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FDA Clears Illumina's MiSeqDx, Assays; Impact on Clinical Labs Remains to be Seen

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In a first for next-generation sequencing, late last month, the US Food and Drug Administration cleared Illumina's MiSeqDx system along with three assays — two cystic fibrosis assays and a Universal Kit that includes the reagents for clinical labs to develop their own assays.

The two cystic fibrosis assays consist of a screening assay that includes 139 known pathogenic variants and a diagnostic assay that covers all the exons and intron/exon boundaries of the CFTR gene.

The Universal Kit, meantime, is a control that goes with the MiSeqDx instrument and enables laboratories to develop their own tests on the system. Laboratories would still have to take additional steps to bring those products through FDA clearance, however.

Illumina said that the cleared MiSeqDx system will be priced at a slight premium compared to the research box, but did not disclose the exact price.

How these approvals will impact clinical labs that offer laboratory developed tests in a CLIA environment still remains to be seen, although there is at least some excitement over the FDA clearance.

"There are very few FDA approved kits in genetics," Madhuri Hegde, executive director of Emory Genetics Laboratory, told Clinical Sequencing News. "So this is a big step forward."

Her laboratory runs a suite of next-gen tests on the MiSeq platform, and she said the details for what the clearance would mean for her lab and what would be required for the lab to switch to the cleared system has yet to be resolved, but did not anticipate that it would be too cumbersome for labs to switch to the cleared system.

Greg Heath, senior vice president and general manager of Illumina's Diagnostics business, told CSN that the clearance would have the most immediate impact on cystic fibrosis testing.

He anticipated that there would first be a "technology substitution." For instance, current tests that screen for cystic fibrosis typically cover the top six most common mutations, while Illumina's test covers the top 139 mutations.

"You'll catch more people," he said, which will enable physicians to help with reproductive planning earlier. "I do think it will be a technology substitution on that front," he said, where labs that currently offer screening tests will switch to the MiSeqDx test.

Because cystic fibrosis screening is already common, there are fewer cases to diagnose, Heath said, but the test will still be useful especially as new drugs are being developed that target specific mutations.

For example, there is a drug that targets a specific mutation in the CFTR gene, but only about 4 percent of patients have that mutation. The drug is very expensive, Heath said, so the diagnostic assay could help determine which patients should receive it.

"I think as more targeted therapies get developed, people will adopt that assay," he said.

In terms of the impact on areas outside of cystic fibrosis, Heath said that having an approved next-gen system will "enable labs to bring up all kinds of sequencing tests where they can have confidence that the instrument has been vetted by the FDA," he said. While there will still be "lab to lab variability on the assay and interpretations … the instrument is standardized, and [labs] will have the confidence that instrument variability has been removed."

For labs to then bring their own assays through FDA clearance, Heath said the process should be simplified. Labs will still have to meet the FDA's requirements for their specific assay, including demonstrating clinical and analytical validity of the assay, but "they will not need to demonstrate performance of the instrument," he said. "The intended use of each assay will determine what regulatory requirements must be met, but having the instrument cleared will definitely facilitate things," he added.

For clinical labs like Emory or GeneDx that are already running LDTs on the MiSeq system and want to migrate to the MiSeqDx, Heath said that the validation associated with switching should be minimal due to the similarity in hardware functionality.

FDA clearance process

In order to bring the system and assays through FDA clearance, Heath said that the company had to demonstrate both analytical and clinical validity of the two cystic fibrosis assays and analytical validity of the MiSeqDx and Universal Kit, including accuracy and reproducibility with representative assays.

He said the company began discussions with the FDA when it was looking to bring an array platform through regulatory clearance. The FDA had questions about variants of unknown significance, which Illumina said would be orders of magnitude more challenging with sequencing, prompting the FDA to request an overview of the technology.

Aside from variants of unknown significance, Illumina also had to demonstrate that the platform could sequence through different regions of the human genome. "We took clinical samples and made our claims based around different regions of the genome," Heath said. For instance, the company had to demonstrate that it could sequence through homopolymeric regions, or regions with high or low GC content.

Heath said that one of the main challenges was getting the FDA comfortable with making accuracy claims around the system's ability to sequence an entire genome by demonstrating it, not on the entire genome, but on different regions in the genome.

Moving forward, Heath said that the clearance of the MiSeqDx system should facilitate any future submissions to the FDA. "We know the kinds of data they want to see and how, so that will expedite the way we collect and present it," he said. He declined to say what other products Illumina is considering submitting for FDA clearance, but said that the company is talking about everything. "It will depend on the business side of things—the economics, the market, and how they're evolving," Heath said.

Future FDA products

In terms of disease-specific assays that Illumina may submit for FDA clearance, it has said in the past that it intends to bring Verinata Healths's verifi test through FDA clearance.

"Reproductive and genetic health is first and foremost what the technology can deliver on," Heath said.

Additionally, he said that oncology will be a big area, followed by infectious disease and transfusion and transplantation medicine.

Specifically in cancer, Heath said that he thinks labs and pharmaceutical companies will look to migrate companion diagnostic tests from PCR to the MiSeqDx, which would allow them to "build more complex assays."

Clinical lab adoption

How and whether clinical labs will adopt the MiSeqDx system still remains to be seen. Hegde said that running tests on an FDA-cleared system could ease the burden on labs' validation processes for launching LDTs in a CLIA and CAP environment.

"We were doing expensive validation on all our next-gen tests," she said. "Now that the [MiSeqDx] is FDA cleared, the amount of validation may not be expensive," she said.

Another uncertainty is whether clinical labs will be more likely to use Illumina's FDA cleared Universal Kit for target selection as opposed to other enrichment kits that are sold as RUO kits but often modified and validated by individual labs for their LDTs. Hegde said that the kit uses Illumina's TruSight chemistry, which she has not used in her lab.

Emory has worked with target selection products from RainDance Technologies and Agilent Technologies.

Andy Watson, COO at RainDance, said that he did not think the clearance would impact current next-gen clinical tests. "I don't think we'll see many labs switching from the current MiSeq to the approved version," he told CSN.

Additionally, he said that RainDance is not currently looking to bring either of its enrichment systems or its targeted gene panels through FDA clearance. It currently sells two droplet PCR-based enrichment systems, the ThunderStorm and the RDT 1000, as well as a number of gene panels, including a cancer hotspot panel, HLA panel, and an autism panel. Aside from Emory, Myriad Genetics is also using RainDance's technology to run its myRisk inherited cancer panel.

Watson said that because there are currently substantial differences between various clinical targeted sequencing assays, even for the same disease, labs will be less likely to move their tests over to the MiSeqDx and Universal Kit.

"Most scientists that I talk to are saying that the enrichment is something that they want to have control over and flexibility," he said.

Nevertheless, Watson said that the FDA clearance of the MiSeqDx and assays is "very good news for the industry."

"It shows the FDA is capable and willing to work with next-gen sequencing and get that through the approval process," he added.

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