The US Food and Drug Administration is reviewing the way it regulates arrays used by Clinical Laboratory Improvement Acts-compliant cytogenetics labs, BioArray News has learned.
For years, CLIA-compliant labs have been offering such array-based clinical cytogenetic tests as laboratory-developed tests without having to obtain FDA clearance for their assays. Now, the FDA is considering increasing its oversight over array-based cytogenetic tests, a shift that could have a broad impact on the use of arrays in clinical cytogenetics, according to several sources.
Specifically, while companies and labs that have offered array-based cytogenetic testing services have been able to order their chips from an external manufacturer and quickly introduce new iterations of their diagnostic assays as more scientific information becomes available, they may be obligated in the future to take those same assays through a 510(k) or pre-market approval process in the US.
Michael McNulty, senior director of clinical applications at Agilent Technologies, told BioArray News last week that the FDA informed Agilent of its ongoing review a few months ago.
"We met with the FDA this summer to discuss the role of microarrays and genetic testing in clinical diagnostics," McNulty said. "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," he said.
Agilent does fabricate arrays for CLIA laboratories that perform laboratory-developed tests, though the array designs and assays are developed and validated by the Santa Clara, Calif.-based firm's customers, McNulty said.
Agilent manufactures chips designed by some of the largest labs to offer array-based clinical cytogenetics in the US. Customers include Signature Genomic Laboratories, Baylor College of Medicine's Medical Genetics Laboratories, and Emory University's Genetics Laboratory. In all of these cases, Agilent "acts as a foundry by printing arrays specified by the individual CLIA lab," McNulty said.
According to McNulty, the timeline for the implementation of the FDA's decision is unknown.
A representative for the FDA's Office of In Vitro Diagnostics, which oversees the regulation of medical devices, confirmed this week that the agency has been reviewing the use of the tests. She said that the LDTs 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.
Michael Watson, executive director of the American College of Medical Genetics, confirmed last week that the FDA had been meeting both with clinical cytogenetics labs and the array vendors that supply them with chips to inform them of the possibility that they may change the regulatory framework for offering cytogenetic tests.
Still, he said, if such changes do occur, it is unclear which route the FDA will require labs like Baylor or Signature to take to keep offering their tests, and added that the process will be complicated both by the fact that the main test providers are academic labs, not companies, and also because the evolving nature of clinical cytogenetics could challenge the traditional way the FDA deals with array-based diagnostic assays.
"It's about to get ugly," Watson told BioArray News last week. "Historically, [the FDA has] has only dealt with manufacturers, but the only way they can deal with manufacturers is to say that they can only sell their products to someone they know won't use it in a clinical application."
If the FDA decides to oversee array-based cytogenetic tests in this manner it could obligate individual labs to continue offering their tests only after receiving 510(k) clearance or obtaining pre-market approval from the agency, Watson said.
According to Watson, arrays used in clinical cytogenetics are different from other array-based testing panels because those using these tests employ a whole-genome approach, looking across a patient sample's genome to identify potentially rare variation that may be responsible for a certain phenotype.
If a lab attempts to seek 510(k) clearance for an assay, it may "run into the fundamental problem of demonstrating that there is a reasonable amount of literature to justify certain targets being on the array," Watson said. "Now that we can pick up previously undetected copy number variants, there's not that much literature on them, and many of them are rare, private variations," he said. "They show you things that haven't been seen before."
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According to Christa Martin, a senior director of the Emory Genetics Laboratory, the process of obtaining FDA clearance for such assays "could be very expensive."
If the arrays have to go through the 510(k) process, "most of the smaller labs won't be able to meet those requirements on their own," she told BioArray News last week. "Most clinical labs haven’t gone through the FDA approval process before. Labs will have to explore who has the money to do it."
Another issue is how labs will be able to achieve clearance for the multiple assays they use in house. Emory, for example, uses several Agilent-manufactured arrays for different services. "It will be interesting to see how labs will respond to their expectations," Martin said.
ACMG's Watson likened the use of arrays in clinical cytogenetics to the practice of medicine. "It is a lot like radiology," he said. "They see things they've never seen before, but they're not regulated the same way because it falls under the practice of medicine. We've hit that point in a lot of the genomic testing that is coming on line."
If the FDA decides that labs should seek 510(k) clearance or obtain a PMA to offer their services, Watson said it could reshape the way arrays are used in clinical cytogenetics. "In the end, we could lose these [tests] from the marketplace," Watson said. "In autism, I think that 10 percent of patients are diagnosed with these technologies," he said. "We'd lose our ability to test for mental retardation.
"All the things we use [array-based] cytogenetics for are the kinds of things that are compromised by not allowing the use of higher-resolution technologies than traditional chromosomal analyses allow," he added.
Taking the concerns of the FDA into consideration while meeting the needs of clinical cytogeneticists to use arrays manufactured by vendors in their services, 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.
"We'll be able to talk through these issues," Watson said of the meeting. "We understand that oversight is important feature of services to the public, but it all doesn't fit into the same box," he said.
Watson said that he hopes the meeting can take place within the next six months.
In the meantime, ACMG is undertaking more activities to "allay some of the FDA's anxieties," he said. "A lot of it is education. We've begun to teach clinical providers how labs go about interpreting the results of these tests by using genome variation databases and how to construct a way of analyzing them," he said. Watson added that ACMG is also in the process of establishing current procedural terminology codes for array comparative genomic hybridization so that it will be easier for insurers to pay labs for their services.
"Hopefully we'll be able to maintain access to this technology and allay the concerns about how it is used," Watson said of the activities.
Agilent's McNulty said that the firm is also doing its part to assuage the concerns of the FDA. "While Agilent is not a diagnostic company, our role as a partner to CLIA laboratories and medical diagnostic companies is to support their efforts with a program to document how Agilent microarrays conform to quality standards and post-market surveillance programs that will be verified by third party and customer audits," McNulty said. "We will continue to work with both our customers and the FDA to assure microarray use is safely and effectively employed in the clinical lab."