Best Evidence Analyses and Commentary
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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 parameters.

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.


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