For years, the US Food and Drug Administration (FDA) has provided leeway to a sub-category of diagnostic tests known as laboratory-developed tests, or simply LDTs. But according to FDA Commissioner Margaret Hamburg, that era of enforcement discretion will soon come to an end.
Under normal circumstances, medical devices can reach the market in one of two ways. Either they obtain FDA approval through the premarket approval (PMA) process-a difficult and expensive pathway that requires clinical data to support an application-or a premarket notification [510(k)] application that aims to show that a device is substantially equivalent to a predicate device, usually avoiding both the cost and clinical data required of PMAs.
There is, however, in practice a long-practices exemption given to a subset of diagnostic devices. Whereas most in vitro diagnostic tests need to be approval or cleared by FDA, LDTs do not. That's because the devices were historically intended to be developed by and exclusively used within a laboratory, and regulators feared that subjecting the devices to regulatory review would stifle their development entirely.
"Initially, laboratories manufactured LDTs that were generally relatively simple, well-understood pathology tests or that diagnosed rare diseases and conditions that were intended to be used by physicians and pathologists within a single institution in which both were actively part of patient care," FDA explained in a 2010 meeting notice. "These tests were ordinarily either well-characterized, low-risk diagnostics or for rare diseases for which adequate validation would not be feasible and the tests were being used to serve the needs of the local patient population."
But in recent years, FDA has noticed LDTs becoming increasingly complex and in some cases nearly indistinguishable from their FDA-cleared or -approved counterparts. Of particular concern to FDA is that many LDTs play critical roles in clinical decision-making in the context of personalized medicine (e.g. genetic testing), which it said raises the risk of incorrect or missed diagnoses, resulting in untimely or improper treatment.
The agency has long asserted its right to regulate the devices, but since 2011 has begun to move strongly toward a system of stricter regulation of LDTs, albeit not quite as strict as the current system for in vitro diagnostic devices. That's because FDA said it "recognizes that while the absence of FDA oversight may make it easier for laboratories to develop and offer tests on a rapid timeline, the absence of a level playing field creates a disincentive to innovation by other manufacturers whose tests are approved or cleared by the agency."
Framework under Development
In a speech before the American Society for Clinical Oncology's (ASCO) annual conference in Chicago, Hamburg called special attention to LDTs, which have increasingly been used as companion diagnostics with newer cancer drugs, and not always to beneficial effects.
Hamburg's speech tracked much of what FDA said in 2010; that is, LDTs are becoming so complex that they have outgrown the fitness of FDA's current regulatory approach, which was designed when tests were simpler and for lower-risk indications.
"Results from these tests are rapidly becoming a staple of medical decision-making, particularly for cancer. And some people with a family history of cancer are using these tests to decide whether to take preventive action," Hamburg explained.
That is fine, except when those tests don't operate as advertised. Hamburg cited the case of OvaSure, an early-stage ovarian cancer screening test that FDA pressured off the market after it was determined to be "flawed."
"FDA does not know how many women may have received erroneous results from the OvaSure test, or how many may have used that flawed information to make critical medical decisions," Hamburg said. "But relying on advanced diagnostics to make critical, life-altering treatment decisions exposes patients to obvious risks if these tests do not perform as expected. False results put patients at risk of a missed diagnosis or a wrong diagnosis that could result in either inappropriate treat or no treatment at all."
To that end, Hamburg said her agency will be "working to make sure that the accuracy and clinical validity of high-risk tests are established before they come to market" under a new risk-based framework that remains under development.
That framework would provide assurances of both safety and effectiveness, Hamburg said. However, she noted that the framework would also try to balance the need for information with innovation and patient access, adding that making sure patients have access to products is an equally important part of the regulatory equation.
Hamburg did not, however, elaborate on when the new LDT framework-possibly a new regulation or just a compliance policy guide-would come into effect.
Hamburg's Speech2013 RAPS: What is a Laboratory Developed Test versus an FDA Cleared Test?