Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘superior (90% vs 88%), a smaller sample size is required to obtain a CI with alower limit at or above –10% (see Table 2, row D).A noninferiority trial (by design) includes the possibility of superiority under thealternative hypothesis. Therefore, when calculating the sample size, it might bereasonable to assume that the experimental treatment has a small advantage. It isthen possible to test for both noninferiority and superiority. However, unequalefficacy should not be assumed simply to reduce sample size, as, if the assumptionis found not to hold, then the study will not be powered to meet the primaryobjective of enabling a clinically conclusive assessment of noninferiority.A further consideration is the methodology that will be used to calculate the CIfor assessing noninferiority. Specifically, there is a need to avoid using an analysismethod that has the property of being more conservative (ie, leads to a wider CI)than that used in calculating the sample size. For the analysis of probabilitydifferences, approximation methods (such as the normal approximation to thebinomial distribution) can be unreliable for extreme probabilities (where theexpected frequency of events for analysis is small and event probabilities areapproaching asymptotic limits). This can lead to substantial differences in thesample size estimates obtained when the calculations are made using anothermethod (eg, the score method [8]).How are noninferiority trials analyzed?Noninferiority and superiority trials differ in terms of the standard method ofanalysis. Superiority is usually demonstrated by reference to a P-value (theprobability of seeing the observed treatment difference, or a more extremedifference, calculated under the null hypothesis of no difference betweentreatments), with a CI also used in order to estimate the range of plausible valuesfor the treatment difference. The smaller, or more significant, the P-value,the more confidence in the conclusion of superiority. However, the reverse doesnot apply – a large P-value does not necessarily correspond to a clinicallyinsignificant treatment difference.In noninferiority trials, a CI is calculated to estimate the range of values in whichthe treatment difference is likely to lie. This CI is used to provide the basis fordrawing the study’s conclusions. If the CI does not include any values for thetreatment difference that are more extreme than the noninferiority limit, thennoninferiority is demonstrated. The confidence level of the CI is usually set at95%, corresponding to a 2.5% one-sided significance level. The specific methodfor calculating the CI will depend on the study design and the endpoints, but the137