Non-inferiority test for a continuous variable with a flexible margin in an active controlled trial: an application to the “Stratall ANRS 12110 / ESTHER” trial

Abstract

Background Non-inferiority trials are becoming increasingly popular in public health and clinical research. The choice of the non-inferiority margin is the cornerstone of such trials. Most of the time, the non-inferiority margin is fixed and constant, determined from historical trials as a fraction of the effect of the reference intervention. But in some circumstances, there may some uncertainty around the reference treatment that one would like to account for when performing the hypothesis testing. In this case, the non-inferiority margin is not fixed in advance and depends on the reference intervention estimate. Hence, the uncertainty surrounding the non-inferiority margin should be accounted for in statistical tests. In this work, we explore how to perform the non-inferiority test for a continuous variable with a flexible margin. Methods We have proposed in this study, two procedures for the non-inferiority test with a flexible margin for continuous endpoints. The proposed test procedures are based on a test statistic and confidence interval approaches respectively. Simulations have been used to assess the performances and properties of the proposed test procedures. An application was done on a real-world clinical data, to assess the efficacy of clinical monitoring alone versus laboratory and clinical monitoring in HIV-infected adult patients. Results Basically, for both proposed methods, the type I error estimate was not dependent on the values of the reference treatment. In the test statistic approach, the type 1 error rate estimate was approximatively equal to the nominal value. It has been found that the confidence interval level determined approximatively the level of significance. For a given nominal type I error α, the appropriate one- and two-sided confidence intervals should be with levels 1−α and 1−2α, respectively. Conclusions Based on the type I error rate and power estimates, the proposed non-inferiority hypothesis test procedures had good performances and were applicable in practice. Trial registration ClinicalTrials.gov NCT00301561. Registered on March 13, 2006, url: https://clinicaltrials.gov/ct2/show/NCT00301561.

Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor–Positive Breast Cancer

“…In noninferiority trials using end point biomarkers, the noninferiority margin is usually not fixed in advance and depends on the reference intervention estimate. 35 The median percentage change in the 3-times-weekly dose regimen was similar to the daily dose even with the most sensitive LLE assay, suggesting that in many individuals 3-timesweekly dosing is capable of suppressing estradiol to the same level of daily dosing. On the other hand, estradiol suppression below detection limit by LLE showed a stepwise dose response in the 3 dose levels.…”

“…The −6% noninferiority margin may be too restrictive considering the large intra-individual and interindividual variability of estradiol suppression. In noninferiority trials using end point biomarkers, the noninferiority margin is usually not fixed in advance and depends on the reference intervention estimate . The median percentage change in the 3-times-weekly dose regimen was similar to the daily dose even with the most sensitive LLE assay, suggesting that in many individuals 3-times-weekly dosing is capable of suppressing estradiol to the same level of daily dosing.…”