Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘randomization procedure and is generally conservative [1]. Although some mightargue that ITT analysis is overly conservative, most would agree that a positiveoutcome of an ITT analysis in a superiority trial is convincing.Unfortunately, no such conservative analysis exists for noninferiority trials.Including data after study drug discontinuation in the analysis, as ITT does, tendsto give a conservative estimate of the treatment difference, which could makea truly inferior treatment appear noninferior. Alternatively, excluding data frompatients with major protocol violations – PP analysis – can bias the results in eitherdirection (eg, in a situation where dropout is related to efficacy outcome).Therefore, noninferiority trials are generally analyzed using both ITT and PPapproaches, and conclusions can be considered more robust when bothapproaches support the noninferiority of the treatment.The CI for the ITT population is (0.9%, 13.0%) (see Figure 1, study Z).This supports the conclusion of noninferiority from the PP population, since theCI lies entirely above –10%.Example (continued)In the CAP example, although the study was set up to show noninferiority, it mayhave been possible to ‘switch’ to a conclusion of superiority (had the PP analysis(W) also supported this conclusion). In situations where the CI only includespositive values of the treatment difference, a statistically significant benefit of thenew treatment over the comparator is demonstrated. The clinical significance ofa treatment difference of this size would need discussion.ConclusionNoninferiority trials provide an alternative study design for indications wheresuperiority trials would not be appropriate (due to ethical or practical constraints).They are often used where efficacious treatments already exist, and thedemonstration of noninferiority, as well as secondary benefits, is sufficient forregulatory approval. However, noninferiority trials suffer from the criticism thattrial results do not show internal validity (since they provide no direct comparisonwith placebo), and also that the analysis approach is not naturally conservative [9].These criticisms can be overcome by [10]:• incorporating a placebo arm into the trial• ensuring that the comparator used is the current standard of careand previously demonstrated as superior to placebo139