What is a key concern specific to noninferiority trials?

Key Concerns Specific to Noninferiority Trials

The risk of false conclusions due to a lack of assay sensitivity is the key concern that is specific to noninferiority trials. 1, 2

Understanding Assay Sensitivity in Noninferiority Trials

Assay sensitivity refers to the ability of a clinical trial to distinguish an effective treatment from a less effective or ineffective treatment. This concept is particularly critical in noninferiority trials for several reasons:

• Unlike superiority trials where biases typically lead to false-negative results, in noninferiority trials, the same biases make treatments appear more similar and can lead to false-positive conclusions 1
• Without a placebo control, it becomes difficult to verify whether the active control actually demonstrated its expected effect in the study population 2, 3
• Poor trial quality (such as protocol violations, poor compliance, insufficient follow-up) can dilute treatment differences, making it easier to incorrectly conclude noninferiority 1

Why Assay Sensitivity Is Uniquely Important in Noninferiority Trials

1. Risk of perpetuating ineffective treatments: Without adequate assay sensitivity, a new treatment might be declared noninferior to an active control even if both treatments are actually ineffective 1

2. Historical evidence concerns: The noninferiority margin is often based on the historical effect of the active control compared to placebo, but selection bias in choosing this historical evidence can lead to inappropriate margins 1

3. Constancy assumption: Noninferiority trials assume that the effect size of the active control in the current trial is similar to its effect in historical placebo-controlled trials, which may not hold true 2, 3

4. Dilution of treatment effects: Various factors can reduce the apparent difference between treatments, including:

   • Protocol violations
   • Poor compliance with intended treatments
   • Crossover between treatment groups
   • Insufficient follow-up 1

Other Concerns in Noninferiority Trials (Not Specific to Them)

• Ethical concerns with placebo controls: This is a general concern in clinical trials and not specific to noninferiority designs 4

• Sample size requirements: While noninferiority trials often require large sample sizes, this is also true for superiority trials designed to detect small differences 1, 4

• Missing data: While important, this concern applies to all trial designs 1

Clinical Implications

The lack of assay sensitivity in noninferiority trials can have serious consequences for patient care:

• It may lead to the approval and widespread use of treatments that are actually inferior to standard care, potentially increasing morbidity and mortality 1

• As demonstrated in the FDA advisory committee discussions, several drugs studied for ventilator-associated pneumonia showed concerning results despite overall noninferiority conclusions 1

• The downstream impact can affect an entire therapeutic area if a succession of noninferiority trials leads to progressive erosion of efficacy (sometimes called "biocreep") 2

To mitigate these risks, regulatory authorities recommend conducting both intention-to-treat and per-protocol analyses in noninferiority trials, as differences between these analyses require close examination 1, 2.