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In Warning Letter, FDA Says ParagonDx ASR Probes for Warfarin Sensitivity Require Premarket Approval

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By Turna Ray

In a warning letter to ParagonDx, the US Food and Drug Administration has deemed four analyte specific reagent probes used in pharmacogenetic testing for warfarin sensitivity as medical devices requiring the agency's approval.

According to the agency, Paragon's ASR probes for gauging the presence of CYP2C9*2, CYP2C9*3, VKORC1 1173, VKORC1 3730 variants "are devices because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body."

FDA's March 18 warning letter was issued following an inspection of Paragon's facilities in Morrisville, NC, in August 2009. The letter explains that FDA's inspection revealed these four probes to be "adulterated" and "misbranded" under the Federal Food, Drug, and Cosmetic Act requiring premarket approval.

Although Paragon is marketing these products as ASRs, the "devices do not meet the definition of an ASR," FDA informed the company. The FDA agency defines ASRs in 21 CFR 864.4020 as "antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reaction with substances in a specimen, are intended to use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens."

Most ASRs are Class I devices that don't require FDA approval or clearance. At the same time, these low-risk devices are "restricted" from being marketed with claims about analytical or clinical performance. "Your devices include several probes that must be used together to detect different genotypes rather than 'an individual chemical substance or ligand,'" the agency said in its letter, referencing an ASR guidance it issued in September 2007.

The guidance document, titled “Commercially Distributed Analyte Specific Reagents: Frequently Asked Questions," restricts manufacturers from claiming multiple functions for a single ASR and from bundling reagents together in order to sell them as an ASR. Products of this kind that detect multiple genetic variants or simultaneously detect multiple gene expressions should be treated as test kits, and manufactures should subject these kits for premarket review, the agency states in the guidance.

Additionally, the guidance advises companies from promoting an ASR "with specific analytical or clinical performance claims, instructions for use in a particular test, or instructions for validation of a specific test using the ASR."

In FDA's inspection, Paragon's marketing of its probes appears to be inconsistent with the legal promotion of ASR products. As such, the agency has asked the company to "take prompt action to correct the violations" cited in the warning letter. Paragon is also to respond to the FDA with a plan for correcting these violations and preventing similar infractions in the future.

Regulation of laboratory-developed tests is currently in flux at the FDA. In general, most laboratory-developed tests are overseen under the Centers for Medicare & Medicaid Service's Clinical Laboratory Improvement Amendment. The FDA, historically, has practiced "enforcement discretion" over the majority of LDTs and regulated high-risk test kits. In 2007, the agency expressed its desire to extend its oversight over a subset of LDTs that are more complex, multi-gene in vitro diagnostics, inciting much debate over FDA's regulatory authority and the impact of increased oversight on the laboratory testing industry (PGx Reporter 2/14/07).

In previous comments to Pharmacogenomics Reporter, Steven Gutman, former director of FDA’s Office of In Vitro Diagnostic Device Evaluation and Safety, has explained that with the ASR guidance the agency tried to clarify under the circumstances which "LDTs were considered medical devices," and when FDA would practice enforcement discretion (PGx Reporter 3/5/08).

"The ASR rule tried to clarify in each of the two paths to market (commercially distributed or LDT), that someone had to take full responsibility for developing the test and for the quality and performance of the test (from soup to nuts)," Gutman previously told PGx Reporter.

An interview request to ParagonDx was not answered. The company last year opened a clinical testing laboratory with the aim of offering warfarin sensitivity testing based on is ASRs (PGx Reporter 1/14/09).

It is not immediately clear how many other ASR manufacturers are similarly marketing probes for warfarin sensitivity testing, but the FDA's regulatory action against ParagonDx suggests that those manufacturers will likely receive similar warnings from the agency.

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