FDA Issues Final ASR Guidance Document – Ambiguities Remain
September 16, 2007FDA announced on September 14, 2007 the release of a final guidance document pertaining to analyte specific reagents (“ASRs”), titled “Guidance for Industry and FDA Staff – Commercially Distributed Analyte Specific Reagents (ASRs): Frequently Asked Questions” (“the ASR Guidance”). A draft version of this guidance document was issued on September 7, 2006, and was widely criticized in stakeholders’ comments. A crucial section of the ASR Guidance – addressing what entities meet the definition of an ASR – was modified in response to these comments. Not all points raised by stakeholders, however, have been incorporated in the final document.
FDA states that the ASR Guidance is designed to “eliminate confusion regarding particular marketing practices among ASR manufacturers.” FDA purports to base the ASR Guidance on the definition of ASRs provided in existing regulations: “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.” In the ASR Guidance, FDA interprets this definition to mean that an ASR has three characteristics:
- an ASR is “used to detect a single ligand or target (e.g., protein, single nucleotide change, epitope);”
- an ASR is “not labeled with instructions for use or performance claims;” and
- an ASR is “not promoted for use on specific designated instruments or in specific tests.”
To clarify these characteristics, FDA provides examples of entities that the Agency considers, and does not consider, to be ASRs. Examples of entities that qualify as ASRs include:
- “a single antibody . . .;”
- “a single forward/reverse oligonucleotide primer pair . . . or [a] single forward or reverse primer individually;”
- “a nucleic acid probe . . . intended to bind a single complementary amplified or unamplified nucleic acid sequence;” and
- “a single purified protein or peptide . . . .”
Examples of entities that do not qualify as ASRs include:
- “Multiple individual ASRs (e.g., antibodies, probes, primer pairs) bundled together in a single pre-configured or optimized mixture so that they must be used together in the resulting [laboratory developed test (‘LDT’)] . . .”;
- “Products that include or require more than a single ASR . . . and/or [have] instructions for use . . .”; and
- “Reagents that are designed to require use in a specific assay or on a designated instrument (e.g., arrayed on beads) . . . .”
To further explain the first example of an entity that does not qualify as an ASR – multiple antibodies, probes, and primer pairs – FDA provides another example: “a set of 5 primer pairs combined in a single tube that are used to detect 5 different viral genotypes . . . .” Since issuing the draft guidance document, FDA has modified its examples of what it does and does not consider to be an ASR. However, the revised examples leave open questions regarding whether many current products sold as ASRs constitute an ASR under FDA’s interpretation of the existing rule. There are still several ambiguities.
The ASR Guidance clarifies that ASRs cannot have specific performance claims, procedural instructions, or interpretations for use, and cannot be offered with software for interpretation of results. Additionally, software and microarrays are not considered ASRs. With respect to instructions, FDA states in the ASR Guidance that “ASR manufacturers should not provide instructions for developing or performing an assay with an ASR.” ASR manufacturers cannot assist laboratories with validation of LDTs. The only information that ASR manufacturers can provide to laboratories includes “peer-reviewed and published/presented literature, that establishes characteristics of the ASR itself, such as information describing the single ligand or target the ASR detects.” This information “may not, however, describe the use of an ASR in a specific test, including information regarding an ASR’s clinical utility and clinical performance as well as specific instructions-for-use and validation protocols.”
Additionally, ASR manufacturers cannot distribute or promote ASRs with for use with general purpose reagents, control material, software, or instrumentation. ASR manufactures are permitted to supply quality control material if it is “promoted independently of specific ASRs.”
In the draft guidance document released on September 7, 2006, FDA stated that ASRs had the characteristics of “a single moiety” and a “single endpoint.” In the final ASR Guidance, these two characteristics have been replaced with “used to detect a single ligand or target.” Many of the comments submitted to the draft guidance document argued that the terms “moiety” and “endpoint” were not included in the existing regulations and had not been defined by FDA. These new terms substantively changed the definition of ASRs. Comments therefore emphasized that the ASR rule could not be changed through the guidance process; notice-and-comment rulemaking would be required. Presumably, in response to these comments, FDA has not included the terms “moiety” or “endpoint” in the final ASR Guidance.
Comments to the draft guidance document also stressed that requiring clearance of approval of products that are currently sold as Class I, 510(k)-exempt ASRs may result in a lack of availability of ASRs, which could delay or deny access to clinically important diagnostic tests, stifle innovation, increase the costs of LDTs, and diminish the quality of health care. Though FDA omitted “moiety” and “endpoint” as characteristics of ASRs, it is still not clear how many products currently sold as ASRs will be deemed by FDA to require clearance or approval (and may therefore be removed from the market). The effect on test availability and quality remains to be seen.
Many stakeholders argued in their comments to the draft guidance document that FDA had not considered the quality measures imposed on laboratories through the Clinical Laboratory Improvement Amendments (“CLIA”). Regulations under CLIA include requirements to ensure consistent laboratory test development. According to several comments, guidance from FDA could conflict with CLIA. The ASR Guidance does not address this. Additionally, stakeholders requested that any final guidance pertaining to ASRs not be applicable upon release; there should be a grace period for implementation. Though the text of the ASR Guidance does not include any grace period, the Federal Register notice announcing the guidance states that “FDA intends to exercise enforcement discretion with respect to premarket approval and clearance requirements for 12 months . . . .”