Needles and haystacks

Individual parameters often do not meet the usability criteria that would make them ideal candidate biomarkers but by combining multiple characteristics, it is possible to develop a firm basis for decision-making, both in drug development and the clinic. By Christina Shasserre

Biological markers, or biomarkers, are measurable characteristics used to distinguish normal biological processes from altered ones. In the clinical setting, protein biomarkers present in serum or plasma are often measured using one of the traditional ELISA/EIA-format tests. Results from these routine tests are used in diagnosis, prognosis, determination of disease stage, risk assessments, and in determining whether the subject will respond positively (or negatively) to a planned course of treatment.

Disease-associated biomarkers identified by primary research are typically altered in only a subset of patients, and most are modulated in multiple diseases or biological states and so lack the specificity required for a diagnostic or prognostic test. The poor utility of most single analytes as diagnostic biomarkers has led researchers to seek disease-specific protein distribution 'fingerprints'. Used together, a panel of biomarkers has the power to better discriminate a specific disease and can potentially do so at an earlier stage. 

The application of biomarkers at the point at which it makes a tangible difference to human health and wellbeing has its roots much earlier in the drug and diagnostic development process. Multiplex biomarker assays have key advantages in that they require less sample material, provide time and cost saving through parallel throughput and provide a level of flexibility that fits into many discovery and development workflows.

Drug development

In the research environment, the use of single and multiplex technologies is critical to the success of most projects. The analysis of key biomarkers involved in specific biological pathways or processes gives researchers a rapid and accurate snapshot of the disease state and whether a candidate compound is effective. More specific tests can give rise to mechanistic insights on the mode of action of compounds, as well as the condition itself. 

Safety profiling

Evaluating the safety aspects of lead compounds is an essential step in drug development.

Multiple organ and system toxicities, including hepatotoxicity, cardiotoxicity, immunotoxicity and nephrotoxicity, are evaluated prior to use of a potential therapy in humans. Due to their potential utility, the use of biomarkers in drug safety testing was included in several projects under the auspices of the Critical Path Initiative (CPI), which is the "...FDA's national strategy for driving innovation to modernize the sciences through which FDA regulated products are developed, evaluated, manufactured and used."

One of the first successful projects was the development of a set of biomarkers that can effectively detect whether a compound of interest can cause damage to the kidney or nephrotoxicity. Through collaboration with the public-private Predictive Safety Testing Consortium (PSTC), both the FDA and EMEA have listed seven biomarkers for kidney damage as being useful in determining kidney damage. As more CPI projects come to fruition we can look forward to firmer guidance on biomarker identity and application in safety testing, with the ultimate goal of lowering the cost of drug development and reducing the number of late development/post-marketing failures due to toxicity concerns.

Time brings technological advances, new ideas and shifts in our understanding of biological systems, and so the number and biomarkers that are available will increase. Just as the use and type of biomarkers have progressed from age/height to blood pressure and heart rate and on to molecular biomarkers, we can expect novel parameters to be discovered, validated and ultimately put to effective use. We look forward to the evolution of biomarkers and their increased application. Perhaps they are the vanguard into our personalized medical future - but for that we need more than one haystack.

For more information on CPI please visit www.fda.gov.

Christina Shasserre is General Manager and Head of Global Biosciences at EMD Chemicals, an international organization serving the global market by providing specialty chemicals for pharmaceutical, biotech, cosmetic, automotive, plastics and various industrial applications.