Termination Based on Event Accrual in Per Protocol Versus Intention to Treat in the ROCKET AF Trial

Background In event‐driven clinical trials, study termination is based on accrual of a target number of primary efficacy events. For noninferiority trials in which superiority is conditionally examined, the ideal cohort in which to track event accrual is unclear. We used data from the ROCKET AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial to determine the effect of primary efficacy‐event tracking in the per‐protocol cohort during the on‐treatment period versus the intention‐to‐treat (ITT) cohort during the ITT period. Methods and Results ROCKET AF was terminated after accruing 429 primary efficacy events (stroke or systemic embolism) in the per‐protocol cohort during the on‐treatment period for noninferiority. We identified the date on which 429 events occurred in the ITT cohort during the ITT period. We performed noninferiority and superiority analyses based on hypothetical study termination on this date. ROCKET AF would have terminated 226 days earlier if events were tracked during the ITT period. Similar to the main trial findings, rivaroxaban would have met noninferiority versus warfarin for the primary efficacy end point (hazard ratio [HR], 0.77; 95% CI, 0.62–0.96; P <0.001). In contrast to the main trial findings, rivaroxaban would have met superiority for the primary efficacy end point (HR, 0.82; 95% CI, 0.68–0.99; P =0.038). In both termination scenarios, rivaroxaban was associated with a lower risk of intracranial hemorrhage and similar risk of other safety end points. Conclusions Clinical trial termination based on event accrual in the ITT cohort versus the per‐protocol cohort may have important implications on trial results depending on rates of study drug discontinuation and event rates off treatment.

A systematic review of noninferiority margins in oncology clinical trials

Aim: A systematic literature review was conducted to identify and characterize noninferiority margins for relevant end points in oncology clinical trials. Materials & methods: Randomized, controlled, noninferiority trials of patients with cancer were identified in PubMed and Embase. Results: Of 2284 publications identified, 285 oncology noninferiority clinical trials were analyzed. The median noninferiority margin was a hazard ratio of 1.29 (mean: 1.32; range: 1.05–2.05) for studies that reported time-to-event end points (n = 192). The median noninferiority margin was 13.0% (mean: 12.7%; range: 5.0–20.0%) for studies that reported response end points as absolute rate differences (n = 31). Conclusion: Although there was consistency in the noninferiority margins’ scale, variability was evident in noninferiority margins across trials. Increased transparency may improve consistency in noninferiority margin application in oncology clinical trials.

Are restricted mean survival time methods especially useful for noninferiority trials?

Background: Restricted mean survival time methods compare the areas under the Kaplan–Meier curves up to a time [Formula: see text] for the control and experimental treatments. Extraordinary claims have been made about the benefits (in terms of dramatically smaller required sample sizes) when using restricted mean survival time methods as compared to proportional hazards methods for analyzing noninferiority trials, even when the true survival distributions satisfy proportional hazardss. Methods: Through some limited simulations and asymptotic power calculations, the authors compare the operating characteristics of restricted mean survival time and proportional hazards methods for analyzing both noninferiority and superiority trials under proportional hazardss to understand what relative power benefits there are when using restricted mean survival time methods for noninferiority testing. Results: In the setting of low-event rates, very large targeted noninferiority margins, and limited follow-up past [Formula: see text], restricted mean survival time methods have more power than proportional hazards methods. For superiority testing, proportional hazards methods have more power. This is not a small-sample phenomenon but requires a low-event rate and a large noninferiority margin. Conclusion: Although there are special settings where restricted mean survival time methods have a power advantage over proportional hazards methods for testing noninferiority, the larger issue in these settings is defining appropriate noninferiority margins. We find the restricted mean survival time methods lacking in these regards.

Methodological and Reporting Quality of Noninferiority Randomized Controlled Trials Comparing Antibiotic Therapies: A Systematic Review

Background Antibiotic noninferiority randomized controlled trials (RCTs) are used for approval of new antibiotics and making changes to antibiotic prescribing in clinical practice. We conducted a systematic review to assess the methodological and reporting quality of antibiotic noninferiority RCTs. Methods We searched MEDLINE, Embase, the Cochrane Database of Systematic Reviews, and the Food and Drug Administration drug database from inception until November 22, 2019, for noninferiority RCTs comparing different systemic antibiotic therapies. Comparisons between antibiotic types, doses, administration routes, or durations were included. Methodological and reporting quality indicators were based on the Consolidated Standards of Reporting Trials reporting guidelines. Two independent reviewers extracted the data. Results The systematic review included 227 studies. Of these, 135 (59.5%) studies were supported by pharmaceutical industry. Only 83 (36.6%) studies provided a justification for the noninferiority margin. Reporting of both intention-to-treat (ITT) and per-protocol (PP) analyses were done in 165 (72.7%) studies. The conclusion was misleading in 34 (15.0%) studies. The studies funded by pharmaceutical industry were less likely to be stopped early because of logistical reasons (3.0% vs 19.1%; odds ratio [OR] = 0.13; 95% confidence interval [CI], .04–.37) and to show inconclusive results (11.1% vs 42.9%; OR = 0.17; 95% CI, .08–.33). The quality of studies decreased over time with respect to blinding, early stopping, reporting of ITT with PP analysis, and having misleading conclusions. Conclusions There is room for improvement in the methodology and reporting of antibiotic noninferiority trials. Quality can be improved across the entire spectrum from investigators, funding agencies, as well as during the peer-review process. There is room for improvement in the methodology and reporting of antibiotic noninferiority trials including justification of noninferiority margin, reporting of intention-to-treat analysis with per-protocol analysis, and having conclusions that are concordant with study results. PROSPERO registration number CRD42020165040.

Novel Antibiotics May Be Noninferior but Are They Becoming Less Effective?: a Systematic Review

ABSTRACT Novel antibiotics approved by noninferiority trials may become less effective over time in two scenarios: (i) the treatment effect in studies of novel antibiotics may be consistently worse than studies of older antibiotics; (ii) when a decreasingly effective control arm is used in a series of noninferiority trials. Our systematic review of 175 noninferiority antibiotic trials found these scenarios to be rare.

Efficacy and safety of lenvatinib versus sorafenib for unresectable hepatocellular carcinoma: A meta-analysis

Background Although sorafenib was recommended as a first-line systemic therapy to prolong overall survival time in unresectable hepatocellular carcinoma (HCC), two randomized phase 3 noninferiority trials demonstrated that lenvatinib was noninferior to sorafenib in unresectable HCC. Methods This study included three trials containing 1462 patients identified by a database search using standard terms. We conducted the data analysis in Review Manager version 5.3 software. Results The outcomes showed that there were nonsignificant differences in OS of 6, 12, 18, 30 and 36 months, PFS of 18, 24, 30 and 36 months and AEs (grade < 3) between the lenvatinib group and the sorafenib group, and there were significant differences in OS of 24 months (p = 0.01), PFS of 6 (p < 0.00001) and 12 (p < 0.00001) months, ORR (p < 0.00001) and DCR (p < 0.00001) between the lenvatinib group and the sorafenib group. Conclusions Lenvatinib was not superior to sorafenib in terms of OS and AEs, and lenvatinib was superior to sorafenib in terms of secondary endpoints, including PFS, ORR and DCR, in unresectable HCC.