Recent U.S. Regulatory Developments Herald Increasing FDA Regulation of Laboratory-Developed Diagnostic Tests and Services

05 October 2007 Publication

The Pulse

Recent regulatory developments continue to signal that, barring congressional or judicial intervention, the U.S. Food and Drug Administration (FDA) intends to bring many more diagnostic test products and systems under regulation as “medical devices” under the Food, Drug, and Cosmetic Act (FDCA).1 The specific class of products are those classified as In Vitro Diagnostic Multivariate Index Assays (IVDMIAs),which include many genetic-based tests as well as many diagnostic test systems/services developed and marketed by clinical laboratories. While many such products are on the market or currently under development, as a matter of traditional FDA enforcement policy very few have been regulated as medical devices to date.2 However, FDA’s current — and still evolving — policy signals a strong possibility that previously unregulated diagnostics could require FDA approval or clearance prior to marketing as well as being subject to other medical device requirements under the FDCA, including compliance with FDA’s Quality Systems Regulations (QSRs), product listing and facility registration, and adverse event reporting.

The specific class of products to be regulated as IVDMIAs was recently redefined by FDA as part of a revised draft guidance document, Draft Guidance for Industry, Clinical Laboratories, and FDA Staff – In Vitro Diagnostic Multivariate Index Arrays (July 26, 2007) (Revised Guidance).3 The Revised Guidance replaces an earlier version issued in September 2006.4 Both versions of the guidance represent a significant shift from traditional FDA enforcement policy, under which FDA did not consider it necessary as a matter of public health and safety to regulate various diagnostic tests and test components, including those now defined as IVDMIAs.

As newly redefined, an IVDMIA is a medical device that (1) combines the values of multiple variables using an interpretation function (algorithm) to yield a single, patient-specific result (e.g., a “classification,” “score,” “index,” and so forth) that is intended for use in the diagnosis of disease or other conditions; and (2) provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user.5 Examples of IVDMIAs identified in the guidance include gene expression profiling assays for breast cancer prognosis; products/systems 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.6 The Revised Guidance also provides multiple examples of devices that are not considered to be IVDMIAs.7 While the Revised Guidance provides a general overview of medical device requirements and their potential application to IVDMIAs,8 it anticipates a transition period of 12 months following the issuance of additional and more detailed guidance on the application of particular device requirements such as QSRs.9

The draft IVDMIA policy was widely opposed by diagnostic test manufacturers and clinical laboratories as unnecessarily burdensome, confusing, and detrimental to the development and commercialization of needed diagnostic technologies.10 Preliminary comments indicate that the Revised Guidance will be equally controversial, and that many details remain to be resolved before it can effectively be implemented. For example, the newly added definitional provision that IVDMIA results are “non-transparent” and “cannot be independently derived and verified by the end user” appear potentially subject to debate, as does the application of various examples newly added to the Revised Guidance. As the guidance itself recognizes, still further detailed guidance will need to be developed in order to apply the medical device QSR regulations to laboratory-developed IVDMIAs, and to resolve potential overlap or conflict with separate regulations applicable to clinical laboratories under the Clinical Laboratories Improvements Act of 1988 (CLIA). Finally, there may be grounds for potential legal challenges to FDA’s interpretation of its “medical device” jurisdiction as well as its use of non-binding guidance documents rather than notice-and-comment rulemaking to impose the requirements at issue.11

In addition to FDA’s ongoing guidance process, a separate but related development has been unfolding at the Center for Medicare Services (CMS), which is responsible for the regulation of clinical laboratories under CLIA. Many comments on FDA’s regulatory policies involving IVDMIAs and other diagnostics not historically regulated as medical devices have argued that such products are already adequately regulated under CLIA. Additionally, parties across the spectrum of public debate about genetic-based testing have proposed that such products and services should primarily be regulated by CMS under a new CLIA “specialty” for genetic testing, and in 2002 CMS announced plans to do so. In August, 2007, however, CMS formally declined to proceed with such rulemaking at this time.12

In summary, as matters now stand, it is clear that many questions about the appropriate role of federal agencies in regulating genetic testing and other innovative diagnostic products and technologies remain to be fully identified, much less resolved. Based upon recent events, however, it appears that FDA is poised to take a far more active role than it has in the past.

1 FDCA § 201(h).

2 Specifically, FDA did not think it necessary as a matter of public health or safety to regulate either the active components of diagnostic tests (“analyte specific reagents” or ASRs), or “home brew” tests developed and marketed by clinical laboratories using commercially marketed ASRs. Most IVDMIAs are considered to be a subset of laboratory-developed test.

3 Available at

4 Available at

5 Revised Draft Guidance at 5.

6 Id. at 5-6.

7 Id. at 6-7.

8 Id. at 7-9.

9 Id. at 10.

10 For a summary of public comments on the 2006 Draft IVDMIA Guidance, see

11 For more detail on these and other points, see American Clinical Laboratory Associations, Comment to FDA Docket No. 2006D-0347 (Aug. 24, 2007), available here.

12 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. See (Petition Denial Letter, Aug. 15, 2007); (Citizen Petition). Key reasons cited by CMS for denying the petition 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 addition specialty regulation, and an unfavorable balance of costs versus benefits.

This article is a part of the October 2007 edition of The Pulse, a newsletter for leaders in the Medical Device Industry.