Defining Non-Inferiority Margins for Skin Adhesion Studies

The non-inferiority trials might be performed as opposed to, or in addition to the superiority trials. The aim in noninferiority trials is to demonstrate that the test product is “not worse” than reference listed drug (RLD) or active control by more than the non-inferiority margin. The non-inferiority studies carry some weaknesses such as assay sensitivity, blinding, defining appropriate non-inferiority margins. Yet, the use of active control in non-inferiority trails might be the only choice to demonstrate the efficacy of a new product when the use of placebo arm is not ethical. Another example is transdermal products where it is recommended that the adhesion performance of the test patch should be compared to the adhesion performance of RLD. One of complexities of non-inferiority trials is to define an appropriate non-inferiority margin (E). The choice of such margin is usually based on historical data from the previous trials and assumes that the same effect will be present in the planned non-inferiority trial. Regulatory guidance documents recommend a non-inferiority test for comparing adhesion performance of transdermal test product compared to adhesion performance of RLD. This paper has a goal to review and compare the existing regulatory guidelines for the conducting non-inferiority trials particularly to compare adhesion performance. The authors suggest the rationale for adhesion data analyses with the clinically meaningful choice of non-inferiority margin. The examples of adhesion data analysis for two simulated Phase I studies are provided. Three unique user-friendly SAS® V9.12 macros help to execute the algorithm of power and sample size calculation for hypothesized non-inferiority margins. The authors are convinced that this novel paper can make non-inferiority trials comparing adhesion performance more clinically relevant.