Biocreep and constancy

The issue of constancy concerns the conditions under which the current active control trial is being conducted compared to the conditions under which the active control was established historically. Things may well have changed. For example, the nature of the underlying disease or the effectiveness of ancillary care may be such that the active control performs rather differently now than it did when the original placebo-controlled trials were undertaken. This may well be true, for example, for antibiotics where populations of patients will have developed resistance to certain treatments. If this were the case then the current non-inferiority trial could lead to a misleading conclusion of effectiveness for the new active when in fact the comparator treatment is ineffective. 

Both of these elements are causing nervousness amongst regulators. So much so that, for example, the FDA Anti-Infective Drugs Advisory Committee (AIDAC) have recently recommended that the non-inferiority design should no longer 

We will focus our attention to the situation of non-inferiority. Within the testing framework the type I error in this case is as before, the false positive (rejecting the null hypothesis when it is true), which now translates into concluding noninferiority when the new treatment is in fact inferior. The type II error is the false negative (failing to reject the null hypothesis when it is false) and this translates into failing to conclude non-inferiority when the new treatment truly is non-inferior. The sample size calculations below relate to the evaluation of noninferiority when using either the confidence interval method or the alternative p-value approach recall these are mathematically the same. 

The sample size calculation requires pre-specification of the following quantities  

The remaining quantities would depend on the primary endpoint and the design assume we are dealing with the parallel group case. 

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