The challenges of determining noninferiority margins: a case study of noninferiority randomized controlled trials of novel oral anticoagulants

Wangge, Grace; Roes, Kit C. B.; Boer, Anthonius de; Hoes, Arno W.; Knol, Mirjam J.

doi:10.1503/cmaj.120142

Cited by 27 publications

(29 citation statements)

References 19 publications

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“…The stricter the preserved fraction, the harder to demonstrate noninferiority. This was demonstrated in the case-study by Wangge et al [20] about noninferiority trials of novel oral anticoagulants. In this case-study, the fixed-margin method was used to re-analyse 16 noninferiority comparisons from 12 trials of new anticoagulants based on 50% and 67% preserved fractions.…”

Section: Defining the Noninferiority Marginmentioning

confidence: 82%

Defining the noninferiority margin and analysing noninferiority: An overview

Althunian

Boer

Groenwold

et al. 2017

Brit J Clinical Pharma

Self Cite

126

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Noninferiority trials are used to assess whether the effect of a new drug is not worse than an active comparator by more than a noninferiority margin. If the difference between the new drug and the active comparator does not exceed this prespecified margin, noninferiority can be concluded. This margin must be specified based on clinical and statistical reasoning; however, it is considered as one of the most challenging steps in the design of noninferiority trials. Regulators recommend that the margin should be defined based on the historical evidence of the active comparator (the latter is often the well‐established standard treatment of the disease), which can be performed by different approaches. There are several factors and assumptions that need to be accounted for during the process of defining the margin and during the analysis of noninferiority. Three methods are commonly used to analyse noninferiority trials: the fixed‐margin method; the point‐estimate method; and the synthesis method. This article provides an overview of analysing noninferiority and choosing the noninferiority margin.

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Section: Defining the Noninferiority Marginmentioning

confidence: 82%

Defining the noninferiority margin and analysing noninferiority: An overview

Althunian

Boer

Groenwold

et al. 2017

Brit J Clinical Pharma

Self Cite

126

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“…There are several approaches to set an NI margin, [7][8][9][10][11] and controversy regarding the best method persists. 6,12,13 This is discussed in more detail in the Critical Appraisal of an NI Trial section.…”

Section: Trial Designmentioning

confidence: 99%

“…Experts have recommended sound statistical reasoning and good clinical judgment in setting an NI margin. 6,13,22,23 Recent draft guidance to industry from the US Food and Drug Administration (FDA) has provided some clarity, 11 but even this approach is not without its critics. 12 We outline several of the common approaches employed to choose an NI margin.…”

Section: Was the Choice Of The Ni Margin Appropriate?mentioning

confidence: 99%

“…Choosing a higher percentage to be preserved (e.g., 67% or 90%) results in a stricter or more conservative NI margin. 6 Another approach is to ask clinicians or patients to consider what degree of efficacy they would be willing to sacrifice in exchange for the potential benefits offered by the new treatment. 10 A Delphi approach with clinical experts and their knowledge of existing treatment options and the underlying disease may provide insight into an NI margin.…”

Section: Was the Choice Of The Ni Margin Appropriate?mentioning

confidence: 99%

“…6 NI trials are not designed to show that the new treatment is equivalent to the standard treatment. NI trials are intended to show whether a new treatment has at least as much efficacy as the standard or is worse by an amount less than a prespecified NI margin.…”

Section: Introductionmentioning

confidence: 99%

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Critically appraising noninferiority randomized controlled trials: a primer for emergency physicians

Deeb

Azad

Barbic

2015

CJEM

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Noninferiority (NI) trials aim to show that a new treatment or drug is not inferior to a standard, accepted treatment. The rapid proliferation of NI trials within the literature makes it imperative for emergency physicians to be able to read, interpret, and appraise critically this type of research study. Using several emergency medicine examples from the recent literature, this article outlines the key differences between traditional, superiority randomized controlled trials and NI trials. We summarize four important points that an emergency physician should consider when critically appraising an NI trial: 1) Does the new treatment have tangible benefits over the standard treatment? 2) Was the choice of the NI margin appropriate? 3) Was the effect of the standard treatment preserved? Does the trial have assay sensitivity? and 4) What type of analysis strategy was employed: intention-to-treat (ITT) or per protocol (PP)? RÉ SUMÉLes essais de non-infé riorité (ENI) visent à dé montrer qu'un nouveau traitement ou un nouveau mé dicament n'est pas infé rieur au traitement de ré fé rence, reconnu. La prolifé ration des ENI dans la documentation rend impé rative la capacité des urgentologues à comprendre, à interpré ter et à é valuer d'un oeil critique ce type de recherche. Ainsi, l'article fera ressortir, à l'aide de plusieurs exemples tiré s de la documentation ré cente en mé decine d'urgence, les principales diffé rences qui existent entre le modè le classique d'essai comparatif, hasardisé , de supé riorité , et le modè le d'ENI. Seront ré sumé s quatre points importants qu'un urgentologue devrait envisager lorsqu'il é value de faç on critique un ENI: 1) Le nouveau traitement offre-t-il des avantages tangibles comparativement au traitement habituel? 2) Le choix de l'intervalle de non-infé riorité est-il pertinent? 3) L'effet du traitement de ré fé rence est-il conservé ? L'essai est-il sensible? 4) Quel type de straté gie d'analyse a é té employé : selon l'intention de traiter ou selon le protocole?

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

Gupta

2016

Wiley StatsRef: Statistics Reference Online

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Noninferiority clinical trials help in detecting a new treatment that have roughly the same effectiveness, yet may offer different advantages. Thus, noninferiority trials can be used in a situation when a new treatment has almost the same effectiveness as its comparator but may offer other advantages over the existing drug such as a novel method of administration or a better safety profile. Some argue that noninferiority trials only benefit pharmaceutical companies as they permit medicines without any added effectiveness to get marketing authorization. There are many basic differences between noninferiority and superiority trials. Noninferiority clinical trials aim to prove that the test product is not unreasonably inferior, or “noninferior” than the comparator by more than a prestipulated margin. From a methodological perspective, compared to superiority trials, noninferiority trials have methodological issues in design and analysis that can influence proper inference and also noninferiority trials are a source of great dispute. One of the pivotal but arduous steps in planning noninferiority trial is itemizing a noninferiority margin: a prelude below which it can be accepted that the experimental drug is not worse than its comparator.

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The challenges of determining noninferiority margins: a case study of noninferiority randomized controlled trials of novel oral anticoagulants

Cited by 27 publications

References 19 publications

Defining the noninferiority margin and analysing noninferiority: An overview

Defining the noninferiority margin and analysing noninferiority: An overview

Critically appraising noninferiority randomized controlled trials: a primer for emergency physicians

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

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