Enabling nationwide AD PET imaging to support most efficient clinical trials by adoption of radically simplified and standardized quality control in commercial production of AD PET tracers.

通过在 AD PET 示踪剂的商业生产中采用彻底简化和标准化的质量控制，使全国范围内的 AD PET 成像能够支持最有效的临床试验。

• 批准号: 10156578
• 负责人: Arkadij Elizarov
• 金额: $ 125.63万
• 依托单位: TRACE-ABILITY, INC.
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10156578
• 关键词: Achievement; Adoption; Alzheimer' s Disease; Alzheimer' s disease patient; Alzheimer' s disease therapy; Amyloid; Amyloid beta-Protein; Automation; Back; Biological Markers; Brain; Brain Pathology; Clinical Trials; Complex; Contrast Media; Country; Coupled; Detection; Development; Disease; Disease Progression; Effectiveness; Environment; FDA approved; Failure; Family; Funding; Future; Goals; Image; Imaging Techniques; Lead; Letters; Life; Manufacturer Name; Measurement; Mission; Molecular; National Institute on Aging; Optics; Outcome; Outcome Measure; Patients; Performance; Pharmaceutical Preparations; Phase; Plant Roots; Population; Positron-Emission Tomography; Predictive Value; Procedures; Process; Production; Quality Control; Quality of life; Radioactive; Reliability of Results; Reporting; Risk; Risk Factors; Running; Site; Solid; Standardization; Structure; System; Technology; Testing; Therapy trial; Tracer; Travel; Treatment Cost; Validation; Work; base; cost; drug development; experience; imaging study; improved; improved outcome; innovation; manufacturing facility; new therapeutic target; novel strategies; prevent; research and development; residence; skills; tau Proteins; therapy outcome

Positron Emission Tomography (PET) is the most powerful imaging procedure relied upon in the management of Alzheimer’s Disease (AD). It provides information on the molecular processes in the brain. PET imaging studies require short-lived radioactive contrast agents called PET tracers. Multiple PET tracers have a strong predictive value in AD. The long-term objective of the proposed work is availability of AD PET imaging to broad AD population, which enables (1) detection of disease in pre-symptomatic stage and (2) most effective clinical trials for development of AD therapies. Both of these impacts lead to improved outcomes for AD patients. Thereby, this project is considered highly relevant to the mission of National Institute on Aging (NIA). Trace-Ability plans to enable nationwide availability of AD PET imaging by eliminating production complexity rooted in release testing of AD PET imaging tracers. The enabling solution will be demonstrated with of [F-18]Flortaucipir (leading tau PET tracer with pending NDA) and [F-18]Florbetaben (FDA-approved Beta Amyloid PET tracer), thereby demonstrating solution’s universal applicability to multiple AD PET products. Proposed solution relies on complete automation of release testing on Tracer-QC platform that has been validated earlier with the most common PET tracer, F 18 Fludeoxyglucose (FDG) and demonstrated with [F-18]Florbetaben. Current experience has identified critical gaps that need to be filled in order to achieve broad commercial adoption of these products. By filling these gaps with R&D focused on 2 specific aims, proposed Direct to Phase II project enables rapid expansion of AD PET imaging to the broad AD population. Specific Aim 1: Achieve overall solution reliability required for broad commercial deployment by demonstrating failure of <0.1% at Trace-Ability and <1% in the field. This aim will first require thorough assessment of the currently known issues and potential risk factors. Next, we will define unique innovative technical solutions to each of the identified risks and issues. Then, implementation of each solution will be followed by a solid proof of its effectiveness. Once all solutions have been implemented, we will test the overall resulting reliability of the system in-house. After proving it to ourselves by demonstrating <0.01% failure rate, we will deploy systems in the field to prove the desired reliability of >99% in a variety of commercial AD PET tracer production environments. Specific Aim 2: Automated QC of AD PET tracers qualified at 4 commercial production facilities with a 30-day regulatory mechanism for adding new sites. The regulatory challenge for adoption of automated QC solution at new sites with new AD PET tracers is two-fold: (1) It requires thorough validation at each new site. (2) There is a 10-month FDA approval process for each new manufacturer. Phase II R&D will yield effective and innovative Performance Qualification (PQ) procedures that deliver solid proof of system’s analytical performance against pre-set acceptance criteria with a small number of special test runs at each new facility. In combination with a Type V DMF containing validation reports, such PQ will allow each new site to switch their release testing to Tracer-QC within 30 days following a CBE30 mechanism.

正电子发射断层扫描（PET）是最强大的成像程序，依赖于在管理 阿尔茨海默病（AD）。它提供了大脑中分子过程的信息。PET成像研究需要 称为PET示踪剂的短寿命放射性造影剂。多种PET示踪剂在AD中具有很强的预测价值。 这项工作的长期目标是为广泛的AD人群提供AD PET成像， 能够（1）在症状前阶段检测疾病和（2）最有效的AD发展临床试验 治疗这两种影响都改善了AD患者的预后。因此，该项目受到高度重视 与国家老龄化研究所（NIA）的使命有关。 Trace-Ability计划通过消除生产复杂性，在全国范围内提供AD PET成像 在AD PET成像示踪剂的发布测试中。将使用[F-18]Flortaucipir来演示使能解决方案 （具有待决NDA的领先tau PET示踪剂）和[F-18]Florbetaben（FDA批准的β淀粉样蛋白PET示踪剂），从而 证明了解决方案对多种AD PET产品的普遍适用性。 拟议的解决方案依赖于已验证的Tracer-QC平台上发布测试的完全自动化 早期使用最常见的PET示踪剂F18氟脱氧葡萄糖（FDG），并用[F-18]Florbetaben证明。 目前的经验已经确定了需要填补的关键差距，以实现广泛的商业采用， 这些产品通过以2个具体目标为重点的研发填补这些空白，拟议的直接进入第二阶段项目使 AD PET成像快速扩展到广泛的AD人群。 具体目标1：实现广泛商业部署所需的整体解决方案可靠性， 可追溯性故障<0.1%，现场故障<1%。要实现这一目标，首先需要全面评估目前 已知问题和潜在风险因素。接下来，我们将为每个已确定的 风险和问题。然后，每一个解决方案的实施将遵循其有效性的坚实证明。一旦所有 解决方案已经实施，我们将测试系统的整体可靠性。在证明了这一点后， 我们将在现场部署系统，以证明>99%的预期可靠性 在各种商业AD PET示踪剂生产环境中。 具体目标2：在4个商业生产设施中对AD PET示踪剂进行自动化QC， 增加新网站的监管机制。在新工厂采用自动化QC解决方案的监管挑战 新的AD PET示踪剂的应用有两个方面：（1）它需要在每个新的站点进行彻底的验证。(2)FDA有10个月的 每个新制造商的批准程序。第二阶段研发将产生有效和创新的性能鉴定 (PQ)提供系统分析性能与预设验收标准的可靠证明的程序， 在每个新设施进行的特殊试运行次数。结合包含验证报告的V型DMF，例如PQ 将允许每个新的研究中心在CBE 30机制之后的30天内将其放行检测切换为Tracer-QC。