Planning of randomized early detection trials

Harvard University, Cambridge, Massachusetts, United States
Statistical Methods in Medical Research (Impact Factor: 4.47). 01/2005; 13(6):491-506. DOI: 10.1191/0962280204sm379ra
Source: PubMed


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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    ABSTRACT: To i) estimate how large the mortality reductions would be if women were offered screening from age 50 until age 69; ii) to do so using the same trials and participation rates considered by the Canadian Task Force; iii) but to be guided in our analyses by the critical differences between cancer screening and therapeutics, by the time-pattern that characterizes the mortality reductions produced by a limited number of screens, and by the year-by-year mortality data in the appropriate segment of follow-up within each trial; and thereby iv) to avoid the serious underestimates that stem from including inappropriate segments of follow-up, i.e., too soon after study entry and too late after discontinuation of screening. We focused on yearly mortality rate ratios in the follow-up years where, based on the screening regimen employed, mortality deficits would be expected. Because the regimens differed from trial to trial, we did not aggregate the yearly data across trials. To avoid statistical extremes arising from the small numbers of yearly deaths in each trial, we calculated rate ratios for 3-year moving windows. We were able to extract year-specific data from the reports of five of the trials. The data are limited for the most part by the few rounds of screening. Nevertheless, they suggest that screening from age 50 until age 69 would, at each age from 55 to 74, result in breast cancer mortality reductions much larger than the estimate of 21% that the Canadian Task Force report is based on. By ignoring key features of cancer screening, several of the contemporary analyses have seriously underestimated the impact to be expected from such a program of breast cancer screening.
    11/2013; 104(7):e437-42.

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