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Lesson 15: Crossover Designs

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.
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Lesson 15: Crossover Designs

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. Reference Piantadosi Steven. (2005) Crossover Designs. In: Piantadosi Steven. Clinical Trials: A Methodologic Perspective. 2nd ed. Hobaken, NJ: John Wiley and Sons, Inc.

15.1 - Overview of the Crossover Designs

The order of treatment administration in a crossover experiment is called a sequence and the time of a treatment administration is called a period. Typically, the treatments are designated with capital letters, such as A, B, etc. The sequences should be determined a priori and the experimental units are randomized to sequences. The most popular crossover design is the 2-sequence, 2-period, 2-treatment crossover design, with sequences AB and BA, sometimes called the 2 2 crossover design. In this particular design, experimental units that are randomized to the AB sequence receive treatment A in the first period and treatment B in the second period, whereas experimental units that are randomized to the BA sequence receive treatment B in the first period and treatment A in the second period. We express this particular design as AB|BA or diagram it as: [Design 1] Sequence AB Sequence BA Period 1 A B Period 2 B A

Examples of 3-period, 2-treatment crossover designs are: [Design 2] Sequence ABB Sequence BAA and [Design 3] Sequence AAB Period 1 A Period 2 A Period 3 B
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Period 1 A B

Period 2 B A

Period 3 B A

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Lesson 15: Crossover Designs

Sequence ABA Sequence BAA

A B

B A

A A

Examples of 3-period, 3-treatment crossover designs are [Design 4] Sequence ABC Sequence BCA Sequence CAB and [Design 5] Sequence ABC Sequence BCA Sequence CAB Sequence ACB Sequence BAC Sequence CBA Period 1 A B C A B C Period 2 B C A C A B Period 3 C A B B C A Period 1 A B C Period 2 B C A Period 3 C A B

Some designs even incorporate non-crossover sequences such as Balaam's design: [Design 6] Sequence AB Sequence BA Sequence AA Sequence BB Period 1 A B A B Period 2 B A A B

Balaams design is unusual, with elements of both parallel and crossover design. There are advantages and disadvantages to all of these designs; we will discuss some and the implications for statistical analysis as we continue through this lesson.

15.2 - Disadvantages
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Lesson 15: Crossover Designs

The main disadvantage of a crossover design is that carryover effects may be aliased (confounded) with direct treatment effects, in the sense that these effects cannot be estimated separately. You think you are estimating the effect of treatment A but there is also a bias from the previous treatment to account for. Significant carryover effects can bias the interpretation of data analysis, so an investigator should proceed cautiously whenever he/she is considering the implementation of a crossover design. A carryover effect is defined as the effect of the treatment from the previous time period on the response at the current time period. In other words, if a patient receives treatment A during the first period and treatment B during the second period, then measurements taken during the second period could be a result of the direct effect of treatment B administered during the second period, and/or the carryover or residual effect of treatment A administered during the first period. These carryover effects yield statistical bias. What can we do about this carryover effect? The incorporation of lengthy washout periods in the experimental design can diminish the impact of carryover effects. A washout period is defined as the time between treatment periods. Instead of immediately stopping and then starting the new treatment, there will be a period of time where the treatment from the first period where the drug is washed out of the patient's system. The rationale for this is that the previously administered treatment is washed out of the patient and, therefore, it can not affect the measurements taken during the current period. This may be true, but it is possible that the previously administered treatment may have altered the patient in some manner, so that the patient will react differently to any treatment administered from that time onward. An example is when a pharmaceutical treatment causes permanent liver damage so that the patients metabolize future drugs differently. Another example occurs if the treatments are different types of educational tests. Then subjects may be affected permanently by what they learned during the first period. How long of a wash out period should there be? In a trial involving pharmaceutical products, the length of the washout period usually is determined as some multiple of the half-life of the pharmaceutical product within the population of interest. For example, an investigator might implement a washout period equivalent to 5 (or more) times the length of the half-life of the drug concentration in the blood. The figure below depicts the half-life of a hypothetical drug.

Actually, it is not the presence of carryover effects per se that leads to aliasing with direct treatment effects in the AB|BA crossover, but rather the presence of differential carryover effects, i.e., the carryover effect due to treatment A differs from the carryover effect due to treatment B. If the carryover effects for A and B are
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Lesson 15: Crossover Designs

equivalent in the AB|BA crossover design, then this common carryover effect is not aliased with the treatment difference. So, for crossover designs, when the carryover effects are different from one another, this presents us with a significant problem. In the example of the educational tests, differential carryover effects could occur if test A leads to more learning than test B. Another situation where differential carryover effects may occur is in clinical trials where an active drug (A) is compared to placebo (B) and the washout period is of inadequate length. The patients in the AB sequence might experience a strong A carryover during the second period, whereas the patients in the BA sequence might experience a weak B carryover during the second period. The recommendation for crossover designs is to avoid the problems caused by differential carryover effects at all costs by employing lengthy washout periods and/or designs where treatment and carryover are not aliased or confounded with each other. It is always much more prudent to address a problem a priori by using a proper design rather than a posteriori by applying a statistical analysis that may require unreasonable assumptions and/or perform unsatisfactorily. You will see this later on in this lesson... For example, one approach for the statistical analysis of the 2 2 crossover is to conduct a preliminary test for differential carryover effects. If this is significant, then only the data from the first period are analyzed because the first period is free of carryover effects. Essentially you be throwing out half of your data! If the preliminary test for differential carryover is not significant, then the data from both periods are analyzed in the usual manner. Recent work, however, has revealed that this 2-stage analysis performs poorly because the unconditional Type I error rate operates at a much higher level than desired. We won't go into the specific details here, but part of the reason for this is that the test for differential carryover and the test for treatment differences in the first period are highly correlated and do not act independently. Even worse, this two-stage approach could lead to losing one-half of the data. If differential carryover effects are of concern, then a better approach would be to use a study design that can account for them. Prior to the development of a general statistical model and investigations into its implications for, we require more definitions.

15.3 - Definitions with a Crossover Design

First-order and Higher-order Carryover Effects Within time period j , j = 2, ... , p, it is possible that there are carryover effects from treatments administered during periods 1, ... , j - 1. Usually in period j we only consider first-order carryover effects (from period j 1) because: 1. if first-order carryover effects are negligible, then higher-order carryover effects usually are negligible; 2. the designs needed for eliminating the aliasing between higher-order carryover effects and treatment effects are very cumbersome and not practical. Therefore, we usually assume that these higher-order carryover effects are negligible. In actuality, the length of the washout periods between treatment administrations may be the determining factor
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as to whether higher-order carryover effects should be considered. We focus on designs for dealing with first-

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Lesson 15: Crossover Designs

as to whether higher-order carryover effects should be considered. We focus on designs for dealing with firstorder carryover effects, but the development can be generalized if higher-order carryover effects need to be considered. We will focus on: Uniformity A crossover design is labeled as: 1. uniform within sequences if each treatment appears the same number of times within each sequence, and 2. uniform within periods if each treatment appears the same number of times within each period. For example, AB/BA is uniform within sequences and period (each sequence and each period has 1 A and 1 B) while

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