FDA-Reviewed Validation Protocols for Liquid Biopsy

BloodPAC Publishes FDA-Reviewed Validation Protocols for Liquid Biopsy
Collaboration with FDA, Industry and Academia Yields a Critical New Standard

CHICAGO – The Blood Profiling Atlas in Cancer Consortium (BloodPAC) published “Generic Protocols for the Analytical Validation of Next-Generation Sequencing-Based ctDNA Assays,” in the September 2020 issue of Clinical Chemistry. Developed by consortium members, the resource serves as set of generic analytical protocols and helps to define industry standards in the development of liquid biopsy tests.

The generic analytic validation protocols are intended to be the starting point for developers or manufacturers of Next Generation Sequencing-based circulating tumor DNA (NGS-based ctDNA) diagnostic tests. Analytic validation is used to determine whether assays perform as intended, assessing the performance limits and overall robustness of the test. The Food and Drug Administration (FDA) has asked BloodPAC to embark on a second phase to develop analytic validation protocols for assays designed to detect and monitor patient status post-treatment, when molecular residual disease (MRD) is present.

“Liquid biopsy technology holds great promise in improving the outcomes of patients with cancer, but without a common ‘yardstick’ with which the FDA can measure analytical performance, real gains for patients will be slow to materialize,” said Jim Godsey, PhD, vice president of assay development at Illumina and co-chair of the BloodPAC Analytical Variables Working Group (BloodPAC AVWG). “These protocols establish a vital piece of infrastructure that will accelerate the development of new tools to improve cancer care and are the tangible fruit of collaboration across industry, academic researchers and the FDA.”

Validation of liquid biopsy poses unique challenges, largely due to the extremely small amount of target DNA or RNA being detected by a cell free assay, which may be as low as 2-3 molecules in each tube of blood. The publication contains five standard methods and 12 protocols providing guidance on different aspects of validation studies, including limits of detection, accuracy and contrived sample functional characterization. The protocols were developed with input from the FDA through the official presubmission process.

“Given the potential utility of these assays for patients and clinical decision-making, we can’t afford to have companies duplicating efforts or have the FDA encumbered by regulatory standards that are out of step with rapidly advancing technology,” said John Simmons, vice president of translational medicine at Personal Genome Diagnostics (PGDx) and BloodPAC scientific co-chair.

“Aligning on gold standard processes will not only help regulators effectively review products for performance, but it will help assay developers create tests that hold up to the highest scientific standards and truly transform cancer care for patient benefit.”

BloodPAC fosters collaboration among representatives from academia, private foundations, pharmaceutical companies, diagnostic companies, payer groups and government agencies. “Those working to develop assays designed to detect and monitor circulating tumor DNA must overcome unique hurdles in order to deliver accurate results,” said Mickey Williams, PhD, director of the Molecular Characterization Laboratory at the Frederick National Laboratory for Cancer Research, who consulted with BloodPAC on the project. “The BloodPAC efforts have produced a thoughtful manuscript that ctDNA assay developers should read for helpful advice on assay analytical validation. The involvement of many diverse stakeholders in BloodPAC has added tremendous value to this effort.”

The standardized practices, protocols and terminology for analytical validation are intended to support not only the pre-submission discussions between manufacturers and the FDA, but also discussions between assay developers and potential industry partners. “BloodPAC was formed to yield exactly this type of outcome,” said Lauren Leiman, executive director of BloodPAC. “These protocols define rigorous scientific standards for ctDNA assays and sets a common playing field that will accelerate the cycle of innovation – through development, approval and clinical use – to yield better outcomes for patients.”

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About the Blood Profiling Atlas in Cancer (BloodPAC):

The Blood Profiling Atlas in Cancer (BloodPAC) is focused on accelerating the development and validation of liquid biopsy assays to improve the outcomes of patients with cancer. BloodPAC is a nonprofit consortium managed by the Center for Computational Science Research, Inc. (CCSR), which is an Illinois-based not-for-profit corporation. Today, over thirty organizations have pledged support by contributing liquid biopsy data, protocols, and expertise into an open data commons.

BloodPAC participants include: American Cancer Society (ACS), Arkansas Bioinformatics Consortium (ARBIC), Association for Molecular Pathology (AMP), AstraZeneca, Bio-Rad, Breast Cancer Research Foundation (BCRF), Bristol Myers Squibb Company, The Center for Genetic Medicine Research at Children's National Medical Center (CNMC), Ceres Nanosciences, Inc., College of American Pathologists (CAP), Eli Lilly and Company, Epic Sciences, The Food and Drug Administration (FDA), Foundation Medicine, Freenome, Friends of Cancer Research, Guardant Health, Horizon Discovery, Illumina, Inivata, Memorial Sloan Kettering Cancer Center, Movember Foundation, National Cancer Institute (NCI), Novartis, Open Commons Consortium (OCC), Personal Genome Diagnostics (PGDx), Pfizer, Prostate Cancer Foundation (PCF), Prostate Cancer Clinical Trials Consortium (PCCTC), Seracare Life Sciences Inc., SolveBio, Streck, Inc., Sysmex Inostics, Tempus, Thermo Fisher Scientific, University of Chicago, University of Southern California, Department of Veterans Affairs (VA), Windber Research Institute.

For more information on how to contribute or participate in BloodPAC, an open consortium, please visit www.bloodpac.org.