Metabolomics data and the biomarker qualification process

Abstract

Since its initial applications in healthcare research over a decade ago, metabolomics has matured into a technology that can now reliably detect and quantify hundreds of metabolites in biofluids and tissue samples. With substantial improvements in analytical capabilities in recent years, metabolomics now has the potential to provide sensitive and specific biomarkers of health and disease status, drug toxicity and therapeutic efficacy. Although many of the clinical biomarkers currently in use are metabolites such as glucose, cholesterol, and creatinine, few, if any, new metabolites (or panel of metabolites) derived from metabolomic analyses have been submitted to the FDA as biomarker candidates. Under a recent FDA draft Guidance for Industry from the Center for Drug Evaluation and Research (CDER), biomarkers discovered using metabolomics, like those derived from genetic, transcriptomic, and proteomic studies, may be submitted to CDER for consideration as new drug development tools and entered into a formal biomarker qualification process. The qualification process begins with a letter of intent from the submitter, followed by discussions with FDA and then the submission of data supporting the performance of the biomarker within a specific context of use. CDER forms a Biomarker Qualification Review Team at the start of the interactive process to advise the biomarker developer on the type of information important to support the proposed context of use, and review the data that evaluates the biomarker for the proposed context of use when the biomarker development appears complete and the full supporting data are submitted. Once qualified, a biomarker can be used in drug development within the qualified context of use without requesting additional regulatory review concerning its suitability.

A combined chemometric and quantitative NMR analysis of HIV/AIDS serum discloses metabolic alterations associated with disease status

“…14 Definitive monitoring of both HIV disease progression and response to treatment currently relies on CD4 count, viral load, protein and other macromolecular markers. 34,35 Metabonomics techniques show promise for HIV/AIDS management 15 and is currently being used to identify and quantify potential biomarkers associated with infection, response to treatment or disease progression; 36 however, the independent association between metabolites and clinical outcome still needs to be validated. The implications of our study suggest that metabonomics may also be useful for identifying the metabolic origin of comorbidities and the impact of therapies designed to treat them.…”

Comparison of accuracy and precision between multipoint calibration, single point calibration, and relative quantification for targeted metabolomic analysis

“…Seventy µL of 300 mM FA in 50% ACN were added for medium acidification [37]. These derivatization steps, with the use of the appropriate isotopic form of DNS-Cl, are common between 12 C2-DNSanalytes, 13 C2-DNS-ISs and 12 C2/ 13 C2-urine samples.…”

“…The lack of well-established analytical frameworks for absolute quantification is a bottleneck in the biomarker qualification process [9][10][11][12][13]. Contrary to method validation for xenobiotics, available guidelines [14,15] are not well suited to address all challenges with endogenous metabolite quantification.…”

Development of a validated LC- MS/MS method for the quantification of 19 endogenous asthma/COPD potential urinary biomarkers

“…Applied metabolomics in medicine aims to link different biochemical pathways with disease diagnosis, severity, and therapeutic response [11,12]. It has demonstrated promising outcomes in biomarker discovery and in personalized medicine [11,13,14]. Among the various biological fluids, urine is ideal for metabolomic analysis.…”