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Illumina Applies CE Mark to MiSeqDx for Cystic Fibrosis Testing; Other MiSeq IVD Assays to Come

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As an indication that next-generation sequencing is making its way into in vitro diagnostics, Illumina said this week that it has applied Europe's CE mark to the MiSeqDx Cystic Fibrosis System, a diagnostic version of its MiSeq sequencer with two associated cystic fibrosis assays and dedicated software.

The company is working on additional IVD assays for the MiSeqDx in the areas of reproductive health and cancer, while it is waiting to hear back from the US Food and Drug Administration about its application for 510(k) clearance for the MiSeqDx and cystic fibrosis tests, which it submitted at the end of last year (CSN 1/9/2013).

The CE mark indicates that the system complies with the requirements of the European Union's in vitro diagnostics directive. The mark is required for all IVD medical devices sold in the European Economic Area, as well as some other countries.

Meeting the standards of the directive means "there is added rigor around the performance characteristics, specifically reproducibility and accuracy," Greg Heath, Illumina's senior vice president and general manager of the diagnostics business, told Clinical Sequencing News. "Clinical labs value ready-to-use, high-performance products to manage patient care, and we think they'll see this as an added certification of performance."

He said the filing for CE marking, which is a self-declaration, is "similar but not identical" to the 510(k) requirements of the FDA.

The MiSeqDx differs from the MiSeq research instrument mainly in its operating software, which has been reconfigured for the clinical market, and its user management software, which allows labs to trace system access. In addition, the instrument's reporter software has been customized with cystic fibrosis-specific algorithms.

While the hardware of the two instruments is basically the same, the MiSeqDx is manufactured under a different quality standard at a site that is ISO 13485-compliant.

The MiSeqDx will sell at a "slight premium" to the research-use instrument, Heath said, and the company anticipates shipping the first MiSeqDx machines to laboratories in Europe this month, having received interest from several sites.

Besides accuracy and reproducibility studies, the European filing and the FDA application involved a clinical trial of the cystic fibrosis tests – the MiSeqDx Cystic Fibrosis Diagnostic Assay and the MiSeqDx Cystic Fibrosis Carrier Screening Assay – that was completed last year. Illumina conducted the trial in collaboration with three US-based partners: a "leading academic site" with expertise in cystic fibrosis, a commercial reference laboratory, and a clinical laboratory that was new to next-gen sequencing technology.

In addition, the company worked with a "leading expert" in cystic fibrosis who is "intimately involved" with developing the CFTR2, or Clinical and Functional Translation of CFTR database, which collects information about pathogenic mutations in the CFTR gene. The database is currently directed by Garry Cutting at Johns Hopkins University.

"We tried to work with leading experts, with a broad range of users, so that we could offer a product that could be useful to everybody and not just limited to experts," Heath said.

The reason Illumina chose cystic fibrosis to develop its first diagnostic assays for the MiSeq is that it is the most common genetic disease in the Caucasian population – where about one in 3,000 newborns have the disease. It also is well characterized, and several IVD products are already on the market, though none of them use next-generation sequencing, Heath said.

He said Illumina's new assays can improve on conventional cystic fibrosis testing because they only require a single platform to perform both carrier screening and diagnostic testing.

The American College of Obstetricians and Gynecologists' Committee on Genetics currently recommends cystic fibrosis pre-conception screening for the 23 most common mutations in all women of reproductive age. It notes that "complete analysis of the CFTR gene by DNA sequencing is not appropriate for routine carrier screening because it may yield results that can be difficult to interpret."

Illumina's cystic fibrosis carrier screening assay is designed to detect 162 functionally verified and clinically relevant variants in CFTR, including the 23 currently recommended for screening by both ACOG and the American College of Medical Genetics and Genomics. "Other carrier screening methods test only for those variants most commonly found in Caucasians, potentially missing CF causative mutations in a wider demographic," according to the company.

Illumina will sell the assay in two kits sizes, for either 96 or 960 tests, and the assay allows for multiplexing of up to 48 samples per run using index tags. The assay uses a proprietary extension-ligation reaction between two oligonucleotide probes to capture and amplify the regions of interest.

Its diagnostic assay sequences all protein coding regions and exon/intron boundaries of the CFTR gene. In addition, it detects two large deletions, two deep intronic mutations, and indels in homopolymeric regions, as well as polyTG/polyT variants.

Illumina will sell this assay, which uses the same proprietary target enrichment method, as a kit for 48 samples, and up to eight samples can be combined in one run.

Illumina's FDA application is currently under review, and the company cannot predict when the MiSeqDx and the cystic fibrosis assays might get cleared in the US. "We've submitted our filing, we've gone back and forth with regard to a few questions that they had, and we're waiting for their feedback on that," Heath said.

While the MiSeqDx instrument will be identical in the US and Europe, the cystic fibrosis assays might differ slightly in the US if the FDA chooses to limit their claims, he said.

In the meantime, Illumina is developing additional IVD assays for the MiSeqDx, both on its own and with partners. Heath said these will be in the areas of reproductive health and cancer, but he provided no timeline for their launch.

He said the reproductive health assays will complement Illumina's existing offerings in that area, for example its BlueGenome pre-implantation screening assays, its Verinata aneuploidy screening test, and its cytogenetics microarrays, which it submitted to the FDA earlier this year, "so we cover the entire continuum of care there."

Heath noted that Illumina already has a number of research-use-only products for cancer predisposition and somatic mutation testing on the market, for example its TruSight Cancer and TruSight Tumor panels (CSN 9/12/2012), and "we're looking at both of those applications and taking them forward as IVDs," with the most work so far done in somatic mutation testing.

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