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FDA's Revised Outlook

FDA’s revised outlook will increase the regulatory supervision of diagnostic products.


The Federal Food, Drug, & Cosmetic (FD&C) Act gives the FDA authority to regulate medical devices, characterized, in short, as an “in vitro reagent or other related article, including any component, part, or accessory that is intended for use in the diagnosis of disease.”

Challenges in the regulation of diagnostic products are increased by recent advances in technology—particularly in the biotechnology and genetic testing fields. Recent FDA proceedings indicate that, barring congressional or judicial intervention, FDA intends to notably tighten its regulatory control of analyte specific reagents (ASRs) and in vitro diagnostic multivariate index assays (IVDMIAs). These groups include many genetic-based tests and other unconventional diagnostic products and technologies that have previously been unregulated, or minimally regulated, by FDA. This article discusses recent developments in FDA’s regulation of such products in the context of the FD&C Act’s overall regulatory scheme for medical devices.

What is an ASR?
ASRs are commercially marketed products that function as building blocks for in vitro diagnostics (IVD) tests, just as active pharmaceutical ingredients are the building blocks of finished drugs and therapeutic biologics. Requirements for ASRs can be found in 21 CFR 810 (In Vitro Diagnostics) and ASRs are defined and classified as medical devices in 21 CFR 864.4020 (Hematology and Pathology Devices). More specifically, ASRs are defined 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.” In simple terms an ASR is the active ingredient of an in-house test. The definition undoubtedly exempts from regulation otherwise-covered products that are sold to IVD manufacturers for use in finished IVDs, or to nonclinical laboratories or others for non-diagnostic use. Since a majority of ASRs are grouped as Class I and 510(k) exempt, they must satisfy general controls and any other requirements stated in the ASR Rule. ASRs are used as components of laboratory-developed tests and must meet the specified criteria stated in 21 CFR 809.30.

21 CFR 809.30

  • ASRs must be labeled as required by the ASR Rule
  • ASRs may be sold only to clinical laboratories certified by the Centers for Medicare and Medicaid Services (CMS) to perform high-complexity testing under the Clinical Laboratory Improvement Amendments of 1988 (CLIA).
  • Laboratory-Developed Tests (LDTs) that incorporate ASRs may only be ordered by licensed medical practitioners, and results must be accompanied by notification that the test was laboratory developed and not cleared or approved by FDA.
  • ASRs may not be promoted using any statement regarding analytical or clinical performance, and advertising and promotional materials must contain required statements.

FDA’s Challenge
FDA has issued a draft guidance entitled “Guidance for Industry and FDA Staff—Commercially Distributed Analyte Specific Reagents (ASRs): Frequently Asked Questions”. This draft guidance was intended to warn manufacturers to particular uses of commercially distributed ASRs that FDA considers a new IVD product, which is not exempt from premarket notification or clearance. These uses include combining, or promoting for use, a single ASR with other products such as other ASRs, software, general-purpose reagents, designated laboratory instruments, controls, etc. Other prohibited uses would include promoting an ASR with specific performance or analytical claims, instructions to use in a particular test, or instructions for the validation of a particular test using the ASR.
FDA explains that some “manufacturers believe that when they combine a Class I [510(k)-exempt] ASR with other products, or with instructions for use in a specific test, the product remains exempt because of the presence of the ASR. However, when an ASR is marketed in the ways described above, FDA views the product as no longer being an ASR within the meaning of 21 CFR 860.4020 and instead views it as an IVD or device component not covered by the ASR regulations and, therefore, not necessarily exempt from premarket notification”.

Examples of products that are not exempt from premarket notification include the following:

  • Multiple individual ASRs (antibodies, probes, primer pairs, etc.) bundled together in a single preconfigured or optimized mixture so that they must be used together in the resulting LDT.
  • Products that include or require more than a single ASR (the product also includes other ASRs, general reagents, control, equipment, or software, or has instructions for use).
  • Reagents designed to require use in a specific assay or on a designated instrument.
  • Control material or calibrators.
  • Products that have specific performance claims, procedural instructions, or interpretations for use.
  • Reagents offered with interpretive software, or software for interpretation of assay results.
  • Microassays

Conclusion
The official role of FDA in regulating novel diagnostic products and technologies has not yet been fully established. However, it seems that FDA is preparing to take a more active role in regulating these products than it has in the past. In view of these changes, the diagnostic industry should not only monitor policy developments at FDA, it must also consider whether future (or existing) products are subject to these newly enforced regulatory requirements.

Points to Consider
 
1.      When will the FDA go from “non-binding guidance documents” to “notice-and-comment” rule imposing present requirements?

2.      What should diagnostic companies do to ensure their products and practices are cohesive with the FDA’s new regulations?

3.      What will happen to an existing product that fails to meet guidance regulations?

Please don't hesitate to hesitate to contact Safis Solutions directly with specific questions about how this new guidance may impact your business plan.