The US Food and Drug Administration (FDA) may be the federal government's regulator of most medical products, but at least one federal agency is looking to conduct basic reviews of the safety and efficacy of one type of medical product FDA says it has the authority to regulate.
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.
However, there is also one subset of medical devices that FDA has long exempted from regulation: lab developed tests (LDTs).
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."
In June 2013, FDA reiterated that it was interested in bringing LDTs under a more rigorous regulatory framework similar to that used to regulate in vitro diagnostics, but the agency has said little else about the plan in the last year.
Members of industry, meanwhile, have flatly contested FDA's authority to regulate LDTs, saying their existence falls under the regulation of the Clinical Laboratory Improvements Act (CLIA), and not the Federal Food, Drug and Cosmetics Act (FD&C Act), the law from which FDA gets most of its statutory and regulatory authority.
New Attempts to Oversee Safety, Efficacy
But while FDA's oversight of the devices remains at issue, another federal agency says it has a vested interest in making sure the devices are safe and effective, if only to minimal standards.
On 18 June 2014, the Department of Defense (DOD) issued a notice of demonstration in the Federal Register indicating that it is interested in allowing its Defense Health Agency (DHA) to evaluate non-FDA-approved LDTs as part of a demonstration project.
That project, it said, "is intended to further evaluate whether it is feasible for DOD to review LDTs not yet examined by the FDA to determine if they meet TRICARE's requirements for safety and effectiveness according to the hierarchy of reliable evidence."
TRICARE acts as DOD's healthcare system, operating on behalf of active and retired personnel, as well as their dependents.
DOD's hope, it said, was that an evaluation process would determine which, if any, LDTs it should cover under its plans. Since few, if any, LDTs are actually approved by FDA, this would apply to the vast majority of LDTs seeking coverage under TRICARE plans.
While DOD attempted a similar project in 2011 with the Centers for Medicare and Medicaid Services (CMS), which controls payment and coverage decisions for Medicare and Medicaid plans in the US, "limited participation" from LDT manufacturers prevented that demonstration project from yielding any actionable data.
At issue, according to the American Clinical Laboratory Association (ACLA), is that TRICARE stopped reimbursing clinical laboratories for more than 100 molecular pathology tests in early 2013 under certain conditions.
TRICARE's new demonstration system could allow wider use of some of those LDTs, but only if companies can show they are safe and effective when held to a standard of "reliable evidence."
The three-year demonstration project will "evaluate the feasibility of establishing a cost-effective and efficient way to review an expanded pool of non-FDA approved LDTs," DOD said. "Non-FDA-approved LDTs will be prioritized and reviewed for analytical validity, clinical validity, and clinical utility," the agency added.
On DOD's Standards of Evidence
So what constitutes "reliable evidence" to DOD? A conceptually similar but watered-down version of FDA's standards, DOD said. It explains:
Reliable evidence is defined in 32 CFR 199.2(b) and includes: “(i) Well-controlled studies of clinically meaningful endpoints, published in refereed medical literature; (ii) Published formal technology assessments; (iii) The published reports of national professional medical associations; (iv) Published national medical policy organization positions; and (v) The published reports of national expert opinion organizations.” The definition goes on to state, “The hierarchy of reliable evidence of proven medical effectiveness, established by (i) through (v) of this paragraph, is the order of the relative weight to be given to any particular source. With respect to clinical studies, only those reports and articles containing scientifically valid data and published in the refereed medical and scientific literature shall be considered as meeting the requirements of reliable evidence.
Not all evidence will be considered, DOD continued.
Specifically not included in the meaning of reliable evidence are reports, articles, or statements by providers or groups of providers containing only abstracts, anecdotal evidence, or personal professional opinions. Also not included in the meaning of reliable evidence is the fact that a provider or a number of providers have elected to adopt a drug, device, or medical treatment or procedure as their personal treatment or procedure of choice or standard of practice.”
DOD noted that some non-FDA approved LDTs will be reviewed under the demonstration for the expressed purpose of diagnosing or managing rare diseases, which are federally defined as those diseases affecting fewer than 200,000 persons in the US at any one time. Because the hierarchy of data "may not be met" in such cases (often due to the rarity of the disease or the difficulty of obtaining evidence), DOD said rare diseases will be handled on a case-by-case basis.
"The DoD's Laboratory Joint Working Group (LJWG) will be responsible for prioritizing and reviewing the non-FDA approved LDTs for the new demonstration," the agency said, with those diseases that have "potential high utilization and high clinical utility" to TRICARE participants gaining first access and, potentially, coverage under TRICARE.
The program will also reportedly extend coverage for prenatal and preconception carrier screening for cystic fibrosis, DOD said.
DOD Federal Register Notice