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Non-Inferiority Trials in Surgical Oncology

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Abstract

The classical randomized controlled clinical trial is designed to prove superiority of an investigational therapy over an established therapy or placebo (here referred to as “superiority trial”). Although the randomized controlled superiority trial has its well-grounded role, clinical trials of non-inferiority are equally important in the advance of medical science. Non-inferiority trials test whether a new intervention is as good as a standard treatment with respect to curing the illness (e.g., overall survival) while offering other benefits over the standard therapy, such as lower toxicity, better side-effect profile, improved ease of administration, or reduced costs. The evaluation of non-inferiority is critical in many settings. In surgical oncology, for instance, treatments often combine advantages (e.g., survival benefit) with disadvantages (e.g., high post-operative morbidity due to extensive surgery, considerable toxic effects of an aggressive chemotherapy regimen). The various aspects of different therapeutic strategies may make a treatment decision difficult, requiring a non-inferiority trial to quantify risks and benefits. However, despite their great importance in clinical cancer research, the concept, design, and objectives of non-inferiority trials remain poorly understood in the surgical community. The goal of this review is to discuss the principles, strengths, and challenges of non-inferiority trials and introduce this highly relevant topic to the surgical reader, using examples from the field of surgical oncology.

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Authors and Affiliations

  1. Department of Surgery, Divisions of General Surgery and Surgical Research, University of Basel, Basel, Switzerland

    Philipp Fueglistaler MD, Michel Adamina MD & Ulrich Guller MD, MHS

  2. Department of Surgery, University of Toronto, Toronto, Canada

    Michel Adamina MD & Ulrich Guller MD, MHS

  3. Department of Surgical Oncology, Princess Margaret Hospital, Rm 3-130, 600, University Avenue, Toronto, ON, Canada

    Ulrich Guller MD, MHS

Authors
  1. Philipp Fueglistaler MD
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  2. Michel Adamina MD
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  3. Ulrich Guller MD, MHS
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Correspondence to Ulrich Guller MD, MHS.

QUALITY OF A NON-INFERIORITY TRIAL—A CHECKLIST FOR THE SURGEON

QUALITY OF A NON-INFERIORITY TRIAL—A CHECKLIST FOR THE SURGEON

  • Is the study designed as a non-inferiority trial? Remember: superiority trials that fail to reach statistical significance do not prove equivalence.

  • Is the clinical effectiveness of the standard treatment well established (assay sensitivity)? Remember: the standard therapy in a non-inferiority trial must perform as expected from previous clinical trials.

  • Are type I error (alpha, false positive) and type II error (beta, false negative) stated in the Method section?

  • Is a non-inferiority margin (delta) defined in the Method section?

  • Is there a sample size calculation based on pre-stated alpha, beta, and non-inferiority margin (delta)?

  • Is the chosen non-inferiority margin smaller than the least clinically meaningful difference? Would the investigational treatment be acceptable if its efficacy was within the boundaries of the chosen delta?

  • Does the study reach its target accrual? Is there a considerable gap between computed sample size and enrolled number of patients?

  • Was the data analysis performed according to the intention-to-treat principle or is it a per protocol analysis? Remember that both evaluations are important in a non-inferiority trial and should result in similar conclusions for robust evidence of equivalence.

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Fueglistaler, P., Adamina, M. & Guller, U. Non-Inferiority Trials in Surgical Oncology. Ann Surg Oncol 14, 1532–1539 (2007). https://doi.org/10.1245/s10434-006-9295-2

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