The Predictive Safety Testing Consortium: I feel safer already

In my post of August 11^th (Biomarker Qualification Consortia: The ADNI Success Story) I alluded to the fact that independent, isolated pharmaceutical companies have few incentives to invest the resources necessary to qualify safety biomarkers intended to be broadly applied by the industry: the competitive nature of the drug development industry tends to suppress any effort that would benefit competitors at the expense of the company investing the resources.  Fortunately, the past decade has seen the emergence of non-competitive consortia that have created the necessary conditions for the industry, academia, and non-profit organizations to collaborate efficiently.

The Predictive Safety Testing Consortium (PSTC), led by the non-profit Critical Path Institute (C-Path), is one of these non-competitive partnerships.  Its mission is to bring together pharmaceutical companies to share and validate safety testing methods under the guidance of the US (FDA) and European (EMA) regulatory agencies.  The PSTC has been working on six major toxicology areas: carcinogenicity, kidney, liver, muscle, vascular, and cardiac.  Its major achievement to date is, in my mind, the successful qualification of a set of new biomarkers of acute kidney injury. 

The PSTC recognized a few years ago that the standard blood tests (i.e. blood urea nitrogen [BUN] and serum creatinine) accepted by the regulatory agencies for the monitoring of kidney toxicity lacked sensitivity.  Indeed, these two factors reflect the overall functional performance of the kidney with minimal sensitivity to potential underlying pathologies.  Significant changes in BUN and/or serum creatinine can only be detected after major injuries to the kidney have occurred, at stage where the kidney has lost a substantial part of its filtering capacity.  Therefore, the PSTC decided to identify and qualify new biomarkers of early kidney toxicity that would be sensitive to injuries to specific segment of the nephron (the basic kidney filtering unit), would reflect the degree of toxicity to the nephron, and would be translatable across multiple species including humans.  To do so, the PSTC screened a large array of factors in the urine of test animals that had been exposed to kidney toxicants known to cause injuries to specific segment of the nephron.  Histopathology was used to determine the magnitude and extent of the kidney injuries, factor-specific histological assays were used to identify the origin of selected factors detected in the urine (fig. 1).

Figure 1

In 2008, the PSTC successfully filed the first EMEA-FDA joint biomarker qualification review under VxDS process which resulted in seven novel biomarkers (see table 1) of acute kidney toxicity to be granted the status of qualified biomarkers by the FDA and the EMEA.  Of note, these new biomarkers were deemed qualified for application to nonclinical studies on a voluntary basis but the agencies considered that more exploratory clinical data was necessary to qualify these biomarkers for clinical application.  In 2010, the Japanese Pharmaceuticals and Medical Devices Agency announced the first ever biomarker qualification decision under PMDA's new consultation process on pharmacogenomics/biomarkers for use in Japan.

Biomarker	Segment specificity
KIM-1	Proximal tubules
Albumin	Glomerulus & proximal tubules
Total Protein	Glomerulus
b2-Microglobulin	Glomerulus & proximal tubules
Cystatin C	Glomerulus & proximal tubules
Clusterin	Distal tubules
Trefoil factor-3	Proximal tubules

Table 1

Scientifically, this collection of new biomarkers is expected to provide an early indication of possible kidney toxicity during drug development and to greatly improve the understanding of the mechanisms underlying the toxicity of certain compounds to the kidney.  Beyond the scientific achievements of the PSTC, this effort has also paved the way for similar joint biomarker qualification submission with the major regulatory: a process that is still in its infancy.

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.