Manufacturers of moderate-risk test kits or components must comply with the same controls but also generally must submit a notice to the FDA before marketing, called a 510(k) clearance, to show that the new test (or component) has the same intended use and technological characteristics as some established test kit or component, or that any differences do not raise significant issues of safety or effectiveness (which may require support from studies, including clinical studies).

The highest-risk test kits or components require approval of a premarket approval application (PMA) before commercial use, which involves conducting clinical trials to show that the test is accurate and reliable. Major modifications to these highest-risk tests, such as modifying labeling for a new intended use, also will require new clinical trials for approval of the modification.

In contrast, diagnostic tests that are developed as LDTs have historically been regulated by CLIA and state law and do not follow an FDA pathway. The CLIA pathway requires establishing the performance specifications of the test. This includes the analytical validity of the assay—how well the test measures what the laboratory says it measures—and may include clinical performance characteristics, such as sensitivity, specificity, and predictive values. Compliance with CLIA requirements also involves maintaining quality systems aimed at ensuring the laboratory results are accurate and reliable. Laboratories offering LDTs must make available a clinical consultant to help the treating physician in ordering appropriate tests, to ensure that test reports include pertinent information for specific patient interpretation, and to provide consultation on matters related to the quality of the test results reported and their interpretation concerning specific patient conditions.

For many years, the FDA maintained it had the authority to regulate LDTs as medical devices but would use enforcement discretion not to require laboratories to obtain clearance or approval for LDTs as long as certain requirements were met (including a prescribed disclaimer to be included in reports of tests developed using FDA-cleared or approved analyte specific reagents). In 2006, however, the FDA announced its intention to regulate, as medical devices, one segment of LDTs, which the Agency described as in vitro diagnostic multivariate index assays (IVDMIAs). IVDMIAs had never been described before the draft guidance was published in September 2006, and the definition was revised in a subsequent draft guidance released in July 2007, so the precise definition remains unclear. The focus of the draft IVDMIA guidance appears to be diagnostic tests comprising two or more underlying variables that are combined using an interpretation function, such as a mathematical algorithm, to produce a patient-specific result. In its draft guidance, the FDA identifies the following examples as fitting under its definition of IVDMIA:

• a gene expression profiling assay for breast cancer prognosis
• a test integrating quantitative results from multiple immuno-assays to obtain a qualitative score that predicts a person's risk of developing a disease or condition
• a test integrating a patient's age, sex, and genotype of multiple genes to predict risk of or to diagnose a disease or condition.

The release of the draft IVDMIA guidance generated substantial confusion and controversy because many in the laboratory community believed this represented an important reversal of long-standing FDA policy of not requiring clearance or approval of LDTs as medical devices. Concerns were also raised that FDA was imposing new regulatory requirements on clinical laboratories that are regulated under CLIA and state laboratory licensure laws through a guidance process, which is inconsistent with the nonbinding status of guidance documents. At the same time, most stakeholders agree that these advanced technology assays may require more oversight than is provided under the existing framework under CLIA and state laws.

The Secretary's Advisory Committee for Genetics, Health, and Society (SACGHS) issued a report this spring identifying gaps in the regulatory oversight framework for genetic tests, including the kinds of biomarker tests discussed here. Among many recommendations, SACGHS has called for creating a registry to allow for the collection of information about these tests, which can help promote transparency and accountability for the truthfulness of claims about biomarker clinical laboratory tests. In addition, a registry could allow for data collection to inform appropriate regulatory pathways for new tests. In addition, a few legislative proposals have been introduced in Congress that also may lead to the development of a new oversight framework for these tests.

Discussions continue among laboratories, medical device manufacturers, other stakeholders, and regulatory authorities at the FDA and the Department of Health and Human Services. Principal issues that remain to be worked out include: (1) which agencies are best equipped to oversee the development and performance of these tests, (2) what standard of evidence should apply to support intended use claims that are meaningful to physicians and patients, (3) how a new oversight framework can be developed and implemented without stifling innovation and delaying the introduction of useful biomarker diagnostics, and (4) how these tests will be reimbursed. Developing answers to these questions will not be an easy task, but the stakes are too high not to meet the challenge.

Paul Radensky, MD, JD, is a partner at McDermott, Will & Emery, Washington, DC, 202.756.8794, pradensky@mwe.com