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.
Text Size: A A A
Published online

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.

Figures in this Article

Sign In to Access Full Content

Don't have Access?

Register and get free email Table of Contents alerts, saved searches, PowerPoint downloads, CME quizzes, and more

Subscribe for full-text access to content from 1998 forward and a host of useful features

Activate your current subscription (AMA members and current subscribers)

Purchase Online Access to this article for 24 hours


Place holder to copy figure label and caption
Figure 1. Possible Outcome Scenarios in Noninferiority Trials
Graphic Jump Location

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.

Place holder to copy figure label and caption
Figure 2. Setting an Acceptable Noninferiority Threshold
Graphic Jump Location

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.



Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
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.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).


Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 8

Sign In to Access Full Content

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles