Development of novel methods to enable robust comparison of real-world Progression Free Survival (rwPFS) and Clinical Trial PFS in Multiple Myeloma

开发新方法以对多发性骨髓瘤的真实无进展生存期 (rwPFS) 和临床试验 PFS 进行稳健比较

• 批准号: 10797236
• 负责人: Ashita Batavia
• 金额: $ 46.81万
• 依托单位: JANSSEN RESEARCH & DEVELOPMENT, LLC
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10797236
• 关键词: Development; novel; methods; enable; robust

Project Summary In multiple myeloma (MM), real-world evidence (RWE) has been successfully used in the post-approval setting to characterize real-world efficacy and provide important safety information. Recent legislation aimed at advancing RWE to support drug development has created opportunities for considering RWE in pre-approval regulatory decision-making.1 Despite these efforts, RWE has been unimpactful in the pre- approval MM setting. In the ABECMA memo, the FDA stated the accompanying RWE study was inconclusive because of measurement bias in real-world Progression Free Survival (rwPFS) limited comparisons to trial data.2 We propose to develop novel methods for comparing rwPFS and trial PFS in MM. The measurement bias that limits comparison of rwPFS and trial PFS can be disaggregated into misclassification bias & surveillance bias. We will address each of these biases as follows: AIM 1: Develop novel methods to correct for misclassification bias of IMWG response criteria among (a) all real-world MM patients and in (b) historically under-represented MM patients • Characterize real-world patterns of missingness in assays collected for MM disease assessment per the International Myeloma Working Group (IMWG) response criteria3 • Replicate real-world patterns of missingness in IMWG response criteria in the control arms (CA) of 3 Janssen trials & quantify the effect of this missingness on progression (miscPROG) • Test likelihood-based and weighting methods to correct misclassification bias through simulation. AIM 2: Develop novel methods to correct for surveillance bias in disease assessment among (a) all real-world MM patients and in (b) historically under-represented MM patients • Characterize the real-world cadence(s) of MM disease assessment • Replicate real-world cadence(s) in CA of 3 Janssen trials & quantify the effect on PFS (survPFS) • Develop surveillance bias correction methods through simulations AIM 3: Validate all bias correction methods developed in AIM 1 & 2 in holdout RWD and compare to the control arms from at least two other Janssen MM trials • Assess comparison of trial CA PFS to bias-corrected and trial-emulated RWD CA PFS Janssen will work closely with renowned academic methods experts, MM researchers and Flatiron Health, a private sector leader in MM RWD, to complete this research (please see ‘Consortium Agreement and Key Personnel’). We intend to make these novel methods available through peer-reviewed publications. This research is fully aligned with Janssen’s Credo and our first responsibility to serve the needs of patients.

项目概要 在多发性骨髓瘤（MM）中，真实世界证据（RWE）已成功用于批准后 设置来表征现实世界的功效并提供重要的安全信息。最近的立法 旨在推进 RWE 以支持药物开发，为考虑 RWE 创造了机会 预审批监管决策。1 尽管做出了这些努力，莱茵集团在预审批方面并没有产生什么影响。 批准MM设置。在 ABECMA 备忘录中，FDA 表示随附的 RWE 研究是 由于现实世界中无进展生存期 (rwPFS) 的测量偏差有限，因此尚无定论 与试验数据的比较。2 我们建议开发新方法来比较 rwPFS 和试验 PFS 在MM。 限制 rwPFS 和试验 PFS 比较的测量偏差可以分解为 错误分类偏差和监视偏差。我们将按如下方式解决这些偏见： 目标 1：开发新方法来纠正 IMWG 响应标准的错误分类偏差 (a) 所有现实世界的 MM 患者和 (b) 历史上代表性不足的 MM 患者 • 描述为多发性骨髓瘤疾病评估而收集的检测中的真实缺失模式 根据国际骨髓瘤工作组 (IMWG) 应对标准3 • 在控制臂 (CA) 中复制 IMWG 响应标准中的真实缺失模式 3 项 Janssen 试验并量化这种缺失对进展的影响 (miscPROG) • 测试基于可能性的加权方法，通过模拟纠正错误分类偏差。 目标 2：开发新方法来纠正 (a) 所有疾病评估中的监测偏差 现实世界的 MM 患者和 (b) 历史上代表性不足的 MM 患者 • 描述多发性骨髓瘤疾病评估的现实节奏 • 在 CA 中复制 3 个 Janssen 试验的真实节奏并量化对 PFS (survPFS) 的影响 • 通过模拟开发监测偏差校正方法 AIM 3：在保留 RWD 中验证 AIM 1 和 2 中开发的所有偏差校正方法并与 至少另外两项 Janssen MM 试验的对照臂 • 评估试验 CA PFS 与偏差校正和试验模拟 RWD CA PFS 的比较 杨森将与著名的学术方法专家、MM 研究人员和 Flatiron 密切合作 Health 是 MM RWD 私营部门的领导者，完成这项研究（请参阅“财团 协议和关键人员”）。我们打算通过同行评审来提供这些新颖的方法 出版物。这项研究完全符合杨森的信条以及我们为客户服务的首要责任 患者的需求。