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Facing Prospect of Increased FDA Regulation, Vendors Look to Clear Cyto Chips for Clinical Use

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By Justin Petrone

Roche NimbleGen has joined rivals Affymetrix, Agilent Technologies, and Illumina in announcing its intention to seek US Food and Drug Administration clearance for the use of its arrays in the clinical diagnosis of genetic abnormalities.

The decision of major array vendors to seek FDA clearance for their cytogenetic array platforms comes at a time when the agency has indicated that it could require labs that offer array-based chromosomal analyses to use cleared tests in the future.

Specifically, Roche NimbleGen said last week that it plans to achieve compliance with Good Manufacturing Process standards for its microarrays, "followed by subsequent submission for clearance or approval of select array products to the US Food and Drug Administration." In particular, the company said that it intends to submit its cytogenetic arrays for FDA approval.

Roche's announcement comes just weeks after Agilent said it too plans to submit a cytogenetics package to the FDA. Agilent said its array manufacturing process has now received ISO 13485 certification as part of its planned submission. ISO 13485 is a standard for quality management systems for the design and manufacture of medical devices set by the International Organization for Standardization (BAN 3/30/2010).

While Roche- and Agilent-manufactured chips are currently used by customers such as Signature Genomic Laboratories and Baylor College of Medicine's Medical Genetics Laboratories in their respective genetic testing services, both companies told BioArray News that their arrays are being sold for research use only. Obtaining FDA clearance is a "logical step" for them to take as they set to move their platforms into the molecular diagnostics arena, they said.

"The cytogenetics market seems to be one market where there is interest to move beyond the current research studies, and in doing so it would require an FDA-cleared or -approved product," Roche NimbleGen spokesperson Kary Staples said last week.

Though Roche NimbleGen has sold since last year a line of CGX arrays designed by Signature, Staples declined to discuss which products the firm plans to submit for clearance.

Robert Schueren, Agilent vice president and general manager of genomics, similarly said that submitting a cytogenetics package to the FDA is the "next logical step as part of Agilent's commitment to arrays for diagnostics." He also declined to discuss the design of the array that Agilent will submit, but said that Agilent has met "specifically with the FDA about the cytogenetic field" and "looks forward to ongoing communication with them as part of our efforts toward FDA clearance of a cytogenetics device based on Agilent's platform."

Like Roche and Agilent, Affy and Illumina also intend to submit their cytogenetic offerings to the FDA for clearance. Affy President and CEO Kevin King told BioArray News this week that Affy is "actively pursuing discussions with the FDA regarding future cytogenetics-related clinical applications," but "cannot predict what decisions the FDA will make regarding timing" of clearance.

Affy "only sells products for research studies and does not support the use of our research-use-only products for clinical testing," King stressed. "Customers assume regulatory responsibility for the sale of these products."

Likewise, Greg Heath, Illumina's senior vice president and general manager of diagnostics, said in February that the company will submit a cytogenetics package to the FDA as part of its preliminary investigational device exception, or pre-IDE, process. As part of that process, test makers can send analytical or clinical protocols to the FDA for review and comment before proceeding with studies and discuss possible regulatory pathways.

Heath said at the time that Illumina's pre-IDE discussion will allow the firm to "start the discussion with the FDA about intended use, structure of clinical trials, and get some guidance from them about how we are going to approach this" (BAN 2/9/2010). The company did not respond to questions in time for this publication about why it now intends to seek clearance for its cytogenetics arrays.

Representatives from Oxford Gene Technology and BlueGnome, two British firms that also sell arrays for cytogenetics research, declined to discuss any contact with the FDA about clearing their products, some of which are manufactured by Agilent.

Under Review

In October 2009, a representative for the FDA's Office of In Vitro Diagnostics, which oversees the regulation of medical devices, told BioArray News that the agency has been reviewing the use of the tests. She said that the laboratory-developed tests used in clinical cytogenetic labs have been offered so far under the "regulatory discretion" of the agency, but that OIVD is now "going through a process of review and discussion" that could result in increased regulation of the tests (BAN 10/13/2009).

Representatives from OIVD this week did not respond to questions about the status of that review in time for this publication.

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Vendors have known about OIVD's review at least since last year. Michael McNulty, senior director of clinical applications at Agilent Technologies, told BioArray News in October that Agilent met with the FDA in summer 2009 to "discuss the role of microarrays and genetic testing in clinical diagnostics" and that the FDA "notified us they have determined that microarray-based assays … are medical devices. Being medical devices, the FDA will require CLIA laboratories to seek clearance for their assays."

Michael Watson, executive director of the American College of Medical Genetics, said it is likely that the possibility of increased regulation of cytogenetic arrays has encouraged vendors to seek FDA clearance.

"I think that was the conclusion after they met with FDA last year and were pushed to certify that the labs buying their arrays understood that they were for research or investigational use only and not for clinical use," Watson told BioArray News this week.

Still, he warned that array platforms that the FDA approves could be different from the open, genome-wide arrays that cytogeneticists have become accustomed to using. "I’ve heard that most of the companies are planning to bring closed [array comparative genomic hybridization] platforms to FDA in the near future as they anticipate that it could be years [before] FDA has digested open-platform genomic testing," Watson said.

"However, it’s my understanding that these will be highly targeted to pre-established clinical targets so will miss much of the clinically significant rare and private copy number variation, depending on the degree to which they are able to include a whole-genome backbone as needed for detection of large rearrangements."

Watson is currently organizing a meeting that will allow test providers, array vendors, and the FDA to discuss a possible solution that will meet the interests of all parties. Watson said the meeting is scheduled to take place in late June and may have some outcome on how the FDA decides to proceed on regulating the space.

"I can’t predict what they’ll do either before or after or meeting but hope that we can end up on the same page around where the technology is and is going and why an open platform is the preferred platform over a targeted array," Watson said.

CLIA-compliant labs like Signature or Baylor have for years offered array-based clinical cytogenetic diagnostic services as laboratory-developed tests without having to obtain FDA clearance for their assays. This freedom has enabled them to order their chips from manufacturers such as Roche or Agilent and introduce new designs as more scientific information becomes available.

If FDA decides to change its policy following its review, these labs may have to take those same assays through a 510(k) or pre-market approval process in the US. So far, though, the FDA has not alerted labs that it intends to enforce any changes in policy.

David Ledbetter, director the division of medical genetics at Emory University School of Medicine in Atlanta, told BioArray News last week that there has not been much "real action" in terms of any changes in the regulatory environment. "Things have been thankfully quiet on the FDA front," he said.

Lisa Shaffer, co-founder, president, and CEO of Spokane, Wash.-based Signature Genomic Labs, similarly said that she was unaware of any changes, and was unsure of how Roche's decision to seek FDA clearance for its platform could impact Signature.

"I haven’t given it much thought as to what it means to us," Shaffer told BioArray News last week. "The process [of obtaining clearance] takes so long and it is unclear where they are in the process."

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