Two weeks after the US Food and Drug Administration released its 25-point action plan for revamping the 510(k) submission process, response from the proteomics-based diagnostics community has ranged from polite applause to a stifled yawn to open disappointment.
The plan, which the agency made public on Jan. 19, detailed a number of draft guidances FDA intends to put out this year covering proposed changes to processes including the appeal of decisions made by the Center for Devices and Radiological Health; the submission of clinical data; the characterization of "intended use"; the identification of safety and effectiveness issues; and the classification system for de novo 510(k) filings, which covers tests that are not high-risk enough to warrant premarket approval, but lack the predicate device that is required in the standard 510(k) approval process.
"Given the situation and the tools FDA has to work with, the plan is impressive," Erik Nilsson, president of diagnostics firm Insilicos, told ProteoMonitor. "My sense is that FDA is trying to thoughtfully improve the 510(k) process. Their discussion of the current process's shortcomings is remarkably blunt."
Among the issues that the agency announced it would be tackling, the most important to protein diagnostics developers, according to Nilsson, include FDA's planned guidelines clarifying what device modifications would warrant a new 510(k) submission and streamlining the de novo classification process.
He also noted as potentially significant the agency's intention to address its rules regarding the rescission of 510(k) clearances, as well as the development of a Class IIb classification that could serve as a regulatory category bridging the gap between medium-risk Class II devices, which require 510(k) approval, and high-risk Class III submissions, which require the more stringent premarket approval.
On these two issues, however, the agency has punted for the time being, noting in its plan that they would be referred to the Institute of Medicine for further consideration. According to Mya Thomae, CEO of in vitro diagnostics regulatory consulting firm Myraqa, the lack of action on the Class IIb front in particular could hinder development of genetic- and proteomic-based diagnostics.
The Class IIb category "could be very helpful for folks developing IVDs, including proteomics-type products," Thomae told ProteoMonitor. "[It] would be sort of an intermediate step between a 510(k) Class II and a [pre-market approval] Class III device, where something that was a little bit higher risk [than a typical Class II device] wouldn't have to go up to the highest standard."
It could also provide a route, she noted, for diagnostics that "don't have a predicate device but that have risk in line with a Class II [device]."
In theory, Thomae said, FDA's de novo classification covers such products. According to Nilsson, however, de novo applications are "currently a slow and kind of baroque process." The hope, Thomae said, was that establishment of the Class IIb category would provide a more formalized procedure, with FDA mitigating the perceived additional risk by requiring the inclusion of manufacturing information above and beyond that normally submitted as part of a 510(k) application.
For Class IIb applications, FDA would likely want diagnostics developers to show, for instance, "that all the materials coming into the product are manufactured under the appropriate quality system regulation," she said. "A lot of the material we work with in diagnostics is labeled 'research use only', and that doesn't necessarily guarantee that it's made under quality systems. So they might want to see that you have the right level of QC on all your incoming materials. They don't have the ability to do that in a Class II application right now."
Yet, while, as Thomae suggested, Class IIb categorization could be a boon for diagnostics developers who would otherwise have to take the PMA route, there was relief in some quarters at the agency's decision to push off addressing the issue.
As John Babitt, Ernst & Young's Medtech Leader for the Americas, told ProteoMonitor sister publication GenomeWeb Daily News, some in the industry feared the new category could lead FDA to demand additional information from firms whose products traditionally would have required just a standard 510(k) submission (GWDN 1/20/2011).
The "biggest impact [of the plan] is what did not happen," Babitt said, explaining that there has been "quite a bit of concern that a lot of devices that are very incremental and truly do qualify for the spirit of what the 510(k) is would be bracketed" into the Class IIb category.
Post-market surveillance – which, like Class IIb categorization, was referred to the IOM for further review – is another item of potential concern, said Insilicos's Nilsson. In particular, he suggested its impact would depend on how it interacted with the agency's coming guidance on 510(k) modifications, due out in June 2011.
"Post-market surveillance sounds expensive, of course, but for [diagnostics] at some point we need to move to an environment of continuous improvement," he said. "To do that we need to gather the data anyway, so sharing that with the FDA isn't that big a deal so long as FDA doesn't charge us more than we can afford to look at it.
"In this scenario, I see post-market surveillance tied to the modifications guidance," he added. "You can combine these two items to create a really sterile environment where exciting new diagnostics just don't happen. More optimistically, you can combine the modifications guidance and post-market surveillance in a way that allows diagnostics products to improve every day."
According to Peter Levine, CEO of diagnostics firm Correlogic, more than any 25-point action plan, what FDA needs is an "attitude adjustment."
While "some of the proposals [the FDA has] made make a lot of sense… what's really required is an attitude adjustment from the top down," Levine told ProteoMonitor. "And I don't really see that in the proposed changes."
Correlogic's FDA travails are well documented as the company spent the better part of the last decade working to get agency approval for its protein biomarker-based ovarian cancer diagnostic OvaCheck.
Originally designed as a CLIA-based diagnostic, OvaCheck has existed in a state of regulatory limbo since 2004 when FDA informed Correlogic that it might have purview over the test. In December 2008, the company filed a 510(k) application with the agency, but was told that the patient population used in the clinical trial for the test was not satisfactory. Currently the company is undertaking the "second arm" of the trial, which involves patient populations being treated by non-specialists.
More than clarifications and streamlining, the 510(k) process needs to be scrapped entirely and rebuilt with regard to molecular diagnostics like OvaCheck, Levine suggested.
"Diagnostic tests should be an entirely separate category for regulatory oversight," he said. "And within that the entire issue of risk needs to be reviewed. You need to start with a clean slate, not building on the past perceptions of the agency."
"These are tests that are providing you information. They aren't being inserted into people's bodies. They aren't being used in the middle of life-and-death situations in the operating room," Levine added. "There's a huge difference between a blood pressure gauge that's being used in the middle of surgery and a molecular test that may suggest a person has cancer, but you can come back in a month and look at symptoms and keep evaluating. That risk profile is very different."
Levine added that "the overall framework of the 510(k) comes out of a much earlier era, and I think we really need to re-evaluate that."
Currently, a draft bill under development by Senator Orrin Hatch (R-UT) aims to address that issue by creating a separate FDA division for so-called "advanced diagnostics." As reported by ProteoMonitor sister publication Pharmacogenomics Reporter, the bill is still being crafted with input from industry groups such as the Coalition for 21st Century Medicine and the Personalized Medicine Coalition and could be introduced in the US Congress some time this year (PGx Reporter 1/19/2011).
The "Better Evaluation and Treatment Through Essential Regulatory Reform for Patient Care Act" would create the Center for Advanced Diagnostics Evaluation and Research, which would review test kits, laboratory-developed tests, and other diagnostics that are deemed to be distinct from devices, and therefore not subject to reviewed by FDA's Center for Devices and Radiological Health.
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