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In New Hurdle for Roche Dx, FDA Will Need To Approve Each of AmpliChip s Two Markers

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Roche Diagnostics’ AmpliChip CYP450 microarray will have to overcome several regulatory obstacles before it can gain market approval from the US Food and Drug Administration. The product must be approved as an in vitro diagnostic device — not as an analyte-specific reagent, as Roche had originally hoped — and data for each test the product performs must first be OK’d by the FDA, according to an agency official.

The news that each test performed by the AmpliChip must be separately approved by the FDA — the P450 currently tests for the presence of two mutations, and Roche has said it plans to release five additional products based on the Affymetrix GeneChip — comes two weeks after the agency told the firm it may not sell the product in the United States as an ASR [see 11/6/03 SNPtech Reporter].

When it was introduced in June, the AmpliChip was heralded by Roche as “an important milestone in Roche’s development of the individualized medicine market.” Roche continues to be optimistic. Greg Heath, the company’s senior vice president for clinical genomics, said the device and the test-approval hurdles “do not change much for us.”

Specifically, Heath said the company is moving in the direction of seeking FDA 510(k) approval for the device as an in vitro diagnostic in the United States, as well as seeking European approval to market the device. “It’s a long-term approach,” Heath told BioArray News, SNPtech Reporter’s sister publication. “It is just not the case that you can launch a whole bunch of ASRs and be there tomorrow.

“Once launched, I can’t think of any substitute technologies on the horizon,” he added. “What we are trying to do is worth doing. This is not going to be easy, there are challenges everywhere we turn.”

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: http://www.fda.gov/cdrh/oivd/amplichip.html].

“I don’t know the full pathway the FDA would embark upon other than their draft molecular diagnostics guidance,” said Ron Eisenwinter, an IVD specialist at consulting firm Boston Healthcare Associates-Expertech, referring to the steps the agency would likely take in reviewing the AmpliChip [see 5/23/03 SNPtech Reporter]. “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, or PMA, process 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 deserve the 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,” Eisenwinter told SNPtech Reporter. “There’s 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 likely begin selling the AmpliChip as an IVD as early as July 2004 if the product and the two tests it contains are approved.

The AmpliChip CYP450 was launched on June 25 as the first microarray-based device targeting clinical applications. The product is designed to probe for polymorphisms in the CYP2D6 and CYP2C19 genes, two genotyping tests that will each have to earn FDA affirmation. According to Janet Woodcock, director of the FDA’s Center for Drug Evaluation and Research, Roche must obtain agency approval for each of these two tests before the AmpliChip has a shot at the IVD market.

The product will test for the 2D6 gene, which plays an important role in the metabolism of many psychiatric drugs, and for the 2C9 gene, which plays a role in the metabolism of Warfarin, the fourth most prescribed cardiovascular agent, but one with a complex dose-response relationship. Both genes have amassed a body of scientific study.

— MOK and KL

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