faith.
CHAPTER 1
Introduction: The Rationale of
Clinical Trials
The evaluation of possible improvements in the treatment of disease has
historically been an inefficient and haphazard process. Only in recent years has
it become widely recognized that properly conducted clinical trials, which
follow the principles of scientific experimentation, provide the only reliable
basis for evaluating the efficacy and safety of new treatments. The major
objective of this book is therefore to explain the main scientific and statistical
issues which are vital to the conduct of effective and meaningful clinical
research. In addition, some of the ethical and organizational problems of
clinical trials will be discussed. The historical perspective, current status and
future strategy for clinical trials provide a contextual framework for these
methodological aspects.
In section 1.1, I discuss what constitutes a clinical trial and how clinical trials
may usefully be classified. Section 1.2 deals with the underlying rationale for
randomized controlled clinical trials and their relation to the scientific method.
Section 1.3 goes on to describe one particular example, a clinical trial for
primary breast cancer, as an illustration of how adherence to sound scientific
principles led to an important advance in treatment.
1.1 TYPES OF CLINICAL TRIAL
Firstly, we need to define exactly what is meant by a 'clinical trial': briefly the
term may be applied to any form of planned experiment which involves patients
and is designed to elucidate the most appropriate treatment of future patients
with a given medical condition. Perhaps the essential characteristic of a clinical
trial is that one uses results based on a limited sample of patients to make
inferences about how treatment should be conducted in the general population
of patients who will require treatment in the future.
Animal studies clearly do not come within this definition and experiments on
healthy human volunteers are somewhat borderline in that they provide only
indirect evidence of effects on patients. However, such volunteer studies (often