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Deeming Arrays Not Ready for Prime Time, Some Dx Shops Go for Older Technologies

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SAN FRANCISCO -- Even though microarray technology is consistently used in R&D by companies developing molecular diagnostics, some shops planning to submit tests for US Food and Drug Administration approval are opting to migrate their tests from arrays to older technologies such as RT-PCR and immunohistochemistry assays.

Furthermore, many diagnostic shops view microarrays as excellent discovery tools, but believe they are too risky to sell into the molecular diagnostics market.

Randy Scott, CEO of Genomic Health, which has been selling its OncoType Dx quantitative RT-PCR test for breast cancer recurrence since late last year, said his firm went with RT-PCR rather than arrays because RT-PCR was more widely established in the field of molecular diagnostics.

"Rather than going down the route of using microarrays, we decided to work with an older technology," Scott told attendees at Cambridge Healthtech Institute's Molecular Medicine Tri-Conference, held here last week.

Scott told BioArray News in a follow-up interview that Genomic Health had used arrays in its discovery process, but that the decision was made to switch to RT-PCR -- in this case, using technology from Roche and Applied Biosystems -- for OncoType Dx for a number of reasons.


"Rather than going down the route of using microarrays, we decided to work with an older technology."

"[One] reason we use RT-PCR is that arrays today don't work well with RNA samples from fixed paraffin-embedded samples," Scott said. He added that Genomic Health believes that RT-PCR provides "better sensitivity [and] specificity on an individual gene-by-gene basis," and that, even though OncoType examines the expression of 21 different genes in a sample, RT-PCR is more useful than arrays in diagnostic applications.

"Arrays are a nice screening technology for research, but we see RT-PCR as a more powerful platform for diagnostics," Scott said.

Scott's sentiments were echoed by Doug Ross, chief scientific officer at Applied Genomics, who also spoke at the Tri-Conference. According to Ross, AGI is planning to eventually submit five individual immunohistochemistry assays to the FDA for classifying breast cancer patients into different treatment categories.

Ross said that Applied Genomics developed the assays using microarray data, but had decided to go with IHC technology because the company felt that it was ultimately easier to distribute and more familiar in the market the company is attempting to serve.

Similarly, TriPath Imaging's Chief Scientific Officer Douglas Malinowksi told conference attendees that his company decided to forego array technology in its oncology screening tests because it wanted to deliver a product to market with which clinicians would be familiar.

"We wanted to develop an assay that meets clinical needs that works with the technology [clinicians] have today," Malinowski said.

Jorge Leon, president of Leomics consulting and acting chief scientific officer at Orion Genomics, said that, despite the FDA clearance of some array-based diagnostics like Roche's AmpliChip, he doubts whether arrays will ever be treated as a serious diagnostic platform.

"I think arrays are fundamentally a discovery tool or development tool to focus the markers to the minimum possible," Leon told BioArray News at the conference last week. "We need arrays to do discovery; we need arrays to do development. But right now I don't think arrays are ready for prime time -- for diagnostics or a CLIA configuration," Leon said.

According to Leon, Orion is currently working on RT-PCR-based screening assays for ovarian and breast cancers. The St. Louis-based firm has its own proprietary discovery array called MethylScope, but Leon said that it is used strictly in-house. He also said that large testing companies like LabCorp and Quest Diagnostics were probably more likely to choose an RT-PCR test over a test on a microarray platform.

LabCorp has been selling Roche's array-based AmpliChip since last year, but these labs are "much more comfortable with RT-PCR right now," Leon said. "I am not saying that they have closed their doors to arrays, but certainly arrays have not yet demonstrated the applicability with the amount of data that RT-PCR has," he said. Before founding Leomics in 2003, Leon served as vice president of applied genomics for Quest Diagnostics.

Steve Anderson, vice president and chief scientific officer at LabCorp, told BioArray News that LabCorp is more familiar with RT-PCR, but that the decision to adopt a test "depends on the application and has a number of factors."

"If it's a smaller number of genes, then RT-PCR is more appropriate," Anderson said. "If the test has a larger number of analytes, then it may be better on an array."

An Affy Anomoly?

But not all diagnostic developers are playing it safe with RT-PCR. Potential applications are currently being developed by Affymetrix partners BioMerieux, Veridex, PathWork Informatics, and Almac Diagnostics to run on Affy's platform.

"There are exceptions," said Leon. "The CYP450 [AmpliChip] from Roche works well. I think that there are going to be some arrays that Affy is developing for other applications that would work. There are also arrays that are being developed by other companies that are low-density arrays that would work," Leon said.

"Arrays have a great future for genotyping, particularly screening mutations," said Genomic Health's Scott. "I do think they are very valuable clinically for genotyping." Genomic Health uses gene expression, not SNP genotyping, to diagnose patients, Scott said.

Betting on demand for array-based testing, Affy recently created a new division, Affymetrix Clinical Laboratories (see BAN 2/7/2006).

Cynthia French, the newly appointed director of Affy's Clinical Labs division, told BioArray News last week that the unit will most likely offer current Affymetrix commercial catalogue and custom assays such as gene expression-monitoring assays, DNA-analysis assays, and chromosomal copy number assays. French said that more details on Affy Clinical Labs activities would emerge this spring, and that the facility in West Sacramento, Calif., adjacent to the company's current manufacturing facilities, is scheduled to open July 1.

Other array firms poking their noses into the diagnostic space include Osmetech, which won 510(k) clearance from the FDA last month to run a cystic fibrosis assay on its eSensor Detection System, as well as CombiMatrix, which founded its CombiMatrix Molecular Diagnostics subsidiary last May (see BAN 1/24/2006, BAN 5/11/2005).

CombiMatrix has also announced plans to offer influenza testing services through its subsidiary, and is working on a melanoma diagnostic with researchers at the University of California, Los Angeles. (see BAN 11/2/2005, BAN 12/14/2005).

In addition to these array-related Dx projects, Heiner Dreismann, CEO of Roche Molecular, told attendees here last week that Roche is making progress in developing a leukemia diagnostic to follow up on the release of the AmpliChip.

Roche did not respond to e-mails and phone calls seeking comment on the AmpliChip by press time.

As far as other companies developing array-based diagnostics, Glenda Anderson, CEO of PathWork Informatics, told BioArray News in November 2005 that PathWork had decided to proceed with an array platform for a test for tumors of unknown origin, due to the high number of genes the test required (see BAN 11/16/2005).

"It requires a large number of genes to do well, so it really lends itself to a microarray platform," she said.

A representative for Veridex, which is developing diagnostic assays on the Affymetrix platform, told BioArray News during the conference that Veridex has two assays, one for breast cancer and one for colorectal cancer, and that it eventually plans to submit the assays to the FDA for clearance.

However, the Veridex spokesperson said it may take several years to submit the array-based test, as the company is first trying to get an RT-PCR assay called GeneSearch cleared by the agency.

Yet even if the proliferation of array diagnostics can familiarize clinicians with the relatively new technology, Orion's Leon said that arrays still face an uphill battle when compared to RT-PCR: cost.

An array-based test for cancer "cannot cost more than $500," Leon said. "It cannot cost more. It has to be the equivalent of imaging or the equivalent of a minimally invasive test," he said.

As BioArray News' sister publication Pharmacogenomics Reporter reported in December, LabCorp currently charges $1,360 for a typical AmpliChip test per patient sample.

He also said that the industry would have to deal with reimbursement issues as they penetrate the market. "How much do you pay for an array? Nobody knows. And that is one thing that needs to be solved," Leon said.

— Justin Petrone ([email protected])