Medical Device Link.

Originally Published IVD Technology May 2004

INDUSTRY NEWS

FDA’s final rule on tests for Factor V Leiden (FVL) DNA mutations, which categorizes them as Class II devices, may mark a turning point for many molecular tests. As molecular tests that were introduced as analyte specific reagents (ASRs) become commonplace on the market, FDA may require that the tests be subject to regulatory scrutiny as finished IVDs. 

“When working on the ASR regulations, FDA’s Dr. Steven Gutman envisioned a natural evolution of new research tools coming out, becoming ASRs, then becoming Class II or Class III IVDs,” says Rich Schifreen, PhD, director of technology and market development at Promega Corp. (Madison, WI).

“FDA has now taken the first step [to reining in ASRs that are now established tests]. They’re saying this is no longer new, it’s no longer research. An assay to determine the single nucleotide polymorphism that codes for FVL mutation is now a Class II test, and if you want to sell an FVL assay, you’re going to have to take it through the 510(k) process.”

Suspicion has risen among those in industry that this guidance might indicate the beginning of a trend for other established molecular tests marketed as ASRs. According to Schifreen, “The big question now is: did FDA just consider this guidance to apply to FVL, or did it intend this to be an example for the entire class of molecular diagnostic genetic tests?” 

Roche Molecular Systems (Pleasanton, CA) worked with FDA to develop the guidance. Roche representatives agree that this might be a first step toward FDA requiring other accepted ASRs to be reviewed in the form of full IVDs. “This is a reasonable way for FDA to get the ball rolling. By developing this guidance, FDA will get its feet wet and get industry comfortable with this shift by developing guidance for the most straightforward type of molecular test,” says Emily Winn-Deen, PhD, senior director for genomics business at Roche Molecular Systems. 

The availability of a finished test may be more appealing for laboratorians, would allow the test to be used by more laboratories, and may bring in a greater fiscal return. However, the cost of going from an ASR to a full IVD may be prohibitive for many tests. 

“By some estimates, a traditional diagnostic that has to go through FDA for approval must have a market size of about $50 million to be profitable. That’s going to be the balancing act. Both FVL and cystic fibrosis tests have large enough markets for some manufacturers, at least the market leaders, to support that cost. A lot of the molecular diagnostic test markets will not be large enough to support FDA filings, depending on what FDA asks for,” says Schifreen.

Although the cost of a traditional premarket 510(k) submission may be steep, Roche found that FDA was expeditious and fair in its review. According to Winn-Deen, “From the beginning of the discussion to the final approval, FDA was very open, so it really is trying to abide by this kinder, gentler, least burdensome approach that Dr. Gutman has been talking about, at least in this case.” 

In addition, company representatives feel that a similar approach would work for other molecular tests. “FDA has provided an extremely reasonable alternative path that is really not a whole lot more work than putting out an ASR. If FDA was to stick to this guidance document for other similar analytes, then I think that people would not consider this framework to be particularly burdensome. In fact, it might encourage more manufacturers to go directly to IVD,” says Winn-Deen.

Yet there is some doubt that FDA is ready to apply similar guidance to other well-established molecular tests that are more complicated or multiplexed. “This guidance may have implications for submissions of other simple genetic tests for one polymorphism, but when you get to something like cystic fibrosis, where you’re looking at multiple mutations there, I don’t think this guidance will have any real impact,” says Winn-Deen.

Nonetheless, there is a sense that FDA will broaden its scope, draw in more-established ASRs, and require that they be submitted for review by the agency as test kits. “My prediction is that Dr. Gutman is going to be judicious. That he’s going to look first at high-risk analytes like HPV and other infectious diseases. Then he’s going to look at market size and apply enforcement judiciously. With that approach, he won’t recreate the problem that started this, which is patients not having access to the best technology,” says Schifreen.

Similar requirements from FDA for other molecular tests may send a blow to smaller IVD manufacturers. “From a business standpoint, this trend is going to push toward consolidation, thereby favoring larger companies with the [fiscal] resources to take their products through the FDA submissions,” says Schifreen. 

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