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Roche s AmpliChip Microarray Faces Regulatory Hurdles for Tech and Tests

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The Roche Diagnostics AmpliChip microarray product will have not one, but several hurdles to cross before it can gain a seal of approval from the US Food and Drug Administration.

The microarray-based product, designed by Roche, and manufactured by Affymetrix, will have to gain FDA approval as an in vitro diagnostic device, and, according to Janet Woodcock, director for the Center for Drug Evaluation & Research of the FDA, the agency will have to validate the data the device provides — for each test it performs.

The AmpliChip CYP450 was introduced to the market on June 25 as the first microarray-based device targeting clinical applications. The device is designed to probe for polymorphisms in the CYP2D6 and CYP2C19 genes, two genotyping tests that will each have to earn FDA affirmation.

When it was introduced, the AmpliChip was heralded by Roche as “an important milestone in Roche’s development of the individualized medicine market.” However, in the five months since, it has largely demonstrated the perils of commercializing a leading-edge healthcare technology with one well-chronicled FDA setback followed by another.

Still, Roche is optimistic. Roche’s Greg Heath, senior vice president for clinical genomics, told BioArray News that the device and the test-approval hurdles “do not change much for us.”

He said that the company is moving in the direction of seeking FDA 510(k) approval for the device as an in vitro diagnostic, as well as seeking European approval to market the device.

“It’s a long-term approach,” he said. And, he added, “Once launched, I can’t think of any substitute technologies on the horizon.”

However, some experts believe that, judging from the letter sent to Roche earlier this month forbidding the sale of the AmpliChip as an ASR, it appears that the FDA would encourage reviewing the product as a de novo 510(k) [view the letter here].

“I don’t know the full pathway the FDA would embark [on] other than their draft molecular diagnostics guidance,” said Ron Eisenwinter, an IVD specialist at the consulting firm Boston Healthcare Associates-Expertech, referring to the steps the agency would likely take in reviewing the AmpliChip. “This [draft document] would probably be the one to follow until the ASR regulations supposedly are to be rewritten.”

Today, microarray-based diagnostics can fit into one of three submission categories — pre-market approval, a 510(k), or a de novo 510(k). The pre-market approval process, or PMA, attracts the highest level of regulatory scrutiny because the products it covers traditionally are life-sustaining devices like heart valves; a 510(k) is a less-stringent application for a device that is equivalent to an existing product and that is not a critical device, like a diagnostic test; and a de novo 510(k) is a new category for devices that do not have a marketed equivalent and that do not merit rigorous PMA regulatory requirements.

More specifically, the de novo 510(k) arises when a 510(k) is deemed not substantially equivalent to existing products — which may be the AmpliChip’s fate considering it has no predecessor. At that point, the sponsor petitions the de novo process to reclassify the device. “Basically, a de novo 510(k) device is a PMA-status device dropped down to the 510(k) level,” said Eisenwinter. “There’re fewer hurdles than a PMA, but it’s hard to say what the requirements are” for the de novo 510(k) “probably because there are no substantially equivalent devices for this.” Eisenwinter added that “the rigors would be for the standard in vitro diagnostic 510(k).

Eisenwinter said it is impossible to know how long the FDA takes to review and clear a de novo 510(k) application because the agency is believed to have approved just one. However, the process for petitioning a 510(k) as a de novo 510(k) may take around eight months — which would mean that Roche may begin selling the AmpliChip as an IVD as early as July 2004 — if the product and the two tests are approved.

The Next Chapter

Heath spoke to BioArray News last week as Roche hosted a media event in San Francisco, inviting global press for a two-day symposium, “How Genomics Are Shaping the Future of Healthcare.” The event was chiefly attended by members of the European press and some US media representatives. The agenda included a day of briefings by executives and scientists from Roche Diagnostics, as well as Steve Fodor, Affymetrix’s chairman and CEO. Additionally, Richard Weinshilboum, the director of the genomics research center at the Mayo Clinic, gave the equivalent of a keynote speech after a champagne reception and a dinner held in the Carnelian Room, a posh restaurant atop a downtown skyscraper. In opening the event, Heath told the journalists that Roche and Affymetrix, its partner in the AmpliChip, have the right combination to “bring personalized medicine to fruition.” The rewards for success were illustrated in a chart from an in-house study that estimated the entire pharmacogenomics market at $400 million by 2013.

“What we are trying to do is worth doing,” he said. “This is not going to be easy; there are challenges everywhere we turn.”

The Alliance

Affymetrix announced its $70 million, 18-year AmpliChip agreement with Roche in January. Under terms of the agreement, Roche paid a one-time fee of $70 million to Affymetrix and would pay additionally for chips, royalties, and milestones. While the announcement in January covered the entire collaboration, there are actually 14 separate agreements between the two companies.

At the symposium, Rob Lipschutz, Affymetrix vice president of business development, said the agreement followed a year-long negotiation. Roche was Affymetrix’s first easy-access customer (an arrangement that is essentially a subscription to buy certain numbers of chips per year at a discount) and the companies had been conducting business with each other since 1993, Lipschutz said. In 2001, executives from the two firms met over dinner in New York City to discuss commercializing the technology.

The two companies have workers collaborating on the project in 10 sites, from Pleasanton, Calif., to Switzerland, he added.

The Goals

The AmpliChip agreement is part of Roche’s effort in personalized medicine, for which Tom Metcalfe, head of Roche’s Biomarker program, laid out a time frame. In the short term, the company will focus on applying pharmacogenetics to existing drugs, and for diagnosis to improve delivery. In the midterm, the next two to five years, the company will work to organize clinical trials better, and work with existing compounds. The long-term efforts are on targets and pathways.

The Present

The AmpliChip CYP450 product is initially aims at genotyping for psychiatric medication, to help in drug and dosing selection, targeting a market of 45 million depressed or schizophrenic patients, approximately 15 million of whom take medication.

The cytochrome P450 gene family, present in every living form of life, with deletions and multiple copies providing a number of variants, makes an ideal target for microarrays, said Walter Koch, Roche Diagnostics senior director of pharmacogenomics.

The array will test for the 2D6 gene, which plays an important role in the metabolism of many psychiatric drugs, and for the 2C19 gene, which plays a role in the metabolism of Warfarin, a 40-year-old drug that is the most frequently prescribed oral anti-coagulant, and the fourth most prescribed cardiovascular agent, but one with a complex dose-response relationship.

Both genes have amassed a body of scientific study, one of the reasons they were the first tests out of gate, said Heath.

— MOK, additional reporting by Kirell Lakhman, editor, SNPTech Reporter.

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