US FDA has issued norms on non-inferiority clinical trials to establish effectiveness of the drug. It provides a guidance to pharma and biotech companies submitting investigational drug applications (INDs), new drug applications (NDAs), biologics licensing applications (BLAs), or supplemental applications on the appropriate use of non-inferiority (NI) study designs to provide evidence of the effectiveness of a drug.
 
The guidance consists of study design, scientific and statistical issues associated with the use of NI studies to establish the effectiveness of a new drug. It also highlights statistical approaches used to determine the NI margin.
 
Usually because a superiority study design which is a drug versus placebo, dose response cannot be used. The guidance gives advice on when NI studies are intended to demonstrate effectiveness of an investigational drug to provide interpretable results. Besides it guides on how to choose the NI margin and to test the NI hypothesis.
 
The regulator has stated that the guidance does not provide recommendations for the use of NI study designs to evaluate the safety of a drug. FDA’s regulations on adequate and well-controlled studies: 21 CFR 314.126 explain four kinds of concurrently controlled trials that provide evidence of effectiveness. These are placebo, no treatment, and dose-response controlled trials. The latter is superiority trials that seek to show that a test drug is superior to the control placebo, no treatment, or a lower dose of the test drug.
 
The objective of such studies is to show that the difference between the new and active control treatment is small to allow the known effectiveness of the drug, based on its performance in past studies.
 
Active controlled trials that are not intended to show superiority of the test drug but rather to demonstrate that the new treatment is not inferior. The intent of an NI trial, however, is not to show that the new drug is equivalent, but rather that it is not materially worse than the control. Therefore, the interest is one-sided, stated the regulatory authority.
 
The critical difference between superiority and NI trials is that a properly designed study, if successful in showing a difference, is entirely interpretable without further assumptions requires no extra-study information.
 
In contrast, the NI study is dependent on knowing something that is not measured in the research, namely, that the active control had its expected effect. When this occurs, the trial is said to have assay sensitivity, defined as the ability to have shown a difference from placebo of a specified size.
 
A successful NI trial is one that shows what appears to be an acceptably small difference between treatments, according to the regulatory guidance.