A Finding of Noninferiority Does Not Show Efficacy - It Shows Noninferiority (of short course rifampin for MDR-TB)

An image of two separated curves from Mayo's book SIST

Published in the March 28th, 2019 issue of the NEJM is the STREAM trial of a shorter regimen for Rifampin-resistant TB.  I was interested in this trial because if fits the pattern of a "reduced intensity therapy", a cohort of which we recently analyzed and published last year.  The basic idea is this:  if you want to show efficacy of a therapy, you choose the highest dose of the active drug to compare to placebo, to improve the chances that you will get "separation" of the two populations and statistically significant results.  Sometimes, the choice of the "dose" of something, say tidal volume in ARDS, is so high that you are accused of harming one group rather than helping the other.  The point is if you want positive results, use the highest dose so the response curves will separate further, assuming efficacy.

Conversely, in a noninferiority trial, your null hypothesis is not that there is no difference between the groups as it is in a superiority trial, but rather it is that there is a difference bigger than delta (the pre-specified margin of noninferiority.  Rejection of the null hypothesis a leads you to conclude that there is no difference bigger than delta, and you then conclude noninferiority.  If you are comparing a new antibiotic to vancomycin, and you want to be able to conclude noninferiority, you may intentionally or subconsciously dose vancomycin at the lower end of the therapeutic range, or shorten the course of therapy.  Doing this increases the chances that you will reject the null hypothesis and conclude that there is no difference greater than delta in favor of vancomycin and that your new drug is noninferior.  However, this increases your type 1 error rate - the rate at which you falsely conclude noninferiority.