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Users' Guides to the Medical Literature |

How to Use a Noninferiority Trial Users' Guides to the Medical Literature

Sohail M. Mulla, BHSc; Ian A. Scott, MBBS, FRACP, MHA; Cynthia A. Jackevicius, PharmD, MSc; John J. You, MD, MSc; Gordon H. Guyatt, MD, MSc
JAMA. 2012;308(24):2605-2611. doi:10.1001/2012.jama.11235.
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Clinical investigators are increasingly testing treatments that have the primary benefit of decreased burden or harms relative to an existing standard. The goal of the resulting randomized trials—called noninferiority trials—is to establish that the novel treatment's effectiveness is not substantially less than the existing standard. Conclusions from these trials are, however, based on noninferiority thresholds specified by authors whose judgments may not coincide with those of patients and clinicians. This article highlights issues related to validity, interpretation, and applicability of results specific to noninferiority trials. Suboptimal administration of standard treatment or exclusive reliance on the analyze-as-randomized approach that is standard for conventional superiority trials may produce misleading results in noninferiority trials. Clinicians should judge whether the novel treatment's impact on effectiveness outcomes—the prime reason for wanting to prescribe it—is sufficiently close to that of standard treatment that they are comfortable substituting it for the existing standard. Trading off desirable and undesirable consequences is an individual decision: given the benefits of a novel treatment, some patients may perceive the uncertainty regarding a reduction in treatment effectiveness as acceptable while others may not.

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Figure 1. Possible Outcome Scenarios in Noninferiority Trials
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The blue dashed line labeled Δ represents the noninferiority threshold or the maximum allowable excess of outcome events arising from the novel treatment compared with the standard treatment. The tinted area represents the noninferiority zone.

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Figure 2. Setting an Acceptable Noninferiority Threshold
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A, Standard treatment decreases the absolute incidence of stroke, relative to placebo, by 3%, with a 95% CI of 2% to 4%. B, The blue dashed line represents the noninferiority zone. In scenario A, the 95% CIs around the difference in strokes between the novel treatment and the standard treatment includes an increase in incidence of strokes by as much as 2% with the novel treatment, thereby failing to retain 50% of the minimal treatment effect of the standard treatment. In scenario B, the same 95% CIs suggest that the novel treatment increases the incidence of strokes by no more than 1%, thus successfully preserving at least 50% of the 2% absolute reduction in stroke with the standard treatment.



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The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
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