CROSSOVER DESIGNS AND BIOAVAILABILITY STUDY WITH STATISTICAL ANALYSIS: A REVIEW

 

About Authors:
Bhupender Kumar*, Prof. Sudeep Bhardwaj, Monish Sharma, Ramchandra
Seth G.L. Bihani S.D. College of Technical Education (Institute Of Pharmaceutical Sciences
And Drug Research), Sri Ganganagar, Rajasthan, 335001
*bhupendra.nimiwal@gmail.com

ABSTRACT:
In a typical crossover design, each subject takes each of the treatments under investigation on different occasions. Comparative bioavailability or bioequivalence studies, in which two or more formulations of the same drug are compared, are usually designed as crossover studies. Perhaps the greatest appeal of the crossover design is that each patient acts as his or her own control. This feature allows for the direct comparison of treatments, and is particularly efficient in the presence of large inter individual variation. However, caution should be used when considering this design in studies where carryover effects or other interactions are anticipated. Under these circumstances, a parallel design may be more appropriate.


Reference Id: PHARMATUTOR-ART-1603

1.   CROSSOVER DESIGNS:
The crossover (or changeover) design is a very popular, and often desirable, design in clinical experiments. In these designs, typically, two treatments are compared, with each patient or subject taking each treatment in turn. The treatments are typically taken on two occasions, often called visits, periods, or legs. The order of treatment is randomized; that is, either A is followed by B or B is followed by A, where A and B are the two treatments. Certain situations exist where the treatments are not separated by time, e.g., in two visits or periods.

For example, comparing the effect of topical products, locations of applications on the body may serve as the visits or periods. Product may be applied to each of two arms, left and right. Individuals will be separated into two groups, (1) those with Product A applied on the left arm and Product B on the right arm, and (2) those with Product B applied on the left arm and Product A on the right arm.


This design may also be used for the comparison of more than two treatments. Crossover designs have great appeal when the experimental objective is the comparison of the performance, or effects, of two drugs or product formulations. Since each patient takes each product, the comparison of the products is based on within-patient variation. The within or intrasubject variability will be smaller than the between or intersubject variability used for the comparison of treatments in the one-way or parallel groups design. Thus crossover experiments usually result in greater precision than the parallel-groups design, where different patients comprise the two groups. The crossover design is more powerful than a parallel design in detecting product differences [Bolton Sanford]. The basic cross-over or simple reversal trial can be defined as one in which two treatments (A and B) are studied, and each animal (cow, experimental unit) receives both treatments in either of the sequences A, B or B, A.


[animsci.agrenv.mcgill.ca/servers/anbreed/statisticsII/crossovr/index.html]

The crossover design is a type of Latin square. In a Latin square the number of treatments equals the number of patients. In addition, another factor, such as order of treatment, is included in the experiment in a balanced way. The net result is an N X N array (where N is the number of treatments or patients) of N letters such that a given letter appears only once in a given row or column. This is most easily shown pictorially. A Latin square for four subjects taking four drugs is shown in table 2. For randomizations of treatments in Latin squares, For the comparison of two formulations, a 2 X 2 Latin square as in table 1 (N = 2) consists of two patients each taking two formulations (A and B) on two different occasions in two “orders”.

Table 1.    2 X 2 Latin square

Occasion period

Patient

First

Second

1

A

B

2

B

A

The balancing of order (A-B or B-A) takes care of time trends or other ‘‘period’’ effects, if present. (A period effect is a difference in response due to the occasion on which the treatment is given, independent of the effect due to the treatment).

The 2 X 2 Latin square shown above is familiar to all who have been involved in bioavailability/bioequivalence studies. In these studies, the 2 X 2 Latin square is repeated several times to include a sufficient number of patients. Thus the crossover design can be thought of as a repetition of the 2 X 2 Latin square.

Table 2.4 X 4 Latin Square: Four Subjects Take Four Drugs

Order in which drugs are taken

Subject

First

Second

Third

Fourth

1

A

B

C

D

2

B

C

D

A

3

C

D

A

B

4

D

A

B

C

Drugs are designated as A, B, C, D.[Bolton Sanford]

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