Choice of δ Noninferiority Margin and Dependency of the Noninferiority Trials

2007 ◽  
Vol 17 (2) ◽  
pp. 279-288 ◽  
Author(s):  
Yi Tsong ◽  
Joanne Zhang ◽  
Mark Levenson
Keyword(s):  
Noninferiority Trials ◽  
Noninferiority Margin

A systematic review of noninferiority margins in oncology clinical trials

2021 ◽  
Vol 10 (6) ◽  
pp. 443-455
Author(s):  
Mahmoud Hashim ◽  
Talitha Vincken ◽  
Florint Kroi ◽  
Samron Gebregergish ◽  
Mike Spencer ◽  
...  
Keyword(s):  
Systematic Review ◽  
Clinical Trials ◽  
Absolute Rate ◽  
Time To Event ◽  
End Points ◽  
Patients With Cancer ◽  
Randomized Controlled ◽  
Noninferiority Trials ◽  
Oncology Clinical Trials ◽  
Noninferiority Margin

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.

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

2020 ◽  
Author(s):  
Anthony D Bai ◽  
Adam S Komorowski ◽  
Carson K L Lo ◽  
Pranav Tandon ◽  
Xena X Li ◽  
...  
Keyword(s):  
Systematic Review ◽  
Pharmaceutical Industry ◽  
Randomized Controlled Trials ◽  
Reporting Quality ◽  
Controlled Trials ◽  
Intention To Treat ◽  
Randomized Controlled ◽  
Noninferiority Trials ◽  
Noninferiority Margin

Abstract 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.

scholarly journals Noninferiority Margins in Trials of Thrombectomy Devices for Acute Ischemic Stroke

Stroke ◽  
2019 ◽  
Vol 50 (12) ◽  
pp. 3519-3526 ◽  
Author(s):  
Chun-Jen Lin ◽  
Jeffrey L. Saver
Keyword(s):  
Ischemic Stroke ◽  
Acute Ischemic Stroke ◽  
Primary Outcome ◽  
Coronary Revascularization ◽  
Functional Independence ◽  
Expert Survey ◽  
Cardiac Devices ◽  
Noninferiority Trials ◽  
First And Second Generation ◽  
Noninferiority Margin

Background and Purpose— Novel endovascular thrombectomy (EVT) devices for acute ischemic stroke are often cleared by regulatory agencies on the basis of noninferiority trials. The relation between the noninferiority margins used in trials and the minimal clinically important differences (MCIDs) determined by experts have not been systematically investigated. Methods— Systematic searches were performed to identify (1) all noninferiority design or noninferiority-presented stroke-EVT trials for acute ischemic stroke, (2) all studies determining the MCIDs for the same outcomes, and (3) all noninferiority coronary revascularization trials. Stroke-EVT trial results were reanalyzed using the broad noninferiority margins originally used and narrower noninferiority margins derived from formal MCID studies. Results— We identified 7 noninferiority-designed or noninferiority-interpreted stroke-EVT controlled trials, enrolling 1766 patients, variously comparing coil retrievers, first- and second-generation stent retrievers, and aspiration devices. In 6 trials, the primary outcome was achievement of reperfusion, using noninferiority margins of 15% (3 trials), 10% (2 trials), and 8% (1 trial). In contrast, a stroke expert survey identified the MCID for reperfusion as 3.1% to 5%, and cardiac trials used noninferiority margins of 3.5% to 4.4%. In one stroke-EVT trial, the primary outcome was functional independence, using a noninferiority margin of 15%. However, 2 stroke expert survey studies identified MCIDs for functional independence as having lower values, 5% and 1% to 1.5%. For both reperfusion and functional independence outcomes, all 7 trials demonstrated noninferiority with the broadest noninferiority margin, but only 4 and 3 trials demonstrated noninferiority with actual expert-derived margins for reperfusion and functional independence, respectively. Conclusions— Noninferiority margins used in EVT device trials have regularly exceeded the MCIDs determined by stroke experts, as well as margins used for cardiac devices. New approaches, such as the use of reasonably adequate performance margins, rather than noninferiority margins, are needed to optimize stroke-EVT trial design integrity and trial performance feasibility.

scholarly journals A Phase 3, Randomized, Double-Blind Study Comparing Tedizolid Phosphate and Linezolid for Treatment of Ventilated Gram-Positive Hospital-Acquired or Ventilator-Associated Bacterial Pneumonia

2021 ◽  
Author(s):  
Richard G Wunderink ◽  
Antoine Roquilly ◽  
Martin Croce ◽  
Daniel Rodriguez Gonzalez ◽  
Satoshi Fujimi ◽  
...  
Keyword(s):  
Clinical Response ◽  
Bacterial Pneumonia ◽  
Double Blind Study ◽  
Phase 3 ◽  
Gram Positive ◽  
Double Blind ◽  
Intention To Treat ◽  
The Difference ◽  
Hospital Acquired ◽  
Noninferiority Margin

