Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘BiocreepThere is some concern about noninferiority studies regarding the occurrence ofa phenomenon known as ‘biocreep’. This is where a slightly inferior new drugbecomes the comparator for the next generation of compounds and so on,sequentially, until the new drugs of the future only have efficacy close to that ofplacebo. Biocreep can occur if a new drug with a lower efficacy rate than thecomparator is approved with a wide δ. The concern can be alleviated when thechosen active comparator is the current gold standard treatment, and δ is chosenappropriately for the indication in question and further reduced if a placebo armis incorporated into the study design.How is the sample size calculated?Conventionally, the sample size of a clinical trial is powered based on the primaryendpoint, with the aim of obtaining a confidence interval (CI) for the treatmentdifference that shows the new treatment’s efficacy to be worse by, at most, δ [1].As in conventional trials, the following statistics are required to determine thesample size (see Chapter 9):• anticipated efficacy of the comparator (ie, proportion for a binary endpoint,and mean and standard deviation for a continuous endpoint)• significance level or threshold (α, Type I error)• power (1 – β, 1 – Type II error)In addition, the clinically relevant δ needs to be specified.As further illustrated by later examples, the resultant sample size is particularlysensitive to the anticipated efficacy of the comparator, the anticipated effect ofthe experimental treatment relative to this, and the choice of δ.Since δ is often assumed to be a fraction of the treatment difference on whicha placebo-controlled superiority trial would be powered, noninferiority trials oftenrequire much larger sample sizes. Conversely, they may require smaller samplesizes than if an active-controlled superiority trial was to be designed, since thesuperiority margin for such a trial may be smaller than δ [6].For noninferiority, the conventional null hypothesis of a superiority trial (ie, thatthe true treatment difference is zero) and the alternative (that it is positive)is essentially replaced by a null hypothesis that it is inferior by an amount ofmore than the defined δ and an alternative that it is not. Guidance recommends135