The US Food and Drug Administration’s draft guidance on in vitro diagnostic multivariate index assays is increasingly being challenged by diagnostic device manufacturers and other stakeholders who say the proposal may be illegal and pose a threat to product research and development.
Though most IVDMIAs under development or already on the market are gene-based, a handful is protein-based, including Correlogic’s OvaCheck test for epithelial ovarian cancer, which means proteomic companies have a stake in how the IVDMIA issue plays out.
The FDA released the guidance last September to signal its desire to begin regulating tests that use algorithms to interpret gene and protein data. Since then companies that manufacture such tests have been in a lather over the potential implications.
At issue is the new role that the FDA wants to play in the regulation of IVDMIAs. Traditionally, the agency has taken a hands-off approach to regulating manufacturers of homebrew tests, which have relied on Clinical Laboratory Improvement Amendments regulations.
In its draft guidance, the FDA said that while it has always had regulatory jurisdiction over such tests, it has elected not to exercise that authority. The draft serves as notice that the agency, compelled by the increasing number of homebrew tests hitting the market and their impact on patient care, has changed its mind.
Last week, stakeholders took their concerns to a public hearing organized by the agency. And on the same day an outfit of 21 device manufacturers, venture capitalists, patient advocates, and clinical laboratories announced they had formed a coalition tilted against the IVDMIA guidance.
The group, which calls itself the Coalition for 21st Century Medicine, will be examining other FDA-related issues and health care topics, such as reimbursement. But it was the IVDMIA draft guidance that triggered its creation, said Paul Radensky, an advisor to the Coalition and a partner in the Miami offices of the law firm McDermott, Will & Emery.
Among the Coalition’s members are companies with proteomics tools and instruments, including Bio-Rad, CombiMatrix Molecular Laboratories, and Ciphergen, which this week announced it was starting clinical trials for its ovarian cancer test developed using the SELDI platform it developed and once owned.
In an e-mail to ProteoMonitor this week, Ciphergen CEO Gail Page said the company is in “frequent discussions” with the FDA about the test and “will adhere to any formal guidance the FDA issues.”
Right to Regulate?
Since the FDA issued the draft guidance, stakeholders have raised a number of concerns, starting with its legal authority to regulate IVDMIAs. In September the Washington Legal Foundation filed a petition with the agency saying the agency “lacked the statutory authority to regulate tests developed by laboratories for their own use and offered only to health care professionals.”
The foundation, a non-profit public interest law and policy center, further said that “clinical labs have long been subject to regulation by another federal agency — the Centers for Medicare and Medicaid Services and its predecessors — pursuant to [CLIA].” Codifying the FDA’s proposal “could undermine effective health care by crippling these labs’ ability to quickly develop tests. …” the foundation said.
Others said that even if the FDA has the statutory authority to regulate IVDMIAs, the agency would be misguided to do so. In its proposal, the FDA said that it is troubled about how IVDMIAs rely on algorithms to calculate specific results, and then report those results in a way that would make it difficult for doctors to understand them without prior knowledge of the test.
Radensky told ProteoMonitorthis week that the use of algorithms does not inherently make such tests riskier than other laboratory tests.
“It’s not clear why something, just because it has different values that are then pulled together in some algebraic equation, is somehow riskier than other laboratory tests,” he said. “The first threshold is trying to understand what the public health concerns that FDA has are, and then based on that … what the most appropriate regulatory pathway is,” he said.
A common criticism from presenters at last week’s FDA hearing was that the draft guidelines are “technology based” and not “risk based.” But Daniel Schultz, director of FDA’s Center for Device and Radiological Health, maintained that “this couldn’t be further from the truth,” and said presenters had misinterpreted the agency’s intent.
“At the end of the day, what we are very, very interested in is providing a regulatory oversight framework that does in fact reflect the risk of the product,” Schultz said at the meeting held outside of Washington. “I will say to some extent — and perhaps we can do a better job of defining this — but there is a link between the changes in technology and the level of risk. We need to explain that. If you don’t understand it, then we haven’t succeeded.”
Diagnostic developers also worry that IVDMIAs would be regulated as Class II and Class III devices. Class II devices have to go through 501(k) pre-market notification. Class III devices have to get pre-market approval, which entails clinical trials.
“It’s not clear why something, just because it has different values that are then pulled together in some algebraic equation, is somehow riskier than other laboratory tests.”
In both instances, companies would be exposed to costly and lengthy review procedures, and for some of them, particularly smaller device manufacturers, going through these processes would be prohibitively expensive, they say. It’s a circumstance Correlogic now faces.
After several months of discussions between the FDA and Correlogic about its OvaCheck test, the agency has told Correlogic that it believes its test must go through the PMA procedure in order to go to market, though the agency has not told Correlogic of any specific safety concerns it has about the test, said Peter Levine, president of Correlogic.
“There is simply no question that having to go through a full PMA before a test can come to market will be very expensive and will likely discourage smaller companies from even attempting to bring innovative technologies to market,” Levine told ProteoMonitor by e-mail this week.
Correlogic’s experience supports the widely asked question of how the FDA’s regulatory authority would dovetail with the existing clearance pathway laid out by CLIA guidelines.
At the FDA meeting, some presenters said the draft guidance is unclear over the definition of an IVDMIA, and does not clearly identify the elements of an IVDMIA that comprise a medical device subject to FDA regulation versus those regulated under CLIA.
Several speakers cautioned that the guidelines, by imposing costly and time-consuming regulatory hurdles, may hobble innovation and make reimbursement even more difficult.
Others said the FDA’s plan could even hurt patient care. “The impact of the guidance on innovation [comes] directly and indirectly through the reimbursement system, and therefore [affects] the timely physician and patient access to the most up-to-date and newer signs of technology,” Mara Aspinall, president of Genzyme Genetics, said.
The controversy surrounding the FDA’s proposal may ultimately be resolved by Congress, where two pieces of legislation that may override the draft guidance are expected to be introduced in the coming months, said Radensky.
Sen. Barak Obama (D-Ill.) is expected to reintroduce a pharmacogenomics bill originally introduced in August that would authorize the Institutes of Medicine to do an analysis of genetic laboratory tests and “come up with a decision matrix” to assess what tests should be regulated by CLIA and what by the FDA, Radensky said.
Separately, Sen. Ted Kennedy (D-Mass.) is expected to introduce a bill that would require laboratories to report to the FDA information about all tests, not just IVDMIAs. If any deficiencies are found, the laboratory would have a chance to address them. If the laboratory does not correct the deficiency to the agency’s satisfaction, the test would then be subject to a 510(k) or PMA, Radensky said.
Turna Ray, editor of ProteoMonitor sister publication, Pharmacogenomics Reporter, contributed to this article.