Skip to main content
Premium Trial:

Request an Annual Quote

FDA Shelves IVDMIA Final Guidelines in Order to Focus on Overall LDT Regulation


Originally published June 17.

By Turna Ray

For the time being, the US Food and Drug Administration is dropping the idea of issuing a final guidance on in vitro diagnostic multivariate index assays and focusing more broadly on the agency's role in ensuring the safety and efficacy of all laboratory-developed tests.

"It's possible that we will issue [an] IVDMIA guidance in the future but with this public meeting [scheduled for July], we are addressing LDTs at once in a public dialogue, instead of dealing with subset by subset," FDA spokesperson Erica Jefferson told PGx Reporter this week. "The laboratory community has been supportive of looking at how to regulate LDTs and not only IVDMIAs."

The FDA said in a Federal Register notice this week that due to "public health concerns … it is time to reconsider its policy of enforcement discretion over LDTs." Simultaneously, in a New England Journal of Medicine editorial, FDA Commissioner Margaret Hamburg and NIH Director Francis Collins wrote in favor of a more consistent approach to regulating genetic tests is necessary now that LDTs are increasing in complexity and being broadly marketed to people in the context of personalized medicine without being reviewed by the FDA (PGx Reporter 06/16/10).

In a meeting scheduled for July 19-20 in Washington, DC, the agency will invite stakeholder input on its regulation of LDTs. After the July meeting and a subsequent comment period ending Aug. 15, the agency is planning to develop guidelines for public comment and "phase in" the regulatory framework outlined in the guidance over time.

FDA's move to regulate all LDTs in a risk-based manner comes after industry stakeholders and advisory groups argued that the agency's selective regulatory approach to regulate only a subset of high-risk LDTs — IVDMIAs — led only to more confusion and created an uneven playing field. In December 2008, Genentech petitioned the FDA to take make its in vitro diagnostics regulations more consistent by extending its oversight over LDTs in a risk-based manner (PGx Reporter 12/17/08). The HHS Secretary's Advisory Committee on Genetics, Health, and Society issued a report in 2008, recommending much the same (PGx Reporter 02/20/08).

The agency's public meeting on LDTs comes three years after the agency convened stakeholders to discuss its regulatory approach for IVDMIAs, lab-developed multiplex tests that employ mathematical algorithms to interpret a person's molecular-based risk for disease or likelihood of response to a drug. That highly contentious meeting led to a second draft guidance on the topic that satisfied few players in industry. Along the way, FDA never finalized its IVDMIA guidance, but as the industry eagerly awaited more clarity on the topic from FDA, agency officials have issued conflicting timelines for when a final guidance may come out.

Now, in light of the regulatory uproar surrounding the direct-to-consumer marketing of genetic tests, it seems FDA is dropping its work on an final IVDMIA guidance in order to clarify its broader regulatory authority over all LDTs, an authority the agency says it has, but hasn't exercised since the implementation of the Medical Device Amendments of 1976.

The FDA has practiced enforcement discretion over the majority of LDTs, which are assays developed and analyzed at laboratories that have been accredited under the Centers for Medicare and Medicaid Services' Clinical Laboratory Improvement Amendment. Although laboratories are certified to develop and analyze these tests, the assays themselves do not hold 510(k) clearance or a premarket approval from the FDA.

Meanwhile, the FDA has focused its regulatory muscle on diagnostic kits, analyte-specific reagents used in LDTs, and IVDMIAs.

The news that FDA is scuttling the IVDMIA guidance right now was received positively by some in the industry.

"We are pleased with FDA's announcement of a public meeting to discuss the potential oversight of all laboratory developed tests," a Genomic Health spokesperson said this week. "We applaud the agency for taking this deliberate approach with substantial stakeholder input, in particular from the laboratory community, to develop a more reasonable and predictable regulatory system for advanced diagnostic tests that is based on the medical decision and role that test plays in making it, rather than the technology used to run the test.

"These efforts signal that FDA recognizes the need to develop policy better suited for physician-ordered diagnostic laboratory tests that supports innovation and ensures adequate transition time for implementation," the Genomic Health spokesperson added.

Under the draft IVDMIA guidelines, Genomic Health's 21-gene breast cancer recurrence test Oncotype DX falls under the IVDMIA category. When FDA was first mulling its IVDMIA guidance in 2006, it sent a letter to Genomic Health inviting the company to discuss the regulatory status of Oncotype DX, which Genomic Health markets as an LDT out of its CLIA-certified laboratory (PGx Reporter 02/01/06). However, since then, although Genomic Health officials have said they are discussing Oncotype DX's status with the agency, the FDA has not formally required the company to submit the test for regulatory approval, and Genomic Health hasn't submitted the test to the agency for review.

However, during this time, since it seemed FDA was moving very much toward regulating IVDMIAs, many companies marketing multiplex in vitro diagnostics took pains to get their tests cleared by the agency. One such company was Agendia, whose breast cancer recurrence test MammaPrint became the first IVDMIA to get FDA's green light (PGx Reporter 02/07/07).

In following years, Pathwork Diagnostics' Tissue of Origin test and the OVA1 ovarian cancer test from Vermillion and Quest Diagnostics were cleared as IVDMIAs by the FDA in 2008 and 2009, respectively. Vermillion pursued IVDMIA clearance of its test even as it was in the midst of bankruptcy proceedings.

Furthermore, Laboratory Corporation of America received a warning letter from the agency in 2008 for marketing its OvaSure ovarian cancer test without sufficient validation. Ovasure, a multi-protein biomarker panel test, seemed to fit FDA's definition of an IVDMIA, even though the agency didn't specifically cite that as the reason for its concern. Instead, the agency said that the company was marketing the test based on the results of a study that doesn’t represent the intended treatment population for the test (PGx Reporter 09/03/08).

During FDA's two-day meeting in July, the agency will provide an overview of the history and current regulatory status of LDTs, and convene experts and the public in discussing four topics, titled "patient considerations," "challenges for laboratories," "DTC marketing of testing," and "education and outreach."