FDA cautiously moved ahead with its controversial plan to actively regulate certain laboratory-developed tests with the release of a revised ¹ draft guidance document July 24.

The draft on in vitro diagnostic multivariate index assays, or IVDMIAs, is the agency's second attempt to describe its plan for overseeing the assay type. The products rely on particularly complex data analysis methods to translate measurements of multiple analytes into a single diagnostic or prognostic score.

The document takes the same basic position as the first draft issued last September: that FDA will regulate IVDMIAs, even when developed in-house by clinical laboratories for their own internal use, as devices - typically with Class II or Class III risk classifications (² Also see "FDA Draft Guidances Assert Oversight Over Multiplex Tests" - Medtech Insight, 11 September, 2006., p. 13).

It clarifies, however, what qualifies as an IVDMIA, and offers a transition period for current manufacturers to comply.

FDA typically does not concern itself with laboratory-developed tests - or "home brews" - instead relying on CMS to oversee lab quality under powers defined in the Clinical Laboratory Improvement Amendments (CLIA).

But the agency says it has simply been exercising enforcement discretion for these products, and no longer plans to do so for IVDMIAs. Instead, anybody developing these tests either as kits or home brews will need to submit 510(k)s or PMAs and comply with FDA's device postmarket requirements.

Diagnostic manufacturers and laboratories strenuously objected to the September draft guidance, accusing FDA of overreaching its authority, or at a minimum moving too quickly and without enough clarity on a major policy change.

Dozens of companies and organizations sent formal comments to FDA in response to the original draft. An organization called the Coalition for 21st Century Medicine, representing about 20 diagnostic manufacturers and 30 medical societies, was formed in opposition to the policy, which the group claimed would impede the development and use of innovative new tests.

At an FDA public meeting in February, the coalition and others pushed the agency to implement the policy through the slower rule-making process rather than with guidance (³ Also see "Laboratory Stakeholders Urge FDA To Ditch IVDMIA Guidance, Pursue Rule" - Medtech Insight, 12 February, 2007., p. 6).

FDA decided that the faster and more flexible guidance approach was the correct one, but to make sure stakeholders' "substantial and valuable input" was fully considered, the agency released a second draft rather than final guidance, says Steve Gutman, director of FDA's in vitro diagnostics office.

"We want to get it right," Gutman said.

In the revised draft, the agency rewrote its definition for IVDMIAs and provided examples of what does and does not qualify. Stakeholders had complained that the original definition was not specific enough, and Gutman worried that many had an overly broad impression of the types of tests affected by the new policy (⁴ Also see "Draft Guidance On Lab-Produced Tests Being Misinterpreted – Gutman" - Medtech Insight, 20 November, 2006., p. 12).

The new draft defines an IVDMIA as an assay that:

"1) Combines the values of multiple variables using an interpretation function 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, or in the cure, mitigation, treatment or prevention of disease, and

"2) Provides a result whose derivation is non-transparent and cannot be independently derived or verified by the end user."

It stresses that a home brew that involves multiple variables but that does not require some sort of proprietary algorithm or pattern recognition step to make a clinical conclusion would not be regulated as an IVDMIA. For instance, assay systems that measure a patient's different types of cholesterol and calculate a ratio are not affected, because they simply facilitate what a health care provider could do independently.

The most tangible example offered of what does qualify is a gene expression profiling assay in which gene activity patterns are analyzed to predict breast cancer prognosis.

Agendia's MammaPrint , which fits this description precisely, became the first FDA-cleared, lab-developed IVDMIA in February.

Coalition for 21st Century Medicine member Genomic Health makes a similar gene expression profiling product called Oncotype DX , which is offered through the company's CLIA-approved labs but is not FDA-cleared.

FDA says in the new draft that it will continue its enforcement discretion for currently marketed IVDMIAs for at least 12 months following publication of a final guidance.

For manufacturers that submit a 510(k) or PMA within that period, the discretion period will be extended for another six months so the products do not have to be removed from use during FDA review.

Further, FDA will not enforce its regulations on home-brew IVDMIAs that address the needs of fewer than 4,000 patients annually, meeting the definition of a humanitarian use device.

The new draft also clarifies that, although IVDMIA makers will need to comply with device adverse event reporting and manufacturing quality requirements, FDA will wait on quality systems enforcement until a final guidance document on quality control for IVDMIAs is published.

"We are, overall, pleased that the FDA has provided additional clarity and that they have incorporated stakeholder feedback, specifically the 18-month transition period, which would allow uninterrupted patient access to currently available tests," said Kim Popovits, president of Genomic Health.

Popovits says the firm is continuing talks with FDA to "determine the appropriate regulatory pathway for Oncotype DX."

FDA's Gutman said he could not comment on whether there have been any additional submissions for lab-developed IVDMIAs beyond MammaPrint, but noted that there has been "great interest" from stakeholders.

The revised draft guidance appeared in the Federal Register July 26. Comments are due Aug. 25.

- David Filmore (d.filmore@elsevier.com)

FDA Takes Second Stab At Multivariate Diagnostic Oversight Guidelines

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