Non-inferiority Trial Design in Drug Development

A Primer for Cardiovascular Healthcare Professionals

Fabio Angeli; Paolo Verdecchia; Gianpaolo Reboldi


Am J Cardiovasc Drugs. 2020;20(3):229-238. 

In This Article

Key Features to Evaluate a Noninferiority TrialTrial

Noninferiority trials are far from easy to interpret, and some key features should be considered when evaluating their results.[14,15]

The efficacy of the standard treatment needs to be previously well-documented, and the advantages of the new treatment over the standard treatment should be clearly recognized.[14,15]

Although it is difficult to specify an appropriate noninferiority margin, its definition is crucial in the design of noninferiority trials. Of note, the definition of the noninferiority margin should be computed using data from (1) one or more placebo-controlled trials of the active comparator or (2) a meta-analysis of several placebo-controlled trials.[14–16]

The noninferiority trial should be similar to the trial(s) or meta-analyses comparing standard treatment and placebo, including design, inclusion and exclusion criteria, dosing, follow-up, and outcomes. This is known as the constancy assumption and is the key to researchers' ability to draw a conclusion about noninferiority. In other words, a constancy assumption requires that the effect of the active comparator in the noninferiority trial is consistent with the effect observed in previous trials.

In this context, the US Food and Drug Administration (FDA) draft guidance on noninferiority clinical trials highlights that the constancy assumption is important in determining assay sensitivity.[13]

Assay sensitivity is commonly referred as the property of the trial to distinguish an effective treatment from a less effective or ineffective treatment. In other words, assay sensitivity is the ability of the clinical trial to demonstrate a difference between treatments if such a difference truly exists.[16]

If a trial is intended to demonstrate efficacy by showing a test treatment to be noninferior to an active control but lacks assay sensitivity, the trial may find an ineffective treatment to be noninferior and could lead to an erroneous conclusion of efficacy.[14,16]

Randomization, allocation, masking, compliance with the study medication, diagnostic criteria, variability of measurements, and endpoint assessment are all factors that can affect assay sensitivity.[16,17]

As recommended by the International Conference on Harmonization (ICH) E10,[17] the presence of assay sensitivity in a noninferiority trial may be deduced from the following determinations:

  1. historical evidence of sensitivity to drug effects, which implies that previous similarly designed trials regularly distinguished effective treatments from less effective or ineffective treatments. Historical evidence of sensitivity to drug effects should be evaluated before beginning a noninferiority trial. It should be demonstrated that, in the specific therapeutic area under study and in appropriately designed and conducted trials, the active treatment intended for use as the active control was reliably found superior to placebo,[17]

  2. appropriate trial conduct; only high-quality trials (e.g., as reflected by good compliance and low rates of discontinuation from study drug) can distinguish effective treatments from less effective or ineffective treatments. Together with historical evidence of sensitivity to drug effects, appropriate trial conduct provides assurance of assay sensitivity in the new active control trial.[17]