Letter from OIVD to Roche Molecular Diagnostics Re: AmpliChip™

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VIA FEDERAL EXPRESS

October 29, 2003

Mr. Heinrich Dreismann
General Manager
Roche Molecular Diagnostics
4300 Hacienda Drive
Pleasanton, California 94588

Re: AmpliChip™ CYP450 ASR v1.0

Dear Mr. Dreismann:

The Office of In Vitro Diagnostic Devices (OIVD) has completed its review of the status under the Federal Food, Drug, and Cosmetic Act (FDCA or Act) of the microarray marketed by Roche Molecular Diagnostics (Roche) under the trade name AmpliChip™ CYP450 ASR v1.0 (the AmpliChip). You have contended that under certain circumstances), the AmpliChip would fit within the definition of analyte specific reagent (ASR) in 21 CFR 864.4020(a) and would, therefore, be class I and exempt from the Act's requirement of premarket notification under 21 CFR 864.4020(b). OIVD has determined that it is unnecessary to decide whether this assertion is correct. Even if the AmpliChip were to qualify as an ASR under the regulation, the product would lose its class I, 510(k)-exempt status by operation of other provisions of the Act and of FDA regulations.¹

Under section 510(l) of the FDCA (21 U.S.C. § 360(l)), a device that is within a type of device that has been classified into class I is not exempt from the premarket notification requirement of section 510(k) of the Act if it is "intended for a use which is of substantial importance in preventing impairment of human health" or if it "presents a potential unreasonable risk of illness or injury." Under an FDA regulation (21 CFR 864.9) applicable to ASRs: "The exemption from the requirement of premarket notification . . . for a generic type of class I or II device is only to the extent that the device has existing or reasonably foreseeable characteristics of commercially distributed devices within that generic type . . . ." According to these provisions, whether an ASR is exempt from premarket notification depends on its intended use or potential risk and on the its technological or other characteristics relative to other ASRs.

The AmpliChip is intended to "identify naturally occurring genetic variations or common mutations" that

"play a crucial role in determining how a person can process or metabolize . . . analgesics, antidepressants, antihistamines, heart and blood pressure medications, antidepressants [sic] and antipsychotics. . . . By recognizing common DNA polymorphisms or mutations . . . , DNA chips can determine if a person is a poor metabolizer (PM) or an ultrarapid metabolizer (UM). PMs have trouble inactivating certain drugs and eliminating them from the body. Generally, a PM is at increased risk for experiencing adverse drug reactions, toxicities and even dangerous side effects of therapies. UMs, on the other hand, with additional functional copies of the genes, have an increased risk of being a nonresponder [sic] because they can inactivate and eliminate a drug before the drug has had a chance to achieve its therapeutic effect."

(Roche Diagnostics, Background Information: Microarray ("DNA Chip") and Roche AmpliChip™ CYP450 Backgrounder (undated).) OIVD believes that the intended use of the AmpliChip, to identify polymorphisms related to drug metabolism, is of substantial importance in preventing impairment of human health.

Moreover, according to information provided by Roche, the AmpliChip is a unique, highly processed, multi-signal device with unusual quality control features. It requires unique and sophisticated configurations of both hardware and software to make accurate use of those features. Roche has stated in labeling that the AmpliChip represents the first broad application of a new diagnostic technology: "Roche Diagnostics' AmpliChip CYP450 is the first wide-scale application of diagnostic microarray technology in the world" (Roche Diagnostics, Background Information: Microarray ("DNA Chip") and Roche AmpliChip™ CYP450 Backgrounder (undated)). Even if the AmpliChip were to fall within the definition of ASR in 21 CFR 864.4020(a), OIVD believes the technological characteristics of the AmpliChip would cause it to differ from existing or reasonably foreseeable ASRs such that the AmpliChip would not be exempt from premarket notification.

The AmpliChip cannot be commercially distributed without an appropriate premarket determination from FDA. We recommend that Roche submit a premarket notification and, if the AmpliChip is found not substantially equivalent, seek de novo classification under section 513(f) of the Act (21 U.S.C. § 360c(f)). The device classification of the AmpliChip depends on the outcome of FDA's premarket review.

We remain committed to working with you as we strive to protect the public health without unnecessarily imposing regulatory burdens on the marketing of products of potential clinical importance. If you have questions, or would like to discuss premarket submission plans for the AmpliChip, please contact me at 301-594-3084.

Sincerely,

Steven I. Gutman, M.D., M.B.A.
Director
Office of In Vitro Diagnostic Device
Evaluation and Safety
Center for Devices and
Radiological Health

¹Although this letter focuses on section 510(l) of the Act, there may be other statutory and/or regulatory provisions that disqualify the AmpliChip from class I, 510(k)-exempt status.