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FDA Gates Swinging Open To Admit Standardized Gene Expression Data

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The genomic-data firewall at the FDA is beginning to breach. firewall at the FDA is beginning to breach.

“I am very positive, I think the FDA will use this data if it is guided correctly,” said Andrew Brooks, an assistant professor in the department of environmental medicine at the University of Rochester, and one of the 14 members of the pharmacology and toxicology subcommittee of the FDA that held its first meeting last week in Rockville, Md.

He said the agency is seeking expertise from academia, the microarray industry, and drug sponsors: “They are welcoming participation in the process and now the ball is in their court.”

Brooks and four other outside committee members joined nine FDA participants in a one-day meeting witnessed by a gallery of as many as 50 people to consider issues surrounding the submission of microarray-based data in the agency’s drug approval process. Currently, such data can be submitted with an Investigational New Drug application but rarely is, as there is no institutional framework of knowledge, or policy guidance for how the agency can use this information, and the pharmaceutical industry has thus far been averse to risking potentially negative regulatory consequences by sharing data in such an environment.

The subcommittee will create recommendations to hand up to the advisory committee for pharmaceutical science, which then will craft the guidance documents that will go through a comment period and industry workshops before being finalized to provide a framework for industry to follow.

The benefits may include: improved candidate drug selection; new sets of biomarkers for toxic response in animals and humans, minimizing the need for animal studies; improved predictability for drug responders and side effects; and a rationalization for drug dosing based on a genetic substrate.

While Janet Woodcock, director of the agency’s Center for Drug Evaluation and Research, said last week that the agency would have a draft guidance prepared by August, Brooks said that might be an aggressive deadline. What is more likely is that by August, there will be rough ideas for guidelines that could be wrapped up within six months, he said.

For this committee meeting, there were no votable items on an agenda that included presentations from representatives of Agilent Technologies, Iconix Pharmaceuticals, Pfizer, Rosetta Inpharmatics, and the Institute for Genomic Research.

Brooks said that the speakers were able to convince the agency of the wisdom of collecting genomic data digitally, via electronic submission, instead of reams of paper-based submissions.

“They heard from the community how they would have to be prepared and what would they have to do,” Brooks said. Atop the list is the creation of a database for storing that information. The agency is involved in a pilot project with Schering-Plough and the Affymetrix platform services provider Expression Analysis of Durham, NC, on a mock submission of microarray data. An initial submission is expected in July with a full mock submission coming in October.

“With [a database in place], the agency will start to expand their understanding of what the data provides and, across trials and applications, what high-throughput gene expression profiling is telling,” said Brooks. “The committee convinced them that it needs to be electronic submission and that the sponsors know that the data will be used to benefit them, not to penalize them. And, once [the FDA] has that microarray data, as well as clinical data, there will be a synergistic effect on judging compounds in the future. There are a lot of pieces that will have to come together.”

One of those pieces will clearly be standardization within labs, and across platforms.

The guidance decisions that eventually issue from the agency will impact on the microarray industry, perhaps even determining the financial future of some toolmakers, and that of a technology that has already provided great insight into the mechanics of gene expression and the effects of disease, and medication — despite being constructed on a platform that is, by stringent clinical standards, very early-stage.

Two microarray standards are emerging from the National Institute of Standards and Technology, a Commerce Department agency that has been spearheading a drive to create gene expression standards, according to Krishna Ghosh, senior director for strategic initiatives and molecular medicine of Agilent Technologies bioresearch solutions unit, and the co-chairman of the NIST project.

After two NIST-sponsored meetings earlier this year with industry, suggested standards are emerging on RNA and microarray/scanner fluorescence in addition to the foundational MIAME standards for database submission.

Ghosh addressed the committee, on behalf of NIST, seeking financial assistance and a commitment for a meeting in July with the FDA to get the NIST standards endorsed.

“We want to get these two groups joining hands,” she told BioArray News.

A collaboration between the agencies, said Brooks, would be a “huge step forward.”

“That would cut a year right off the top of however long the [FDA’s] process is going to take,” he said.

In terms of databases, a draft will be considered at the September MAGE meeting that would extend existing MIAME standards to the realm of toxicology.

The NIST working group on RNA is considering proposals for two RNA standards, one for within laboratories, and an external standard. The internal standard would be a pool of standard sequences agreed on by all commercial array manufacturers that would also be available to home-brew users. It would provide an internal measure of the quality of any array experiment with respect to sensitivity, dynamic range, and specificity. The external standard would be a complex pool of highly characterized RNA targets to be used as an external reference for any RT-PCR or array-based methods.

Ghosh said once standards are created, an outside company would do the manufacturing.

For scanners, NIST would develop an “artifact” to standardize measurements of uniformity and signal/noise; and measure a scanner’s limits of detection. It would also identify appropriate fluorescent materials based on Cy3 and Cy5 dyes. A committee, including a dozen scanner manufacturers such as Affymetrix, Agilent, Axon, PerkinElmer, BioRad, Arrayit, and others, has created a set of specifications for a standard microarray slide that would be coated uniformly and include two instruments — one created for the middle of the dynamic range, and one for very dim signals. Glass flatness would not exceed plus or minus 10 microns, on a preferred substrate of glass. The slides would be 1x3 inches and fitted to other users who do not follow that format. The microarray/scanner fluorescence standards group is expected to select a fluorescent material for the artifact from a choice of organic photo stable fluorescent dyes, silica doped with metal oxides, or quantum dots/nanocrystals.

Members of the FDA subcommittee include: Meryl Karol, associate dean of the Graduate School of Public Health, University of Pittsburgh; Andrew Brooks, assistant professor of environmental medicine, University of Rochester; Jay Goodman, professor of pharmacology and toxicology, Michigan State University; Jerry Hardisty, a veterinarian and a toxicologist with Experimental Pathology Laboratories of Durham, NC; Michael Waters, assistant director for database development, National Center for Toxicogenomics, NIEHS; and Tim Zacharewski, professor of biochemistry and molecular biology, Michigan State University.

— MOK

 

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