Abstract
Expensive and lengthy clinical trials can delay regulatory evaluation of innovative technologies, affecting patient access to high-quality medical products. Simulation is increasingly being used in product development but rarely in regulatory applications. To conduct a computer-simulated imaging trial evaluating digital breast tomosynthesis (DBT) as a replacement for digital mammography (DM) and to compare the results with a comparative clinical trial. The simulated Virtual Imaging Clinical Trial for Regulatory Evaluation (VICTRE) trial was designed to replicate a clinical trial that used human patients and radiologists. Images obtained with in silico versions of DM and DBT systems via fast Monte Carlo x-ray transport were interpreted by a computational reader detecting the presence of lesions. A total of 2986 synthetic image-based virtual patients with breast sizes and radiographic densities representative of a screening population and compressed thicknesses from 3.5 to 6 cm were generated using an analytic approach in which anatomical structures are randomly created within a predefined breast volume and compressed in the craniocaudal orientation. A positive cohort contained a digitally inserted microcalcification cluster or spiculated mass. The trial end point was the difference in area under the receiver operating characteristic curve between modalities for lesion detection. The trial was sized for an SE of 0.01 in the change in area under the curve (AUC), half the uncertainty in the comparative clinical trial. In this trial, computational readers analyzed 31 055 DM and 27 960 DBT cases from 2986 virtual patients with the following Breast Imaging Reporting and Data System densities: 286 (9.6%) extremely dense, 1200 (40.2%) heterogeneously dense, 1200 (40.2%) scattered fibroglandular densities, and 300 (10.0%) almost entirely fat. The mean (SE) change in AUC was 0.0587 (0.0062) (P < .001) in favor of DBT. The change in AUC was larger for masses (mean [SE], 0.0903 [0.008]) than for calcifications (mean [SE], 0.0268 [0.004]), which was consistent with the findings of the comparative trial (mean [SE], 0.065 [0.017] for masses and -0.047 [0.032] for calcifications). The results of the simulated VICTRE trial are consistent with the performance seen in the comparative trial. While further research is needed to assess the generalizability of these findings, in silico imaging trials represent a viable source of regulatory evidence for imaging devices.
Highlights
Expensive and lengthy clinical trials for imaging products often hinder regulatory evaluation, are burdensome, and delay patient access to novel, high-quality devices
The change in area under the curve (AUC) was larger for masses than for calcifications, which was consistent with the findings of the comparative trial
The results of the simulated Virtual Imaging Clinical Trial for Regulatory Evaluation (VICTRE) trial are consistent with the performance seen in the comparative trial
Summary
Expensive and lengthy clinical trials for imaging products often hinder regulatory evaluation, are burdensome, and delay patient access to novel, high-quality devices. A recent submission to the US Food and Drug Administration (FDA) of a DBT system as a replacement for digital mammography (DM), for example,[2] relied on a clinical trial involving 400 women in 7 clinical sites receiving double exposure to ionizing radiation over many years, with 31 participating radiologists. We refer to this trial as the comparative trial. Leveraging recent progress in computer modeling and simulation as an alternative source of regulatory evidence with growing widespread support,[3,4,5] we report on an in silico replication of the comparative trial to demonstrate the potential of this emerging approach
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