Regulatory Validation of Standardized Clinical Immunohistochemistry Controls

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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.