Regulatory Validation of Standardized Clinical Immunohistochemistry Controls

描述（由申请人提供）：该项目的长期目标是通过免疫组织化学（IHC）对手术活检进行一致的标准化诊断测试。实现这一目标的方法在临床实验室检测领域得到了很好的理解：(1)试剂和方案的标准化，(2)自动化以减少人为错误，(3)使用标准化控制来提供测试性能反馈。在过去二十年中，这三种方法中的前两种用于免疫健康检测。这个拨款项目的重点是第三个——标准化控制。目前的实践教导非标准化控制。每个组织病理学实验室通常从自己的石蜡块档案中的剩余组织样本中获取测试对照。这与临床血液实验室的做法截然不同，临床血液实验室大量生产标准化和经过验证的对照品，并通过商业供应商销售。由于每个人体组织都是有限的资源，目前的做法本质上是不标准化的。我们已经开发了一种创新的技术解决方案来解决这个问题，并在一系列论文中进行了总结。在进行了内部测试和与美国病理学家学会（College of American Pathologists）进行的全国性研究之后，这项技术遇到了监管障碍。作为一种“革命性的”（而不是“进化的”）检测控制，FDA设置了很高的监管门槛，这使得该项目在以前的形式下在商业上不可行。使用相同的化学物质，我们重新设计了这项技术，以解决之前的监管障碍。该I - II期快速通道提案的具体目的是围绕这种重新设计的新型分析控制的实验验证，以达到监管目的。I期目标包括新产品设计的分析验证，包括敏感性、特异性、稳定性和可重复性的评估。II期的目标是临床验证，这将独特地测试和验证标准化在免疫组化控制中的作用。虽然我们最初的重点是乳腺癌检测领域，但这一努力打开了一个全新的市场，包括其他免疫球蛋白c控制产品。申请团队由一个广泛的多学科团队组成，包括原始研究团队，来自塔夫茨临床与转化科学研究所（CTSI）的统计和数据库管理人员，外科病理学家，法规事务顾问和IHC商业运营专家。第二阶段还包括与美国病理学家学院的合作。在第二阶段结束时，我们将获得所有FDA监管提交数据，以过渡到商业化。该项目将导致创建第一套fda批准的国家标准化免疫组化测试控制。在将临床实验室从自制实践转换为自制实践的过程中，其影响将是变革性的，特别是对于要求更高准确性的较新的定量测试。

DESCRIPTION (provided by applicant): The broad, long-term goal of this project is consistent, standardized diagnostic testing of surgical biopsies by immunohistochemistry (IHC). The methods to achieve this goal are well understood in the field of clinical laboratory testing: (1) standardization of reagents and protocols, (2) automation to reduce human errors, and (3) the use of standardized controls to provide test performance feedback. Over the last two decades, the first two of these three methods were implemented for IHC testing. This grant project focuses on the third - standardized controls. Current practice teaches non-standardized controls. Each histopathology lab typically procures test controls from leftover tissue samples in its own paraffin block archives. This is a strikingly different practice from clinical blood laboratories, where standardized and validated controls are produced in large quantities and sold through commercial vendors. Since each human tissue is a limited resource, present practice is inherently non-standardized. We have developed an innovative technical solution to this problem, summarized in a series of papers. After both in-house testing and a national study performed with the College of American Pathologists, the technology ran into a regulatory roadblock. As a "revolutionary" (rather than "evolutionary") assay control, the FDA set a high regulatory bar that made the project commercially unfeasible in its previous form. Using the same chemistry, we have re-designed the technology so as to address the previous regulatory roadblock. The Specific Aims of this Phase I - II Fast-Track proposal revolve around experimental validation, for regulatory purposes, of this re-designed new class of assay control. The Phase I Aims include analytical validation of the new product design, including an assessment of sensitivity, specificity, stability, and reproducibility. The Phase II aims address clinical validation, which will uniquely test and validate the role of standardization in IHC controls. Although our focus is initially in the area of breast cancer tests, this effort opens an entirely new market, to include other IHC controls products. The applicant group comprises a broad, multi-disciplinary team, including the original research team, statistical and database management staff from the Tufts Clinical & Translational Science Institute (CTSI), surgical pathologists, a regulatory affairs consultant, and an IHC commercial operations specialist. Phase II also includes a collaboration with the College of American Pathologists. At the conclusion of Phase II, we will have all of the FDA regulatory submission data for transition to commercialization. This project will lead to the creation of the first set of FDA-cleared nationall standardized IHC test controls. In converting clinical laboratories from a homebrew practice, the impact will be transformative, especially for the newer quantitative tests that demand a higher level of accuracy.