Type I error in sample size re-estimations based on observed treatment difference.

Sample size re-estimation based on an observed difference can ensure an adequate power and potentially save a large amount of time and resources in clinical trials. One of the concerns for such an approach is that it may inflate the type I error. However, such a possible inflation has not been mathematically quantified. In this paper the mathematical mechanism of this inflation is explored for two-sample normal tests. A (conditional) type I error function based on normal data is derived. This function not only provides the quantification but also gives mathematical mechanisms of possible inflation in the type I error due to the sample size re-estimation. Theoretically, based on their decision rules (certain upper and lower bounds), people can calculate this function and exactly visualize the changes in type I error. Computer simulations are performed to ensure the results. If there are no bounds for the adjustment, the inflation is evident. If proper adjusting rules are used, the inflation can be well controlled. In some cases the type I error can even be reduced. The trade-off is to give up some 'unrealistic power'. We investigated several scenarios in which the mechanisms to change the type I error are different. Our simulations show that similar results may apply to other distributions. Copyright 2001 John Wiley & Sons, Ltd.