Qualification of Composite Quantitative Imaging Biomarkers for Diagnostic Enrichment in Nonalcoholic Steatohepatitis (NASH) Clinical Trials (DDTBMQ000112)

总结 这项U 01拨款提案的长期目标是减少实现所需的肝活检数量。 非酒精性脂肪性肝炎（NASH）药物开发试验的目标招募， 通过FDA CDER生物标志物鉴定计划进行的复合定量成像生物标志物;重复 该过程适用于与NASH药物开发试验相关的其他使用情况;并监测和评估 在NASH药物开发试验中使用FDA合格的定量成像生物标志物，以帮助进一步完善 鉴定这些生物标志物的过程。我们的近期目标是准备，提交，并获得 批准此处提出的复合定量成像生物标志物的鉴定计划 在我们的意向书中。这项工作是通过正在进行的一致性度量的开发来利用的 来自定量成像生物标志物联盟（QIBA），等待1500万美元的NIMBLE研究的结果 由美国国立卫生研究院基金会进行，并由众多制药行业合作伙伴资助， FDA关于医学研究中使用背景的指南。该建议的核心假设是， 研究和待定的NIMBLE研究结果的定量成像生物标志物描述在我们的 意向书对于诊断富集的目的来说足够成熟，值得准备一份 鉴定计划。PAR-21-178鼓励我们将赠款提案的重点放在填补 提交鉴定计划。因此，我们选择了四个主要目标来解决十四个问题 FDA向我们提供的关于生物标志物描述和使用背景相关的分析、临床和 统计考虑。我们四个主要目标的成功里程碑是FDA的认可 我们对他们问题的回答。该项目的潜在影响很大，因为它解决了一个关键问题， NASH药物开发进展的障碍。该项目的成功完成将有助于改变 目前NASH药物开发试验中诊断富集的范例，并将加速 为最需要的患者开发安全有效的医疗产品。如果这件事的目的 如果符合补助金建议，将证明准备完整的资格证书包是合理的。如果这个包裹也是 接受，我们的方法，以确保生物标志物的批准可能会加快其他生物标志物的资格， 其他使用情况，包括早期检测、诊断、分期、监测和治疗反应， NASH，从而促进临床试验的筛选、招募和执行，以加速药物发现。

SUMMARY The long-term goals of this U01 grant proposal are to reduce the number of liver biopsies required to achieve target enrollment in nonalcoholic steatohepatitis (NASH) drug development trials by rigorously qualifying composite quantitative imaging biomarkers through the FDA CDER Biomarker Qualification Program; repeat this process for other contexts of use related to NASH drug development trials; and monitor and assess the use of FDA-qualified quantitative imaging biomarkers in NASH drug development trials to help further refine the process by which these biomarkers are qualified. Our immediate goal is to prepare, submit, and obtain approval for the Qualification Plan being proposed here for the composite quantitative imaging biomarkers proposed in our Letter of Intent. This work is leveraged by ongoing development of metrics of conformance from the Quantitative Imaging Biomarkers Alliance (QIBA), pending results from the $15M NIMBLE Study being conducted by the Foundation of the NIH and funded by numerous pharmaceutical industry partners, and FDA guidance on contexts of use in medical research. The central hypothesis of this proposal is that prior research and pending NIMBLE Study results on the quantitative imaging biomarkers described in our Letter of Intent are sufficiently mature for purposes of diagnostic enrichment to merit preparation of a Qualification Plan. We are encouraged in PAR-21-178 to focus our grant proposal on filling gaps for the Qualification Plan submission. Hence, we chose four Primary Aims to address the fourteen questions provided to us by FDA concerning biomarker descriptions, and context-of-use-related analytical, clinical, and statistical considerations. Our milestone of success for each of our four Primary Aims is acceptance by FDA of our responses to their questions. Potential impact of this project is high because it addresses a critical barrier to progress in NASH drug development. Successful completion of this project will help change the current paradigm of diagnostic enrichment in NASH drug development trials, and will accelerate the development of safe and effective medical products for the patients who need them the most. If the aims of this grant proposal are met, preparation of a Full Qualification Package will be justified. If that package is also accepted, our methodology to secure biomarker approval may expedite qualification of other biomarkers for other contexts of use including early detection, diagnosis, staging, monitoring, and treatment response for NASH, thereby facilitating screening, enrollment, and execution of clinical trials to accelerate drug discovery.