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Pages 1-16

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From page 1...
... High-dimensional data are particularly prone to overfitting; as a result, a computational model emerging from the research and discovery phase may function well on the samples used for the discovery research, but is inaccurate on any other sample. A carefully designed and executed series of studies is necessary to develop a clinically useful omics-based test for patient management and care, with the goal of improving patient outcomes.
From page 2...
... While pharmaceutical and medical device companies follow well-established medical product development pathways and have many process controls in place for strong oversight of development, clinical validation, and manufacturing, academic institutions are not as accustomed to overseeing the development of medical products. The frequent lack of a clear biological rationale further distinguishes omics-based tests from most other clinical laboratory tests based on a single analyte.
From page 3...
... The failure of scientific collaboration, review processes by journals, regulatory oversight, institutional systems for protection of patient-participants, and institutional systems for management of conflicts of interest in a recent case involving the premature use of gene expression-based tests in clinical trials at Duke University led the National Cancer Institute (NCI) to request establishment of this Institute of Medicine (IOM)
From page 4...
... With support from NCI, FDA, the Centers for Disease Control and Prevention, the U.S. Department of Veterans Affairs, the American Society for Clinical Pathology, and the College of American Pathologists, the IOM committee's charge was to recommend sound principles for appropriate development and evaluation in translating omics-based tests from the research laboratory into clinical trials, with the ultimate goal of guiding therapeutic decisions to improve patient outcomes.
From page 5...
... The final stage is assessment of the clinical utility and use of the validated omics-based test within a clinical trial, with multiple design options depending on the intended clinical use of the test and availability of specimens from previous clinical trials. Statistics and bioinformatics validation occurs throughout both development stages.
From page 6...
... Prospective/ Prospective Prospective Retrospective Clinical Trial; Clinical Trial; Study with Test Does NOT Test Directs Direct Patient Patient Archived Management Management Specimens IDE Needed? No No Yes FDA Approval/Clearance or LDT Process for Clinical Test Additional High-Quality Evidence to Evaluate Clinical Utility of the Test Practice Guidelines and Reimbursement Clinical Use TE: The computational procedures are locked down in the discovery phase, meaning they are recorded and longer changed in the subsequent development steps.
From page 7...
... Under exceptional circumstances it may be necessary to move into the test validation phase without first confirming the candidate test on an independent sample set if using an independent test set in the discovery phase is not possible, but this increases the risk of test failure in the validation phase. In the test validation phase, the omics-based test undergoes analytical and clinical/biological validation.
From page 8...
... Both components of omics-based tests used to direct patient management in a clinical trial setting should be validated during the test validation phase using the following steps: in a clinical laboratory, and then should undergo analytical validation and clinical/biological validation. The clinical test methods can be optimized based on feedback from the analytical validation performance characteristics, but must be fully defined, completely validated analytically and biologically/clinically with acceptable performance of the test, and locked down prior to assessment of the clinical utility and use of the test in a clinical trial.
From page 9...
... b. Test validation should be performed in a CLIA-certified clinical laboratory, beginning with a defined candidate omics-based test from the discovery phase.
From page 10...
... 4.c. Institutions that conduct biomedical omics research, including test develop ment and clinical trials, should train, recognize, and support the faculty-level careers of individuals from the multiple collaborating disciplines, including biostatistics, bioinformatics, pathology, omics technologies, and clinical trial ists, and ensure that they are: i.
From page 11...
... 6.b. FDA should communicate the IDE requirements for use of omics-based tests in clinical trials to the Office of Human Research Protections (OHRP)
From page 12...
... Critical considerations for moving a fully defined omics-based test into clinical trials for assessing clinical utility and use are outlined in Figure S-1 and Recommendation 3 (see Box S-1) and fully described in Chapter 4.
From page 13...
... If an institution does not have the infrastructure or capability to follow the recommended Test Development and Evaluation Process defined in this report, then the committee believes that institution should consider not engaging in the translation of omics-based discoveries into validated tests intended for clinical use. As the Duke case study clearly demonstrates, existing procedures in some institutions may not adequately ensure the scientific integrity of translational omics.
From page 14...
... These include the series of gene expression–based tests used in clinical trials at Duke University; the commercial tests Oncotype Dx, MammaPrint, Ova1, AlloMap Testing, CorusCAD, and the Tissue of Origin Test; and the first OvaCheck test, which did not reach clinical use and for which errors were found in the methods used in the discovery phase. HER2 testing also is included as a case study to illustrate the challenges associated with a single-biomarker test, which could be magnified in omicsbased tests.
From page 15...
... Furthermore, the committee believes that scientific progress in omics-based test development will improve if these recommendations are broadly adopted because they ensure wide availability of data and computational models for the scientific community to explore, clarify the regulatory steps that must be followed along the process, and clarify responsibilities for the parties involved in this process. The committee hopes this report will provide a guide to the entire pathway for the development of omics-based tests, from discovery to clinical trials, to assist the many parties contributing to this translational research in understanding the complete pathway and not just their focused contributions.


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