More efficient, smaller multicancer screening trials.

backgroundThe NHS-Galleri Trial has demonstrated feasibility of a trial design in which all participants provide a "sample" for screening, but only samples from the intervention arm are tested and acted upon during the trial. We assessed the efficiency of analysis methods when the control arm may be retrospectively tested at the time of analysis.

methodsAnalyses considered were (1) the traditional method (random allocation, with all events included), (2) the "intended-effect" method (nested in those individuals who tested positive in both arms and all events therein), and (3) the targeted method (by random allocation but with an endpoint "test-positive event"). These methods are compared using approximate statistical methods and scenario analysis.

resultsProvided that the number of individuals who die from cancer after a test-positive sample is a small fraction of the total number who die from cancer, intended-effect and targeted analyses require a much smaller sample size to evaluate cancer-specific mortality than the traditional approach. Intended-effect analysis has a smaller sample size requirement than targeted analysis does. This gain is substantial only when the risk of cancer death in individuals testing positive is high.

conclusionIntended-effect or targeted analysis may substantially reduce the sample size needed to evaluate cancer-specific mortality in blood-based screening trials. Targeted analysis requires many fewer retrospective tests and avoids potential problems arising from the need to inform those individuals whose stored samples test positive. Trialists should consider the trade-off of costs between sample size and retrospective testing requirements when choosing the analysis method.