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.