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FDA Clears Half of AmpliChip for Sale as an IVD; Rival Dx Shops Bear Down


Pharmacogenomics is starting 2005 with a bang.

Two days before Christmas, the US Food and Drug Administration cleared Affymetrix’s GeneChip 3000Dx chip reader and half of Roche Molecular Diagnostics’ CYP450 AmpliChip for use as an in vitro diagnostic device.

Though the FDA only cleared the 2D6, but not the 2C19, gene within the CYP450 family for which the AmpliChip tests, the move marks the first time that a microarray and its reader have won FDA clearance for IVD use. Roche can sell the CYP450 AmpliChip for research purposes only, and must wait until the second half of the chip receives clearance, according to a person inside the company. Roche delined to comment on the matter. According to the FDA, the clearance could open the door for additional microarray-based IVDs.

“That’s fantastic news,” said Greg Hines, CEO of Toronto, Canada-based Tm Bioscience, a Roche competitor with CYP450 diagnostics of its own. “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.”

Indeed, when Roche, the biggest diagnostics maker in the world, lands in a market, it does so on purpose. It has a destination and it leaves a trail. Companies such as Tm Bioscience, which hopes to follow in Roche’s and Affy’s footsteps, may now find it a bit easier to get through the FDA gauntlet.

In the meantime, 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. A scant 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. Financial terms of the agreement were not disclosed.

When the FDA updates its 510(k) database after the holidays, 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. “Do we need to do just two pivotal trials with X number of patients to show statistical significance?” said Hines. “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?”

Moreover, Roche sank a significant amount of time, effort, and cash into AmpliChip’s approval, and might not have done so unless it saw a significant market for the tests (see Pharmacogenomics Reporter, 5/20/2004). “They don’t normally pursue niche markets or esoteric markets,” said Michael Murphy, president and CEO of Morrisville, NC-based Gentris, also a Roche rival.

Who’s Paying?

With the all-important question “Who’s paying?” hanging in the air, Roche will certainly seek reimbursement for its test. Should Roche attain a current procedural terminology code from the American Medical Association, which it must do before its customers can hope to be reimbursed for using the test, reimbursement may come easier for genetic diagnostics made by other companies, said Murphy.

Gentris is in the “late stages” of clinical trials with its own CYP450 test, and hopes to apply for IVD approval in the United States soon, said Murphy. The company hopes to launch products — once approved — by the “middle of 2005,” he said.

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, referring to the three months ending March 31. 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 or 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 approval will also give the FDA “some muscle” to put behind the pharmacogenomics submission guidelines that it plans to release early this year, he said [see story in this issue's Snippets, FDA Publishes PGx Guidance in Federal Register; Document Now Due Early 2005].

“Asking the pharmaceutical industry to incorporate genetic testing into their clinical trial programs is pretty moot” without FDA-approved tests, said Hines. “A drug company cannot submit a regulatory filing using assays that are research-use-only assays. They have to be CGMP-manufactured, and it would certainly help if they were IVDs.”

Further Down the Drug Chain

At least 41 drugs are CYP2D6 substrates, according to a website ( developed by David Flockhart, chief of the division of clinical pharmacology at the Indiana University School of Medicine. At least 34 drugs inhibit the enzyme and two are inducers, according to the site.

About 30 percent of approved drugs move through the CYP2D6 pathway, and about one in 10 patients is at risk of an adverse drug reaction, estimated Murphy. In the United States, about 280 million prescriptions a year are written for “CYP2D6-type” drugs, with an average of about three drugs per patient, he said.

Still, there must exist a link between specific drug prescriptions and particular test outcomes, and clinicians must be aware of this link in order for genetic diagnostics to become commonplace clinical features. “There are 20 years of research supporting the fact that [CYP450 genes have] an effect — [but] there aren’t enough trials where a dose is the result of the research,” said Flockhart, who helped develop the CYP450 AmpliChip.

This is not the case in Europe, where the European Agency for the Evaluation of Medicines has “extensively” recommended adjusting doses of tricyclic antidepressants, according to CYP450 genotype, said Flockhart. “So, in that sense, we’re behind in this country,” partly because tricyclics are not used much in the United States, where selective serotonin inhibitors are preferred for depression treatment, he said.

Will Docs Buy It?

Now that an approved microarray-based IVD is hitting the US market, some companies hope to close the gap between genetic information and prescriptions. The private bioinformatics company Seryx puts information from scientific literature together with patient medical history and genotype information to try to predict drug responses and interactions, said Reggie Downey, Seryx vice president of sales and marketing. The idea is to provide doctors with drug response and even dosage information in the absence of broad physician education on the subject.

Seryx is “delighted” with Roche’s approval, said Downey. Extensive physician education would happen “in an ideal world — the reality is, they just want to know what to do,” he said.

Would physicians want patient CYP450 genotype information, if it were readily available? “If I could have every patient who walked into my office have a full scan of their relevant P450 enzymes … it would certainly enhance practice,” depending on cost and test reliability, said Alan Gelenberg, professor and head of the department of psychiatry at the University of Arizona. “For the slow metabolizers and the super metabolizers, I would start at a different dose,” using conservative estimates in the absence of solid clinical trial data, he said.

The real application of the test at the bedside is likely to be in patients with too little response or with overwhelming side effects, because those are the cases in which payors are more easily convinced of a test’s cost effectiveness, said Gelenberg. “For the most part, your doctor and mine don’t make the important healthcare decisions — they’re mostly made by managed care, including government,” said Gelenberg. Depending on Roche’s evaluation of the market, it may produce pharmacoeconomic studies for payors in several months to a couple of years, he said.

Poor Demand?

“The bottom line, to date, has been that, from a clinical demand point of view, we have not seen a lot of clinical demand” for CYP450 testing, said Paul Billings, senior geneticist and vice president for biotechnology and healthcare strategy at LabCorp. That slow demand is due to factors including “evidence, patient requests, quality, and liability concerns,” said Billings. The company gets "very few requests for P450," and as a result, LabCorp sends these to third party who conducts CYP450 testing, he said.

“I think it’s one of those situations that is quite ripe for those kinds of health-economics assessments of how it should be done,” said Billings. LabCorp will evaluate the Roche/Affy diagnostic, as well as those made by their competitors, and is “intending to proceed, in partnership with other interested parties, to look at which areas would be best to apply this,” he said. Examples of these areas include choosing between second-line therapies for depression, and dosage recommendations for fast- or slow-metabolizers on multiple drugs. LabCorp prefers FDA-approved diagnostics for these investigations, he added.

— CW


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