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How Might FDA Letter Affect Roche, and What of Its Competitors?


At A Glance

Name: Ron Eisenwinter

Title: Consultant on FDA and regulatory issues, Boston Healthcare Associates-Expertech

Age: 49

Background: BS in cell biology and biochemistry from Boston University.


Steven Gutman’s July 8 letter to the chief of Roche Diagnostics is “pivotal,” and will set the tone for the way in which the agency views ASRs and other molecular diagnostics, according to many industry experts.

In fact, some insiders say that Gutman, who heads the FDA’s Office of In Vitro Diagnostics Device and Safety, has been hinting for some time that companies may be stretching the definition of what an analyte specific reagent is in order to plant their diagnostic on the market without enduring regulatory scrutiny. The untitled letter to Roche is seen as the first manifestation of these hints — and it’s not likely to be the last.

To be sure, the nature of the letter reflects the junction where advances in microarray technology meet the FDA’s inexperience in dealing with them as stepping stones to in vitro diagnostics. In broader terms, the letter will also impact the entire molecular diagnostics industry, especially Roche competitors that are developing similar “ASR” tests.

And considering the FDA has regulated ASRs since 1998, its letter to Roche will stand as the first test of its ability to define and regulate them. SNPtech Reporter caught up with ASR expert Ron Eisenwinter, a regulatory specialist with Boston Healthcare Associates-Expertech.

What is the FDA’s stance on ASRs, and has it changed at all since the regulations were enacted in 1998?

[Steven Gutman, director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety, an arm of the Center for Device Evaluation and Radiological Health], gave a talk about five or six months ago on reeling in the ASRs [see the PowerPoint presentation from the meeting here]. The hint started there, that some of the molecular diagnostics [companies] were abusing the ASR reg. And the agency has known about that for a while, but hasn’t done too much unless very, very specific diagnostic claims were made. And I think that is where Roche is going to get into trouble — that they made diagnostic claims. …

What I’ve seen in the industry is that, if you make a claim for marker X, Y, Z, you can get by with the ASR claim. But if you say marker X, Y, Z is [for example] for Huntington’s Chorea, then it starts going over to the IVD world.

And that means that it’s going away from the ASR world?

Yeah. The more you start making diagnostic and disease claims — or long-term diagnostic claims, where you’re saying, ‘30 years from now you may get breast cancer or testicular cancer’ — that’s also been talked about quite heavily. In fact, I was giving a talk [at a recent meeting] and Joe Hackett [founder of the FDA’s OIVD group] was there giving some snippets of information along that line [click here for PowerPoint or PDF versions of this meeting].

Some people I’ve spoken with say that the Roche ad that triggered the FDA open letter was too aggressive. Is there any validity to this claim? And, forgetting for a minute that the entire issue is still up in the air — as far as I’m aware, Heinrich Dreismann, general manager of Roche Molecular Diagnostics, is still working to set a meeting date — can Roche’s competitors draw a lesson from this, for example, composing their own ads for ASRs or chip-based diagnostics with less detail?

I think so. [Looking at the ad], Roche is already using diagnostic words [click here to read the original press release]. They’re using IVD-style wording. And that’s what FDA said in its letter: ‘You’re using the word “diagnose,” you’re using the words “clinical use,” you’re talking about disease states and monitoring disease states.’ That’s all more IVD than it is analyte specific reagent.

And in that case the AmpliChip would require FDA marketing approval?

Well, ASRs are regulated, but they’re all class I exempt, except for those for certain infectious diseases or [those] used in blood banks. Which is why all the companies are going that path. They need to maintain a quality system, which Roche does — they have class II and class III products — but under the ASR regs, they can be umbrella’d under the class I exempt, which means they don’t have to submit a 510(k). Now, the interesting thing about the ASR regs when they came out … is that in the preamble, which a lot of companies were using as a crutch, FDA did not discuss genetic testing in the ASR regs. So the FDA does, in itself, have a little bit of a problem because they never officially came out with how they were going to regulate genetic tests — at least under the ASR regs.

So, genetic tests were sort of in limbo when the ASR regs came out, but the FDA has quite a variety of guidance documents for IVD molecular diagnostic tests. I think they’re going to have to clear up the air as well, because they have made it confusing.

That’s an interesting point, because some people would argue that the FDA is playing catch-up with certain aspects of molecular diagnostics, and that its open letter to Roche should be taken with a grain of salt. Is the FDA still on the lower part of the molecular diagnostics learning curve, and does the existence of this letter illustrate this?

Yep. I think this is going to be a pivotal decision-maker on how the FDA is going to manage molecular diagnostic testing — and especially now that they came out with an array guidance [see SNPtech Reporter, May 23, 2003]. It’s draft right now, but it obviously showed that the agency was going to regulate microarrays as IVDs.

To be blunt, how can this have happened to a company like Roche? It’s the market leader in molecular diagnostics; it’s one of the biggest pharmas in the world; it has an army of regulatory lawyers. Is this carelessness, or an illustration that in the molecular diagnostics industry, being so young and rapidly changing, even big companies are open to these kinds of letters?

Well, it’s interesting. I’m reading the paragraph here [from the Roche press release]: ‘Roche will sell [this chip] as an ASR in the United States for use by CLIA-high-complexity laboratories … [and] expects the test to be available as an in vitro diagnostic in the United States and Europe later in 2004.’ Now, my guess is that they probably were very aware of, and probably wanted to take the risk. There’s another angle to this, and one that even the FDA admitted: They didn’t regulate these systems five years ago, because they were highly complex, and there was a lot of human intervention. You had to do a lot of mixing and amplification and purging and cleaning. It was a very difficult test that required a highly trained individual. I’m getting a little bit of hinting of this here: [Roche] is going to start [the AmpliChip] out as an ASR in a CLIA lab, which means you have to have highly trained technicians running it. But there’s also rumor that Roche is getting, especially in their Amplicor technology, more and more automated, and the system will become easier to use. My guess is that Roche probably said, ‘Hey, this is really a complex test that not everybody can do, and that’s why we think it’s an ASR.’

What might happen if the FDA, after meeting with Dreismann, says that the AmpliChip is not, in fact, an ASR, and that it’s an IVD?

Roche would have to stop sales and advertising, and submit a 510(k) or [pre-market approval].

How long would these scenarios set back the product?

If it’s a 510(k) … and no one else is selling them, and they don’t have a predicate, then it’s a PMA, and you’re talking 3 years-plus (Editor’s note: Roche is widely believed to be the first company to market a microarray-based diagnostics test, and Heino von Prondzynski, Roche Diagnostics’ CEO, said in the press release: “We remain committed to being the first company to fully develop and commercialize … [microarray technology] for clinical applications.”).

I think you’re going to see some very good arguments by Roche lawyers about why [the AmpliChip] is an ASR, and I think that’s going to be the play of action: ease of use versus difficulty of use, intended use, [and] the labeling claims, [which may allow Roche to] get away with it as an ASR just by changing the labeling in their advertising to read, ‘This detects CYP2D6.’

That sounds like one of the cheapest, fastest, and most painless ways of rectifying this issue.


Just changing the wording in the press release and the advertising?



Most recent SNPtech Reporter articles on the FDA, Roche Diagnostics, and AmpliChip:


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