March 2007 Clinical Laboratory News: FDA Weighs Reaction to Regulation of Multivariate Index Assays

March 2007: Volume 33, Number 3

FDA Weighs Reaction to Regulation of Multivariate Index Assays
Public Meeting Draws Large Crowd
By Julie McDowell

At a public meeting in early February, FDA officials confronted both support and concern from more than 30 stakeholders about proposed efforts to regulate a new class of tests known as in vitro diagnostic multivariate index assays (IVDMIAs). Although draft guidance on these regulations was initially released last September, the agency extended the initial 90-day comment period and opted to hold a public meeting that drew representatives from lab and physician groups, emerging diagnostic companies, legal groups, as well as patient advocacy groups. Given the many concerns raised prior to the meeting, representatives applauded FDA’s decision to extend the comment period until March 5 to give stakeholders additional time to comment on the guidance.

Since the draft guidance on these tests was released, there has been concern that the proposed regulations are a way for FDA to regulate laboratory-developed tests, and thereby step into directly regulating laboratories. Since the FDA published a 1997 rule on analyte-specific reagents (ASRs)—a primary ingredient of most in-house developed tests—the agency has generally exercised enforcement discretion over these “home brew” tests. In addition, primary oversight of in-house developed tests currently rests with CMS under CLIA, so additional oversight by FDA would create an undue regulatory burden and confusion, say some observers. However, FDA officials have pointed out that IVDMIAs did not exist when the 1997 ASR rule was published, and since they are medical devices, they are subject to different FDA regulations (CLN, November 2006).

Representatives from AACC and ACLA testified in support of the FDA’s efforts to clarify existing confusion about the agency’s oversight of laboratory-developed tests. ASCLS President Elissa Passiment stated that her organization agreed with the FDA that IVDMIAs should not be regulated under the ASR rule. But overall, stakeholder concerns about the IVDMIA draft guidance largely center on three issues: whether or not the agency circumvented the formal rulemaking process when introducing these regulations, how additional regulations by the FDA will hinder technological innovation, and FDA oversight of labs that are already subject to CLIA regulations.

“ACLA recommends that FDA issue a proposed rule to address this important subject matter through the formal notice and comment rulemaking process rather than through sub-regulatory guidance,” said Alan Mertz, ACLA President. He went on to say that the FDA should work with CMS to enhance CLIA regulations. “This approach has the potential to address the concerns that prompted FDA to issue the draft guidance in the context of the regulatory framework specifically designed for clinical laboratories and the services they provide…systematic and rigorous enforcement of these requirements by CMS could approximate the independent validation of clinical relevance that FDA seeks to achieve for IVDMIAs through the IVDMIA draft guidance.”

AACC representative William Clarke, PhD, Laboratory Director, Johns Hopkins University (Baltimore, Md.), also expressed concern that the FDA was moving too quickly in the area, without examining the full implications of these proposed regulations.

Regulating Some Testing Algorithms

IVDMIAs are complex test systems that use clinical data to empirically identify an algorithm, and employ that algorithm to integrate different data points in order to calculate a patient-specific result. There is only one FDA-cleared IVDMIA currently on the market—the MammaPrint test developed by Agendia (Amsterdam, The Netherlands). This test, which received FDA clearance just three days prior to the IVDMIA public meeting, uses microarray analysis to study the behavior of certain genes in breast cancer tumors in order to predict whether the existing cancer will metastasize.

In response to concerns about increased oversight of home brew testing, FDA officials stated that IVDMIAs fall within the scope of the agency’s enforcement authority. But Courtney Harper, PhD, an FDA official who spoke at the public meeting, insisted that the agency is attempting to regulate a narrow—yet growing—category of tests and not all tests that employ software-driven algorithms. For example, tests that are not IVDMIAs include those for standard creatinine clearance determination, as well as devices that determine a LDL cholesterol concentration by calculating total and HDL cholesterol and triglycerides.

After the March 5 deadline, FDA officials will review all the comments and begin finalizing the guidance. While officials haven’t established a formal timeline for this final document, Harper emphasized that this is a high priority for the agency.

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