Clinical Trials

Clinical Trials: A Practical Guide ■❚❙❘Advantages of using composite endpointsThere are two main advantages of using a composite endpoint. An endpoint withmultiple outcomes means that more outcome events will be observed in total.Since the number of patients needed in the trial decreases as the number of eventsoccurring in the control group increases, a composite endpoint allows us toevaluate a new treatment by using a smaller number of patients in the trial.For example, if the expected 1-year rate of events (death alone) is 1%, a samplesize of 21,832 subjects will be required to show a 40% reduction in death(a type I error rate = 0.05 with 90% power). (For an explanation of how todetermine the sample size for a clinical trial, see Chapter 9.) If, on the otherhand, we look at the combined outcome of death or heart attack, which may beexpected to occur at an annual rate of 10%, then this study would require a samplesize of 2,028 subjects to capture a 40% reduction. This does, of course, assumethat both the rate of deaths and the rate of heart attacks are expected to bereduced equally by 40%, which may not always be the case, and so this needs tobe factored into the sample size calculation.The other advantage of combining several outcomes is that a more comprehensiveevaluation of a treatment can be given across more than just one category ofoutcome. For example, for a study on colon carcinoma, the outcome variablescould be any of the following categories [4]:• clinical (eg, symptoms of constipation)• pathologic (eg, histologic evaluation from colon biopsy)• visual (eg, endoscopic evaluation of tumor size)• biochemical (eg, laboratory evaluation of tumor markers or signsof liver damage due to secondary tumors)If the trial is adequately sized, the action of the treatment can then be assessed oneach and every outcome.Limitations of composite endpointsIn a composite endpoint of multiple outcomes we make the assumption thatavoiding any one outcome has an equal importance as avoiding any otheroutcome. However, this is rarely the case. For example, in the case of coloncarcinoma, avoiding constipation might not be as important as shrinking thetumor mass or delaying death – although, from a patient’s point of view, avoidingconstipation might be critical since constipation might lead to the need for asurgical solution if not resolved by drugs.The second assumption made when using composite endpoints is that allindividual outcome measures are related to the disease process and are equally41