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 (AACC) to write a special article recently published for 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.
Previously, CPTC investigators in collaboration with the FDA developed and published two mock 510 (k) review documents with comments from the FDA that provide insight into the regulatory process (Clinical Chemistry, Feb. 2010). The main thrust of this article is to provide updates of regulatory science on multiplex protein-based quantitative assays, beyond what was discussed in the original mock submissions. Mulitplexed protein-based quantitative assays sidentify and measure the amount of proteins in a solution (i.e. blood, urine, or body tissue) to help aid in disease diagnosis and also in determining response to drug therapy. It is important for all stakeholders interested in developing and applying these technologies for clinical research, regardless of their protein targets or platforms, be involved in this discussion from the beginning. This article is beneficial to the research community and industry on topics.
The article three major messages:
- 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;
- 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;
- 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.
There are additionally helpful resources available including CLSI documents, mock submission review documents, etc.
Understanding regulatory science is important in moving discovery results into physical products (e.g., medical devices, assays) that will be used in the clinic to improve patient outcome. As witnessed by the recent Request for Funding Announcement from the National Institutes of Health, that focuses specifically on Regulatory Science, it is clear that in translating discoveries more emphasis will need to be placed in this field.
Moving forward, CPTC is in the process of planning a workshop designed to further efforts between the government agencies and the extramural community to focus on the topic of proper study design of proteomic experiments. This workshop hopes to shed some light on the appropriate biostatistical considerations on sample size and cohort selection for the proteomics community at every stage of the biomarker development pipeline. Additionally at the upcoming American Association of Clinical Chemistry Annual Meeting there will be a joint session highlighting advances and barriers that exist in regulatory science for proteomics researchers. As Dr. Boja states, "Although the program focuses on the preclinical proteomic space, it would be extremely beneficial to design these preclinical studies correctly so that only robust and meaningful biomarker candidates can move downstream to more stringent, larger-scale clinical qualification studies (FDA)." The outputs from this paper and the upcoming meetings suggest that many of the barriers of knowledge preventing further development are being removed, and hopefully meaningful proteomic discoveries will be translated into improved patient outcomes.
To learn more about the Journey, click here to listen to a Podcast by Drs. Emily Boja and Henry Rodriguez as they further discusses this topic in an AACC podcast.