After FDA issued the 1997 analyte specific reagent (ASR) regulations, high-complexity CLIA-certified laboratories were able to take advantage of a quick route for introducing molecular diagnostics to the clinical market. Specifically, by using lab-created reagents or industry-supplied ASRs, clinical laboratories produced molecular diagnostic tests that did not require FDA premarket review.

As a result of these developments, parallel but unequal universes of regulatory pathways for introducing IVDs to the market emerged. Under the CLIA regulatory model, laboratories offering diagnostic testing services based on in-house-developed assays (so-called home-brew tests) are only required to establish the analytical performance for their tests, and not the clinical sensitivity and specificity. Meanwhile, the FDA regulatory pathway requires a detailed and lengthy premarket review of not only a test system's analytical sensitivity and specificity but also its clinical sensitivity and specificity.

The paradox of the existing dual de facto regulatory pathways is that many of the tests introduced via the CLIA model are often the same tests produced by IVD manufacturers, which are subject to strict FDA oversight and clinical validation requirements. This bifurcated pathway has led to an ongoing dispute over the appropriate regulatory and clinical credentialing thresholds for laboratory-developed molecular diagnostic assays. In the past, FDA exercised its regulatory discretion over home-brew tests. This discretion was based on the agency's need to balance the public health risk of these tests with its own comfort level that lab personnel were developing and conducting tests that did not lead to harmful results. If such tests presented a significant public health risk, FDA has reserved the right to assert jurisdiction rather than rely on the laboratories to assure that a test was not a serious risk.

New Guidances

In recent years, the increased sophistication and innovation of laboratory-developed tests have raised public health concerns at FDA. Consequently, the agency has re- evaluated its hands-off approach to such tests. In September 2006, FDA issued an updated guidance for ASRs and a new guidance for in vitro diagnostic multivariate index assays (IVDMIAs). Publishing these guidances is certainly a step by the agency to modify its previously ill-defined approach to lab-developed tests, and may provide boundaries for legitimate ASRs.

Jonathan S. Kahan, JD, is a partner at Hogan & Hartson (Washington, DC) and codirector of the firm’s food, drug, medical device, and agriculture group. He can be reached at jskahan@hhlaw.com.

In these guidances, FDA has not proposed oversight of all home-brew assays. Instead, the agency has attempted to identify a narrow scope of complex laboratory-developed assays in which the interpretation of the results is not transparent, the end-users do not know how to interpret the results, and proprietary data-interpretation algorithms are required. Many of these complex tests are intended to guide drug treatment, or are designed for the diagnosis or prognosis of cancer and other complex diseases. In FDA's view, such tests may meet the regulatory definition of a medical device.

Susan D. Tiedy-Stevenson is the senior director, regulatory sciences, at Hogan & Hartson (Washington, DC). She can be reached at sdtiedystevenson @hhlaw.com.

Since the IVDMIA guidance is only in draft form and FDA has not proposed a fair enforcement process, it is unlikely that any clarity or consensus understanding of the playing field will soon be made. Indeed, companies with business models based on laboratory-developed tests believe that FDA is overreaching its authority and that the draft guidance is overly broad and will deprive patients of timely access to the best available medical care. On the other hand, IVD manufacturers may see FDA's latest position as leveling the playing field. Nonetheless, manufacturers are reluctant to embrace the agency's proposed policies wholesale without a clear indication about how they may affect their lab customers and the use of their ASR products in creating home-brew assays.

FDA has been actively seeking comments from all interested parties on defining and clarifying those laboratory-developed tests over which the agency is seeking oversight, and recommendations on implementing such oversight. The parallel universes of different pathways for regulating home brews and commercially developed assays may eventually become a single universe in which all tests are subject to FDA oversight and regulation. The laboratory sector would bear the greatest regulatory burden in this area. However, IVD manufacturers should also question whether FDA's current infrastructure could support oversight of lab-developed tests without affecting the premarket review processes for their own commercially developed assays.