Controversial Statistical Issues in Clinical Trials

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Covering a number of controversial issues that are commonly encountered when conducting clinical trials, this book serves as a useful desk reference and an assessment of the current state of the art. It discusses the appropriateness of traditional statistical hypotheses (which primarily focus on efficacy) for clinical evaluation of both efficacy and safety, instability of classical sample size calculation based on information from a small pilot study, and integrity of randomization and blinding. The author illustrates the issues using real-world examples and up-to-date data. He also provides recommendations of possible resolutions of these issues.

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Editorial Reviews

From the Publisher
"… 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

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Product Details

Meet 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.

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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



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