A new guidance document published by the US Food and Drug Administration (FDA) establishes standards by which manufacturers of in vitro diagnostic (IVD) devices intended to detect the presence of Borrelia burgdorferi should test and validate their devices.
B. burgdorferi is a bacterium most commonly associated with Lyme disease, an infectious disease commonly transmitted by ticks that can cause serious complications if left untreated. The disease can be difficult to detect, particularly as it can remain dormant for days, if not weeks, before symptoms begin to establish themselves. Early stages of the disease may also be confused with other ailments, as they include fever, fatigue, and headaches.
At its worst, untreated Lyme disease can cause severe joint pain, heart problems and damage to the central nervous system, so early diagnosis can be important in order to start a patient on a course of antibiotics.
The problem is that current tests to detect B. burgdorferi aren't well-validated or particularly accurate. As explained in January 2013 by Medscape, the current best tests rely on serologic assays that are limited in their ability to detect current exposure, while most other tests have avoided FDA's regulatory scrutiny by marketing themselves as lab-developed tests (LDTs).
In the absence of a well-defined regulatory pathway for new tests, some healthcare professionals, including those at the Centers for Disease Control and Prevention (CDC), said they were worried about the effects of false-positive and -negative results on patient health.
"Failure of devices for the detection of B. burgdorferi antibodies to perform as expected, or failure to correctly interpret results may lead to incorrect patient management decisions and inappropriate public health disease reporting," FDA explains in its new guidance document. "In the context of individual patient management, a false negative report could lead to a delay or failure to provide treatment. A false positive report could lead to unnecessary or inappropriate treatment."
Guidance: Validate the Tests
FDA's new guidance document recommends studies for establishing the performance characteristics of in vitro diagnostic devices for the detection of antibodies to B burgdorferi in humans.
"A manufacturer who intends to market an in vitro diagnostic device for detection of antibodies to B. burgdorferi must conform to the general controls of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and, unless exempt, obtain premarket clearance or approval prior to marketing the device (sections 510(k), 513, 515 of the FD&C Act; 21 U.S.C. 360(k), 360c, 360e)," FDA explained.
In light of the risks associated with false positives and negatives, FDA said it is "critical" to the safe and effective use of the product that they be held to performance standards as evidenced by the successful completion of studies.
FDA said studies on the devices should show them to be precise, have well-understood reactions to Lyme disease and other related antibodies, and generate reproducible results. Of particular concern is the sensitivity of the device, which should be assessed in a minimum of 100 confirmed Lyme disease specimens.
Other factors will also need to be assessed, FDA explained.
"We recommend that you substantiate statements in your labeling about specimen storage and transport by assessing whether the device can maintain acceptable performance over the range of storage times and temperatures recommended to users," it wrote.
Geographic differences must also be accounted for. The strain of B. burgdorferi that exists in the US is markedly different from the one that exists in the EU, and tests must label which strain they are intended to identify.
Change in the Way FDA Regulates LDT Devices? Not Likely
The agency's language seems to indicate that it will not revoke its use of enforcement discretion for lab-developed tests (LDTs) intended to detect Lyme disease, a sort of sub-set of IVDs not intended for use outside of commercial settings.
Regulators have in recent years been cracking down on some LDTs, arguing that without proper validation they could be causing harm to public health. The tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA) of 1998, which is to say largely unregulated by FDA and instead regulated by the Centers for Medicare and Medicaid Services (CMS).
The agency said companies will still need to seek a waiver for their devices under CLIA, and should consult with the Division of Microbiology Devices at the Center for Devices and Radiological Health (CDRH) to determine the design of any studies intended to support that waiver application.