Non-inferiority Trial Design in Drug Development

A Primer for Cardiovascular Healthcare Professionals

Fabio Angeli; Paolo Verdecchia; Gianpaolo Reboldi

Disclosures

Am J Cardiovasc Drugs. 2020;20(3):229-238. 

In This Article

Abstract and Introduction

Abstract

Noninferiority trials, in which a new treatment is compared with a standard active treatment, are becoming increasingly popular in cardiovascular medicine. A noninferiority trial seeks to test whether the effect of a new drug is not unacceptably worse than that of an active comparator by more than a predefined noninferiority margin. Noninferiority trials are typically used when a new drug is anticipated to have an efficacy profile similar to its comparator and offers advantages over the existing drug (better toxicity profile, less expensive, less invasive, simpler regimen, shorter treatment duration, different resistance profile). Given the high number of noninferiority trials, it is vital that clinicians fully understand the clinical impacts of the results. Nonetheless, assessing noninferiority in a trial is complex, in both the design and the analysis phases. The crucial issue in the design of a noninferiority trial is the definition of the noninferiority margin, accounting for both statistical (summarizing the historical evidence of the active comparator from randomized controlled trials) and clinical (choosing the fraction of the effect of the old drug that should be "preserved" by the new drug) considerations. We review the role of noninferiority trials in the development of new cardiovascular treatments and discuss a variety of key issues involved in the design and conduction of noninferiority trials, using some examples from real clinical trials in cardiovascular medicine.

Introduction

The term "noninferiority trial" refers to a randomized controlled trial (RCT) in which a new treatment is compared with a standard active treatment rather than a placebo or untreated control group.[1–3] Noninferiority trials are generally used when a new drug is anticipated to have an efficacy profile similar to its comparator and offer advantages over the existing drug (better toxicity profile, less expensive, less invasive, simpler regimen, shorter treatment duration, different resistance profile).[4,5]

Noninferiority trials have become popular in recent decades, especially in cardiovascular medicine.[1] A common misunderstanding is that this plethora is due to safety and efficacy regulations, which would suggest that a new therapy first needs to show noninferiority before it can be tested in a superiority trial.[1] Noninferiority trials were originally designed for studies in which it is unethical to include a placebo arm. Specifically, for conditions where a "gold standard" therapy already exists, it would be unethical to perform a placebo-controlled trial with a newly introduced treatment. Thus, a noninferiority trial seeks to test whether the effect of a new drug is not unacceptably worse than that of an active comparator by more than a predefined noninferiority margin.[6]

The increased use of noninferiority analysis has been accompanied by a proliferation of research on the design and analysis of noninferiority studies.[1,4,5] The large increase in publications of noninferiority trials suggests the growing importance for clinicians of understanding this type of trial.

The main aim of this overview is to analyze the role of noninferiority trials in the development of new cardiovascular treatments, including some scientific, statistical and practical considerations.

Specifically, we elucidate some aspects of noninferiority trials that contribute to the validity of the results. We also describe practical problems pertaining to setting up and conducting a noninferiority trial.

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