Methods of defining the non-inferiority margin in randomized, double-blind controlled trials: a systematic review

Abstract

BackgroundThere is no consensus on the preferred method for defining the non-inferiority margin in non-inferiority trials, and previous studies showed that the rationale for its choice is often not reported. This study investigated how the non-inferiority margin is defined in the published literature, and whether its reporting has changed over time.MethodsA systematic PubMed search was conducted for all published randomized, double-blind, non-inferiority trials from January 1, 1966, to February 6, 2015. The primary outcome was the number of margins that were defined by methods other than the historical evidence of the active comparator. This was evaluated for a time trend. We also assessed the under-reporting of the methods of defining the margin as a secondary outcome, and whether this changed over time. Both outcomes were analyzed using a Poisson log-linear model. Predictors for better reporting of the methods, and the use of the fixed-margin method (one of the historical evidence methods) were also analyzed using logistic regression.ResultsTwo hundred seventy-three articles were included, which account for 273 non-inferiority margins. There was no statistically significant difference in the number of margins that were defined by other methods compared to those defined based on the historical evidence (ratio 2.17, 95% CI 0.86 to 5.82, p = 0.11), and this did not change over time. The number of margins for which methods were unreported was similar to those with reported methods (ratio 1.35, 95% CI 0.76 to 2.43, p = 0.31), with no change over time. The method of defining the margin was less often reported in journals with low-impact factors compared to journals with high-impact factors (OR 0.20; 95% CI 0.10 to 0.37, p < 0.0001). The publication of the FDA draft guidance in 2010 was associated with increased reporting of the fixed-margin method (after versus before 2010) (OR 3.54; 95% CI 1.12 to 13.35, p = 0.04).ConclusionsNon-inferiority margins are not commonly defined based on the historical evidence of the active comparator, and they are poorly reported. Authors, reviewers, and editors need to take notice of reporting this critical information to allow for better judgment of non-inferiority trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s13063-017-1859-x) contains supplementary material, which is available to authorized users.

Rivaroxaban was found to be noninferior to warfarin in routine clinical care: A retrospective noninferiority cohort replication study

“…This margin was used in the ROCKET AF trial, which was defined based on the limit of the 95% CI of the risk ratio of warfarin vs placebo in the reduction of stroke, or systemic embolism that was pooled from six placebo-controlled trials in patients with AF (ie, noninferiority was analyzed using the fixed-margin method). 18,33,34 To assess the primary outcome, a minimum of 2300 patients in each group will provide a power of at least 80% to demonstraste noninferiority of rivaroxaban to warfarin. These calculations were based on the noninferiority margin HR 1.46, one-sided significance level of 0.025, a mean follow-up time of 2 years, and an event rate of the primary outcome of 2.3% per patient-years in both study groups with an anticipated HR of 1.…”

Inclusion of non-inferiority analysis in superiority-based clinical trials with single-arm, two-stage Simon’s design

“…Although the NI question can be relevant in the phase II setting, 5 it is not usually considered on designing single-arm clinical trials in early clinical development. 30,31 Previous forays into precision medicine have shown that correctly identifying the target population and associated predictive biomarkers may be more critical for treatment success than simple demonstration of superior e cacy against an alternative. 22,23 Consequently, designing a proof-of-concept phase II study that permits NI analysis, if the superiority criteria cannot be met, will allow for more informed decisions that consider e cacy and other parameters, such as safety, cost, and biomarker strategy.…”

Ultrasound-Guided Erector Spinae Plane Block Versus Thoracic Paravertebral Block on Postoperative Analgesia After Laparoscopic Nephroureterectomy: Study Protocol of A Randomized, Double Blinded, Non-Inferiority Design Trial

“…In a pilot investigation of our patients, the mean (± standard deviation) of the cumulative 24h opioid (sufentanil) consumption after laparoscopic nephroureterectomy was about 25.7 (±2.0) μg with TPVB, and 35 (±14.0) μg with non-block respectively. The non-inferiority margin was set as 5 (unit: μg; clinical practice treated it as an acceptable difference) [27]. With a signi cance level of α=0.05 and a power of 1-β= 90%, the sample size required to detect difference was 77 patients in each group.…”