Comparison of Outlier Detection Methods in Crossover Design Bioequivalence Studies


 Bioequivalence, Outliers, Likelihood distance, Estimated distance, Principal, Component.

How to Cite

Rasheed, T. Ahmad, & J.S. Siddiqi. (2013). Comparison of Outlier Detection Methods in Crossover Design Bioequivalence Studies . Journal of Pharmacy and Nutrition Sciences, 3(2), 163–170.


The significance of bioequivalence (BE) studies is rising due to large scale production and utilization of generic products all over the world. The correct identification of outlying data in BE studies is substantial for deciding two products either bioequivalence or bioinequivalent. For the detection of outliers in BE studies with the crossover designs different methods have been suggested in the literature. In the present work, we compared three outlier detection tests; (i) the Likelihood distance (LD) test (ii) the estimated distance (ED) test and the principal component analysis (PCA) test. In this work, the PCA test has been first time compared with the LD and ED test. For the purpose of comparison, we used two-way and three-way BE crossover data sets on linear and logarithmic scales. During the course of work it was found interesting and note-worthy that the performances of the ED and PCA tests in the sense of outlier detection are better than the LD test and this performance persists even for the log-transformed data. The results of our simulation study also indicated that the performance of the ED test for outliers’ identification is better than the other two tests.


FDA. Guidance for industry on statistical approaches to establishing bioequivalence.Center for Drug Evaluation and Research, Food and Drug Administration, Rockville, Maryland 2001.

Schall R, Endrenyi L, Ring A. Residuals and outliers in replicate design crossover studies. J Biopharm Stat 2010; 20(4): 835-49.

Lund RE. Tables for an approximate test for outliers in linear models. Technometrics 1975; 17: 473-76.

Chow S-C, Liu J-P. Design and analysis of bioavailability and bioequivalence studies (3rd ed.). New York: Dekker 2009.

Chow SC, Tse SK. Outlier detection in bioavailability/ bioequivalence studies. Stat Med 1990; 9(5): 549-58.

Enachescu D, Enachescu C. A new approach for outlying records in bioequivalence trials. Paper presented at the The XIII International Conference "Applied Stochastic Models and Data Analysis" 2009.

Ramsay T, Elkum N. A comparison of four different methods for outlier detection in bioequivalence studies. J Biopharm Stat 2005; 15(1): 43-52.

Liu JP, Weng CS. Detection of outlying data in bioavailability/bioequivalence studies. Statist Med 1991; 10(9): 1375-89.

Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

Copyright (c) 2013 Rasheed, T. Ahmad , J.S. Siddiqi