By John Russell

May 12, 2008 | Speaking at Cambridge Healthtech Institute's annual Molecular Medicine Tri-Conference*, Frederico Goodsaid of FDA delivered one of the clearest explanations yet of agency thinking on its evolving Voluntary Exploratory Data Submissions (VXDS) program. Also, he emphasized the change from "Genomic" or VGDS to "Exploratory" or VXDS in the program title - FDA is keenly aware the variety of biomarker data types is expanding quickly.

Since its inception in 2005, the VXDS program has sparked both hope and worry. On the one hand, sponsors hope to use biomarker data for a wide variety of purposes (surrogate endpoints, responder versus non-responder identification, etc.) but also fear how such voluntary data might be used against them when filing INDs or NDAs. Goodsaid, who is the associate director for operations in genomics, Office of Clinical Pharmacology, Office of Translational Science, Center for Drug Evaluation and Research, reviewed FDA expectations.

"In a voluntary exploratory data submission meeting, the data is received from a company and it's tracked and archived by the FDA, and the Interdisciplinary Pharmacogenomic Review Group goes over that data and has a face-to-face meeting with the sponsor that has submitted that information. That face-to-face meeting includes a review of the data that was received... We have a chance to first of all learn from the sponsors about the different kinds of platforms that are being used to generate the data and platforms that are being used to analyze the data and to interpret it. [It] also allows us to show the sponsors the capability that we have in doing this kind of analysis," he said.

One area in which both industry and FDA have learned a great deal is in microarray processing techniques such as RNA isolation, according to Goodsaid, while far less consensus has emerged around analysis approaches used to identify lists of differentially expressed genes. Yet once you have such a list, turning that into biological knowledge is at least as important, and still challenging.

"How many pathways are affected? What types of pathways are affected? What is the preferred mechanism of action and toxicity of the gene expression changes? What is the tissue specificity of the pathways and the gene function in relation to biological processes? How does the magnitude and/or pattern of those perturbations compare to the treatments of reference compounds?" asked Goodsaid.

FDA is hoping the new generation of pathway tools can answer these questions. No single tool can do so now, and FDA intends to use many of the open source and commercial tools available. "Ultimately, we need to come up with a consensus interpretation that is based on where all these databases lead you," he said.

He walked through a case history of how pathway tools might be used in an instance where two compounds are structurally related, but one binds to a target receptor and the other does not, and a sponsor submits differential gene expression data for both. He walked though how FDA might use pathway tools to understand what's going on. He also pointed out some of the shortcomings of existing tools. It's probably worthwhile to read Goodsaid's full remarks, which can be accessed at our website.

FDA clearly believes pathway tools can become an important part of the regulatory review process and Goodsaid noted this as the driving rationale behind the agency's recent CRADA with Ingenuity Systems. Initial goals to adapt Ingenuity's platform to support the VXDS program, deploy IPA and provide training, and build an API for integration with NCTR's ArrayTrack application are completed.

Now the two are working on building an IPA-based solution for regulatory review of biomarker, pharmacogenomic, and toxicogenomic data. Content is being expanded as well. "The idea is to expand the content of the tool to make sure it covers the drug, chemical, and biomarker universe that we're interested in," indicated Goodsaid.

*CHI's Molecular Medicine Tri-Conference, San Francisco, March 25-28.

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This article appeared in Bio-IT World Magazine. 
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