The SEQDESIGN procedure assumes that with a total number of stages , the sequence of the standardized test statistics has the canonical joint distribution with information levels for the parameter (Jennison and Turnbull 2000, p. 49):

• is multivariate normal

• 

• ,   

In terms of the maximum likelihood estimator, , , the canonical joint distribution can be expressed as follows:

• is multivariate normal

• 

• ,   

Furthermore, in terms of the score statistics , , the canonical joint distribution can be expressed as follows:

• is multivariate normal

• 

• ,   

That is, the increments , , ..., and are independently distributed.

If the test statistic is computed from the data that are not from a normal distribution, such as a binomial distribution, then it is assumed that the test statistic is computed from a large sample such that the statistic has an approximately normal distribution.

If the increments , , ..., and are not independently distributed, then it is inappropriate to use group sequential methods in the SEQDESIGN procedure. One such example is the Gehan statistic, which is a weighted log-rank statistic for censored data. Refer to Jennison and Turnbull (2000 pp. 232–233, 276–277) and Proschan, Lan, and Wittes (2006 pp. 150–151) for a description of statistics with nonindependent increments.

If a trial stops at an early interim stage with only a small number of responses observed, it can lead to a distrust of the statistical findings, which rely on the assumption that the sample is large (Whitehead 1997, p. 167). A group sequential design can be specified such that at the first interim analysis, there are a sufficient number of responses to ensure that the analysis to be conducted is both reliable and persuasive (Whitehead 1997, p. 167).

Alternatively, a method such as the O’Brien-Fleming method can be used to derive conservative stopping boundary values at very early stages to make the early stop less likely. That is, the trial is stopped in early stages only with overwhelming evidence.

A simple example of the group sequential tests is the test for a normal mean, . Suppose are observations of a response variable Y in a data set from a normal distribution with an unknown mean and a known variance . Then the maximum likelihood estimate of is the sample mean

The sample mean has a normal distribution with mean and variance :

An equivalent hypothesis for is , where . The MLE statistic for ,

where the information .

For a group sequential test with stages, there are observations available at these stages. At stage , the sample mean is computed as

where is the value of the th observation available at the th stage and is the cumulative sample size at stage , which includes the observations collected at previous stages and the observations collected at the current stage.

The maximum likelihood estimate

where the information

is the inverse of the variance.

Thus, the standardized statistic

The covariance of and , can be expressed as

where and .

Since is independent of , and

Thus the statistics has the canonical joint distribution with information levels for the parameter . See the section Applicable One-Sample Tests and Sample Size Computation, the section Applicable Two-Sample Tests and Sample Size Computation, and the section Applicable Regression Parameter Tests and Sample Size Computation for more examples of applicable tests in group sequential trials.