Division of Imaging, Diagnostics, and Software Reliability, Office of Science and Engineering Laboratories, Center for Devices and Radiological Health, US Food and Drug Administration, Silver Spring, Maryland.
JAMA Netw Open. 2018 Nov 2;1(7):e185474. doi: 10.1001/jamanetworkopen.2018.5474.
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.
DESIGN, SETTING, AND PARTICIPANTS: 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.
昂贵且冗长的临床试验可能会延迟对创新技术的监管评估，从而影响患者获得高质量医疗产品的机会。模拟技术在产品开发中越来越多地得到应用，但在监管应用中却很少。
进行计算机模拟成像试验，评估数字乳腺断层合成术（DBT）作为数字乳腺摄影术（DM）的替代方法，并将结果与临床比较试验进行比较。
设计、地点和参与者：模拟虚拟成像监管评估临床试验（VICTRE）试验旨在复制一项使用人类患者和放射科医生的临床试验。通过快速蒙特卡罗 X 射线传输获得的 DM 和 DBT 系统的基于图像的虚拟版本被计算读取器解释，该读取器检测病变的存在。总共生成了 2986 名基于合成图像的虚拟患者，这些患者的乳房大小和射线照相密度代表了筛查人群，并且压缩厚度从 3.5 到 6 厘米，使用解析方法生成，其中解剖结构在预定义的乳房体积内随机创建，并沿头尾方向压缩。阳性队列包含一个数字插入的微钙化簇或有毛刺的肿块。
试验终点是病变检测两种方式的曲线下接收者操作特征曲线面积差异。试验规模为比较临床研究中曲线下面积（AUC）变化的标准误差（SE）为 0.01。
在这项试验中，计算读取器分析了来自 2986 名虚拟患者的 31055 例 DM 和 27960 例 DBT 病例，这些患者的乳腺成像报告和数据系统密度如下：286（9.6%）为极度致密，1200（40.2%）为不均匀致密，1200（40.2%）为散在纤维腺体密度，300（10.0%）为几乎完全脂肪。AUC 变化的平均（SE）为 0.0587（0.0062）（P < .001），有利于 DBT。肿块的 AUC 变化大于钙化（平均[SE]，0.0903 [0.008]），与比较试验的结果一致（肿块的平均[SE]为 0.065 [0.017]，钙化的平均[SE]为-0.047 [0.032]）。
模拟 VICTRE 试验的结果与比较试验的结果一致。虽然还需要进一步研究来评估这些发现的普遍性，但基于计算机的成像试验代表了成像设备监管证据的一个可行来源。
