September Monthly Topic:
Final Guidance Clarifies FDA’s Current Thinking on
the Regulation of Analyte Specific Reagents and Marketing Practices
The Food and Drug Administration (FDA) recently issued a final guidance document outlining the agency’s current thinking on the regulation of analyte specific reagents (ASRs), which are materials used to perform certain in vitro diagnostic tests. The new guidance, issued September 14, 2007, does not depart from the agency’s past approach to ASRs, but is intended to clarify the existing regulations and inform manufacturers of practices that FDA views as inconsistent with the marketing of an ASR. FDA’s guidance comes in response to recent industry practices with regard to the marketing of ASRs. Over the past few years, multiple companies have come under scrutiny for marketing various types of products as ASRs that the agency believes should not be regulated as such. In particular, companies have questioned whether products that test for multiple analytes on a single physical entity, such as a microarray, are considered ASRs and thus exempt from premarket notification requirements. FDA’s response to this question is a resounding “no.”
FDA defines ASRs as “antibodies, both polyclonal and monoclonal, specific receptor proteins, ligands, nucleic acid sequences, and similar reagents which, through specific binding or chemical reactions with substances in a specimen, are intended for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.” 21 CFR 864.4020(a). To clarify this definition, the new guidance provides that ASRs are the “active ingredients” of tests used to identify one specific disease or condition. Thus, it is FDA’s view that ASRs are: (1) used to detect a single ligand or target; (2) not labeled with instructions for use or performance claims; and (3) not promoted for use on specific designated instruments or in specific tests.
Most ASRs are classified as Class I medical devices, subject to general controls, but exempt from 510(k) premarket notification requirements. However, improper marketing of an ASR voids this exempt status. In fact, if marketed in a way that FDA considers inappropriate for ASRs, a device will be viewed by FDA as a type of in vitro diagnostic device, subject to premarket notification or approval requirements. According to the guidance, diagnostic test makers should avoid several marketing techniques that void an ASR’s exempt status, including: (1) combining, or promoting for use, a single ASR with another product—such as other ASRs, general purpose reagents, controls, designated laboratory instruments, or software; or (2) 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. A manufacturer who wishes to market a product in a manner that risks removing the ASR from its Class I exempt status should consider discussing the classification of their product with FDA prior to marketing the device.
ASR manufacturers may only sell ASRs to: (1) in vitro diagnostic manufacturers; (2) clinical laboratories regulated under the Clinical Laboratory Improvement Amendments of 1988 (CLIA) as qualified to perform high complexity testing; (3) clinical laboratories regulated under VHA Directive 1106; and (4) other organizations that use the reagents to make tests for purposes other than providing diagnostic information to patients and practitioners. The guidance states that, in selling ASRs to these entities, manufacturer may not promote specific ASRs for use together in developing a test or include instructions for developing or performing an assay with an ASR. Additionally, ASR manufacturers should not make specific claims regarding the analytical or clinical performance for their ASRs. However, ASR manufacturers may supply quality control materials or reagents that can be used with their ASRs, provided that these materials are promoted independently of specific ASRs and in accordance with existing FDA classifications for quality control material.
Similarly, the guidance clarifies that FDA does not view products promoted for use with a particular instrument as ASRs. As a result, promotion of specific laboratory instruments for use in conjunction with particular ASRs will call into question the Class I exempt status of the ASR. Information, including peer-reviewed and published or presented literature that establishes characteristics of the ASR itself may be provided to laboratories if these materials do not describe the use of an ASR in a specific test or include information regarding an ASR’s clinical utility, clinical performance, specific instructions-for-use, or validation protocols.