Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘Another factor to consider is that although the unit of randomization is the cluster(eg, hospital), the unit of outcome measure is the patient. Therefore, we need toadjust for the cluster size and number, as well as how closely related the patients’outcomes are within a cluster. This correlation can be measured by a statisticcalled the intra-cluster correlation coefficient (ICC), which can be calculated usingdifferent formulas for different types of outcome variables [1–4].The impact of using a CRT design on sample size can be substantial; it dependson the size of the clustering effect, as measured by the ICC, and the number ofclusters available, as seen in the following formula:N cluster= (1 + [m – 1] × ICC) × N simplewhere:• N simpleand N clusterare the sample sizes for simple randomizationand cluster randomization, respectively• m is the number of subjects in each cluster• (1 + [m – 1] × ICC) is the design effect• ICC measures the correlation of the patient’s outcome within a clusterThe design effect indicates the amount by which the sample needs to be multiplied.Thus, a CRT with a large design effect will require many more subjects than a trialof the same intervention that randomizes individuals.ExampleConsider the PROMIS-UK study, a trial of an educational intervention toimplement a clinical guideline. An individual randomized trial would require348 patients (N simple) to detect a change of 0.30 in the composite score for patientswho are managed with all five therapies (with 80% power and 5% significance).However, this design would be inappropriate because of the potentialfor contamination.For this study, it was estimated that the ICC was about 0.15 and 20 patients wereavailable per cluster (ie, m = 20). Based on these assumptions, the sample sizeadjusting for clustering is 67 clusters or 1,340 patients (N cluster), ie, almost fourtimes that of the individual randomized trial. We can also see from the formulathat the larger the ICC, the more patients are needed.145