I cite the following statement about the interim analysis due to two reasons:
1. Hazard ratio sometimes is very tricky. When hazard ratio is used, everything could be reversed, making the interpretation of the results difficult. In one of my studies, when hazard ratio is calculated for time to relapse, I have to calculate the hazard ratio for Placebo / Active to make the results explanable. In the example below, the greater the hazard ratio, the better. While it is still called 'non-inferiority', everything seems to be flipped.
2. It is interesting to see that the pre-specified alpha levels are used to avoid the calculation of the alpha spending function.
The null hypothesis is that treatment with Drug A is inferior to treatment
with Drug B with respect to the duration of disease-free survival (HR >
1.305). The alternative hypothesis is that there is no difference between
treatment with Drug A and treatment with Drug B with respect to the duration
of disease-free survival (HR = 1).
Statistical Efficacy Analyses:
The two treatment groups will be compared for the duration of
disease-free survival based on the two sided 95% confidence interval for
the treatment disease-free survival hazard ratio from a Cox proportional
hazards regression model stratified for repeat TURBT (no/yes), high
grade papillary tumors (no/yes), CIS (no/yes), and region (North
America/Europe/Australia). Drug A will be considered to be non-inferior to
Drug B if the upper bound of the two sided 95% confidence interval for the
stratified disease-free survival hazard ratio of Drug A versus Drug B is below
1.305. Drug A will be considered to be superior to Drug B if the upper bound
of the two-sided 95% confidence interval for the stratified disease-free
survival hazard ratio of Drug A versus Drug B is below 1.0.
Two planned interim analyses will be conducted by the DMC; one will be
performed six months prior to reaching the foreseen sample size of 811
patients and another when at least 50 percent of the expected efficacy
endpoints, defined as a diagnosis of non-muscle or muscle invasive
tumors or death, have occurred. Analysis will be limited to the
evaluation of futility and extreme efficacy. For the futility analysis
(or obvious treatment failure), a recommendation will be made to stop
the trial if the Primary Analysis is deemed futile at the p<0.001 level.
The extreme efficacy analysis will be assessed for success at the
p<0.0001 level for the Primary Analysis and a recommendation will be
made to stop the study. There will be no adjustment for overall alpha
spending for any of these analyses."