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In a Step Toward ‘Demystifying’ IVDMIAs, FDA Grants Class II Status to Breast Cancer Prognostics

A “special controls” guidance issued by the US Food and Drug Administration last week assigned Class II status to gene-expression tests that provide breast cancer prognosis information, but are not used to make treatment decisions.
The guidance also shed some light on the agency’s current thinking regarding in vitro diagnostic multivariate index assay devices, or IVDMIAs — tests that it considers more complex than other types of laboratory developed assays and therefore subject to FDA jurisdiction. The agency released a draft guidance on IVDMIAs last fall, but some in the industry have criticized its lack of clarity
The new guidance, Class II Special Controls Guidance Document: Gene Expression Profiling Test System for Breast Cancer Prognosis, was issued three months after the agency approved Agendia’s MammaPrint test for breast cancer recurrence, making it the first FDA-approved IVDMIA.
Originally deemed a Class III product requiring premarket approval, MammaPrint was granted Class II status – requiring only 510(k) premarket notification – after the company petitioned the agency regarding the safety and effectiveness of the product.
FDA determined that MammaPrint — as well as future genomic breast cancer prognostics — can be considered as Class II devices if they comply with a set of “special controls” that are outlined in the guidance document.
“The special controls guidance affirms that FDA has assigned tests that provide prognostic information only to Class II,” Paul Radensky, a health law attorney with McDermott, Will, & Emery, told Pharmacogenomics Reporter in an e-mail this week.
Although the special controls guidance grew out of the FDA’s review of Agendia’s product, the document will have a broad industry impact, conferring de facto Class II status to all breast cancer prognostic tests and absolving device makers from having to go through FDA’s more rigorous premarket approval process.
“That Agendia’s device was granted Class II status is significant for the whole industry and obviously for us,” Caroline Popper, regulatory affairs senior advisor at Exagen, told Pharmacogenomics Reporter this week.
Popper added that Exagen, whose eXagenBC breast cancer recurrence test is currently under review at FDA, was pleased that the special controls guidance contained recommendations that the company had anticipated and planned for in its own submission.
“We were happy and reassured that things were following in an anticipated course,” she said. “We fully anticipate that ours will be a Class II.”
However, since the guidance only applies to prognostic tests, Genomic Health’s Oncotype DX test may still have to garner premarketing approval since it provides both cancer recurrence prognosis and predicts if a patient will benefit from chemotherapy. FDA specifies in the special controls guidance that Class II status is only for prognostic tests, and not for predictive tests used for diagnosis or to detect response to therapy.
This distinction provides some clarity on how FDA might regulate certain algorithm-based laboratory-developed genetic tests, called in vitro diagnostic multivariate index assays. Steve Gutman, director of FDA’s Office of In Vitro Diagnostics, told Pharmacogenomics Reporter sister publication GenomeWeb News last week that the special controls guidance will “provide a general framework” for how the OIVD handles IVDMIAs.
Agendia Paves the Way
FDA crafted the special controls guidance with input from Agendia, following clearance of the MammaPrint test, as required under the de novo 510 (k) process. According to Agendia, the recommendations in the guidance reflect the issues raised during FDA’s review of MammaPrint.
“The special controls guidance provides clarity to the market on FDA’s expectations concerning premarket notification requirements for gene expression profiling test systems used for breast cancer prognosis,” an Agendia spokesperson told Pharmacogenomics Reporter this week. “Agendia strongly believes that these recommendations provide assurance for the safety and effectiveness for these kinds of devices.”
The FDA cleared Agendia’s MammaPrint test in February, making it the first IVDMIA to receive a nod from the agency. In a Federal Register notice last week, the agency explained that it had originally classified MammaPrint as a Class III device, which would have required full premarket approval. However, Agendia filed a petition requesting that the device be reclassified as a Class II, which only requires 510(k) premarket notification.
By issuing the guidance, FDA determined that MammaPrint and future genomic breast cancer prognostics are Class II devices “with the establishment of special controls” outlined in the guidance document.
“Any firm submitting a 510(k) premarket notification for a gene expression profiling test system for breast cancer prognosis will need to address the issues covered in this special controls guidance,” the agency said in the document.
A 510(k) premarket submission demonstrates to FDA that the device is at least as safe and effective, and substantially equivalent to a legally marketed device, and is not subject to PMA. However, under the de novo 510(k) process, products that have no “predicate” on the market are required to establish “special controls” outlining the pathway for clearance.
“The special controls guidance provides a pathway to clearance under a 510(k) route for an IVD or any laboratory-developed test that fits the scope of the guidance,” Radensky said. “The special controls guidance provides a pathway, but it does not mandate the pathway that must be followed for clearance.”
OIVD’s Gutman told GenomeWeb News that the guidelines are not currently supported by any regulations. “The FDA does not usually draft regulations to outline technical review requirements,” but prefers to issue guidances which are less binding but are easier to revise, he explained.
Genomic Health Excluded?
According to Gutman, the review process for prognostic tests is “contingent on the intended use of the device,” and the “design of the studies and data sets required will be influenced by a particular use.”
In the document, FDA notes that the guidance “does not address predictive markers, which are distinguished from prognostic markers, because predictive markers predict response to therapy.”
If the eXagenBC test is approved, there will be four genomic-based breast cancer-recurrence assays on the market, including products made by Genomic Health, Agendia, and Quest. Of these, Genomic Health’s test is the only one that is both prognostic for breast cancer recurrence and predictive for chemotherapy benefit.
The impact of the guidance on Genomic Health’s breast cancer assay was not immediately clear. The company did not respond to requests for an interview. However, tests used to make treatment decisions, like Oncotype DX, will likely have to garner a PMA.

