The agency’s recent moves signal increased regulatory oversight of diagnostic products.

Jane Baluss

June 1, 2008

11 Min Read
Assessing FDA Regulation of Diagnostic Tests and Services



The Federal Food, Drug, and Cosmetic Act (FD&C Act) gives FDA broad authority to regulate medical devices, which are defined in part as any “in vitro reagent or other related article, including any component, part, or accessory, which is . . . intended for use in the diagnosis of disease.”1 Notwithstanding this expansive definition, FDA has traditionally required little regulation for many diagnostic products that the agency views as minimal public safety risks or adequately controlled by other means.

That rationale, however, has been increasingly challenged by the proliferation of novel and highly sophisticated diagnostic technology—notably in the biotechnology and genetic testing fields. In particular, recent regulatory developments have signaled that, barring congressional or judicial intervention, FDA intends to significantly increase its regulatory oversight of two specific categories of diagnostic products: analyte specific reagents (ASRs) and in vitro diagnostic multivariate index assays (IVDMIAs). Taken together, these categories potentially encompass many genetic-based tests and other cutting-edge 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.

FDA Regulation of Diagnostic Products

Many commercially marketed diagnostic products are explicitly regulated as medical devices under the general framework of the FD&C Act, while others are classified as general-purpose reagents, equipment, or components that are not considered to be medical devices because they have a variety of applications and are not marketed for specific diagnostic uses. However, over the last several years, FDA has developed additional industry guidance addressing particular diagnostic entities whose status is arguably less clear or is otherwise problematic from a regulatory standpoint. In particular, the agency has grappled with questions about whether and how to intensify its regulation of certain diagnostic-related products, and if so, how to effectively articulate resulting policies and requirements for manufacturers and clinical laboratories that may not currently view themselves as medical device manufacturers.

The ASR Rule and Revised Draft Guidance

ASRs are commercially marketed products that function as building blocks of in vitro diagnostic (IVD) tests, just as active pharmaceutical ingredients are the building blocks of finished drugs and therapeutic biologics. Special requirements for ASRs are outlined in 21 CFR 810 (In Vitro Diagnostics), while ASRs are defined and classified as a distinct category of medical devices under 21 CFR 864 (Hematology and Pathology Devices). FDA collectively refers to these provisions as the ASR rule. 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 for use in a diagnostic application for identification and quantification of an individual chemical substance or ligand in biological specimens.2

This definition specifically exempts from regulation otherwise-covered products that are sold to IVD manufacturers for use in finished IVDs, or to nonclinical laboratories or others for nondiagnostic use.

Most ASRs are classified as Class I and 510(k) exempt (with a few exceptions for Class II and Class III tests used to protect the blood supply or diagnose serious diseases). As such, they must satisfy general controls plus the additional requirements specified in the ASR rule in connection with their use as components of laboratory-developed tests (LDTs, also sometimes called home-brew tests). Specifically, 21 CFR 809.30 states that:

  • 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).

  • 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.

On September 14, 2007, FDA issued a revised version of a 2006 draft guidance document titled Guidance for Industry and FDA Staff—Commercially Distributed Analyte Specific Reagents (ASRs): Frequently Asked Questions. The ASR draft guidance was intended to alert manufacturers to particular uses of commercially distributed ASRs that FDA considers to constitute a new IVD product that is not exempt from premarket notification or clearance. Such uses include combining, or promoting for use, a single ASR with another product such as other ASRs, general-purpose reagents, controls, designated laboratory instruments, software, etc. Another use would be promoting an ASR with specific analytical or performance claims, instructions for use in a particular test, or instructions for validation of a specific test using the ASR.

As explained by FDA,

[S]ome manufacturers have believed 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 an 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 another type of . . . IVD or device component not covered by the ASR regulations and, therefore, not necessarily exempt from premarket notification.

The revised draft guidance offers several examples of such products, including the following:

  • Multiple individual ASRs (e.g., 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 (i.e., 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 (e.g., arrayed on beads).

  • 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.

  • Microarrays.

The guidance also provides examples of entities that FDA does consider to be ASRs in the absence of specific clinical or analytical performance claims. These include (but are not limited to): a single antibody (whether tagged or untagged); a single forward-reverse oligonucleotide primer pair for amplification of a single amplicon; a single tagged or untagged nucleic acid probe intended to bind a single complementary amplified or unamplified nucleic acid sequence; and a single purified protein or peptide.3

FDA invariably describes its draft and final guidance documents as mere statements of the agency's “current thinking” and not legally binding on FDA or the public. As a practical matter, however, FDA enforcement staff frequently rely on both draft and final guidance statements as a basis for regulatory pronouncements and even enforcement actions. Moreover, even though FDA is careful to say that the ASR draft guidance is intended to clarify the existing ASR rule rather than create new requirements, industry critics view it as a potentially substantial expansion of FDA jurisdiction over diagnostic products that are currently regulated solely under CLIA. In any case, the guidance stands as a clear signal to ASR manufacturers and laboratories that use ASRs in LDTs that such products cannot be assumed to be exempt from premarket approval under the FD&C Act.

