Clinical Trials in Oncology

207 Pages·1997·4.468 MB·English

by  Stephanie Green, Jacqueline Benedetti, John Crowley (auth.)

Clinical Trials in Oncology
Clinical Trials in Oncology
Stephanie Green
J acqueline Benedetti
and
John Crowley
Southwest Oncology Group Statistical Center
Fred Hu tchinson Cancer Research Center
Seattle, Washington
USA
Springer-Science+Business Media, B.V.
First edition 1997
© 1997 Springer Science+Business Media Dordrecht
Originally published by Chapman & Hall in 1997.
Softcover reprint of the hardcover 1s t edition 1997
Typeset in LaTeX 2E by Focal Image Ltd, London
ISBN 978-0-412-99631-3 ISBN 978-1-4899-3352-2 (eBook)
DOI 10.1007/978-1-4899-3352-2
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9
Printed on permanent acid-free text paper, manufactured in accordance
with ANSI/NISO Z39.48-1992 and ANSI/NISO Z39.48-1984 (permanence of
Paper).
For my father, who inspired ine to be a statistician. (SC)
In memory of my mother-in-law, Norma Benedetti, and Stacy
Thepp, whose deaths due to cancer are a constant reminder of
how much work there is left to do. (JB)
In memory of my father, who died too young of pancreatic
cancer. (J C)
Contents
Acknowledgments xi
1 Introduction 1
1.1 Abrief history of clinical trials 1
1.2 The Southwest Oncology Group 5
1.3 Example trials 6
1.4 The reason for this book 8
2 Statistical Concepts 9
2.1 Introduction 9
2.2 The Phase II trial: estimation 16
2.3 The Phase III trial: hypothesis testing 20
2.3.1 Response as the outcome 20
2.3.2 Survival as the outcome 25
2.4 The proportional hazards model 32
2.5 Sampie size calculations 33
2.6 Concluding remarks 35
3 The Design of Clinical Trials 37
3.1 Introduction 37
3.1.1 Objectives 37
3.1.2 Eligibility, treatments and endpoints 38
3.1.3 Differences to be detected or precision of estimates 38
3.1.4 Method of treatment assignment 39
3.1.5 Assumptions for sampie size calculation 39
3.2 Endpoints 39
3.3 Phase I trials 42
3.4 Phase II trials 43
3.4.1 The standard Southwest Oncology Group Phase II
M
~~
3.4.2 Other Phase II designs 47
3.4.3 Conclusion 48
3.5 Phase III trials 49
3.5.1 Randomization 49
viii Contents
3.5.2 Two-arm trials 55
3.5.3 'Equivalence' trials 58
3.6 Conclusion 61
4 Multi-arm Trials 63
4.1 Introduction 63
4.2 Types of multi-arm trial 64
4.3 Significance level 66
4.4 Power 67
4.5 Interaction 69
4.6 Other model ass ump ti ons 72
4.7 To screen or not to screen 73
4.8 Timing of randomization 74
4.9 Conclusion 76
5 Interim Analysis and Data Monitoring Committees 79
5.1 Planned interim analyses 79
5.2 Data monitoring committees: rationale and responsibilities 84
5.3 Monitoring committees: composition 87
5.4 Examples 92
5.4.1 Stopping early for positive results 92
5.4.2 Stopping early for negative results 94
5.4.3 Stopping an equivalence trial early for positive results 94
5.4.4 Stopping based on toxicity and lack of compliance 96
5.4.5 Emergency stopping based on unexpected toxic
deaths 98
5.5 Concluding remarks 99
6 Data Management and Quality Control 101
6.1 Introduction: why worry? 101
6.2 Protocol development 104
6.2.1 Objectives 105
6.2.2 Background 105
6.2.3 Drug information 106
6.2.4 Stage definitions 106
6.2.5 Eligibility criteria 106
6.2.6 Descriptive factors, stratification factors and subsets 107
6.2.7 Treatment plan 107
6.2.8 Treatment modification 108
6.2.9 Study calendar 108
6.2.10 Endpoint definitions 109
6.2.11 Statistical considerations 109
6.2.12 Discipline review 109
6.2.13 Registration instructions 110
Contents ix
6.2.14 Data submission instructions 110
6.2.15 Special instructions 111
6.2.16 Regulatory requirements 111
6.2.17 Bibliography 111
6.2.18 Forms 111
6.2.19 Appendix 111
6.2.20 Additional comments on SWOG study 8811 111
6.3 Basic data items 112
6.4 Data forms 114
6.5 Protocol management and evaluation 117
6.6 Quality assurance audits 122
6.7 Training 122
6.8 Data base management 123
6.8.1 Data base structures 123
6.8.2 Data collection, transmission and entry 124
6.9 Conclusion 125
6.10 Appendix: Examples 126
6.10.1 Treatment table for 8811 126
6.10.2 Sampie study calendar 126
6.10.3 Sampie flow sheet 127
6.10.4 Sampie notice of death form 128
6.10.5 Sampie checklist 129
6.10.6 Sampie tables 131
7 Reporting of Results 133
7.1 Timing of report 133
7.1.1 Phase Ir trials 134
7.1.2 Phase III trials 134
7.2 Required information 135
7.2.1 Objectives and design 135
7.2.2 Eligibility and treatment 136
7.2.3 Results 136
7.3 Analyses 137
7.3.1 Exclusions, intent to treat 137
7.3.2 Summary statistics: estimates and variability of
estimates 138
7.3.3 Interpretation of results 140
7.3.4 Secondary analyses 142
7.4 Conclusion 142
8 Pitfalls 143
8.1 Introduction 143
8.2 Historical controls 143
8.3 Competing risks 150
x Contents
8.4 Outcome by outcome analyses 154
8.4.1 Survival by response comparisons 155
8.4.2 'Dose intensity' analyses 158
8.5 Subset analyses 163
8.6 Surrogate endpoints 164
9 Exploratory Analyses 167
9.1 Introduction 167
9.2 Some background and notation 167
9.3 Identification of prognostic factors 170
9.3.1 Scale of measurement 170
9.3.2 Choice of model 173
9.4 Forming prognostic groups 175
9.5 Meta-analysis 177
9.5.1 Some principles of meta-analysis 178
9.5.2 An example meta-analysis: portal vein infusion 179
9.5.3 Conclusions from the portal vein meta-analysis 181
9.5.4 Some final remarks on meta-analysis 182
9.6 Concluding remarks 182
10 Summary and Conclusions 185
References 189
Index 201
Acknowledgments
We would like to extend thanks to Bill Fortney, who made many invaluable
comments and suggestions which greatly improved this book. Thanks also
to Charles A. Coltman Jr., the Chair of the Southwest Oncology Group,
who has been an inspiration and a source of support and encouragement
throughout. We sincerely appreciate the patience and understanding of our
families of the time and effort spent in writing this book. Special thanks to
Mike LeBlanc, Joth Jacobson, Janet O'Sullivan and Anita Pang for help
with figures and tables, and to Kim Margolin, the study coordinator of
SWOG 8811, who reviewed the Data Management and Quality Control
chapter.
A special tribute to all the patients who have been enrolled in Southwest
Oncology Group trials over the past 40 years; their participation in our
trials has helped immeasurably in the struggle against this still dreaded
group of diseases.
All royalties from the sale of this book will go to Cancer Research and
Biostatistics, a non-profit corporation founded to support the research
activities of the Southwest Oncology Group Statistical Center.