Potential spillover effects on diagnostic delay for cancer during the NHS-Galleri trial: a quasi-experimental difference-in-differences study

ObjectiveTo examine whether regions participating in the NHS-Galleri trial of a cell-free DNA-based multi-cancer early detection (MCED) test experienced changes in cancer diagnostic delay rates that could indicate the presence of spillover due to constraints on care delivery. DesignQuasi-experimental difference-in-differences analysis. SettingEngland, April 2021-September 2024. ParticipantsAll 21 cancer alliance regions in England, 8 of which participated in the trial. Main outcomesCancer diagnostic delay rates (primary outcome) and referral rates (secondary outcome). Primary analysis focused on the group of three cancer types (head and neck, lung, upper gastrointestinal) that are prespecified in the trial protocol, have higher signal detection for cell-free DNA-based testing, and were not subject to routine screening. A difference-in-differences analysis was used to compare outcomes in regions participating in NHS-Galleri to regions that did not participate, before and after the start of the trial. ResultsDiagnostic delay rates increased in the first six months of the trial for the primary group of three cancer types in participating regions compared to non-participating regions (adjusted difference-in-differences 3.4 percentage points, 95% CI: 1.9-5.0, p<0.001). These differences persisted from 6 to 12 months after trial start and receded over the following two years. No significant change in referral rates for this group of cancer types was observed. ConclusionsParticipation in the NHS-Galleri trial was associated with increased diagnostic delay rates for the primary group of high-detection cancer types. The trial may have led to higher demand for limited diagnostic resources (e.g. imaging, endoscopy) required for follow-up of suspected cancer arising from positive MCED test results or usual care processes. If patients in the control group faced delayed diagnosis as a result, this would represent spillover during the first year of the trial and could lead to overestimation of MCED benefit. Summary BoxO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIThe NHS-Galleri trial randomized over 140,000 adults to receive usual cancer screening or usual screening plus a new cell-free DNA-based multi-cancer early detection test in 8 out of 21 regions in England. C_LIO_LIDuring the trial, higher use of scarce cancer diagnostic services by the intervention group could have led to reduced availability of services for members of the control group and patients not enrolled in the trial. C_LIO_LIThe potential for this form of spillover to bias trial results and affect patient access to care is not addressed in the medical literature, guidance on clinical trial methods, or the NHS-Galleri trial protocol. C_LI What this study addsO_LIIn the first year of the trial, participating regions experienced a modest increase in region-wide diagnostic delay rates for cancer types having higher signal detection for cell-free DNA-based testing. C_LIO_LIIncreased diagnostic delays could contribute to stage shift for some control group patients and lead to overestimation of the Galleri tests effect on early detection of cancer. C_LIO_LIFuture trials of multi-cancer early detection tests and other interventions that affect utilization of limited healthcare resources should address the potential for spillover due to constraints on care delivery to affect patient outcomes and trial results. C_LI