A suggested draft guidance document submitted to the FDA this summer, which petitions for a new regulatory category of in vitro diagnostic tests called in vitro analytic tests, has halted at its first regulatory road block, the general counsel’s office of the Food and Drug Administration, BioArray News has learned.
“A preliminary legal analysis of IVAT has indicated questions about whether this model is consistent with extant regulations and law. This is being further evaluated,” Steve Gutman, director of the FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety, said in an e-mail message Monday. Gutman said he was unable to comment further.
The initial filing of industry’s suggestions earlier crossed paths with another FDA action, a regulatory letter the agency sent to Roche Diagnostics seeking a meeting to discuss the propriety of the company’s marketing its microarray-based AmpliChip product as an analyte specific reagent [see BAN, 7/10/2003].
The two events have put the FDA squarely in the middle of the path microarrays are following from the research market to the larger clinical market where the hope is that microarray-based tools, backed by impeccable science, with gold-standard manufacturing practices and protocols, can provide information and medical insights to improve diagnosis, treatment, and prevention.
But the route from here to there is complicated by laws and regulations that were formulated before this technology blossomed.
The suggested IVAT has been seen by some as a way to smooth and perhaps narrow this regulatory road for microarray and other technology.
As first reported in BioArray News in August (see BAN, 8/6/2003), regulatory officials from Roche Diagnostics, Roche Molecular Diagnostics, BD, and Gen-Probe collaborated on a document (click here to view) that suggested this new category of in vitro diagnostic test — in vitro analytical test — and a new regulatory pathway for its approval.
The suggested guidance, with a cover letter dated June 17, 2003, defines an IVAT as: “an in vitro diagnostic test for which analytical validity has been established.” It suggested that IVATs should be approved for marketing through an analytical 510(k) clearance “based on review of the same analytical data that FDA now examines in premarket notification submissions.”
The document was drafted in the form of an official agency guidance, down to the front-page inclusion of Director Gutman’s e-mail address.
“IVAT is apparently not proceeding,” said Glen Freiberg, vice president of regulatory quality and government affairs at Gen-Probe, who joined regulatory executives from the other firms in drafting the draft guidance.
The decision was announced Friday afternoon at the FDA Industry IVD Roundtable, an industry-sponsored meeting attended by FDA officials and closed to the media, BioArray News learned.
Freiberg told BioArray News that industry would decide its next step in a conference call scheduled for Tuesday, Oct. 28.
One option, he said, would be to attempt to amend the Federal Food, Drug and Cosmetic act, the law under which the FDA operates, to change the system regulating in vitro diagnostic devices, “proposing that all IVDs, other than certain listed analytes, would be exempt from FDA review and approval and that you would do a dossier instead,” he said. “You would self-certify that you have complied with GMP [good manufacturing practices], and FDA wouldn’t look at your claims or your labeling other than for certain high risk products, like TB and blood screening.”
The test system for microarrays, he said, would be exempt from FDA review, unless it was “testing for something that was on one of those lists, in which case a dossier would have to be provided, but FDA still wouldn’t have authority to tell you what claims you would have to make.
“The odds of this happening are very low,” he said, “but by shooting at little higher target, we might have the opportunity to negotiate more with the FDA and on the lesser targets.”
What Is an IVD?
According to an article by Gutman in the journal Clinical Chemistry [1999;45:746-749] IVDs are “developed as kits or systems intended for use in multiple laboratories [that] require review by the FDA before being marketed to ensure appropriate performance and labeling. IVDs developed as in-house, or so-called ‘home-brew’ tests, or laboratory test services are considered medical devices but historically have not been subject to premarket review as a matter of enforcement discretion. FDA has established a new regulatory paradigm for in-house tests based on classification of the active ingredients or building blocks of these tests as analyte-specific reagents, which are exempt from premarket review but subject to both manufacturing and labeling control. Currently, genetic tests are received and reviewed by the FDA in the same manner as other in vitro diagnostic tests.”
In 1997, the FDA published the Analyte Specific Reagent Rule, which put into place increases in regulatory requirements for manufacturers and laboratories in 1998. In 2001, the Secretary’s Advisory Committee on Genetic Testing produced a report recommending that FDA apply its pre-market review process to new ASR-based genetic tests. That committee, however, was replaced by the Secretary’s Advisory Committee on Genetics, Health, and Society, but the previous advisory committee’s recommendations remain on the table and the FDA is seeking comment on whether genetic tests have a risk profile that might warrant additional oversight through changes in the ASR rule.
The Roche AmpliChip, manufactured by Affymetrix, may be the critical test of the FDA’s ability to adapt, and regulate, a technology that is evolving rapidly.
FDA officials freely admit a lack of deep and intimate knowledge of this technology, which is just beginning to come to the diagnostics market packaged as an ASR. However, FDA followers say that Gutman has been hinting for some time that companies may be stretching the definition of ASR in order to ease products into market, and the untitled letter to Roche, which can be read here, is seen as the first manifestation of these hints.
Greg Heath, senior vice president of clinical genomics of Roche Molecular Diagnostics, told BioArray News in September [See BAN, 9/10/2003] that the company had explained its reasons to the FDA for marketing the AmpliChip as an ASR, and was waiting on a reply from the agency, while at the same time, preparing an IVD submission.
Freiberg told BioArray News that he is of the opinion that “chips and the receptacles they go into really don’t belong as an ASR, and should be treated as any other test system, and those have always gone through the FDA.”
Others see few clear lines of demarcation.
“There is a complexity in IVDs that you don’t find in other devices; there are fuzzy areas,” Bill Pignato of Exact Sciences said last week at the annual Regulatory Affairs Professional Society conference in Baltimore.
The IVAT guidance, he said, was “thinking out of the box” for methods that are “revolutionary.”
Don St. Pierre, deputy director of OIVD, speaking at the same conference, agreed.
“It’s such a complex issue,” he said. “It’s not just ASRs, microarrays, and home-brews. It’s all interrelated and we need a plan that incorporates all,” he said. “I don’t know if the FDA can answer all questions. There are other agencies out there that can help and they fall under one department [Heath and Human Services] which is good at bringing them all together.”
But, St. Pierre added, “with [existing] statutes and regulations, you can’t get hurt too bad.”