For better or for not-worse:
A patient is taking warfarin
prophylactically for a stroke or an embolism. The treatment is working well; however the patient
complains about how many visits they have to make to get their INR tested. You have heard of newer anticoagulation drugs with fewer
monitoring parameters, but how can you know if they are as effective as warfarin?
Making a direct comparison:
Non-inferiority trials (NI)
compare a new drug to the current standard of care and determine whether it is no worse, within an
acceptable margin. Directly comparing the two
treatments allows researchers to determine if the new treatment works just as effectively, while
simultaneously providing comparative data about the side effects, costs, and monitoring
The good and the bad: NI trials use an active control instead of
placebo in the comparison. This method is useful
because it enables investigators to study the efficacy of a new treatment or medication without
denying necessary treatment to patients when an established treatment exists. However, there is a major caveat with removing the placebo
group. In order to assume efficacy of the active
control, the study population used in an NI trial must be as similar as possible to the populations
used in historical data for the active control.
The most controversial aspect of the NI study
is the non-inferiority margin, which serves as the threshold of allowable inferiority for the drug
being studied. The margin is meant to represent the
magnitude of statistical difference that can exist between the two drugs without having a
significant clinical impact. Since NI trials are fairly
new, no standard method for determining the NI margins exist.
The researcher prospectively sets the margin (an educated opinion of acceptable confidence
intervals), describes the process by which it was determined, and allows the reader to exercise
their clinical judgment.
Conclusion: Non-inferiority trials are conducted more
frequently in clinical research than ever before. New treatments are marketed as potential
replacements for a standard of care by demonstrating ‘non-inferior’ efficacy and
possessing other beneficial characteristics. Only through meticulous examination can an educated
decision based on reliable results justify a promising change of therapy.
1. Gomber-Maitland M, Frison L, Halperin JL, et al.
Active-control clinical trials to establish equivalence or noninferiority: Methodological and
statistical concepts linked to quality. Am Heart J 2003; 146: 398-403
2. U.S. Department of Health and Human Services Food and Drug
Administration. Guidance for industry non-inferiority trials clinical trials. Rockville:
CDER and CBER, 2010. Print.