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FDA Clears Agendia’s MammaPrint as Industry Frets Over Agency's IVDMIA Draft Guidance

The US Food and Drug Administration last week said it cleared Agendia’s MammaPrint breast cancer recurrence test for clinical use, marking the first time the agency has approved what it has dubbed an in vitro diagnostic multivariate index assay.
The Dutch company also became the first European diagnostics shop to successfully navigate the US regulatory agency with a microarray-based diagnostic.
Both facts were underscored over the past week as other European diagnostic shops considered Agendia’s success a roadmap, while a newly formed industry group urged the FDA to reconsider a draft guidance in which it outlined that it, and not CLIA regulations, should oversee these kinds of tests.
The MammaPrint clearance “is a major step forward in resolving the regulatory hurdle on IVDMIAs that has concerned the industry,” Dag Christiansen, marketing director for Norwegian diagnostics firm DiaGenic, told BioArray News in an e-mail this week. “It is also encouraging that the first company was from Europe and that the FDA approval was built on a CE marking.”
According to Agendia CEO Bernhard Sixt, by pursuing a CE Mark for MammaPrint, as well as other international product and laboratory standards, the company put its flagship assay on strong turf to make it through the FDA submission process, which is widely considered to be more rigorous than obtaining a CE Mark.
“Agendia's primary objective from the very first day was and is to deliver according to the highest standards,” Sixt wrote in an e-mail to BioArray News last week. “This becomes visible looking to our CE-marking of all our products, the [International Standards Organization] 17025 accreditation, and Clinical Laboratory Improvement Amendment-[informed] registration of our central laboratory.
“Following this route ensured that most of the requested data were already in our drawer, and only some very US-specific issues remained to be solved,” he added. 
The MammaPrint test uses an expression signature from 70 genes to help physicians decide whether and how breast cancer will recur. Agendia currently does all MammaPrint testing through its central laboratory in Amsterdam, which analyzes biopsies sent by clinicians.
Sixt wrote there would be “no exceptions” to this model “in the near term,” although the firm is considering a number of routes for selling to the US market, including using distributors or establishing a direct presence.
Agendia most recently signed distribution deals in Australia and South America (see BAN 2/6/2007, BAN 11/21/2006). Similar distribution deals exist in the UK and South Africa.
Agendia also currently offers CupPrint, a gene expression-profiling service to assist in determining the primary tumor in patients diagnosed with cancer of unknown primary. However, Sixt said that the company has no plans to seek FDA clearance for CupPrint at this time.
Seal of Approval?
While MammaPrint’s path to the US market isn’t immediately clear, Sixt told BioArray News that news of the test’s clearance by the FDA will benefit it in other markets, starting with Europe.
He said that Agendia would begin increasing its presence in Europe because he believes that “the market acceptance is greatly helped by the FDA approval.”
That view was echoed by DiaGenic’s Christiansen, who said the company is currently developing two separate tests for breast cancer and Alzheimer’s disease. He told BioArray News this week that the firm would consider FDA approval to be “world-wide accepted recognition” of a technology that would help sell tests globally.
“The FDA is held in great respect throughout the world,” Kari Paukkeri, CEO of Finnish biotech Jurilab, noted in an e-mail BioArray News this week. “Approval of any product by the FDA will facilitate its approval and acceptance elsewhere.”
Still, Paukkeri voiced some concern about the way the FDA goes about approving tests like MammaPrint.

“The challenge is to draw up appropriate regulation in order to support and encourage such innovation while ensuring adequate rigor in the development process.”

Noting that MammaPrint is “a new generation of diagnostic test,” Paukkeri said that “the challenge is to draw up appropriate regulation in order to support and encourage such innovation while ensuring adequate rigor in the development process.

In Paukkeri’s opinion, the regulatory process for multivariate index assays should be able to “determine that the test is providing correct, relevant, and reliable information” while remaining “practical and affordable so as not to exclude small firms with good ideas from the potential market.”
The question over how to regulate assays like MammaPrint was brought into sharp relief last week during an FDA-sponsored meeting discussing the IVDMIA draft guidance, "Draft Guidance for Industry, Clinical Laboratories, and FDA Staff – In Vitro Diagnostic Multivariate Index Assays." Diagnostic Multivariate Index Assays."
As reported last week by BioArray News’ sister publication Pharmacogenomics Reporter, stakeholders participating in the meeting in Gaithersburg, Md., claimed that the draft in its current form is untenable, even potentially illegal.
Presenters criticized the document for failing to clearly define what the FDA considers IVDMIA’s; for not explaining how the agency’s regulations would dove-tail with CMS’ Clinical Laboratory Improvement Amendments guidelines; and for its potential to serve as a disincentive to innovation in personalized medicine.
Additionally, a consortium has been formed to petition the FDA to reconsider or amend the guidance. The group, calling itself the Coalition for 21st Century Medicine, comprises industry players such as Nanogen, CombiMatrix, and Sequenom, and takes issue with the FDA becoming a stronger regulator in a market traditionally overseen by Clinical Laboratory Improvement Amendments regulations.
In an e-mail to BioArray News this week, Agendia’s Sixt brushed aside the claims of the Coalition for 21st Century Medicine, arguing that the regulatory status quo “is not in the best interest of the patients nor the industry” when it comes to genomic tests. 
“Agendia has now several years of experience [in] marketing molecular diagnostics to physicians worldwide,” he wrote. “The field is and should be quite conservative to take up new products as they will have impact on patients' lives.
“Agendia has deliberately chosen the FDA route to obtain an objective quality assessment, not only in US, but also in Europe, as such approvals will greatly increase market acceptance of those tests,” he added.

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