What is a laboratory-developed test (LDT) any why are so many people up in arms about regulating LDTs?
A LDT is an in vitro diagnostic test developed by a single laboratory, often at an academic medical center like Mayo Clinic, and intended for clinical use. LDT regulation has been a source of controversy among the FDA, Congress, and industry stakeholders.
The debate started in 2014, after the FDA proposed guidance on a new LDT regulatory framework.
The genesis of the FDA’s guidance is a general lack of assurance over a LDT’s safety and efficacy, particularly as such tests have become complex, widely marketed, and more commonly used to diagnose patients.
Sometimes LDTs provide an indication of whether a patient may have a life-threatening condition, like ovarian or breast cancer, but it may be tough for clinicians and consumers to know whether the tests do what they say they do.
The American Clinical Laboratory Association (ACLA) believes the FDA set the evidence bar too high, and has established key principles of regulatory reform. According to the labs, it is only rational to assure the test’s clinical and analytical validity, rather than assess LDTs as medical devices.
Traditional diagnostic test manufacturers that have long been held to FDA standards are pleased that laboratories would be regulated under the proposed guidance, thus creating a level playing field.
The lab industry’s views are more in line with a discussion draft in the House of Representatives—a proposal that is fundamentally similar to one floated by the Diagnostic Test Working Group (DTWG) earlier this year.
In any case, myriad stakeholders have all but assured this will be a tough issue to tackle moving forward, as the major players have not yet come close to coalescing around any proposal.
Look to 2016-17 as the soonest that there could be some clarity on the issue.
FDA Guidance
The FDA created a firestorm when it published draft guidance outlining regulation for LDTs on October 3, 2014.
The guidance defines LDTs, details premarket review requirements, and addresses existing Clinical Laboratory Improvement Amendments (CLIA) requirements among other things. In it, LDTs are described as a subset of in vitro diagnostic devices (IVDs) “intended for clinical use and designed, manufactured and used within a single laboratory.”
The FDA proposes a risk-based, phased-in approach for the regulation of LDTs that outlines notification and registration requirements, pre-market requirements, and post-market requirements such as adverse event reporting.
Under this framework, LDTs would either go through a formal notification process or meet registration and listing requirements. Within six months of finalization, all laboratories would be required to have notified the FDA on LDTs currently provided. After this time, labs will be required to submit notification prior to marketing new tests.
With respect to risk-classification, the framework establishes expert advisory panels to assess low-, moderate-, and high-risk tests. High-risk LDTs would essentially be characterized as class III medical devices. Pre-market review for the highest-risk tests would begin 12 months after guidance becomes finalized.
The risk-classification framework is still incomplete, as FDA has stated that it would be another 18 months after finalization of guidance before another draft guidance would be issued. Factors will include tests intended for high-risk diseases, whether the test would be the sole determinant of a clinical decision, alternative diagnostic tools available, and the potential consequences of a wrong result.
The FDA guidance has received criticism from the American Medical Association (AMA), and other groups. The AMA states that the guidance would limit patient access, and ACLA believes the FDA does not have the legal authority to implement regulations on LDTs in the first place. There is also concern over harmonizing CLIA regulations with the new guidance, and the possibility of duplicate or redundant regulations.
Jeffrey Shuren, MD and JD, Director at the Center for Devices and Radiological Health at the FDA, testified at a recent hearing on LDTs at the Energy and Commerce committee. Shuren stated that he wanted to have a dialogue around the FDA proposal. “If what we are proposing doesn’t hit the mark right, then let us talk about what is the best way to hit that mark…Whatever we get at the end of the day, someone is not going to be happy because there are so many different perspectives, but we are going to try to hit it [as] best as we can,” Shuren stated.
Working Group Proposal
The Diagnostic Test Working Group (DTWG) floated a proposal that represented more of a compromise between labs and the FDA guidance. Some of the DTWG participating companies include Becton Dickinson, Roche, Mayo Clinic, LabCorp, Quest, Myriad, and ARUP labs.
The premise of this framework is that the labs are not manufacturing devices, rather providing testing services, and so putting LDTs under the existing device regulations proposed by the FDA is not suitable. The proposal states, “As compared to traditional therapeutic medical devices, IVCTs (in vitro clinical tests) fulfill different purposes, are developed differently, and have different clinical outputs, so the same regulatory system doesn’t rationally meet the needs of both therapeutic medical devices and in vitro clinical tests.”
Under the DTWG proposal, a new category is created for IVCTs, which would be regulated, in part, by a new center at FDA. The activity-based framework—meaning, regulation based on activities involved in IVCT development and use rather than the type of entity developing tests—also grants jurisdiction to CMS and the states.
According to the proposal, FDA would oversee the development of IVCTs from design to production, as well as some post-market activities. CMS would regulate lab operations, including the performance of the IVCT. Lastly, the states would retain jurisdiction over the practice of medicine—medical judgment and interpretation of test results.
The proposal also employs a risk-based approach under which an advisory panel would classify tests as high-, moderate-, or low-risk. The medical device pre-market standard of safe and effective, according to the DTWG proposal, is inapplicable to IVCTs.
House Proposal & Lab Framework
The latest legislative proposal in the House of Representatives uses the IVCT language from the DTWG proposal, and was similar in construct. A new agency center for IVCTs would be created within 90 days after enactment.
The risk classification is also broken down by high-, moderate-, and low-risk, and takes into account the severity of the disease or condition, whether the test is the sole determinant for directing clinical treatment, how well-characterized the test is, as well as the consequence of a wrong result on patient outcomes.
Although the House proposal does not use the activity-based separation of FDA, CMS, and state jurisdiction from the DTWG plan, the practice of medicine would not fall under FDA regulation. The House proposal includes a section on unique identifiers for tests that would identify the product through distribution or use.
ACLA’s key principles for diagnostic reform are very much in line with the less onerous H.R. draft and DTWG proposal.
In order to continue driving innovation, the framework maintains that LDTs are not medical devices and the evidence bar should not be set as high as they are for medical devices — “safe and effective” versus a reasonable assurance of clinical and analytical validity.
Next Steps
It’s difficult to see how the FDA guidance or stakeholder proposals will move forward, as LDT regulation has pitted many different stakeholders—patient groups, test manufacturers, government agencies and labs, to name a few—against one another.
Some stakeholders, like the Association for Molecular Pathology (AMP) and the College of American Pathologists, support enhancing CLIA and opposes FDA oversight except for perhaps the highest risk tests i.e., those with a hidden proprietary algorithm. AMP would also like to see a formal rulemaking process.
Others, like AdvaMed, the American Society of Clinical Oncology, and the American Association for Cancer Research, support risk-based FDA regulation—essentially similar to the guidance released last year—of all tests.
Regardless we are at least 1-2 years away from any consensus regulatory path, so the debate will only continue.
Ipsita Smolinski is Managing Director for Capitol Street, a healthcare research and consulting firm in Washington, DC.