New Biomarker to Guide Antibiotic Prescription Decisions: Procalcitonin as Barometer of Infection

In the early online issue of September 22^nd of BMC Medicine (link; provisional paper), Philip Schuetz, Werner Albrich, and Beat Mueller review the present and the future promises of procalcitonin (PCT) as a potential generalized biomarker of infection and potential guide to antibiotic prescription in clinical settings.  As the authors point out, the field currently lacks reliable biomarkers of bacterial infection that can be assessed rapidly from easily accessible samples, resulting in suboptimal management of antibiotics administration.  Therefore, beyond the direct benefit of expediting the diagnosis of bacterial infection, PCT could be used to develop an antibiotic prescription algorithm that would potentially optimize antibiotics usage by eliminating their use in circumstances where they are not needed (fig. 1)

While strong evidences from randomized clinical trials support the use of PCT to guide the prescription of antibiotics for the treatment of lower respiratory tract infections (upper respiratory tract infection, pneumonia, COPD exacerbation, and acute bronchitis), and severe sepsis, more work needs to be done to establish PCT as a clinically relevant tool in the management of infections such as bacteremia, abdominal infection, neutropenia, and postoperative fever.

Thierry Sornasse for Integrated Biomarker Strategy

Biomarker Qualification Consortia: The ADNI Success Story

Over the past decade, the rate of biomarker discovery has accelerated considerably thanks to the development of new methods such as advanced mass spectrometry techniques.  However, the effort dedicated to the qualification of these newly discovered biomarkers (i.e. the process of confirming the predictive value of a biomarker candidate) has remained insufficient.  Disease biomarker qualification most often requires access to a large population of patients representing the full spectrum of disease stages encountered in every day medical practice.  While a few large organizations can muster the resources necessary to assemble such large patient samples, most biomarker qualification efforts require close collaboration between multiple stakeholders.  Similarly, the qualification of safety biomarkers, intended to be broadly applicable across the industry, presents an investment that few companies are willing to take on their own.  Hence, the gap in biomarker qualification can only be eliminated by promoting the collaboration between all drug development stakeholders.

The past ten years have seen the emergence of a series of non-competitive biomarker qualification efforts driven by consortia of academic, industrial, and non-profit organizations (see table 1 for examples)

Name	Main Sponsor	Focus
Biomarker Consortium	Foundation for the National Institute of Health	Cancer Immunity/Inflammation Metabolic Disorders Neurosciences
Predictive Safety Testing Consortium	Critical Path Institute	Predictive drug safety
Alzheimer’s Disease Neuroimaging Initiatitive	National Institute on Aging	Alzheimer’s Disease
Parkinson Progression Marker Initiative	Michael J. Fox Foundation	Parkinson’s Disease

Table 1

Among these examples, one effort stands out due its ground-breaking impact on the field of biomarker development.  The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a vast longitudinal study focused on monitoring the evolution of Alzheimer’s disease (AD) patients, Mild Cognitive Impairment (MCI; a common precursor of AD) patients, and age-matched healthy volunteers (see also the article in Lancet of March 2011 about ADNI).  Since its inception in 2004, ADNI enrolled 200 AD patients, 400 MCI patients, and 200 age-matched controls who were followed every 6 months for 2, 4, and 4 years, respectively.  At the onset of the project, the consortium established a set of standardized procedures aimed at monitoring cognition, cerebrospinal fluid (CSF) biomarkers, and brain structure biomarkers.  These standardized procedures have been used uniformly across 57 North-American clinical sites who committed to sharing their results through a common data repository (see also the public presentation by Dr. Michael W. Weiner for more detail about the science).  Over the years, these procedures have been adopted by additional ADNI participants in Europe, Japan, Australia, China, and Korea.  

This treasure trove of inter-connected standardized data has resulted in an amazing number of publications (212 accepted publications as of August 2011; source ADNI.org) which have already have fundamental impact in the field of AD science.  For example, the National Institute on Aging and the Alzheimer’s Association proposed in July 2010 to amend the official diagnosis criteria for AD to reflect the advances in biomarkers of AD.  Also, the work on CSF biomarkers has revealed that the level of amyloid-beta fragment Ab42 is a reliable predictor of conversion from MCI to AD.  Finally, the work on brain structure biomarkers using standardized MRI has demonstrated that changes in key structures of the brain (cortex, ventricles, hippocampus) are much more sensitive than conventional cognitive assessment tools, potentially enabling clinical studies requiring significantly fewer patients.  In 2010, ADNI received additional funding to extend the monitoring of patients already enrolled in the program and to enroll additional volunteers to explore more advanced biomarkers such as high resolution MRI, functional imaging, and amyloid aggregate imaging.

Beyond these remarkable scientific achievements, ADNI has demonstrated beyond doubt that academia, the industry, and non-profit organizations can collaborate efficiently in a non-competitive environment.  Convincing all stakeholders that sharing their data with each other was not an easy task but this proved to be one of the key elements to the success of this project.

Biomarker Development: validate and qualify (or is it the other way around)

Biomarker development is fundamentally the parallel processes of developing a technically reliable biomarker measurement method and establishing the significance of a biomarker relationship with a specific biological process. The former process is generally referred to as "validation" or more precisely "method validation" while the FDA suggested that the latter be referred to as "qualification".

The problem is that the term "qualification" means something quite different to my PK bioanalytical colleagues. Indeed, it refers to the process of testing the performance of an assay under stringent conditions to record the its variability without setting "pass/fail" criteria as it would be done for a validation process. 


To make matter worse, the FDA itself seems to struggle with the term"qualification" in its proposed three stages of biomarker qualification:

• Exploratory: fit for internal decision only
• Assay development à assay qualification
• Limited or no clinical data
• Probable valid: fit for regulatory decision applied to early clinical development
• Well established assay performance
• Initial significance of clinical test result
• Known valid: fit for regulatory decision applied to late clinical development
• Measurement independently reproduced
• Agreement by scientific community.

In other words, when a biomarker is qualified it becomes valid. Confusing isn't it?

In my mind, the only practical way to resolve this semantic issue is to simply be more precise by specifying whether we are referring to a process related to a method:

• Method qualification
• Method validation

Or, referring to a process related to the scientific relevance of a biomarker:

• Scientific qualification

Thierry Sornasse for Integrated Biomarker Strategy

Cancer biomarkers: not such a great model to follow

The development and use of biomarkers in the field of cancer is well ahead of any other indications. In particular, several cancer biomarkers have been co-developed as companion diagnostics associated with specific drugs:

• Her2 expression test (e.g. HercepTest) supporting Herceptin (trastuzumab) prescription for breast cancer
• BCR-Abl / Philedelphia chromosome supporting Gleevec (imatinib) prescription for CML
• BRAF V600E expression supporting PLX4032 (vemurafenib) administration for melanoma (not approved yet)

While these companion diagnostics represent a major progress in the area of personalized medicine, all three cases provide a relatively poor model for the development of advanced biomarkers / companion diagnostics in other diseases. Indeed, for these three biomarkers, there is a direct connection between the biomarker: presence of target and the biological process of interest: sensitivity to the drug. Unfortunately, in many other diseases, this direct relationship does not exist or at least has remained elusive until now. Thus, the experience from the cancer biomarker field teach us very little about the complex process of biomarker biological qualification (i.e. the process of establishing the significance of a biomarker relationship to the biological process of interest). In my mind, the process of biomarker qualification is, and will be for the foreseeable future, the most  important aspect of biomarker development for which the lessons learned from the cancer biomarker field are not a great model to follow.


Thierry Sornasse for Integrated Biomarker Strategy