Features of Design and Analysis of Cross-Over Trials:

• Thoroughly updates the first edition with more data sets and new discussions on bioequivalence
• Includes a thorough treatment of modern methods for dependent non-normal data
• Uses examples from real trials to illustrate the techniques discussed
• Incorporates examples demonstrating analyses performed using SAS and includes the SAS code

Completely revised and updated, the long-awaited second edition of Design and Analysis of Cross-Over Trials retains its predecessor's careful balance of theory and practice while incorporating new approaches, more data sets, and a broader scope.

Enhancements in the second edition include:

• A new chapter on bioequivalence
• Recently developed methods for analyzing longitudinal continuous and categorical data
• Real-world examples using the SAS system
• A comprehensive catalog of designs, datasets, and SAS programs available on a companion Web site

Contents

Introduction

• What is a Cross-Over Trial?
• With which Sort of Cross-Over Trial are We Concerned?
• Why Do Cross-Over Trials Need Special Consideration?
• A Brief History
• Notation, Models and Analysis
• Aims of this Book
• Structure of the Book

The 2 x 2 Cross-Over Trial

• Plotting the Data
• The Analysis Using t-Tests
• Sample Size Calculations
• The Analysis of Variance
• Aliasing of Effects
• Consequences of preliminary testing
• Analyzing the residuals
• A Bayesian Analysis of the 2 x 2 Trial
• The Use of Baseline Measurements
• The Use of Covariates
• Nonparametric Analysis
• Binary Data

Higher-Order Designs for Two Treatments

• 'Optimal' Designs
• Balaam's Design for Two Treatments
• The Effect of Preliminary Testing in Balaam's Design
• Three-Period Designs with Two Sequences
• Three-Period Designs with Four Sequences
• A Three-Period Six-Sequence Design
• Which Three-Period Design to Use?
• Four-Period Designs with Two Sequences
• Four-Period Designs with Four Sequences
• Four-Period Designs with Six Sequences
• Which Four-Period Design to Use?
• Which Two-Treatment Design to Use?

Designing Cross-Over Trials for Three or More Treatments

• Variance-Balanced Designs
• Optimality Results for Cross-Over Designs
• Which Variance Balanced Design to Use?
• Partially Balanced Designs
• Comparing Test Treatments to a Control
• Factorial Treatment Combinations
• Extending the Simple Model for Carry-Over Effects
• Computer Search Algorithms

Analysis of Continuous Data

• The Fixed Subject Effects Model
• The Random Subject Effects Model
• Analyses for Higher-Order Two-Treatment Designs
• The General Linear Mixed Model
• Analysis of Repeated Measurements within Periods
• Cross-Over Data as Repeated Measurements
• Case Study: an Analysis of a Trial with Many Periods

Analysis of Categorical Data

• Binary Data: Subject Effect Models
• inary Data: Marginal Models
• Categorical Data

Bioequivalence Trials

• What is Bioequivalence
• Testing for Average Bioequivalence
• Power and Sample Size for ABE in the 2 x 2 Design
• Individual Bioequivalence
• Population Bioequivalence
• ABE for a Replicate Design
• Kullback-Leibler Divergence for Evaluating Bioequivalence
• Modelling Pharmacokinetic Data

Appendices

• Least Squares Estimation
• SAS Code for Assessing ABEm IBE, and PBE in Replicate Cross-Over Trials

Index

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