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Gene Logic, FDA Fall Behind in Effort To Standardize Toxicogenomics Data

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A collaboration between Gene Logic and the US Food and Drug Administration designed to standardize certain gene-expression data has fallen behind schedule, but the project’s lead investigator at the FDA said the agency is still committed to the effort, Pharmacogenomics Reporter has learned.

The delay, which has set the research back at least several months, likely means that drug makers eager for FDA guidance about standardized ways to submit toxicogenomic data — a linchpin of pharmacogenomics research — will have to wait a little longer.

“I guess we’re a little off schedule,” said Karol Thomson, the lead Center for Drug Evaluation and Research scientist on the project. “It’s probably gone a little slower than we originally projected, but [we’re] still actively engaged in the project. We’re not really worried about it.”

Gene Logic also conceded that the program is off schedule, and said it shared responsibility for the delay with the FDA. “I think it has slowed down a little, but I think it has slowed down for a good reason,” said Donna Mendrick, vice president of toxicogenomics at Gene Logic and project leader at the company. She said Gene Logic and the FDA had never agreed to “develop a consensus for data mining” — an important factor in the program — until after they began the collaboration last June.

Last August, when the partners announced their plan, Thomson said her team would be able to review Gene Logic’s toxicogenomics data and determine by June whether the results “will be of value to propose as a voluntary part of a genomics submission.” Considering that Gene Logic submitted its initial dataset last week, and that the FDA has only recently begun analyzing the data, Thomson said the research has fallen behind by at least several months.

The delay came to light after Gene Logic last week said it had given the FDA a gene-expression dataset derived from its collection of vehicle-treated rat liver samples. These data, which were handed off to the agency as part of the collaboration, are part of Gene Logic’s GeneExpress System, and “correspond to specific FDA-selected gene fragments that are common to multiple microarray platforms,” the company said.

Gene Logic went on to say that researchers and biostatisticians at CDER “will mine, evaluate, and utilize portions of the data as part of an effort to compile a list of invariant genes … across multiple microarray platforms, thereby establishing a set of historical controls data.” According to the partners, the goal is to “identify benchmark genes against which to evaluate genomic data quality.”

By standardizing these data, the FDA hopes to encourage pharmaceutical companies to voluntarily submit microarray-based toxicogenomic data as part of certain pre-clinical trials. Thomson said the data will eventually be presented to Janet Woodcock, the acting deputy commissioner for operations, who may include them in her pharmacogenomics draft guidance [see 11/6/03 PGx Reporter].

Over the next several months, the Thomson’s team will review Gene Logic’s data to try and identify “quality” endogenous markers. “It’s going to take a lot of validation from here on, and looking at other sources of control data to be able to use those in a comfortable way,” Thomson told Pharmacogenomics Reporter last week. “This is a kind of starting point.”

Data Dependence

“The main problem that researchers have run into while looking at pharmacogenomics and toxicogenomics data over the past several years has been that there are a lot of variables that cause the data to be different,” Doug Dolginow, senior vice president of pharmacogenomics at Gene Logic, said last August.

The FDA has enlisted Gene Logic in an effort to meet this “problem” head-on by identifying the variables. “What the FDA is trying to understand is, on a biological basis, can you identify certain genes that are always at a certain rank order of abundance?” Mendrick said last week. “They want to develop a list of genes in each of the organ types we’re talking about” — liver, brain, kidneys, and testes — “as well as genes that show similar abundance patterns between these organs.”

To that end, the FDA will compare gene-expression data found in Gene Logic’s GeneExpress library of control and vehicle-treated tissue samples against genes in microarrays manufactured by Affymetrix, Agilent, and GE Healthcare. The goal is to locate genes that are common across each of the platforms, and to identify the expression of these genes in the GeneExpress library.

When this program was announced last year, the FDA said it would compare gene-expression data found in GeneExpress against genes in microarrays manufactured by Affymetrix, Agilent, and Amersham Biosciences, which has since been acquired by General Electric and folded in a new division called GE Healthcare. At the time, the object was to locate genes common across each of the platforms, and to identify the expression of these genes in the GeneExpress library. To date, the FDA has only reviewed genes on Affy’s GeneChip because Affy’s data is what Gene Logic has in its database, and because the other two companies have not yet provided their data.

“We need these other platforms to contribute their control animal data to … develop the list,” said Thomson, adding that the FDA would get these data not from the actual companies — Agilent and GE — but from firms that use their platforms. She said certain companies, which she declined to name, have “already expressed interest in sharing that data.”

“We hope to get that part started during the summer,” she said.

The Gene Logic/Affy portion of the program “is really like a test case [and] we have to make sure it works,” Thomson said. “And we still don’t really know that.”

She said her group at the FDA has begun reviewing Gene Logic’s data — she was looking at the dataset when she was interviewed for this article last Friday — and said “I think we’re definitely going to be able to come up with a straw-man list of genes that we can further test. There’s definitely some internal consistency.”

Gene Logic and the FDA said they will initially focus on genes linked to organs associated with toxicity, such as the liver, brain, kidneys, and testes. By looking across these samples, the partners hope to rank genes by their expression frequency across each of the three microarray platforms. The dataset provided to the FDA last week was part of the liver studies being conducted by Gene Logic. Mendrick said studies of the three remaining organs will be conducted and submitted after the partners “develop a consensus approach on data mining.” She said Gene Logic and the FDA will meet next week to discuss the status of this consensus.

What Pharmas Want

The issue of voluntary submission of microarray-based toxicology data has been a thorn in the side of many drug makers, and many say it is a key element in the FDA’s broader strategy of infusing pharmacogenomics technologies into drug trials. Some large drug makers, in fact, said they refuse to voluntarily submit gene expression-based toxicology data without clear guidance from the FDA, fearing that the data might inadvertently hurt their approval chances [see 3/4/04 PGx Reporter].

The upshot for pharma companies contemplating results from the Gene Logic-FDA collaboration is straightforward: Drug makers performing toxicity studies that want to submit toxicogenomic data to the FDA would be able to run their control samples across their own microarray, and show that the invariant genes are represented at the right rank order and at the right level when compared against the study set provided by the three platform companies.

“That would be an indicator that the quality of the data being submitted is consistent with the quality of the data been submitted by other studies,” Dolginow explained last year.

Thomson said she expects the validation process to last about a year. She said the FDA plans to publish a proposed gene list as the genes come into focus, giving pharma companies a chance to compare their data with Gene Logic’s.

Thompson said her group will send the standards to “a lot” of disparate labs that will investigate how it stands up across different lesser-known platforms. She said these participants include drug makers, academic labs, bioinformaticists, contract research organizations, members of the National Life Sciences Institute, and a variety of gene-expression tool vendors. She declined to name the labs but confirmed that Affy, Iconix, Rosetta, GE Healthcare, and Agilent are among them.

She said the program has generated “a lot of interest” among other microarray companies, who believe that their platforms may also contribute to the pharmacogenomics milestone of standardized gene-expression and toxicology data. “We hope to expand [the project] to other platforms,” Thomson said last week. “We first have to get this to a certain stage with Gene Logic.”

— KL

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