Non-Inferiority Trials

ICH E10 states that “the general principles involved in choosing a control group for clinical trials intended to demonstrate the efficacy of a treatment and to discuss related trial design and conduct issues.

So question arises what are these control groups and what is the purpose?

Purpose of control groups: To allow discrimination of patient outcomes (for example, changes in symptoms, signs, or other morbidity) caused by the test treatment from outcomes caused by other factors, such as the natural progression of the disease, observer or patient expectations, or other treatment.

Types of controls: The type of control treatment may be any of the following four: (1) placebo, (2) no treatment, (3) different dose or regimen of the study treatment, or (4) a different active treatment.

Purposes of Clinical Trials: Two purposes of clinical trials should be distinguished: (1) assessment of the efficacy and/or safety of a treatment and (2) assessment of the relative (comparative) efficacy, safety, risk/benefit relationship or utility of two treatments.

(Superiority trial can serve both the efficacy related purposes of clinical trials)

Superiority Trial: A trial using any of the control types may demonstrate efficacy of the test treatment by showing that it is superior to the control (placebo, no treatment, low dose of test drug, active drug).

& Success of superiority trials demonstrates that trial had assay sensitivity.)

Assay sensitivity is a property of a clinical trial defined as the ability to distinguish an effective treatment from a less effective or ineffective treatment. It depends on the trial design, outcomes used in trials, conduct of trial etc.

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If Success of superiority trials demonstrates that trial had assay sensitivity and there is no chance of false positive due to lack of assay sensitivity, then why do we need non- inferiority trials?

Inferiority Trial: But non-inferiority trials can be of interest because of following reasons:

  • It is not ethically possible (anymore) to do a placebo-controlled trial.
  • E is not expected to be better than C on a primary efficacy end point, but is better on secondary end points or is safer.
  • E is not expected to be better than C on a primary efficacy end point but is cheaper to produce or easier to administer.

Issues with Non-inferiority trials

  • A successful non-inferiority trial (i.e., one that has shown non-inferiority) does not contain evidence of assay sensitivity. Hence, Historical Evidence of sensitivity to drug effects and appropriate trial conduct (as mentioned in historical evidence).

There are several issues regarding the literature search that will need to be discussed by the applicant:

  1. Selection bias.
  2. Constancy of trial design and clinical practice over time.
  3. Constancy of effects over time.
  4. Publication bias.

Non-inferiority trials are often analyzed using ITT and per-protocol approaches, and only if both approaches support noninferiority is the trial considered positive. As ITT does, tends to bias the results toward equivalence, which could make a truly inferior treatment appear to be non-inferior.

Calculation of non-inferiority margin

The ‘historical’ confidence interval compares the reference product with placebo (r minus p). The planned trial comparing the test and reference products will also produce a confidence interval (for t minus r). If these intervals are combined, an indirect confidence interval comparing the test product and placebo can be obtained (t minus p). Delta can be defined as the lower bound of t minus r that ensures that the lower bound of the indirect confidence interval of t minus p will be above zero. As the comparison is indirect it might be wise to be conservative and select some value smaller than that suggested by this indirect calculation. For example, the margin could be 50% or 25% of the reference treatment effect compared to placebo.

In some extreme situations it may be acceptable to run a superiority trial specifying a significance level greater than 0.05 as an alternative to defining a non-inferiority margin.

Following are the links to regulatory guidelines around topic:

EMA: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003636.pdf

FDA: https://www.fda.gov/downloads/Drugs/Guidances/UCM202140.pdf