In a move that could foreshadow a tightening of regulations on diagnostic testing, the Food and Drug Administration is questioning whether Roche began selling a novel genetic test without proper approval.
In a letter sent to Roche last week and posted on the F.D.A.'s Web site, the agency said it appeared that the company had improperly classified its genetic test in a way that allowed it to circumvent the need for a regulatory review. It called in Roche officials to discuss the matter.
The posting of the letter appears to be a warning to test developers that the F.D.A. is beginning to look skeptically at a common industry practice of taking advantage of rules that speed tests to market without having to prove that they work.
"I think the agency's concerned enough about the issue as a whole that it's starting to take some visible regulatory action," said Steven I. Gutman, director of in vitro diagnostic device evaluation and safety for the F.D.A. and the letter's author.
Roche's test, introduced late last month, is intended to predict how an individual will react to certain drugs so that doctors can adjust doses accordingly. It is one of the first tests to be sold that focuses on so-called personalized medicine.
The test is also significant because it employs a gene chip, a sliver of glass dotted with specks of DNA that is used to detect genes. Until now, such chips have been used mainly for basic research, not diagnoses.
Diagnostic tests that are sold widely to hospitals, doctors' offices and commercial laboratories must go through an F.D.A. approval process. But tests developed by a single laboratory and offered as a service by that laboratory do not require such approval, although the laboratory has to meet certain quality standards. These tests are sometimes known as home-brew tests.
Companies that develop tests they want to sell to many laboratories can take advantage of the home-brew system. Instead of selling a complete test requiring F.D.A. approval, they sell the basic ingredients of a test to clinical laboratories. The labs then use the ingredients to make home-brew tests. The ingredients, usually chemicals or pieces of DNA, are called analyte-specific reagents and are only lightly regulated.
Roche, one of the leaders in the diagnostic testing business, is marketing its gene-chip test in such a way. But the F.D.A. said the test appeared to be a complete medical device that should have gone through the regulatory approval process.
Greg Heath, head of clinical genomics at Roche Molecular Diagnostics in Pleasanton, Calif., maintained in a statement that "the F.D.A. is not saying, at this point, that our conclusion is inappropriate, just that they would like to discuss the subject further."
The outcome of the discussions will be closely watched. "I think it's an excellent test case to see what direction the F.D.A. and manufacturers will go," said Lawrence Silverman, scientific director of the molecular diagnostic laboratory at the University of Virginia.
Dr. Silverman said that while labs knew how to deal with some reagents, they were not familiar with this test and would have trouble ensuring that testing was done properly. "Roche is putting out a product that, quite frankly, we don't know how to validate," he said. "It's a technology more advanced than we're used to."
The issue arises as some experts are calling for tougher regulation of genetic tests. The skeptics say there are already tests being marketed based on unsubstantiated science, like some that help consumers tailor their diets or their skin creams.
"You don't have to look very widely on the Web to see bizarre genetic tests," Francis S. Collins, director of the National Human Genome Research Institute, said last month at the biotechnology industry's convention in Washington. "It runs the risk of fouling the whole nest."
An advisory committee on genetic testing to the secretary of health and human services recommended in 2000 that the F.D.A. begin regulating certain genetic tests, even those developed as home brews. Dr. Gutman of the F.D.A. said the agency was considering proposing rules to regulate not just genetic tests but all "high risk" diagnostic tests, which are ones that can seriously affect patient or public health.
The testing industry generally defends the home-brew system, saying it allows tests to be developed rapidly and economically in reaction to new genetic information. Some tests, like those for rare genetic diseases, would not be economical to develop if F.D.A. approval were required.
"The risk you run is that the greater level of federal oversight of those tests, the less likely someone might be to try to develop the test," said Vince Stine, director of government affairs at the American Association for Clinical Chemistry.
The Roche test, the AmpliChip CYP450, uses a gene chip made by Affymetrix and looks for mutations in two genes that are involved in metabolizing up to 25 percent of existing drugs. People with genetic variations that cause fast breakdown of the drugs might need a higher dose. Those with slow metabolism could take a lower dose to prevent toxic levels of a drug from building up in their body.
Another question about regulation might arise with tests now being developed to diagnose SARS. Some test developers have said that they will not seek F.D.A. approval, but will instead offer the tests as home brews, reagents or as research tests for studying the SARS virus — though not for diagnosis.
Murray Lumpkin, principal associate commissioner of the F.D.A., while acknowledging the need for SARS tests, said the agency would still want to review tests that would be widely distributed. "If a test is going to be used for patient-management decisions or quarantine decisions or isolation decisions, those are tests we'd consider significant," he said in an interview a few weeks ago. "We believe people ought to have confidence in the test that's being used."
There is little current competition in the initial niches that DNAPrint has selected to compete. At present DNAPrint is the only company in the world with IP for operating Admixture Mapping screens, and DNAPrint believes that the use of AIMs is crucial for the development of tests for complex, common traits (such as drug response) that meet expected clinical performance criteria. [From the 10k filing}
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