Carry-over in cross-over trials in bioequivalence: theoretical concerns and empirical evidence

There is now general agreement that pre-testing for carry-over in the AB/BA design is harmful and that efficient analysis of this design must proceed on the assumption that carry-over has not affected the results to any appreciable degree. A general consensus has not been achieved in the case of higher-order designs. Since particular forms of carry-over can be estimated on a within patient basis and unbiased within patient treatment estimators are possible, some statisticians favour pre-testing and some favour automatic adjustment for carry-over. We present theoretical arguments that show that, just as in the AB/BA case, the strategy of pre-testing is biased as a whole and also that the loss in terms of efficiency in adjusting is not negligible. We also present data from two large series of bioequivalence studies to provide empirical evidence that in this context carry-over is either absent or rare. We conclude that adjusting or testing for carry-over in bioequivalence studies is at worst harmful and at best pointless, and that this may also apply to other kinds of study. Copyright degreesC, 2004 John Wiley Sons Ltd.