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Collaborating to Advance Regulatory Science in Proteomics

Despite great strides in proteomics and the growing number of articles citing the discovery of potential biomarkers, the actual rate of introduction of Food and Drug Administration (FDA) approved protein analytes has been relatively unchanged over the past 10 years. One of reasons for the lack of new protein-based biomarkers approved has been a lack of information and understanding by the proteomics research community to the regulatory process used by the FDA. To address this issue, Dr. Emily Boja in the NCI Office of Cancer Clinical Proteomics Research, worked with CPTC investigators along with collaborators from the FDA, Scientist from the National Heart, Lung, and Blood Institute, the Center for Medicare & Medicaid Services, and clinical chemist from the American Association for Clinical Chemistry to write a special article published in the Journal Clinical Chemistry. In this special report entitled, The Journey to Regulation of Protein-Based Multiplex Quantitative Assay, the authors provide insight into what are the key issues and questions that must be addressed in moving biological analytes and platforms from research to cleared FDA test.

The article has three major messages:

1. these multiplex protein-based assays are complex requiring expertise in instrument operation and sometimes interpretive software to derive a classifier non-transparent to the end-users;
2. establishing a standardized evaluation paradigm should help ensure the highest level of performance for providing the most accurate results for patients, as it is likely difficult for clinical labs to validate these assays on their individual analytical platforms and to demonstrate clinical relevance by performing large-scale preclinical/clinical studies that may need to involve multiple laboratories;
3. assay developers should carefully consider FDA's analytical validation criteria for the device's intended use for their preclinical/clinical studies prior to assay submission.

To learn more about the Journey visit http://www.aacc.org/publications/clin_chem/podcast/pages/default.aspx to listen to Drs. Emily Boja and Henry Rodriguez as they further discusses this topic in a free podcast.

Mock 501(k) pre-submissions

A key aspect of moving the field of clinical proteomics forward is to ensure that there is both clear communication and understanding of necessary regulatory requirements to move research from the lab to the clinic for investigators, on one hand, and that the proteomic technologies utilized by research investigators are understood by regulators. To help move the field forward, the National Cancer Institute and the Food and Drug Administration (FDA) started an Interagency Oncology Task Force (IOTF) in 2003, with a Molecular Diagnostics subcommittee formed in 2007, to help address some of the analytical issues related to the diagnostics community.

Since the start of the IOTF, there have several joint publications from the Office of Cancer Clinical Proteomics Research.  Additionally, a joint workshop was held on October 2008 in Cambridge, MA. The purpose of this workshop was to discuss requirements for analytical validation of protein-based multiplex technologies in the context of their intended use. This workshop focused on technology-specific analytical validation processes to be addressed when seeking FDA clearance/approval for the medical devices (or assays) prior to their use in clinical settings. In making this workshop unique, a case study approach was used to discuss issues related to:

• Validating protein-based multiplex technologies
• Specimen and population issues
• Statistical issues
• Understanding the regulatory pathway to commercialization

In follow up to the IOTF workshop, a summary report and two mock 510(k) pre-submissions with FDA review comments were published in the February 2010 issue of the journal Clinical Chemistry. These documents now serve as a springboard for the clinical proteomics community in the development of protein-based multiplexed In Vitro Diagnostic (IVD) tests.  The two articles include:

Analytical Validation of Protein-Based Multiplex Assays: A Workshop Report by the NCI-FDA Interagency Oncology Task Force on Molecular Diagnostics

This meeting report explores the issues raised at the workshop and details the recommendations that came out of the discussions, such as a workshop summary discussing the analytical evaluation issues that specific proteomic technologies should address when seeking US Food and Drug Administration approval.

Protein-Based Multiplex Assays: Mock Presubmissions to the US Food and Drug Administration

Investigators from NCI’s Clinical Proteomics Technology Assessment for Cancer program submitted 2 detailed protein-based multiplex assay descriptions (i.e., immunoaffinity arrays and immunoaffinity multiple reaction monitoring mass spectrometry) as examples to the Office of In Vitro Diagnostic Device Evaluation and Safety, FDA. The objective was to evaluate the analytical measurement criteria and studies needed to validate protein-based multiplex assays.  These mock submissions provided a mutually beneficial way for members of the proteomics and regulatory communities to identify the analytical issues that the field should address when developing protein-based multiplex clinical assays.