Planning of randomized early detection trials

Abstract

Consider a randomized clinical trial to evaluate the benefit of screening an asymptomatic population. Suppose that the subjects are randomized into a usual care and a study group. The study group receives one or more periodic early detection examinations aimed at diagnosing disease early, when there are no signs or symptoms. Early detection clinical trials differ from therapeutic trials in that power is affected by: i) the number of exams, ii) the time between exams and iii) the ages at which exams will be given. These design options do not exist in therapeutic trials. Furthermore; long-term follow-up may result in a reduction of power. In general, power increases with number of examinations, and the optimal follow-up time is dependent on the spacing between examinations. Clinical trials in which the usual care group receives benefit are also discussed. Two designs are discussed, for example the ‘up-front design’ in which all subjects receive an initial exam and then are randomized to the usual care and study groups and the ‘close-out design’ in which the usual care group receives an exam which is timed to be given at the same time as the last exam in the study group. Both families of designs significantly reduce the power. Power calculations are made for two clinical trials, which actually used these two designs.

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