Abstract Background Hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP) are associated with high mortality rates. We evaluated the efficacy and safety of tedizolid (administered as tedizolid phosphate) for treatment of gram-positive ventilated HABP/VABP. Methods In this randomized, noninferiority, double-blind, double-dummy, global phase 3 trial, patients were randomized 1:1 to receive intravenous tedizolid phosphate 200 mg once daily for 7 days or intravenous linezolid 600 mg every 12 hours for 10 days. Treatment was 14 days in patients with concurrent gram-positive bacteremia. The primary efficacy end points were day 28 all-cause mortality (ACM; noninferiority margin, 10%) and investigator-assessed clinical response at test of cure (TOC; noninferiority margin, 12.5%) in the intention-to-treat population. Results Overall, 726 patients were randomized (tedizolid, n = 366; linezolid, n = 360). Baseline characteristics, including incidence of methicillin-resistant Staphylococcus aureus (31.3% overall), were well balanced. Tedizolid was noninferior to linezolid for day 28 ACM rate: 28.1% and 26.4%, respectively (difference, –1.8%; 95% confidence interval [CI]: –8.2 to 4.7). Noninferiority of tedizolid was not demonstrated for investigator-assessed clinical cure at TOC (tedizolid, 56.3% vs linezolid, 63.9%; difference, –7.6%; 97.5% CI: –15.7 to 0.5). In post hoc analyses, no single factor accounted for the difference in clinical response between treatment groups. Drug-related adverse events occurred in 8.1% and 11.9% of patients who received tedizolid and linezolid, respectively. Conclusions Tedizolid was noninferior to linezolid for day 28 ACM in the treatment of gram-positive ventilated HABP/VABP. Noninferiority of tedizolid for investigator-assessed clinical response at TOC was not demonstrated. Both drugs were well tolerated. Clinical Trials Registration NCT02019420.

Noninferiority Trials

JAMA ◽  
2015 ◽  
Vol 313 (23) ◽  
pp. 2371 ◽  
Author(s):  
Amy H. Kaji ◽  
Roger J. Lewis
Keyword(s):  
Noninferiority Trials

scholarly journals Excess Deaths Associated With Tigecycline After Approval Based on Noninferiority Trials

2012 ◽  
Vol 54 (12) ◽  
pp. 1699-1709 ◽  
Author(s):  
P. Prasad ◽  
J. Sun ◽  
R. L. Danner ◽  
C. Natanson
Keyword(s):  
Noninferiority Trials ◽  
Excess Deaths

scholarly journals Low-Dose 3D Rotational Angiography in Measuring the Size of Intracranial Aneurysm: In Vitro Feasibility Study Using Aneurysm Phantom

2021 ◽  
Vol 16 (1) ◽  
pp. 59-63
Author(s):  
Hee Jong Ki ◽  
Bum-soo Kim ◽  
Jun-Ki Kim ◽  
Jai Ho Choi ◽  
Yong Sam Shin ◽  
...  
Keyword(s):  
Intracranial Aneurysm ◽  
Endovascular Treatment ◽  
Low Dose ◽  
Three Dimensional ◽  
3D Measurement ◽  
Rotational Angiography ◽  
3D Rotational Angiography ◽  
Conventional Dose ◽  
Noninferiority Margin

Purpose: Three-dimensional (3D) measurement of intracranial aneurysms is important in planning endovascular treatment, and 3D rotational angiography (RA) is effective in accurate measurement. The purpose of this study was to evaluate the feasibility of low dose 3D RA (5 seconds 0.10 μGy/frame) in measuring an intracranial aneurysm using an in vitro phantom.Materials and Methods: We investigated an <I>in vitro</i> 3D phantom of an intracranial aneurysm with 10 acquisitions of 3D RA with a conventional dose (5 seconds 0.36 μGy/frame) and 10 acquisitions with a low-dose (5 seconds 0.10 μGy/frame). 3D size and neck diameters of the aneurysm were measured and compared between the 2 groups (conventional and low-dose) using noninferiority statistics.Results: The aneurysm measurements were well-correlated between the 2 readers, and noninferiority in the measurement of aneurysmal size of low-dose 3D RA was demonstrated, as the upper margin of the 1-sided 97.5% confidence interval did not cross the pre-defined noninferiority margin of 0.2 mm by the 2 readers.Conclusion: Low-dose (5 seconds 0.10 μGy/frame) cerebral 3D RA is technically feasible and not inferior in in vitro 3D measurement of an intracranial aneurysm. Thus, low-dose 3D RA is promising and needs further evaluation for its clinical utility in the planning of endovascular treatment of an intracranial aneurysm.

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