The U.S. Food and Drug Administration (FDA) late last week officially issued its draft framework for how the agency plans to regulate laboratory-developed tests (LDTs).
The 41-page framework, which was released on Oct. 3 and is now subject to a 120-day public comment period that will extend into the middle of next February, is expected to shape the final rules the agency is expected to issue next year.
Most medical devices currently require some form of approval for the agency and vetting for safety and effectiveness before they can be sold to providers and members of the public. Tests that are sold in kit form to doctors or directly to consumers already require FDA approval.
The FDA announced last July that it intended to regulate LDTs in much the same way as it does medical devices, saying it was required to ensure patient safety, and rejecting the long-held tradition of analytically testing LDTs per CLIA regulations as no longer satisfactory. It noted that laboratory tests have grown more complicated over the
decade and that the playing field was unbalanced, pitting some tests that had been submitted for FDA approval against those that had not. Altogether, the FDA estimated that there are some 11,000 LDTs on the market that have been created by more than 2,000 different labs. Many of those tests, it noted, were marketed nationwide, and some globally.
The draft framework has allowed for a modest number of operational exemptions from the FDA’s plan to regulate LDTs based on their potential risk to patient safety. The FDA does not consider a test to be an LDT if:
- An entity that owns several clinical laboratories creates a test that is then transferred to another lab within its network;
- An academic institution develops a test that it then licenses to a private venture that owns a CLIA-certified laboratory, which then begins manufacturing and distributing the test; and
- An entity that creates LDTs and medical devices will continue to follow the existing regulations for medical devices.
Also exempted are any assays that screen for serious diseases or medical conditions in a patient who is asymptomatic and does not have access to any other test to confirm a diagnosis.
The guidance also places LDTs into three classifications, with the highest-risk assays, Class III, and the more moderate-risk Class II LDTs requiring FDA premarket approval and reporting of adverse patient events.
Filing and adverse-risk reporting of lower-risk Class I LDTs is mostly optional. The FDA plans to use a “public process” and advisory boards to determine the classification of new LDTs, although details were not provided in the document.
Labs developing LDTs have to begin notifying the FDA about tests they are developing and adverse events six months after the final guidework goes into effect, and begin filing for premarket reviews one year afterward. Some of the more arcane parts of the guidework will be phased in over the better part of a decade.
Lab Officials Are Concerned
Despite the exemptions and the stretched-out periods for the requirements, laboratory sector officials are concerned that the impact on their businesses could be profound.
“It is going to have a chilling effect on our ability to continue offering all the tests we currently offer,” said Edward Ashwood, M.D., chief executive officer of Salt Lake City-based ARUP Laboratories. According to Ashwood, ARUP has nearly 1,400 LDTs. Sixty-one are considered high-risk tests and another 584 are classified as moderate-risk tests.
Francisco Velázquez, M.D., chief executive officer of PAML, the large Spokane, Wash.-based laboratory, believes that if the validations the FDA requires for medical devices are replicated for LDTs, it could become burdensome to certify many tests.
“We already do validations for LDTs, as good practice, but if we have to go beyond that, with prospective validation studies, or with larger numbers of subjects, or extend the temperature ranges for the tests or its reagents, that will be an impact, and it could become quite cumbersome,” he said.
Altogether, PAML has about 250 LDTs on its menu, including 100 that focus on mass spectrometry and another 150 in broader areas of application, such as chemistry, hematology, and infectious diseases.
Smaller Labs May Be Disproportionately Impacted
Somewhat ironically, Velázquez believes the regulations could become burdensome for smaller labs, many of which have used their LDTs to try to maintain an edge in the health care market.
“This will be limiting to particularly smaller labs, hospitals, and clinics and others, and they may not have the resources to comply. Facilities with less resources are going to be less likely to go off-label,” he said. “This will favor some of the bigger labs and players, and that is a paradox.”
But even the larger labs may be challenged by the rules. ARUP’s Ashwood noted that a large number of the lab’s validation studies date back 25 years or more and were conducted by an employee who is now deceased, making appropriate submissions to the FDA unlikely if they are required. He estimates that ARUP could wind up abandoning as many as 400 of its LDTs. These abandoned tests are not ordered frequently and therefore don’t have the margin to cover the cost of preparing premarket submissions.
Ashwood also noted that one popular high-risk LDT of ARUP’s, a genotyping test for hepatitis C, would require a premarket approval study and a clinical trial. The test competes with a kit manufactured by medical device giant Abbott, according to Ashwood. ARUP would not be able to complete a clinical trial in the time specified by the draft guidance and may be forced to pull the LDT and offer the Abbott kit instead.
By contrast, Ashwood noted that tests for glucose and creatinine levels—which could lead to significant health problems to a patient if misapplied—are considered to be moderate-risk LDTs.
The laboratory sector as a whole has also voiced its own concerns.
“Diagnostic innovation has thrived under the current regulatory framework and there is great concern in the lab community that additional and duplicative regulation will hamper the ability of researchers and scientists to continue their groundbreaking work,” said Alan Mertz, president of the American Clinical Laboratory Association (ACLA).
The College of American Pathologists (CAP) struck a slightly more conciliatory tone than the ACLA. “The [College] will work to ensure LDT oversight assures quality laboratory testing for patients in a manner that is consistent with principles outlined by the CAP,” said association President Gene Herbek, M.D. The proposed FDA guidance embodies a number of those key principles. Where there are differences, the CAP will work with stakeholders so requirements do not impede innovation or increase administrative burden on laboratories. The CAP will provide its recommendations and propose changes to improve the guidance during the public hearing and comment period.
As an alternative to FDA regulation, Mertz and the ACLA have advocated for changing and tightening up CLIA regulations in order to properly address the vetting and marketing of LDTs.
Velázquez believes that the CAP could also play a role in supervising LDTs.
“CAP has evolved their process and checklists over the past 30 years for the advance of new technology, and I think most laboratorians would be amenable of evolution instead of a whole new process,” he said.
Alberto Gutierrez, the FDA’s director of the Office of In Vitro Diagnostics, did not respond to a request seeking comment for this article.
Meanwhile, lab executives such as Ashwood said they will be advocating on their own, particularly as the public comment period moves along.
“I am going to try and rally this industry on the importance of this issue and write lengthy comments on the public draft guidance,” Ashwood said. “We really have to dissect out the guidance and give feedback.”
Takeaway: The FDA’s move to regulate laboratory-developed tests will continue to receive ongoing pushback from the industry as the agency moves toward developing final rules.