Design and Analysis of Clinical Trials.....Crossover Designs Lesson 15

Lesson 15: Crossover Designs

Introduction

A crossover design is a repeated measurements design such that each experimental unit (patient) receives different treatments during the different time periods, i.e., the patients cross over from one treatment to another during the course of the trial. This is in contrast to a parallel design in which patients are randomized to a treatment and remain on that treatment throughout the duration of the trial.

The reason to consider a crossover design when planning a clinical trial is that it could yield a more efficient comparison of treatments than a parallel design, i.e., fewer patients might be required in the crossover design in order to attain the same level of statistical power or precision as a parallel design.(This will become more evident later in this lesson...) Intuitively, this seems reasonable because each patient serves as his/her own matched control. Every patient receives both treatment A and B. Crossover designs are popular in medicine, agriculture, manufacturing, education, and many other disciplines. A comparison is made of the subject's response on A vs. B.

Although the concept of patients serving as their own controls is very appealing to biomedical investigators, crossover designs are not preferred routinely because of the problems that are inherent with this design. In medical clinical trials the disease should be chronic and stable, and the treatments should not result in total cures but only alleviate the disease condition. If treatment A cures the patient during the first period, then treatment B will not have the opportunity to demonstrate its effectiveness when the patient crosses over to treatment B in the second period. Therefore this type of design works only for those conditions that are chronic, such as asthma where there is no cure and the treatments attempt to improve quality of life.

Crossover designs are the designs of choice for bioequivalence trials. The objective of a bioequivalence trial is to determine whether test and reference pharmaceutical formulations yield equivalent blood concentration levels. In these types of trials, we are not interested in whether there is a cure, this is a demonstration is that a new formulation, (for instance, a new generic drug), results in the same concentration in the blood system. Thus, it is highly desirable to administer both formulations to each subject, which translates into a crossover design.

Learning objectives & outcomes

Upon completion of this lesson, you should be able to do the following:

• Distinguish between situations where a crossover design would or would not be advantageous.
• Use the following terms appropriately: first-order carryover, sequence, period, washout, aliased effect.
• State why an adequate washout period is essential between periods of a crossover study in terms of aliased effects.
• Evaluate a crossover design as to its uniformity and balance and state the implications of these characteristics.
• Understand and modify SAS programs for analysis of data from 2 × 2 crossover trials with continuous or binary data.
• Provide an approach to analysis of event time data from a crossover study.
• Distinguish between population bioequivalence, average bioequivalence and individual bioequivalence.
• Relate the different types of bioequivalence to prescribability and switchability.