FDA Suggests Complete Overhaul of IVD Regulation

After years of trying to find a way to regulate lab-developed tests (LDTs), the Food and Drug Administration (FDA) is trying a new approach— by suggesting a complete overhaul of the way the agency oversees all diagnostic testing.

Since 1992, the FDA has attempted to get a handle on LDTs, most recently through a draft guidance document issued in October 2014 that outlined a framework for phasing in oversight of LDTs, with the highest-risk tests required to get pre-market approval (PMA), a process through which a laboratory would need to establish the safety and effectiveness of the tests. The agency has long maintained that it has enforcement discretion in regulating LDTs, which are specialized tests designed, manufactured, and used within a single laboratory. Whereas in vitro diagnostic (IVD) manufacturers believe LDTs should have to meet the same approval criteria as their test kits, most labs with LDTs maintain that these tests should be outside the FDA’s regulatory purview since they are used in-house and are not commercially distributed.

Latest efforts to gain oversight

In late 2016, following the presidential election, the FDA announced that it would not finalize the 2014 draft guidance. In January 2017, in the last week of the Obama administration, the agency issued a discussion paper laying out key elements of a possible revised future LDT regulatory framework, including exempting certain low-risk categories of LDTs from regulation and phasing in a riskbased approach over a period of several years.

Meanwhile, on Capitol Hill, two members of Congress were working on a legislative approach to oversight of LDTs. Reps. Larry Bucshon (R-IN) and Diana DeGette (D-CO) in March 2017 released a draft of the Diagnostic Accuracy and Innovation Act (DAIA), which would allow the FDA to regulate LDTs through a new category of in vitro clinical tests.³ Under the measure, a new FDA center would be created to regulate test development and manufacturing, while the Centers for Medicare & Medicaid Services (CMS) would continue to oversee lab operations through its CLIA program. A coalition of more than 80 groups, including manufacturers, providers, and laboratory and patient advocates, sent a letter to key lawmakers earlier this year calling for some kind of congressional action on oversight of diagnostic testing, though not specifically endorsing this particular bill.

A facelift for IVD approval

The FDA in May provided high-level comments on the DAIA, and in August it provided more detailed recommendations in the form of a 59-page technical assistance (TA) document, which some policy experts say actually advocates a complete overhaul of the system currently used to approve diagnostic tests.

“We note that rather than providing technical amendments to [the bill], FDA has drafted a distinctly different framework,” said the American Clinical Laboratory Association (ACLA) in a statement. “ACLA recognized that the FDA TA offers valuable insight into the priorities of FDA and certain concepts that could be incorporated into the Discussion Draft. However, given the many questions and concerns raised by the TA, ACLA believes that the framework set forth in the DAIA Discussion Draft should remain the starting point.”

Jeffrey Gibbs, an attorney with Hyman, Phelps & Mc- Namara and author of the FDA Law Blog (www.fdalawblog.net), says the FDA went much further than just providing technical comments on the legislation, instead recommending different statutory language that would substantially change the regulatory regime for IVDs.

“FDA’s TA document is not tinkering with the regulatory regime for IVDs,” writes Gibbs. “It is a revamp of how all IVDs should be regulated, LDTs and distributed diagnostic products alike. For LDTs, it would mean a new regulatory framework.”

Some labs have voluntarily submitted 510(k)s or PMAs to the FDA, notes Gibbs. If the FDA’s proposal were adopted, labs and manufacturers would be subject to the same criteria that IVD test kits are subject to regarding when applications would need to be submitted. Labs would also be subject to other FDA requirements beyond the submission of marketing applications.

In comments submitted to sponsors of the bill, the Association for Molecular Pathology (AMP) agrees that there is a need to modernize regulations of both LDTs and IVD test kits, but says it remains concerned that establishing a single regulatory pathway for both IVDs and LDTs would never meet the needs of either as they are fundamentally different from each other.

“AMP believes that IVD test kits and [LDTs] should be regulated under two distinct pathways and does not believe that FDA is the appropriate agency to oversee the vast majority of [LDTs],” the association says.

Learning the lingo

Putting kits and LDTs on the same footing, though, is not the most striking aspect of the FDA’s most recent proposal, notes Gibbs. “Rather, it is FDA’s rewriting of the IVD regulatory process, both for entering and remaining on the market. Many of the regulatory terms and constructs that have governed IVD regulation for decades would be discarded. A whole new vocabulary would be adopted, complete with their own statutory definitions, e.g., ‘in vitro clinical test’ and ‘developer’ and ‘test group’ and ‘analytical validity’ and ‘first-of-a-kind.’ This legislation, although it borrows from some past concepts, should be viewed as revolutionary, not evolutionary.”

For example, the FDA proposed to replace the term “predicate device”—used to indicate “substantial equivalence” to a device or test that has already been approved— with the term “test group,” which means the tests being compared must have in common the substance measured, the type of specimen, the test method, the test purpose, the disease or condition, and the place of use. As a result, falling within or outside a test group could actually become a factor in determining whether a modification to a marketed device needs prior approval, says Gibbs.

“There are multiple pieces to the new jigsaw puzzle the FDA has proposed,” he notes. “When all the pieces are placed together, will they create a coherent image? In its transmittal explanatory note, FDA states, ‘DAIA could have the unintended consequence of creating inconsistencies in the marketplace.’ FDA’s proposal also needs to be carefully vetted for its own possible unintended consequences.”

Ultimately, the FDA’s latest recommendations will just add to the discussion as lawmakers determine how to move forward on approval and oversight of IVDs. Given that the current system is outdated, there does appear to be growing momentum among various stakeholders for overhauling how IVDs are regulated. But at this point, the devil is in the details.