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FDA Sensed Firms Bent 98 ASR Rules; Gutman s Group Rewriting Regulation

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The US Food and Drug Administration’s July 8 letter to the chief of Roche Diagnostics will likely set the tone for the way the agency oversees analyte specific reagents in the future, according to industry experts.

Additionally, in a separate resolution that will broadly impact many molecular diagnostics firms, the agency has decided to rewrite the original ASR regulation written in 1997 and enacted in November 1998, SNPtech Reporter has learned.

Some insiders believe that Steven Gutman, who heads the FDA’s Office of In Vitro Diagnostics Device Evaluation and Safety, which drafted the Roche letter, has been hinting for some time that companies may be stretching the definition of ASR in order to ease a product onto market. The untitled letter to Roche, which can be read here, is seen as the first publicly released manifestation of these hints.

The FDA “has known about [alleged rule bending] for a while, but hasn’t done too much unless very, very specific diagnostic claims were made” in advertising or other literature, said Ron Eisenwinter, a regulatory specialist at Boston Healthcare Associates-Expertech.

“I think that is where Roche is going to get into trouble — that they made diagnostic claims” about a product they claim is an ASR. [See transcript of interview with Eisenwinter on page 6.] Meantime, Bill Pignato, vice president of regulatory affairs at Exact Sciences, agreed, saying he believes the FDA thinks there has been a “misrepresentation of the [ASR] rule.”

To be sure, the letter illustrates the junction where rapid advances in microarray technology meets the FDA’s admitted inexperience in dealing with them as stepping stones, or components of in vitro diagnostics. In broader terms, the letter — and certainly the soon-to-be amended ASR regulations — might impact the entire molecular-diagnostics industry, especially Roche competitors developing similar “ASR” tests.

“This will be a very interesting case study in the coming months,” said Pignato. “Clearly, ASRs are an important regulatory priority within the Office of In Vitro Diagnostics.”

Under Scrutiny

The crux of the OIVD letter to Roche Diagnostics General Manager Heinrich Dreismann is the FDA’s apparent confusion over how the company can market its AmpliChip product as an ASR. In the letter, the FDA contends that Roche claimed in a June 25 press release that the AmpliChip is a multi-signal device that may only be used on the Affymetrix platform [read the press release here].

“The AmpliChip microarray appears to be an assembled device that is part of a specific test system,” Gutman said in the letter.

The letter also intimated that the AmpliChip is a “‘diagnostic tool’ that provides information about an individual’s genetic make-up for selection of drug therapies to treat ‘cardiovascular disease, high blood pressure, depression, ADHD, and more.’

“Given these claims,” the letter continues, “it appears that the AmpliChip CYP450 is a medical device” that may require pre-market approval. “Based on the press release and other materials about the AmpliChip obtained from your company, FDA is concerned that your device would not properly be classified as an ASR,” the FDA concluded.

Though the FDA does not comment on open compliance issues, Gutman last week told BioArray News, SNPtech Reporter’s sister publication, that such communiqués are of an informal and advisory nature, and that they wield authority.

“I can assure you that in the few that I have dealt with, they are not without clout,” Gutman told BioArray News.

“It’s no surprise to anybody in the diagnostic industry that the FDA is looking very closely at their regulation on ASRs,” said Pignato. In fact, he said, the FDA is currently revising the original 1998 ASR regulation [read the original document here]. “For a number of reasons, the agency feels that … there’s a need to rewrite the rule.”

Pignato, who regularly attends OIVD roundtable discussions, stressed that the AmpliChip issue did not spur the agency to rewrite the lengthy regulatory document. Pignato said that although the agency had been considering amending it “for the past six months,” he said Gutman announced at a roundtable meeting July 11 — three days after sending the Roche letter — that he plans to rewrite the document. Commenting on that meeting, Pignato said “it’s very clear that [the FDA is] in the process of rewriting the rule and issuing it as a proposed regulation.” He said it will be an amendment of the existing regulation, and will be required to go through the standard public comment period.

“Because of the change in the landscape in the technology, I think the FDA really feels there’s a need to revise the rule and bring further clarity on what an ASR is and what an ASR is not,” Pignato said.

An FDA official did not return a telephone call seeking comment.

It remains to be seen whether Roche will be censured — or what its punishments might be — if the FDA concludes the diagnostics giant overstepped its bounds. The agency does not comment on ongoing compliance issues.

Roche may encounter one of three likely outcomes, according to interviews with industry insiders, analysts, and consultants. One option is that nothing will happen, and that both parties will agree “it was a misinterpretation on the part of the FDA,” according to an analyst who spoke on the condition of anonymity.

Another potential outcome is that the AmpliChip, as it is currently marketed, will require to undergo a pre-market review. The third option lay someplace between the first two.

Expertech’s Eisenwinter said, hypothetically, that if the FDA concludes that the AmpliChip could not be marketed as an ASR, Roche would be required to halt selling the product and submit a 510(k). But if Roche’s product is the first of its kind on the market, “then it’s a PMA, and you’re talking 3 years-plus” to get approved, Eisenwinter told SNPtech Reporter.

Roche is widely believed to be the first company to market a microarray-based diagnostic test for clinical use, and Heino von Prondzynski, Roche Diagnostics’ CEO, said in the statement: “We remain committed to being the first company to fully develop and commercialize … [microarray technology] for clinical applications.”

The statement itself reads that the AmpliChip is “the world’s first pharmacogenomics microarray for clinical applications.”

Said Eisenwinter: “I think you’re going to see some very good arguments by Roche lawyers about why [the AmpliChip] is an ASR.”

Christiane Koesling, a Roche spokeswoman, said the company would work with the FDA. “They are not saying that our conclusions are not appropriate but they would like to discuss it. We look forward to working with the FDA.”

“Roche remains committed to working with the FDA to develop this exciting technology for clinical diagnostic applications,” added Greg Heath, head of Clinical Genomics at Roche Molecular Diagnostics in Pleasanton, Calif.

Industry Reacts

Though the ultimate outcome of the letter remains open to speculation — Dreismann and Gutman have not yet set a date to meet — one thing is certain: The industry, especially Roche and its competitors, will be keeping their ears open.

“Clearly it will catch the attention of the industry,” said Pignato. “It will make people look at their technology and maybe come in and talk to the agency, and maybe force people to think twice, or to make sure that what they’re doing is properly labeled.”

Understandably, industry was careful in the way it presented its opinions. “We believe there is a huge potential for these products to enable new solutions for improved diagnosis and patient care,” Affymetrix said in a written comment to BioArray News.

Amersham Biosciences, which sells a Codelink P450 SNP-microarray product intended for the research market, noted in an e-mail to BioArray News: “ASRs are under consideration, but we have made no decision at this point.”

David Ludvigson, executive vice president of San Diego-based Nanogen, said that the company will be watching the process closely. The company has five microarray-based products marketed as ASRs, and Ludvigson said it has received no compliance letters from the FDA.

A spokesman for Tm Bioscience, a Toronto-based microarray shop, said it hopes that any FDA action will ensure a level playing field. The company has previously said it plans to roll out its own mutation-detection kit for P450-2C9 at the end of the year, and a kit for P450-2C19 in the first half of 2004.

Meantime, Charlie Barnett, a founder of Healthspex, a Knoxville, Tenn.-based startup that is commercializing diagnostic biochip technology licensed from Oak Ridge National Laboratory, said that the AmpliChip issue will not cause his outfit to readjust its course. Healthspex is building a prototype biochip that will initially go to market as an ASR for cystic fibrosis, he said..

—KL and MOK

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