Controversial Statistical Issues in Clinical Trials: 1st Edition (Hardback) book cover

Controversial Statistical Issues in Clinical Trials

1st Edition

By Shein-Chung Chow

Chapman and Hall/CRC

611 pages | 26 B/W Illus.

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pub: 2011-06-15
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In clinical trial practice, controversial statistical issues inevitably occur regardless of the compliance with good statistical practice and good clinical practice. But by identifying the causes of the issues and correcting them, the study objectives of clinical trials can be better achieved. Controversial Statistical Issues in Clinical Trials covers commonly encountered controversial statistical issues in clinical trials and, whenever possible, makes recommendations to resolve these problems.

The book focuses on issues occurring at various stages of clinical research and development, including early-phase clinical development (such as bioavailability/bioequivalence), bench-to-bedside translational research, and late-phase clinical development. Numerous examples illustrate the impact of these issues on the evaluation of the safety and efficacy of the test treatment under investigation. The author also offers recommendations regarding possible resolutions of the problems.

Written by one of the preeminent experts in the field, this book provides a useful desk reference and state-of-the art examination of problematic issues in clinical trials for scientists in the pharmaceutical industry, medical/statistical reviewers in government regulatory agencies, and researchers and students in academia.


"… it is very valuable that the book calls the reader’s attention to the numerous problems which are relevant every day and I recommend to make this book available to personnel in all biometrical university departments, CROs and operating departments in the pharmaceutical industry to enable them to cope with the most important controversial aspects in planning and execution of clinical studies."

—Rainer Muche, ISCB News, December 2013

"This volume deals with an important area—issues in clinical trials research which are perhaps not fully resolved. … it is wide ranging, covering all aspects of clinical trials, and has excellent links and references to regulatory aspects. It will therefore provide a useful reference work for clinical trials researchers."

—David J. Hand, International Statistical Review, 2012

"I would recommend this book since it covers a number of areas that have not been covered in as much detail elsewhere. In particular, I thought the chapters on molecularly targeted therapies, follow-on biologics, multiregional clinical trials and good statistical practices were well written and useful."

—William Mietlowski, Journal of Biopharmaceutical Statistics, Issue 5, 2012

"Written by one of the preeminent experts in the field, this book provides a useful desk reference and state-of-the art examination of problematic issues in clinical trials for scientists in the pharmaceutical industry, medical/statistical reviewers in government regulatory agencies, and researchers and students in academia."

Zentralblatt MATH

Table of Contents


Pharmaceutical Development

Controversial Issues

Aim and Structure of the Book

Good Statistical Practices

Statistical Principles

Good Statistical Practices in Europe

Implementation of GSP

Bench-to-Bedside Translational Research

Biomarker Development

One-Way/Two-Way Translational Process

Lost in Translation

Animal Model versus Human Model

Bioavailability and Bioequivalence

Bioequivalence Assessment

Drug Interchangeability

Controversial Issues

Frequently Asked Questions

Hypotheses for Clinical Evaluation and Significant Digits

Hypotheses for Clinical Evaluation

Statistical Methods for Testing Composite Hypotheses of NS

The Impact on Power and Sample Size Calculation

Significant Digits

Instability of Sample Size Calculation

Sample Size Calculation

Instability and Bootstrap-Median Approach

Simulation Study

An Example

Integrity of Randomization/Blinding

The Effect of Mixed-Up Randomization

Blocking Size in Randomization

Test for Integrity of Blinding

Analysis under Breached Blindness

An Example

Clinical Strategy for Endpoint Selection

Clinical Strategy for Endpoint Selection

Translations among Clinical Endpoints

Comparison of Different Clinical Strategies

A Numerical Study

Protocol Amendments

Moving Target Patient Population

Analysis with Covariate Adjustment

Assessment of Sensitivity Index

Sample Size Adjustment

Seamless Adaptive Trial Designs

Controversial Issues

Types of Two-Stage Seamless Adaptive Designs

Analysis for Seamless Design with Same Study Objectives/Endpoints

Analysis for Seamless Design with Different Endpoints

Analysis for Seamless Design with Different Objectives/Endpoints

Multiplicity in Clinical Trials

General Concept

Regulatory Perspective and Controversial Issues

Statistical Method for Adjustment of Multiplicity

Gatekeeping Procedures

Independence of Data Monitoring Committee

Regulatory Requirements

DMC Composition and Charter

DMC’s Functions and Activities

Independence of DMC

Two-Way ANOVA versus One-Way ANOVA with Repeated Measures

One-Way ANOVA with Repeated Measures


Statistical Evaluation

Simulation Study

An Example


Validation of QOL Instruments

QOL Assessment

Performance Characteristics

Responsiveness and Sensitivity

Utility Analysis and Calibration

Analysis of Parallel Questionnaire

An Example

Missing Data Imputation

Last Observation Carry Forward

Mean/Median Imputation

Regression Imputation

Marginal/Conditional Imputation for Contingency

Testing for Independence

Controversial Issues

Recent Development

Center Grouping

Selection of the Number of Centers

Impact of Treatment Imbalance on Power

Center Grouping

Procedure for Center Grouping

An Example

Non-Inferiority Margin

Non-Inferiority Margin

Statistical Test Based on Treatment Difference

Statistical Tests Based on Relative Risk

Mixed Non-Inferiority Margin

Recent Developments

QT Studies with Recording Replicates

Study Designs and Models

Power and Sample Size Calculation

Adjustment for Covariates

Optimization for Sample Size Allocation

Test for QT/QTc Prolongation

Recent Developments

Multiregional Clinical Trials

Multiregional (Multinational), Multicenter Trials

Selection of the Number of Sites

Sample Size Calculation and Allocation

Statistical Methods for Bridging Studies

Dose Escalation Trials

Traditional Escalation Rule

Continual Reassessment Method

Design Selection and Sample Size

Enrichment Process in Target Clinical Trials

Identification of Differentially Expressed Genes

Optimal Representation of In Vitro Diagnostic Multivariate Index Assays

Validation of In Vitro Diagnostic Multivariate Index Assays

Enrichment Process

Study Designs of Target Clinical Trials

Analysis of Target Clinical Trials


Clinical Trial Simulation

Process for Clinical Trial Simulation

EM Algorithm

Resampling Method: Bootstrapping

Clinical Applications

Traditional Chinese Medicine

Fundamental Differences

Basic Considerations

Controversial Issues

Recent Development

The Assessment of Follow-On Biologic Products

Regulatory Requirements

Criteria for Biosimilarity

Scientific Issues

Assessing Similarity Using Genomic Data

Generalizability/Reproducibility Probability

The Estimated Power Approach

The Confidence Bound Approach

The Bayesian Approach


Good Review Practices

Regulatory Process and Requirements

Good Review Practices

Obstacles and Challenges

Probability of Success

Go/No-Go Decision in Development Process

POS Assessment



About the Author

Shein-Chung Chow, Ph.D., is a professor in the Department of Biostatistics and Bioinformatics at Duke University School of Medicine. Dr. Chow is also an adjunct professor of clinical sciences at Duke–National University of Singapore Graduate Medical School and the editor-in-chief of the Journal of Biopharmaceutical Statistics. He has authored or co-authored more than 200 papers and 19 books, including the recently published Handbook of Adaptive Designs in Pharmaceutical and Clinical Development. He earned his Ph.D. in statistics from the University of Wisconsin–Madison.

About the Series

Chapman & Hall/CRC Biostatistics Series

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Subject Categories

BISAC Subject Codes/Headings:
HEALTH & FITNESS / Herbal Medications
MATHEMATICS / Probability & Statistics / General
MEDICAL / Pharmacology