Noninferiority Margin and Other Methodological Issues in Designing Noninferiority Trials: A Review

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.

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

Clinical Infectious Diseases ◽

10.1093/cid/ciaa1353 ◽

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.

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Choice of δ Noninferiority Margin and Dependency of the Noninferiority Trials

Journal of Biopharmaceutical Statistics ◽

10.1080/10543400601177384 ◽

2007 ◽

Vol 17 (2) ◽

pp. 279-288 ◽

Cited By ~ 11

Author(s):

Yi Tsong ◽

Joanne Zhang ◽

Mark Levenson

Keyword(s):

Noninferiority Trials ◽

Noninferiority Margin

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Noninferiority Margins in Trials of Thrombectomy Devices for Acute Ischemic Stroke

Stroke ◽

10.1161/strokeaha.119.026717 ◽

2019 ◽

Vol 50 (12) ◽

pp. 3519-3526 ◽

Cited By ~ 1

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.

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The Costs of Family Planning Programs: Methodological Issues with an Application to Barbados

Journal of Biosocial Science ◽

10.1017/s0021932000005915 ◽

1977 ◽

Vol 9 (01) ◽

Keyword(s):

Family Planning ◽

Methodological Issues ◽

Family Planning Programs

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Methodological issues in electronic fetal heart rate monitoring

Journal of the Society for Gynecologic Investigation ◽

10.1016/s1071-5576(97)86612-9 ◽

1998 ◽

Vol 5 (1) ◽

pp. 169A-169A ◽

Cited By ~ 1

Author(s):

R VICTORY ◽

E DERRICK ◽

J LOW

Keyword(s):

Heart Rate ◽

Fetal Heart Rate ◽

Fetal Heart ◽

Heart Rate Monitoring ◽

Methodological Issues ◽

Fetal Heart Rate Monitoring

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Narratives and Goals

Social Psychology ◽

10.1027/1864-9335/a000116 ◽

2013 ◽

Vol 44 (5) ◽

pp. 303-310 ◽

Cited By ~ 4

Author(s):

Simon M. Laham ◽

Yoshihisa Kashima

Keyword(s):

High Achievement ◽

Central Feature ◽

Behavioral Task ◽

Methodological Issues ◽

Goal Priming ◽

Behavioral Assimilation ◽

Construct Accessibility

Goals are a central feature of narratives, and, thus, narratives may be particularly potent means of goal priming. Two studies examined two features of goal priming (postdelay behavioral assimilation and postfulfillment accessibility) that have been theorized to distinguish goal from semantic construct priming. Across the studies, participants were primed with high achievement, either in a narrative or nonnarrative context and then completed either a behavioral task, followed by a measure of construct accessibility, or a behavioral task after a delay. Indicative of goal priming, narrative-primed participants showed greater postdelay behavioral assimilation and less postfulfillment accessibility than those exposed to the nonnarrative prime. The implications of goal priming from narratives are discussed in relation to both theoretical and methodological issues.

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Effects of Psychotherapy on Brain Activation Patterns in Anxiety Disorders

Zeitschrift für Psychologie ◽

10.1027/2151-2604/a000240 ◽

2016 ◽

Vol 224 (2) ◽

pp. 62-70 ◽

Cited By ~ 2

Author(s):

Thomas Straube

Keyword(s):

Anxiety Disorders ◽

Neuronal Plasticity ◽

Functional Neuroimaging ◽

State Of The Art ◽

Methodological Issues ◽

Future Directions ◽

Activation Patterns ◽

New Learning ◽

Analytical Strategies ◽

Sample Characteristics

Abstract. Psychotherapy is an effective treatment for most mental disorders, including anxiety disorders. Successful psychotherapy implies new learning experiences and therefore neural alterations. With the increasing availability of functional neuroimaging methods, it has become possible to investigate psychotherapeutically induced neuronal plasticity across the whole brain in controlled studies. However, the detectable effects strongly depend on neuroscientific methods, experimental paradigms, analytical strategies, and sample characteristics. This article summarizes the state of the art, discusses current theoretical and methodological issues, and suggests future directions of the research on the neurobiology of psychotherapy in anxiety disorders.

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