This article has been updated to include comments from Illumina and Agilent representatives.
While the US Food and Drug Administration's recent clearance of Affymetrix's CytoScan Dx Array for use in pediatric constitutional cytogenetics could help the company win over new clients in the US, it could also benefit the firm's business abroad.
CEO Frank Witney told BioArray News this week that the FDA's clearance of CytoScan is an "important milestone for adoption in other key countries around the world where they are now evaluating advanced tools and tests like this."
Witney added, "We are hopeful this clearance will pave the way for broader utilization of CytoScan Dx Array as a significant advance" over karyotyping and fluorescence in situ hybridization.
One market in particular where FDA clearance could have an impact is China. The Chinese Food and Drug Administration (SFDA) requires that clinical products achieve regulatory clearance in their country of origin before they can be submitted to the SFDA for clearance.
Last year, the SFDA cleared Affymetrix's GeneChipScanner 3000Dx system, the instrument upon which the CytoScan assay is run, for clinical use. Simon Sheng, general manager of the firm's Shanghai office, told BioArray News during a site visit that the clearance of the 3000Dx was a "big advantage" for the firm, and portrayed his company as being "a couple steps ahead" of its main competitors in the array-based cytogenetics market — Agilent Technologies and Illumina.
Like Affymetrix, Illumina submitted an array-based assay for constitutional cytogenetics to the FDA last year. Company executives have to date portrayed interaction regarding the submission as being positive, but the San Diego vendor has not yet achieved clearance.
An Illumina spokesperson told BioArray News this week that the company remains in discussions with the FDA.
Agilent Technologies, which sells its own catalog arrays for cytogenetics and manufactures chips for other providers, such as Oxford Gene Technology, has not yet submitted its platform to the FDA for clearance, but has discussed plans to do so later this year.
Heidi Kijenski, Agilent's clinical genomics marketing director, told BioArray News this week that the "project is on track and we do plan on submitting our assay to the agency this year."
The reviewing process
Microarrays have increasingly been adopted for use in prenatal and pediatric constitutional cytogenetics as well as cancer cytogenetics over the past decade. And professional societies and organizations — such as the American College of Medical Genetics, the American College of Obstetricians and Gynecologists, and the Society for Maternal-Fetal Medicine — have recommended CMA as a first-tier test under certain conditions for pediatric and prenatal cytogenetic testing.
Affymetrix first launched a product for the cytogenetics market in 2007 that was based on its SNP 6.0 array, a chip initially targeted to researchers undertaking genome-wide association studies. In 2011, it introduced a next-generation product, called CytoScan HD, tailored specifically to the needs of cytogeneticists. The array includes more than 2.6 million copy number markers, of which 750,000 are genotypeable SNPs and 1.9 million are non-polymorphic probes.
The company has enjoyed success in the cytogenetics market, with related sales now contributing more than a tenth of its overall revenues. Earlier this month, the company pre-announced fourth quarter revenues of $91 million, an 8 percent increase compared to the fourth quarter of last year. During a presentation the JP Morgan Healthcare Conference last week, Witney noted that CytoScan sales had contributed to the firm's performance and that they were up 35 percent through the first three quarters of the year.
COO Andy Last noted at the conference that the company has been taking market share from Agilent in the cytogenetics market, stating, "Momentum is in our favor."
Though Affymetrix customers use CytoScan in pediatric and prenatal constitutional testing, as well as cancer cytogenetics, its recent FDA clearance is only for pediatric constitutional testing. Last told BioArray News this week that the company has no immediate plans to seek clearance of CytoScan for other indications, though he said the firm expects the clearance to "accelerate adoption" of the platform.
Customers have been using Affymetrix, Agilent, and Illumina arrays as components of laboratory-developed tests in a CLIA setting. However, in 2009 the FDA informed the three main vendors that it considered chromosomal microarrays to be medical devices, meaning that the companies would have to submit their chips to the agency for 510(k) clearance or pre-market approval.
Debates ensued about how best to assess the performance of chromosomal microarrays, as the tools' ability to detect multiple anomalies, as well as variants of unknown significance, diverged from other diagnostics, where analytes are employed to detect markers associated with known conditions, such as drug metabolism. Some, such as Arthur Beaudet, head of the department of medical genetics at Baylor College of Medicine, likened chromosomal microarrays to magnetic resonance imaging machines, arguing that the tools be assessed for their ability to accurately measure SNPs and CNVs.
According to a Jan. 17 statement, the FDA ultimately reviewed CytoScan from such a perspective, evaluating it through its de novo classification process, a regulatory avenue for what it considers low- to moderate-risk medical devices. For the de novo submission, the FDA reviewed CytoScan's ability to detect "numerous chromosomal variations of different types, sizes, and genome locations when compared to several analytically validated test methods." The FDA determined that the assay could analyze a patient's entire genome and "adequately detect chromosome variations in regions of the genome associated with intellectual and developmental disabilities."
As part of its evaluation, the FDA also compared CytoScan to tests that are commonly used to detect chromosomal variations associated with developmental delay or intellectual disability. A comparison of test results from 960 blood samples showed that CytoScan had "improved ability over commonly used tests, including karyotyping and FISH chromosomal tests, to detect certain chromosomal abnormalities," the agency noted.
In its statement the FDA also cautioned that CytoScan should not be used for stand-alone diagnostic purposes, pre-implantation or prenatal testing or screening, population screening, or for the detection of or screening of acquired or genetic aberrations occurring after birth, such as cancer.
The test results should be combined with other clinical and diagnostic findings, consistent with professional standards of practice, including confirmation by alternative methods, evaluation of parental samples, clinical genetic evaluation, and counseling as appropriate, the FDA stated.
Another FDA stipulation was that the interpretation of test results be performed "only by healthcare professionals who are board certified in clinical cytogenetics or molecular genetics."