DDTBMQ000011: Advance tumor volume change as measured by CT as a pharmacodynamic biomarker for new oncologic drug clinical trial therapy of solid tumors to Stage 2 of FDA biomarker qualification

项目摘要/摘要 本项目的总体目标是推进生物标志物资质的应用 DDTBMQ000011从FDA生物标记物资格鉴定过程的当前阶段1到阶段2。 这个项目的范围是基于FDA BQP审查小组的建议，这些建议是 在接受遗留生物标记物资格提案的确定函中传达 根据从随后的情况通报会议收到的补充意见，进入507进程，以及 在FDA的指导文件上。将进行FDA BQP建议的研究以评估 奇巴档案的CT容量测定生物标记物变化定义(CTVOL)和 使用反应性、稳定性或进行性疾病类别的RECIST系统。 这两种办法之间的分歧将进一步细分为：(1)实质性 不一致，RECIST和CT容量法之间的不一致不能归因于 提高了CT容量测量的敏感度，以及(Ii)由于改进而可能引起的分歧 CT容量测定仪的敏感性。预测分歧的因素将被识别出来。空的 假设有实质性分歧的病变比例是15%；可供选择 假设存在实质性分歧的病变比例为15%。图像将是 回顾收集自先前在第三阶段接受连续CT成像的受试者的研究 药物试验。三名读者将被招募，他们具有非常不同的经验水平，参与 234例准读者研究。研究读者将测量每个目标病变上的 使用两个图像分析软件工具进行基线和后续扫描。一维和 将在每个时间点测量并记录每个目标病变的体积 凯斯。根据这些数据，将构建变化的测量时，相同的读者 每个时间点的测量，以及不同读取器在以下时间进行测量的时间 基线和随访。然后，变化的估计将被分为三类 (部分或完全反应、稳定或进展)使用两种方法(RECIST和QIBA 配置文件索赔)。将报告两种方法在分类上的不一致。 多变量Logistic回归模型适用于评估病变特征的贡献 (大小、形状、位置)、CTVOL测量的变化幅度、扫描仪型号、图像 分析软件，成像是否符合QIBA-PROFILE-CONFORM，读卡器协议(相同 或在两个时间点的不同读取器)。拟议的工作具有很大的潜力来验证 一种新的定量成像生物标志物(即CT容量测定)的重复性 在治疗试验中确定肿瘤反应或进展。

Project Summary/Abstract The overall objective of this project is to advance the biomarker qualification application DDTBMQ000011 from the current Stage 1 to Stage 2 of the FDA biomarker qualification process. The scope of this project is based on recommendations from the FDA BQP review team that were communicated in the Determination Letter for accepting the legacy biomarker qualification proposal into the 507 Process, on additional advice received from the subsequent debriefing meeting, and on FDA guidance documents. A FDA BQP-suggested study will be conducted to assess agreement between the QIBA Profile’s CT volumetry biomarker definition of change (CTvol) and the RECIST system using the categories of responsive, stable, or progressive disease. Disagreements between the two approaches will be further broken down as: (i) substantive disagreement, where the disagreement between RECIST and CT volumetry cannot be attributable to improved sensitivity with CT volumetry and (ii) disagreement potentially due to improved sensitivity with CT volumetry. Factors predictive of disagreement will be identified. The null hypothesis is that the proportion of lesions with substantive disagreement is >15%; the alternative hypothesis is that the proportion of lesions with substantive disagreement is <15%. Images will be retrospectively collected from prior studies of subjects undergoing serial CT imaging in Phase 3 drug trials. Three readers will be recruited with very different levels of experience to participate in a prospective reader study of 234 cases. Study readers will measure each target lesion on the baseline and follow-up scans using two image analysis software tools. Both unidimensional and volume measurements of each target lesion at each timepoint will be taken and recorded for each case. From these data, measurements of change will be constructed when the same reader makes the measurements at each time point, as well as when different readers make the measurement at baseline and follow-up. The estimates of change will then be classified into three categories (partial or complete response, stable, or progression) using the two approaches (RECIST and QIBA Profile claim). The disagreement in classification between the two approaches will be reported. Multiple-variable logistic regression models will be fit to assess contribution of lesion characteristics (size, shape, location), magnitude of change as measured by CTvol, scanner model, image analysis software, whether imaging was QIBA-Profile-conformant or not, and reader protocol (same or different reader at two time points). The proposed work has great potential to validate the reproducibility of an emerging quantitative imaging biomarker (i.e., CT volumetry) to more precisely determine tumor response or progression in therapy trials.