Design and Analysis of Cross-Over Trials (Chapman Hall/CRC Monographs on Statistics Applied Probability)

The first edition of Design and Analysis of Cross-Over Trials quickly became the standard reference on the subject and has remained so for more than 12 years. In that time, however, the use of cross-over trials has grown rapidly, particularly in the pharmaceutical arena, and researchers have made a number of advances in both the theory and methods applicable to these trials.

Completely revised and updated, the long-awaited second edition of this classic text 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 at www.crcpress.com

The authors' exposition gives a clear, unified account of the design and analysis of cross-over trials from a statistical perspective along with their methodological underpinnings. With SAS programs and a thorough treatment of design issues, Design and Analysis of Cross-Over Trials, Second Edition sets a new standard for texts in this area and undoubtedly will be of direct practical value for years to come.

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

Introduction

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

Introduction

’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

Introduction

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

Introduction

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

Introduction

Binary Data: Subject Effect Models

Binary Data: Marginal Models

Categorical Data

Further Topics

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

REFERENCES