Translation of proteomic biomarkers into FDA approved cancer diagnostics: issues and challenges

Abstract

Tremendous efforts have been made over the past few decades to discover novel cancer biomarkers for use in clinical practice. However, a striking discrepancy exists between the effort directed toward biomarker discovery and the number of markers that make it into clinical practice. One of the confounding issues in translating a novel discovery into clinical practice is that quite often the scientists working on biomarker discovery have limited knowledge of the analytical, diagnostic, and regulatory requirements for a clinical assay. This review provides an introduction to such considerations with the aim of generating more extensive discussion for study design, assay performance, and regulatory approval in the process of translating new proteomic biomarkers from discovery into cancer diagnostics. We first describe the analytical requirements for a robust clinical biomarker assay, including concepts of precision, trueness, specificity and analytical interference, and carryover. We next introduce the clinical considerations of diagnostic accuracy, receiver operating characteristic analysis, positive and negative predictive values, and clinical utility. We finish the review by describing components of the FDA approval process for protein-based biomarkers, including classification of biomarker assays as medical devices, analytical and clinical performance requirements, and the approval process workflow. While we recognize that the road from biomarker discovery, validation, and regulatory approval to the translation into the clinical setting could be long and difficult, the reward for patients, clinicians and scientists could be rather significant.

Targeted Proteomics for Multiplexed Verification of Markers of Colorectal Tumorigenesis

“…However, most studies stop short of verifying the candidates in a systematic and reproducible manner, an essential step for translating biomarker discoveries to clinical application (6,8,9,21). Verification, however, is an arduous process, which is made even more difficult by the lack of appropriate tools for identifying and reproducibly quantifying levels of candidate proteins across multiple samples (6,21).…”

“…However, most studies stop short of verifying the candidates in a systematic and reproducible manner, an essential step for translating biomarker discoveries to clinical application (6,8,9,21). Verification, however, is an arduous process, which is made even more difficult by the lack of appropriate tools for identifying and reproducibly quantifying levels of candidate proteins across multiple samples (6,21). Enzyme-linked immunosorbent assays (ELISAs) are still the preferred methods for preclinical verification of candidate biomarkers, but the antibodies used for these assays are characterized by high specificity requirements and elevated production costs, which render them less than ideal for testing large numbers of tumor biomarkers (19,22).…”

Garbage in, garbage out: A critical evaluation of strategies used for validation of immunohistochemical biomarkers

“…Although great efforts have been made in the last decade to discover novel cancer biomarkers for use in clinical practice, a striking number of these efforts fail to make it into the clinic (Fuzery et al., 2013). One of the causes of this failure of translation could be the limited knowledge that scientists working in biomarker discovery have in analytical, diagnostic and regulatory requirements for clinical assays (Fuzery et al., 2013).…”

“…Although great efforts have been made in the last decade to discover novel cancer biomarkers for use in clinical practice, a striking number of these efforts fail to make it into the clinic (Fuzery et al., 2013). One of the causes of this failure of translation could be the limited knowledge that scientists working in biomarker discovery have in analytical, diagnostic and regulatory requirements for clinical assays (Fuzery et al., 2013). Over the last few decades a number of key FDA approved cancer biomarkers have been introduced into the clinic for differential diagnosis of specific tumours, leading to improvement of cancer detection and staging, identification of tumour subclasses, prediction of outcome after treatment, and selection of patients for different treatment options.…”

“…Over the last few decades a number of key FDA approved cancer biomarkers have been introduced into the clinic for differential diagnosis of specific tumours, leading to improvement of cancer detection and staging, identification of tumour subclasses, prediction of outcome after treatment, and selection of patients for different treatment options. However, of these approved biomarkers, only five are individual IHC‐based biomarkers (Fuzery et al., 2013) (Table 1). The earliest FDA approved biomarkers for IHC application were assays to detect the estrogen receptor (ER), progesterone receptor (PR) and HER‐2/neu (c‐erbB‐2).…”