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.

项目摘要 在多发性骨髓瘤（MM）中，真实世界证据（RWE）已成功用于批准后 以表征真实世界的疗效并提供重要的安全性信息。最近的立法 旨在推进RWE以支持药物开发的研究为考虑RWE创造了机会， 1尽管做出了这些努力，但RWE在批准前的监管决策中一直没有产生影响。 审核MM设置。在ABECMA备忘录中，FDA表示，伴随的RWE研究是 由于现实世界无进展生存期（rwPFS）的测量偏倚有限，因此不确定 与试验数据的比较。2我们建议开发新的方法来比较rwPFS和试验PFS 在MM。 限制rwPFS和试验PFS比较的测量偏倚可分解为 错误分类偏见和监督偏见。我们将按如下方式解决这些偏差： 目的1：开发新的方法来纠正IMWG反应标准的错误分类偏倚 在（a）所有真实世界MM患者和（B）历史代表性不足的MM患者中 ·表征为MM疾病评估收集的测定中的缺失的真实世界模式 根据国际骨髓瘤工作组（IMWG）响应标准3 ·在以下控制组中复制IMWG响应标准中的真实世界失踪模式： 3项Janssen试验和量化这种缺失对进展的影响（miscPROG） ·测试基于可能性的方法和加权方法，以通过模拟纠正错误分类偏差。 目的2：开发新的方法来纠正疾病评估中的监测偏倚， 真实世界MM患者和（B）历史代表性不足的MM患者 ·表征MM疾病评估的真实世界节奏 ·在3项Janssen试验的CA中复制真实世界的节奏并量化对PFS的影响（survPFS） ·通过模拟开发监督偏差校正方法 AIM 3：将AIM 1和2中开发的所有偏倚校正方法用于保持RWD，并与 来自至少另外两项Janssen MM试验的对照组 ·评估试验CA PFS与偏倚校正和试验模拟RWD CA PFS的比较 Janssen将与著名的学术方法专家、MM研究人员和Flatiron密切合作 健康，一个私营部门的领导者在MM RWD，以完成这项研究（请参阅'财团 协议和关键人员”）。我们打算通过同行评审， 出版物。这项研究完全符合杨森的信条和我们的首要责任， 患者的需要。