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

项目摘要 在多发性骨髓瘤(MM)中，真实世界证据(RWE)已成功地用于后批准 设置以表征真实世界的疗效并提供重要的安全信息。最近的立法 旨在推进莱茵集团以支持药物开发，为#年考虑莱茵集团创造了机会 审批前的监管决策1尽管有这些努力，莱茵集团在审批前的 审批MM设置。在ABECMA的备忘录中，FDA表示，随附的RWE研究是 由于现实世界无进展生存(RwPFS)有限的测量偏差，因此没有定论 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中。 限制rwPFS和试验性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：开发新的方法来纠正IMWG反应标准的错误分类偏差 在(A)所有真实的多发性骨髓瘤患者和(B)历史上代表性不足的多发性骨髓瘤患者中 ·在为多发性骨髓瘤疾病评估收集的化验中，描述真实世界的缺失模式 根据国际骨髓瘤工作组(骨髓瘤工作组)反应标准3 ·在IMWG的控制臂(CA)的响应标准中复制现实世界的失配模式 3个Janssen试验&量化这种缺失对进展的影响(MiscPROG) ·测试基于似然的方法和加权方法，以通过模拟纠正错误分类偏差。 目标2：开发新的方法来纠正(A)ALL疾病评估中的监测偏差 真实世界多发性骨髓瘤患者和(B)历史上代表性不足的多发性骨髓瘤患者 ·描述MM疾病评估的真实节奏(S) ·复制真实世界的节奏(S)，在3个扬森试验的CA中，量化对PFS的影响(SurvPFS) ·通过模拟制定监视偏差校正方法 目标3：验证在目标1和2中开发的所有在抵抗RWD中开发的偏差校正方法，并比较 来自至少另外两个Janssen MM试验的对照手臂 ·评估试验性CA PFS与经过偏差校正和试验仿真的RWD CA PFS的比较 Janssen将与著名的学术方法专家、MM研究人员和熨斗密切合作 健康，MM RWD的私营部门领导者，来完成这项研究(请参阅 协议和关键人员‘)。我们打算通过同行评审使这些新方法可用 出版物。这项研究与詹森的信条完全一致，我们的首要责任是为 患者的需求。

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.