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In Surprise Draft Guidance, FDA Suggests It, Not CLIA, Should Regulate Multivariate Index Assays

The US Food and Drug Administration last week issued a draft guidance to industry that signaled its wish to begin regulating tests that use algorithms to interpret gene and protein data.
The devices, which the FDA calls in vitro diagnostic multivariate index assays, are relatively new to the market and are currently used by CLIA labs as homebrew tests. But some FDA officials believe they are growing at such a rapid pace that they have raised concerns about their impact on patient care.
If codified, the draft would mean some manufacturers would need to file such devices and tests for clearance with the FDA instead of complying with traditional CLIA regulations.
In addition to companies developing genetic tests, the draft guidance also has repercussions for companies such as Correlogic Systems that have or are developing protein diagnostic tests. Indeed, Correlogic has been in discussions with the FDA for several months over one of its tests.
“It appears to be signaling a new era,” said Gail Javitt, director of law and policy at the Genetics and Public Policy Center at John Hopkins University. “It does signal a regulatory change. It will mean that companies will need to submit information to FDA for review and demonstrate the analytical and clinical validity of their tests.”
While only a few such tests are currently available, their numbers are expected to grow. “More and more of these kinds of medical tests are being made available each year,” Daniel Schultz, director for the Center for Devices and Radiological Health at the FDA, said in a press release last week. “It is important for the companies and labs making the tests to clearly understand the regulatory requirement in place so that the tests they develop are as safe and effective as possible.”
Courtney Harper, associate director for toxicology at the Center for Devices and Radiological Health at the FDA, emphasized that the draft aims to clarify regulations that already exist and clear up the definition of IVDMIAs and the FDA’s role in regulating them. The document can be found here.
The FDA, she said, is not seeking to issue new regulations or additional regulatory powers. The agency already regulates certain diagnostic tests sold to laboratories, hospitals, and doctors that it deems medical devices, but historically the FDA has chosen to leave the makers of IVDMIAs to police themselves.
“This guidance is actually intended to clarify the fact that these are medical devices, whether they are developed in a laboratory or developed in a company and sold to a lot of companies,” Harper said. “That’s been something that some companies have not been understanding.”
Because IVDMIAs also cover a broad array of tests, there may be confusion about which ones are covered under the regulations, she added.
“Some of them are RNA expression arrays [or] they might be proteomic tests. But others might just be tests that measure demographic data, genotypes, or maybe even immunoassays for proteins,” Harper said.
Under the draft regulation, IVDMIAs are defined as devices that use multiple genes, proteins, and other clinical information from a patient, then use an algorithm or software to analyze the data to diagnose a disease or cure, prevent, or mitigate it.
Javitt of John Hopkins said that the FDA is particularly interested in knowing more about the algorithm or software component of such tests because they make it impossible for health care providers to evaluate the tests for themselves.
Those components, because they are proprietary and inaccessible to outside parties, eliminate the transparency of the safety and effectiveness of such tests, Javitt said, and the “FDA will likely want information demonstrating that that works, that you actually do get a correct answer … that actually reflects what action you should take.”
Review and Approve
Medical devices are currently put into one of three classes, with class I devices not needing any review or approval by the FDA. The FDA said how an IVDMIA is classified “would depend on its intended use[s] and on the level of control necessary to assure the safety and effectiveness of the device.”
The agency said it believes most IVDMIAs would require at least an FDA review before they can go on the market and in some cases would need full FDA approval before it could go to market.
“For example, a device intended as an indicator of a patient’s risk of cancer recurrence may be a class II device [requiring a review], while the same device intended to predict which patients should receive chemotherapy might require pre-market approval,” the agency said in its draft guidance.
It is unclear whether those companies that already have IVDMIAs on the market would have to pull them off the market for additional testing.

“It will mean that companies will need to submit information to FDA for review and demonstrate the analytical and clinical validity of their tests.”

“We just released this guidance and time will tell what will happen,” Harper said.
Reaction from companies making IVDMIAs to the draft guidance was muted.
Kevin Lorenc, a spokesman for PerkinElmer said the company was still evaluating the draft. “If any of our products is subject to this proposed regulation, we believe we are prepared to incorporate and comply with any requirements,” he said.
The FDA has already made moves to investigate tests currently on the market that it believes are IVDMIAs. Correlogic has been in discussion with the FDA for several months over possible regulation of the company’s OvaCheck, a protein-based blood test for epithelial ovarian cancer. In an e-mail, company President Peter Levine said that “if the FDA is going to regulate in this area, industry and the public are best served when regulations are clear and procedures and processes are defined.”
At an analyst conference held by ThinkEquity Partners this week, Randy Scott, CEO of Genomic Health, said that the FDA had contacted the company in January over its Oncotype DX breast cancer test. The test uses a gene expression profile to determine the likelihood of breast cancer recurrence.
Scott also questioned the need for a new regulatory set-up saying companies such as Genomic Health already have to abide by CLIA regulations. He said that it was too early to evaluate the impact of the FDA’s actions.
“Certainly, there’s always a balance between innovation and regulation so increasing regulation will have a net impact of taking a longer time to get to market for new tests,” Scott said. “On the other hand, we don’t know how that would net out ultimately in terms of [whether it] would…mean faster adoption and faster reimbursement.”
Comments on the IVDMIA draft guidance can be submitted to OIVD here. The comment period closes Dec. 11. The final guidance will be released some time in 2007, Harper said.

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