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Non Inferiority Trials

Key person: Primrose Beryl

Collaborators: Werner Vach


Non inferiority trials investigates whether a new treatment is at least as good as the standard established treatment in terms of efficacy while offering other relevant advantages over the standard therapy, such as lower toxicity, better side-effect profile, improved ease of administration, or reduced costs. Non inferiority trials have become more common and are on the rise.

However, despite the number of years since it has evolved into existence, the concept, design, and objectives of non-inferiority trials remain poorly understood. Non-inferiority trials have inherent methodological and statistical difficulties which have been discussed often. Along with the usual requisites of a clinical trial, the validity of a non-inferiority study result is dependent on the establishment of the efficacy of the standard treatment, comparability of the characteristics of the historical study comparing the standard and placebo, the appropriate choice of margin and the appropriate choice of analytical techniques.

The first and foremost important step in establishing non-inferiority is setting a prespecified margin of acceptable inferiority which ideally should reflect the least clinically relevant difference and preserves superiority in comparison to the placebo. The margin has to be decided apriori during the designing of the trial and needs careful, critical and stringent criterias. It determines the sample size of the trial and at the end establishes the meaning of non-inferiority, i.e. the objective of the trial. Although there is sufficient literature discussing the dangers of the choice of a wide non-inferiority margin, there seems to be a paucity of action taken along these lines. During this imperative evolving stage of non-inferiority trials, we focus on:


  • The current practice of choice of non-inferiority margins
  • Simulation studies to determine the risk of inferiority among successful non-inferiority trials
  • Developing additional criteria in choosing a more clinically relevant, valid and reliable non-inferiority margin
  • A "cost-benefit approach" to determine non-inferiority
  • Re-introducing the patient perspective in the choice of non inferiority margin
  • The role of ethical committees in regulating the conduct of non-inferiority trials