“It makes the unknown features of a new set of draft guidelines, the IVDMIA draft guidance, less mystical. It kind of puts it all out there, and makes a roadmap relatively clear for device manufacturers.”

“It would appear that tests that are used in the context of treatment decision-making may require premarket approval under Class III,” Radensky said.
Oncotype DX analyzes a specific set of genes within a tumor to determine a recurrence score between zero and 100 that corresponds to a specific likelihood of breast cancer recurrence within 10 years of the initial diagnosis. The test also assesses if women will likely benefit from certain types of chemotherapy.
During an earnings call last year, Genomic Health acknowledged that its prognostic/predictive test places it in a precarious position with the FDA.
In its draft IVDMIA guidance, the FDA “did say that the tests that have a predictive claim to a drug benefit versus a prognostic could be considered a Class II or III device. But [FDA] leaves themselves a lot of flexibility,” Genomic Health CEO Randy Scott noted in the call [see PGx Reporter 11-08-2006]. 
Genomic Health began selling Oncotype DX, which is performed in its own CLIA-approved lab, as a homebrew test without first seeking FDA approval. The status of the test is currently under discussion at the FDA.
In a letter to the company last year, OIVD said it considers Oncotype DX a device under section 201(h) of the Federal Food, Drug, and Cosmetic Act [see PGx Reporter 02-01-2006]. The agency requested Genomic Health set up a meeting with OIVD “to discuss the nature and appropriate regulatory status of your technology, and the least burdensome ways that Genomic Health may fulfill any premarket review requirements that may apply.” 
Demystifying IVDMIAs
With the IVDMIA draft guidance, the FDA appears to be trying to rein in other firms from taking the same regulatory route as Genomic Health took with its test. The classification of Class II and Class III breast cancer recurrence tests in the “special controls” guidance sheds some light on how the agency might regulate IVDMIAs.
FDA has expressed its intent to regulate IVDMIAs, reasoning that they are more complex than other types of laboratory developed assays. At a public hearing in February, device manufacturers criticized draft guidelines discussing the regulation of such products, claiming that FDA oversight would be too cumbersome for companies, stifle innovation, and hinder patients’ access to such products [see PGx Reporter 02-14-07].
According to Exagen’s Popper, the content of the special controls guidance clarifies FDA’s thinking on IVDMIAs.
“It makes the unknown features of a new set of draft guidelines, the IVDMIA draft guidance, less mystical,” Popper said. “It kind of puts it all out there, and makes a roadmap relatively clear for device manufacturers.”
During FDA’s public meeting in February, industry stakeholders noted that the guidance was not clear about what FDA considered an IVDMIA or how FDA regulation of such products would dovetail with existing CLIA regulations.
“The takeaway for Exagen is that FDA is following through with what they said they would do in a very transparent manner, and it makes us feel very good about how we prepared our [510(k)] submission,” Popper said.
- Matt Jones, reporter for PGx Reporter sister publication GenomeWeb News, contributed to this article. 

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