The US Food and Drug Administration's recent clearance of the first microarray-based test and instrument platform for in vitro diagnostic uses marked a major advance for microarray makers, and while the industry is optimistic about the prospects of selling products to this field, there are some very real reasons why a dose of caution should counter the exuberance.
A chance to compete in the estimated $20 billion molecular diagnostics market and move beyond traditional gene expression research applications has been a key goal of microarray manufacturers for several years. The FDA -- and previous to that European regulatory authorities -- made that goal attainable with the Dec. 23 clearance of Affymetrix's GeneChip 3000Dx instrument platform and half of Roche Molecular Diagnostics' CYP450 AmpliChip (see BAN 9/8/2004 and BAN 1/5/2005).
The FDA had cleared the 2D6 gene, but didn't approve the 2C19 gene until this week, finally enabling Roche to sell the CYP450 AmpliChip in the US for diagnostic purposes.
Meanwhile, Affymetrix wasted no time granting non-exclusive rights to its GeneChip platform to Johnson & Johnson subsidiary Veridex under the company's "Powered by Affymetrix" program. Only five days after the FDA announcement, Affy said it had given Veridex "long-term and comprehensive" access to its platform to create and market in vitro diagnostics for undisclosed cancers.
The FDA said that the clearance of Affy's and Roche's products could open the door for additional microarray-based IVDs. When the FDA updates its 510(k) database in the near future, it will make available basis-for-approval information from the filing experience of Roche and Affy, and others in the microarray space will know quite a bit more about just what is required for IVD approval.
"There's still a little ambiguity as to what the FDA is really looking for," said Michael McNulty, senior director of molecular diagnostics for Agilent, a microarray competitor to Affymetrix that is currently evaluating the diagnostics space and a potential entry. "I actually look at this very positively, because everybody on both sides of the spectrum -- the IT manufacturers and the CLIA labs, the people running those labs -- are saying `What do we do? We need some guidance,' and we're starting to get that guidance."
He added, "Usually what we see is something developed in the life sciences area that moves to a home-brew application where the few -- maybe there's 50 to 100 home-brew labs in the country -- that have a very high level of expertise really shake up the technology before it heads to the 5,000 hospitals. So, I would like to find out what the FDA's philosophy is around some of these very highly sophisticated home-brew labs."
In regard to the FDA's clearance of Affymetrix's and Roche's products, he said, "I got the impression that was an effort to go directly to the clinical diagnostics market, [and that's] a big difference between [what they're doing] and the esoteric home-brews and the 5,000 hospital labs."
McNulty said that Agilent would work with an established diagnostics player to bring its microarray-based products to that market, although he declined to name any firms the company has talked with. "You have to approach this market in a team fashion. You've seen Affy hook up with Roche. It would be very difficult to enter the healthcare market alone."
He cited cancer and cardiovascular disease as two areas where microarray-based diagnostics are likely to have a significant impact. But he also urged caution over how payors might respond to the new technologies, and said that educating the codemakers at the American Medical Association would be a key to the potential growth of microarray-based diagnostics.
"We're watching how they interpret all the probes and the reimbursement structure. If it's not done correctly, the IVDs won't move," he said.
Lingering questions also were raised by Greg Hines, CEO of Toronto, Canada-based Tm Bioscience, a Roche competitor with CYP450 diagnostics of its own. "Do we need to do just two pivotal trials with X number of patients to show statistical significance?" said Hines in an interview with BioArray News' sister publication Pharmacogenomics Reporter (see PGx Reporter 1/6/2005). "Or do we follow the de novo 510(k) process, whereby the bulk of the data around association studies for each of the biomarkers is good enough?"
But, he optimistically added, "The process now has really been delineated by this approval that allows us to do a 510(k) and get our cytochrome P450 test approved [as an IVD]. That's the track that we're on."
Hines said Tm Bioscience would apply for IVD approval for its entire stable of microarray tests, which includes its three single-gene CYP450 tests, a cystic fibrosis test, and a thrombophilia test -- although none has been submitted to the FDA yet.
"We're looking for an approval in Q1," he said. For Tm Bioscience's products, there is little point in attaining analyte-specific reagent status, because the company's facility has been ISO-13485 certified and FDA audited, said Hines.
Tm sells about 300,000 to 400,000 of its CYP450 tests annually, although the CYP450 market should "take off significantly" as AmpliChip settles in and competitors achieve IVD approval, said Hines. The company currently sells its CYP450 assays to the Mayo Clinic, the University of Louisville, and "four of the top six" labs in the United States, he said.
The other question hanging over the industry is whether physicians will use the microarray-based tests, particularly the CYP450 test. Thus far, there hasn't been great demand for CYP450 tests that are already on the market, Paul Billings, a senior geneticist and vice president for biotechnology and healthcare strategy at LabCorp, told Pharmacogenomics Reporter.
"Evidence, patient requests, quality, and liability concerns," all have had an effect on demand for the tests, said Billings.
Susan Morgensztern, a Seattle-based independent consultant to the diagnostics and pharmacogenomics industry, pointed out that physicians have known about CYP450 tests for more than 20 years, but they have to be "motivated to order a test, explain it to their patient, hassle with their payor, and finally choose therapeutics accordingly. Physician behavior is very slow to change,"she said.
Morgensztern also voiced some skepticism about the immediate role of microarrays in molecular diagnostics. "Until there is a clinical need for the content on microarray platforms, and until that need is proven and physicians and payors are adequately educated to order and pay for the test, adoption rates will be slow," she said.
Having a test on a chip may make a complex technology simpler, but that does not necessarily mean it's more attractive, Morgensztern added.
But while some questions remain about how successful of a future microarrays will have as molecular diagnostics, some competitors have already stated their intention to jump into the field.
Nanogen recently acquired analyte-specific reagent maker Epoch Biosciences for roughly $97 million (see BAN 9/15/2004). The firm has had a difficult time penetrating the clinical diagnostics market and believes that the launch of the NanoChip 400, a microarray-based molecular diagnostics platform (see BAN 11/3/2004) combined with the acquisition of Epoch Biosciences, will provide it with the ability to make greater inroads.
GE Healthcare, with its CodeLink microarray platform, would seem like a natural choice to pursue molecular diagnostic applications for its arrays. The firm declined to comment specifically on its efforts in this area, but e-mailed a general statement to BioArray News, stating, "We feel that the decision to support this technology demonstrates the relevance of molecular diagnostics to the immediate needs of the healthcare community."
A host of smaller players in the microarray arena, including PamGene (through a collaboration with Olympus), Toshiba, and Agendia have all stated their intention to eventually market clinical diagnostic products. Other microarray firms contacted for this article did not respond by press time.
-- EW, CW