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Predictive Safety Testing Consortium Submits First Biomarkers to FDA for Qualification

ATLANTA (GenomeWeb News) – The Predictive Safety Testing Consortium, a collaboration of industry, academia, and government research groups with the goal of developing safety biomarkers for preclinical studies, has submitted its first biomarker “qualification package” for US Food and Drug Administration review, according to several PSTC participants who spoke at the Drug Industry Association annual meeting, held here this week.
The PSTC submitted the biomarkers to the FDA on June 15, marking the first such submission for the public-private consortium, which kicked off last March and now counts 16 pharmaceutical companies among its participants.
In addition to nephrotoxicity, the PSTC also has working groups developing biomarkers for hepatotoxicity, vascular injury, and non-genotoxic carcinogenicity.
The submission also marks something of a milestone for the FDA, which has developed a “pilot” biomarker-qualification process, but has yet to “test” it, Federico Goodsaid, senior staff scientist in the genomics group at FDA’s Office of Clinical Pharmacology, said in a talk at the meeting.
A paper describing the FDA’s proposed qualification process was published in the AAPS Journal in March.
On Friday, the PSTC’s nephrotoxicity working group submitted information on 23 proposed biomarkers that are correlated with early kidney damage and could serve as alternatives to the current standards in preclinical animal testing, which include blood urea nitrogen, or BUN, and serum creatinine levels.
Frank Sistare, executive director of safety assessment at Merck, explained during a talk at the DIA meeting on Tuesday that there is strong demand among drugmakers for biomarkers that can indicate kidney injury much sooner than current markers, which may not generate a signal until more than half the kidney cells are damaged.
Goodsaid noted during the meeting that biomarker qualification was the “top goal” of the FDA’s Critical Path Opportunities List, released last March, and noted that the PSTC activities are “vital” for improving the FDA’s understanding of biomarkers.
Goodsaid explained that “qualified” biomarkers must be shown to reduce time, costs, or adverse events in drug development, and must also be shown to work better than current biomarkers. In addition, he said, they must be qualified fairly narrowly “in the mechanistic context in which they are to be applied.”
He noted that the FDA has a particular interest to establish a procedure for qualifying safety biomarkers, which differ from efficacy biomarkers in that they must be applicable across many drugs.
Efficacy biomarkers, he noted, fall under the agency’s Drug-Diagnostic Co-Development Concept Paper, which is expected to be released as a draft guidance later this year, but the agency has not provided any recommendations to date on safety biomarkers.
The FDA plans to hold a face-to-face review of the nephrotoxicity biomarker data in July.
Merck’s Sistare said that several of the 23 proposed biomarkers submitted by the nephrotoxicity working group, including kidney injury molecule-1, clusterin, and trefoil factor 3, outperformed BUN and serum creatinine in internal experiments at Merck and Novartis. He added that “a panel of biomarkers” may ultimately be necessary to account for variations in time course and across different species.   
William Mattes, director of toxicology at the non-profit Critical Path Institute, which is coordinating the PSTC, noted that even though the focus of the project is currently on preclinical biomarkers, the “long-term goal” of the consortium is to move these markers into the clinical setting.
In a talk at DIA on Wednesday, Mattes said that while the nephrotoxicity group is the furthest along, the other PSTC working groups are making progress. So far, the hepatotoxicity group has identified four candidate biomarkers, the carcinogenicity group has selected two mRNA signatures using microarrays that it plans to evaluate further using RT-PCR, and the vascular injury group is still “examining genomic data” with the goal of identifying candidate biomarkers in collaboration with the Vasculitis Clinical Research Consortium, he said.

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