FDA is narrowing the focus of its proposed guidelines for manufacturers of gene-based tests from its original 2003 draft in response to comments from industry members and scientists, according to a revised ¹ draft guidance document issued Feb. 9.

Newly available tests reflect emerging interest in the field of pharmacogenetics, the practice of using an individual's genetic make-up to personalize medical therapy.

Roche Diagnostics' AmpliChip CYP450 , for predicting a patient's response to various classes of therapies, was one of the first pharmacogenetic tests to be FDA-cleared in December 2004. More recently, Third Wave Technologies' Invader UGT1A1 assay, for helping a physician determine the appropriate dose a patient should receive of Pfizer's chemotherapy drug Camptostar , was cleared in August 2005 (² Also see "FDA Clears Third Wave Invader Pharmacogenetic Test" - Medtech Insight, 29 August, 2005., p. 26).

In addition, Genzyme, which will be marketing the Invader for Third Wave, has launched three tests in the past five months through its high-complexity CLIA-certified laboratory, not under FDA oversight, to identify patients that are likely to respond to certain cancer drugs.

Each of these assays tests the presence or absence of a single gene mutation or multiple gene mutations simultaneously to help a doctor predict a patient's reaction to a drug.

Current research is exploring the use of more intricate measurements to analyze complicated patterns in the expression, or activity, of hundreds or thousands of genes throughout a person's genome to help further individualize therapy decisions.

The newly updated draft guidelines, entitled "Pharmacogenetic Tests and Genetic Tests for Heritable Markers," provide recommendations for submitting premarket review applications for AmpliChip and Invader-type tests. But unlike 2003 draft guidelines, the new draft does not address more technically complicated gene expression microarrays.

FDA said in the original draft guidance - "Multiplex Tests for Heritable Markers, Mutations and Expression Patterns" - that it would issue a revised draft rather than proceed straight to a final guidance because the "public health will benefit from the dialogue."

Numerous stakeholders, including Bayer Diagnostics and the American Association for Clinical Chemistry, stressed to the agency in written comments that the two technologies - genetic mutation assays and gene expression tests - are too different in design and purpose to be considered in the same document.

Steve Gutman, director of the Office of In Vitro Diagnostic Device Evaluation & Safety, says a draft guidance focused on gene expression microarrays is in the early stages of development, but there is still a big learning curve for this technology. No such products have been submitted for marketing clearance as of yet, although some companies have expressed interest, he says.

For the simpler genetic tests, the updated draft says that most first-to-market products will be cleared in the same manner as the AmpliChip and Invader - via 510(k) applications under the de novo classification process (³ Also see "Roche Launches Test Assessing Drug Metabolism; Psychiatrists Targeted" - Medtech Insight, 17 January, 2005., p. 28).

This approach allows devices without a predicate to be labeled as Class II products not requiring a PMA if evidence submitted by the sponsor indicates this is appropriate to assure safety and efficacy. If the intended use of the diagnostic translates into a high risk assessment, a PMA may still be required.

The de novo process typically depends on clinical evidence from the manufacturer, but for gene markers whose utility has already been well established in the scientific literature, sponsors might be able to submit peer-reviewed journal articles to lighten the burden of the application, the draft explains. In the case of newer markers, further clinical study will likely be necessary.

The revised guidelines also describe FDA's expectations for how test manufacturers should assess a genetic assay's analytical performance measures, such as precision, as well as how to validate software components of a test system, among other issues.

Comments on the document are due to the agency by May 10.

New Genetic Test Guidance Narrows Focus To Mutation Marker Assays

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