Josh P. Roberts has an M.A. in the history and philosophy of science, and he also went through the Ph.D. program in molecular, cellular, developmental biology, and genetics at the University of Minnesota, with dissertation research in ocular immunology.
Say you come up with a proteomic or epigenetic pattern that seems to correlate well with disease susceptibility, prognosis or likelihood that a given treatment is appropriate, and you want to make this available to physicians. One way to do that is to go through the U.S. Food and Drug Administration (FDA) pre-market approval (PMA) or pre-market notification (510(k)) process for in vitro diagnostics (IVD) devices—by all accounts a long, drawn-out, expensive procedure.
Another way to get a test to market is to develop it as a “homebrew”, which the FDA calls a Laboratory Developed Test (LDT). Many of these are low-volume (esoteric) tests, tests with little intellectual-property protection, tests that require specialized training to perform or simply tests for which the science evolves quicker than the FDA filing procedure allows.
Although LDTs are much faster and less expensive to develop and do not need to meet all of the hurdles of an FDA-cleared or -approved IVD—such as Phase III testing demonstrating clinical efficacy—they do have their own set of standards to adhere to. Here are some of the benefits and pitfalls in going the LDT route.
CLIA and LDTs
An LDT is essentially an IVD that is made and used only within the lab that developed it. Labs that perform testing on patient samples—there are almost 250,000 in the United States, including those in clinics and hospitals, as well as large commercial test providers—are regulated under a program commonly known as CLIA (Clinical Laboratory Improvement Amendments). Before offering an LDT to the public, labs need to establish the performance characteristics relating to the LDT’s analytical validity as performed under a given set of conditions, by a certain staff, using particular equipment and on a specific patient population. And although the tests do not need prior approval (beyond the lab being CLIA-certified), the documentation must be available for scrutiny during the lab’s biennial recertification review.
“The regulations tell us what we need to do to validate our tests,” explains Kevin Halling, vice chair for research and development at Mayo Clinic Department of Laboratory Medicine and Pathology. There basically are six parameters that any lab that is trying to bring an LDT to market must establish, Halling says. These are: the accuracy, precision, reference range and reportable range of the test—the same as would be required to be presented in the package insert of an FDA-cleared/approved IVD—as well as its analytic sensitivity and specificity, plus any other characteristics (such as specimen stability or linearity) that would be important for that assay to establish.
Conspicuously absent from that list is clinical validity. “That’s not a CLIA requirement,” Halling notes. “All that is in CLIA is analytical validation.”
Clinical validity
On the other hand, the College of American Pathologists (CAP)—which has “deemed status,” allowing it to inspect and certify labs on behalf of CLIA’s administrators—does have an expectation of clinical utility in its Laboratory Accreditation Program Checklists, Halling adds.
Of course, the raison d’etre of any lab test is to give the requesting physician information that can help make treatment decisions. Halling estimates that more than half the tests Mayo Clinic offers are IVDs, and he has “no problem with FDA-approved tests, if they’re available.” But the economics make it nearly impossible to develop an IVD for most of the low-volume tests Mayo Clinic offers; thus, LDTs exist because “there’s a clinical need, yet there’s no commercial provider for the vast majority of those tests.”
This can be for a variety of reasons. Going through the FDA process may be too expensive, slow or cumbersome. The test may be a common one that can easily and inexpensively be performed by almost any CLIA lab. Or it may be a rarely requested test; in that case, it makes more sense for one or a few labs with the appropriate expertise to work up an LDT and interrogate samples from around the world.
Sometimes, too, there is an FDA-approved test, but it doesn’t perform as well as the LDT. “Because it’s so hard to get one approved, they have a hard time keeping up with the science. For example, there’s an FDA-approved test for BRAF mutations in melanoma, but it doesn’t detect all the mutations that are therapeutically important,” Halling explains. “And it’s easy for us to develop an assay … that will pick up more of the mutations that the clinicians want to know about.”
Clinical adoption
Especially when there is significant intellectual property involved, an LDT can be developed with the intention of it becoming the standard of care. Biodesix’ VeriStrat uses MALDI-MS to detect a proteomic signature of the host inflammatory response to tumors. To bring the test to market, the company engaged in a fulsome product-development process, similar to the way a device manufacturer prepares and applies for FDA approval. They “put it through a rigorous validation process—including a double-blinded, randomized prospective trial” that showed a significant difference in survival outcomes in patients with non-small cell lung cancer (NSCLC), says Biodesix vice president of business development and strategic marketing Paul Beresford. “Whether it’s for regulatory agencies, payors or physicians, you will not enjoy commercial success or become part of the clinical treatment paradigm” without such extensive validation.
Biodesix needed to demonstrate to Medicare, its largest payor, that in additional to extensive clinical validation, use of VeriStrat made pharmacoeconomic sense and actually impacted physicians’ clinical decision-making. Only after Biodesix attained that high hurdle did the Medicare contractor agree to cover and begin to pay for the test. Now the company is making the same case with private payors.
“While there certainly are legal routes to market as a Laboratory Developed Test through CLIA, if you intend to have your test become part of a drug label as a companion diagnostic, then you should anticipate a route to market that includes the FDA,” Beresford said. In fact, earlier this year Biodesix announced such an arrangement with the pharmaceutical company Aveo. The partnership will co-develop and commercialize a new test, BDX004, to help select those NSCLC patients that may benefit from Aveo’s drug, ficlatuzumab. Biodesix will continue to offer VeriStrat as an LDT.
There ultimately are any number of reasons a test may be developed as an LDT, from being the first step in an FDA submission to providing a much-needed, esoteric assay. Whatever the reason, the LDT mechanism ensures physicians can access the very latest scientific developments. For the patients that stand to benefit, that can only be good news.