Understanding & Interpreting Non-Inferiority Trials

Preparation

Take this interesting QUIZ
Read the RE-DUAL PCI trial
7 questions to ask when evaluating a noninferiority trial. J Fam Pract 2014;63:E4–8.
Read the CONSORT-Noninferiority extension
Read How to Use a Noninferiority Trial
if you feel like you’ve got this all figured out, read EXAMINE

By the end of the session, upon study and reflection, students should be able to

Name scenarios where non-inferiority trials are preferred over superiority trials, and scenarios where they are not.
Explain what an MCID/non-inferiority margin is and roughly how they are determined, especially the “setting the margin” and “imputed placebo” approaches.
Graphically depict the non-inferiority assumptions and the primary endpoint result for a clinical trial in terms of whether the intervention is non-inferior or not.
Explain the role of ITT analysis vs. on-treatment analysis in superiority vs. non-inferiority trials.
Describe the difference between superiority and non-inferiority trials in terms of what it means to be “conservative” and in terms of Type 1 and Type II errors.
Be able to calculate the confidence intervals around any non-significant trial endpoint and personally evaluate it from the viewpoint of non-inferiority. Use my [stats calculator] for this.
ADVANCED: Explain what a p-value on a non-inferiority finding means.
ADVANCED: Think about the methodologic, practical, and ethical issues in TECOS and EXAMINE

Required Prior Knowledge & Skills

Self-test that you can do these things before showing up for the session, because NI trial design/interpretation is a special case of these concepts.

be able to accurately explain what a p-value is
be able to state what the usual null and alternative hypotheses are in a superiority trial
be able to explain what it means to make a Type I and Type II error both in lay-language, and in terms of the null & alternative hypotheses
explain why ITT analysis is the gold-standard approach in superiority RCTs

During the Sessions

We’ll discuss the foundational concepts behind NI trials in terms of

clinical & design considerations
ethical appropriateness
statistical considerations

We’ll do roundtable discussion using roughly a CONSORT-NI approach, so please come prepared to discuss the assigned trial. We will concentrate on the issues unique to NI trial design and interpretation.

Bring vexing and/or interesting issues and questions for discussion.

Common Misconceptions and Sticking Points

how does the definition of conservative differ in a NI trial from a superiority trial?
precisely why (practically and philosophically) is the on-treatment (non-ITT) analysis so important in an NI trial?
what does it mean to report a “p-value for non-inferiority”

Challenge Yourself

how does the definition of conservative differ in a NI trial from a superiority trial?
what does it mean to report a “p-value for non-inferiority”?
What are the scientific and ethical issues here? [EXAMINE](http://www.nejm.org/doi/full/10.1056/NEJMoa1 305889)
A million points if you can figure out how they devised their NI-margin of 1.46 in RE-LY & ROCKET-AF.