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Design and Analysis of Clinical Trials: Concepts and Methodologies, 2nd Edition

Design and Analysis of Clinical Trials: Concepts and Methodologies, 2nd Edition

Shein-Chung Chow, Jen-Pei Liu

ISBN: 978-0-471-47328-2

Jan 2005

752 pages

Select type: O-Book


Praise for the First Edition of Design and Analysis of Clinical Trials

"An excellent book, providing a discussion of the clinical trial process from designing the study through analyzing the data, and to regulatory requirement . . . could easily be used as a classroom text to understand the process in the new drug development area."
Statistical Methods in Medicine

A complete and balanced presentation now revised, updated, and expanded
As the field of research possibilities expands, the need for a working understanding of how to carry out clinical trials only increases. New developments in the theory and practice of clinical research include a growing body of literature on the subject, new technologies and methodologies, and new guidelines from the International Conference on Harmonization (ICH).

Design and Analysis of Clinical Trials, Second Edition provides both a comprehensive, unified presentation of principles and methodologies for various clinical trials, and a well-balanced summary of current regulatory requirements. This unique resource bridges the gap between clinical and statistical disciplines, covering both fields in a lucid and accessible manner. Thoroughly updated from its first edition, the Second Edition of Design and Analysis of Clinical Trials features new topics such as:

  • Clinical trials and regulations, especially those of the ICH
  • Clinical significance, reproducibility, and generalizability
  • Goals of clinical trials and target population
  • New study designs and trial types
  • Sample size determination on equivalence and noninferiority trials, as well as comparing variabilities

Also, three entirely new chapters cover:

  • Designs for cancer clinical trials
  • Preparation and implementation of a clinical protocol
  • Data management of a clinical trial

Written with the practitioner in mind, the presentation assumes only a minimal mathematical and statistical background for its reader. Instead, the writing emphasizes real-life examples and illustrations from clinical case studies, as well as numerous references-280 of them new to the Second Edition-to the literature. Design and Analysis of Clinical Trials, Second Edition will benefit academic, pharmaceutical, medical, and regulatory scientists/researchers, statisticians, and graduate-level students in these areas by serving as a useful, thorough reference source for clinical research.


Preface to the First Edition.

1. Introduction.

1.1 What are Clinical Trials?

1.2 History of Clinical Trials.

1.3 Regulatory Process and Requirements.

1.4 Investigational New Drug Application.

1.5 New Drug Application.

1.6 Clinical Development and Practice.

1.7 Aims and Structure of the Book.

2. Basic Statistical Concepts.

2.1 Introduction.

2.2 Uncertainty and Probability.

2.3 Bias and Variability.

2.4 Confounding and Interaction.

2.5 Descriptive and Inferential Statistics.

2.6 Hypothesis Testing and p-Values.

2.7 Clinical Significance and Clinical Equivalence.

2.8 Reproducibility and Generalizability.

3. Basic Design Considerations.

3.1 Introduction.

3.2 Goals of Clinical Trials.

3.3 Target Population and Patient Selection.

3.4 Selection of Controls.

3.5 Statistical Considerations.

3.6 Other Issues.

3.7 Discussion.

4. Randomization and Blinding.

4.1 Introduction.

4.2 Randomization Models.

4.3 Randomization Methods.

4.4 Implementation of Randomization.

4.5 Generalization of Controlled Randomized Trials.

4.6 Blinding.

4.7 Discussion.

5. Designs for Clinical Trials.

5.1 Introduction.

5.2 Parallel Group Designs.

5.3 Cluster Randomized Designs.

5.4 Crossover Designs.

5.5 Titration Designs.

5.6 Enrichment Designs.

5.7 Group Sequential Designs.

5.8 Placebo-Challenging Design.

5.9 Blinded Reader Designs.

5.10 Discussion.

6. Designs for Cancer Clinical Trials.

6.1 Introduction.

6.2 General Considerations for Phase I Cancer Clinical Trials.

6.3 Single-Stage Up-and-Down Phase I Designs.

6.4 Two-Stage Up-and-Down Phase I Designs.

6.5 Continual Reassessment Method Phase I Designs.

6.6 Optimal/Flexible Multiple-Stage Designs.

6.7 Randomized Phase II Designs.

6.8 Discussion.

7. Classification of Clinical Trials.

7.1 Introduction.

7.2 Multicenter Trial.

7.3 Superiority Trials.

7.4 Active Control and Equivalence/Noninferiority Trials.

7.5 Dose-Response Trials.

7.6 Combination Trials.

7.7 Bridging Studies.

7.8 Vaccine Clinical Trials.

7.9 Discussion.

8. Analysis of Continuous Data.

8.1 Introduction.

8.2 Estimation.

8.3 Test Statistics.

8.4 Analysis of Variance.

8.5 Analysis of Covariance.

8.6 Nonparametrics.

8.7 Repeated Measures.

8.8 Discussion.

9. Analysis of Categorical Data.

9.1 Introduction.

9.2 Statistical Inference for One Sample.

9.3 Inference of Independent Samples.

9.4 Ordered Categorical Data.

9.5 Combining Categorical Data.

9.6 Model-Based Methods.

9.7 Repeated Categorical Data.

9.8 Discussion.

10. Censored Data and Interim Analysis.

10.1 Introduction.

10.2 Estimation of the Survival Function.

10.3 Comparison between Survival Functions.

10.4 Cox’s Proportional Hazard Model.

10.5 Calendar Time and Information Time.

10.6 Group Sequential Methods.

10.7 Discussion.

11. Sample Size Determination.

11.1 Introduction.

11.2 Basic Concept.

11.3 Two Samples.

11.4 Multiple Samples.

11.5 Censored Data.

11.6 Dose-Response Studies.

11.7 Crossover Designs.

11.8 Equivalence and Noninferiority Trials.

11.9 Multiple-Stage Design in Cancer Trials.

11.10 Comparing Variabilities.

11.11 Discussion.

12. Issues in Efficacy Evaluation.

12.1 Introduction.

12.2 Baseline Comparison.

12.3 Intention-to-Treat Principle and Efficacy Analysis.

12.4 Adjustment for Covariates.

12.5 Multicenter Trials.

12.6 Multiplicity.

12.7 Data Monitoring.

12.8 Use of Genetic Information for Evaluation of Efficacy.

12.9 Sample Size Re-estimation.

12.10 Discussion.

13. Safety Assessment.

13.1 Introduction.

13.2 Extent of Exposure.

13.3 Coding of Adverse Events.

13.4 Analysis of Adverse Events.

13.5 Analysis of Laboratory Data.

13.6 Discussion.

14. Preparation and Implementation of a Clinical Protocol.

14.1 Introduction.

14.2 Structure and Components of a Protocol.

14.3 Points to Be Considered and Common Pitfalls during Development and Preparation of a Protocol.

14.4 Common Departures for Implementation of a Protocol.

14.5 Monitoring, Audit, and Inspection, 617

14.6 Quality Assessment of a Clinical Trial.

14.7 Discussion.

15. Clinical Data Management.

15.1 Introduction.

15.2 Regulatory Requirements.

15.3 Development of Case Report Forms.

15.4 Database Development.

15.5 Data Entry, Query, and Correction.

15.6 Data Validation and Quality.

15.7 Database Lock, Archive, and Transfer.

15.8 Discussion.




"It stands ready to satisfy the appetite of any pharmaceutical scientist with a respectable statistical appetite." (Journal of Clinical Research, June 2008)

"Biostatisticians, applied statisticians, and clinical scientists will find this book very valuable, and it is suitable for a graduate level clinical trial course." (Journal of Statistical Computation and Simulation, September 2005)

"…a comprehensive introduction…highly recommended…" (Statistical Methods in Medical Research, Vol. 14, 2005)

"…I will find this book a handy resource for future consulting with medical researchers." (Journal of the American Statistical Association, June 2005)

"…the authors have done a commendable job of blending large amounts of statistical and regulatory information in a way that is easy to comprehend and directly applicable…" (Clinical Chemistry, April 2005)

"…provides a comprehensive overview of the rather general area of clinical trials…an essential reference text." (Journal of Applied Statistics, Vol.32, No.3, April 2005)

"Numerous real-life examples and illustrations form clinical case studies are included…" (Zentralblatt Math, Vol.1050, 2005)

"…certainly comprehensive...should be a standard reference for both clinical scientists and biostatisticians…" (Technometrics, February 2005)