Re-estimating the sample size of an on-going blinded trial based on the method of randomization block sums.

We extend a method we had previously described (Statist. Med. 2005) to estimate the within-group variance of a continuous endpoint without breaking the blind in a randomized clinical trial. Specifically, we: (a) explain how the method may be used for a wider set of designs than we had previously indicated; (b) obtain a within-group, covariate-adjusted, blinded variance estimator; (c) illustrate use of the method for sample size re-estimation; and (d) describe a procedure to determine whether or not the blinded variance estimator works well not just on average but for the data set at hand. The proposed method is simple to use and makes no additional assumptions than is made for unblinded analysis. Simulations show that for realistic sample sizes there is virtually no inflation in the Type I error rate. When weighing the burden imposed by interim unblinded re-estimation with the loss in precision with blinded re-estimation, it may be advantageous for some trials to use the blinded method. Copyright (c) 2008 John Wiley & Sons, Ltd.