The IVDMIA Draft Guidance

In addition to the revised ASR draft guidance, FDA published a revised version of the guidance document titled Draft Guidance for Industry, Clinical Laboratories, and FDA Staff—In Vitro Diagnostic Multivariate Index Arrays in July 2007 (originally published in 2006). As with the revised ASR draft guidance, the revised IVDMIA draft guidance represents a significant shift from traditional FDA policy, specifically that of enforcement discretion (i.e., nonenforcement) for LDTs.


Key Guidances for Diagnostic Regulations

As newly redefined, an IVDMIA is a test or test system that combines the values of multiple variables using an interpretation function (algorithm) to yield a single, patient-specific result (e.g., a classification, score, index, etc.) that is intended for use in the diagnosis of disease or other conditions; and provides a result whose derivation is nontransparent and cannot be independently derived or verified by the end-user.4

Examples of existing IVDMIAs that lack premarket clearance or approval to date include gene expression profiling assays for breast cancer prognosis; products that predict disease risk by integrating results from multiple immunoassays; and those that predict risk or diagnose disease by integrating age, sex, and genotype of multiple genes. The revised guidance also provides multiple examples of devices that are not considered to be IVDMIAs.

The original IVDMIA draft guidance drew a large number of public comments. Although some manufacturers of established test products supported heavier regulation of emerging IVDMIAs, many diagnostic test manufacturers opposed FDA's approach as unnecessarily burdensome, confusing, and detrimental to the development and commercialization of needed diagnostic technologies. Similar concerns were expressed by clinical laboratories already regulated under CLIA. Laboratories also noted that LDTs may be the only access to diagnosis for diseases with
relatively small patient populations.

For a summary of comments, go to

The revision was intended to address those concerns, but preliminary indications are that it will be equally controversial on a number of grounds. The newly added definitional criteria appear especially open to debate, as do the accompanying examples. Indeed, the revised draft expressly recognizes that additional and more-detailed guidance is necessary before most existing IVDMIAs can be brought under regulation. The guidance contemplates a “transition period” of at least 12 months after the guidance becomes final. Also, there may be grounds for potential legal challenges to FDA's interpretation of its medical device jurisdiction, as well as its use of nonbinding guidance documents rather than notice-and-comment rule making to impose the requirements at hand.

These potential problems notwithstanding, FDA does not intend to ignore specific products and practices that it considers to be violative, as evidenced by a warning letter issued on October 11, 2007, to Exact Sciences Corp. (Marlborough, MA). Without specifically saying so, the warning letter directly applies principles from both draft guidances. In the letter, FDA asserts that the Exact product, which is an assay for colorectal screening, is a Class III unapproved medical device (and not an LDT subject to enforcement discretion) both because the product is marketed to clinical laboratories with instructions for use, validation information, and performance claims, and also because it requires the use of specified equipment and reagents. It is also worth noting that the product came to FDA's attention as a result of a CMS CLIA inspection of one of Exact's customers.

Related Developments in CLIA Regulation

In addition to FDA's evolving guidance in connection with diagnostic devices, a separate but related development has been unfolding in connection with CMS's regulation of clinical laboratories under CLIA. Many comments on FDA's regulatory policies involving ASRs and IVDMIAs have argued that additional regulation of such products under the FD&C Act is unnecessary because their safety and efficacy are adequately assured by clinical laboratories' compliance with CLIA requirements.

Additionally, parties across the spectrum of public debate about genetic-based testing have proposed that such products and services should primarily be regulated by establishing a new CLIA specialty regulation for genetic testing. Indeed, CMS announced its intention to develop such a regulation in 2002, and appeared to be in the process of doing so over the succeeding years.

In August 2007, however, CMS abruptly reversed its position and formally declined to proceed with such rule making for the indefinite future. This position was stated in response to a 2006 citizen petition submitted to CMS by the Genetics and Public Policy Center, asking CMS to develop a CLIA specialty regulation and proficiency standards for genetic testing.

Key reasons for abandoning the regulation cited by CMS were a lack of evidence that the requested regulation would significantly advance the resolution of key issues in genetic testing, the current adequacy of general CLIA requirements without an additional specialty regulation, and an unfavorable balance of costs versus benefits for additional requirements.


As matters stand now, it is clear that the appropriate role of federal agencies in regulating genetic testing and other innovative diagnostic products and technologies remains to be fully identified.

Based on recent events, however, it appears that FDA is poised to take a far more active role in regulating these products than it has in the past. Accordingly, the diagnostic industry should monitor ongoing policy developments at the agency and consider whether existing or future products might potentially be subject to new or more-stringent regulatory requirements under FDA's medical device authority.

Jane Baluss is special counsel in Foley & Lardner LLP's Washington, DC, office. She can be reached at [email protected].


1. Federal Food, Drug, and Cosmetic Act (FD&C Act) sect. 201(h).

2. Code of Federal Regulations, 21 CFR 864.4020(a).

3. Guidance for Industry and FDA Staff—Commercially Distributed Analyte Specific Reagents (ASRs): Frequently Asked Questions (Rockville, MD: FDA, Center for Devices and Radiological Health, 2007).

4. Draft Guidance for Industry, Clinical Laboratories, and FDA Staff—Multivariate Index Assays (Rockville, MD: FDA, Center for Devices and Radiological Health, 2007).

Copyright ©2008 Medical Device & Diagnostic Industry

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