In October of last year, the Food and Drug Administration (FDA) released a draft guidance entitled Framework for Regulatory Oversight of Laboratory Developed Tests (LDTs). 1  LDTs are defined by FDA as in vitro diagnostic devices (in other words, laboratory tests) that are “intended for clinical use and designed, manufactured, and used within a single laboratory.” 

In contrast, most tests performed in clinical laboratories are developed and validated by commercial manufacturers, submitted for evaluation and approval by the FDA, and then distributed or sold commercially for use in many different laboratories. 

Strictly speaking, the current FDA definition of LDTs does not include procedural alterations that a laboratory might apply to otherwise FDA-approved tests; however FDA has indicated that it intends to regulate such tests as though they were true LDTs.  Typical examples of traditional LDTs include gram stains, manual differential cell counts, manual testing for certain chemical analytes, manually performed microbiology cultures, and so on.  With the advent of genomics and personalized medicine, however, LDTs have expanded greatly to include molecular genetic testing for numerous diseases and with various intended uses, from diagnosis to classification to management of cancer, infectious diseases, and other—often rare—conditions.

CLIA Validation

Since the mid-1970s, the FDA has asserted regulatory authority over tests performed in clinical laboratories, under the Medical Device Regulation Act.  However, the FDA has largely chosen not to regulate LDTs (practicing what it refers to as “enforcement discretion”).  Under the Clinical Laboratory Improvement Amendments of 1988 (CLIA-88), laboratories are already required to perform full analytical validation for all tests (both FDA-approved and non-FDA approved tests, including LDTs). Depending on the nature of the particular test, this CLIA-mandated validation may involve determination of a test’s analytical accuracy, sensitivity (the lowest level or concentration at which a particular compound or abnormality can be detected), specificity (including assessment for interfering substances), precision, reportable range, and reference range. 

While CLIA requires this level of analytical validation, it does not require clinical validation (the determination that a given test is useful for diagnosis, monitoring, management, or classification of a particular disease or medical condition) or delineation of the clinical intended use—areas traditionally within the purview of FDA. 

For nearly the past 40 years, FDA has determined that the nature of traditional LDTs (the fact that they are, by definition, developed and validated for use locally in a single laboratory facility) largely mitigated the risk of allowing this type of non-FDA-approved testing. However, with the explosion of highly complex (and often proprietary) molecular diagnostics, including companion diagnostics (the linking of a particular laboratory test to a particular therapy for a particular disease), FDA is now giving notice of its intention to increase regulation of LDTs.

FDA Proposed Nine-Year Framework

Going forward, FDA has proposed a risk-based approach for enhanced regulatory oversight. Under language used in the Medical Devices Amendments of 1976, FDA will classify LDTs under one of three categories: Class I, class II, and class III, with class I representing lowest risk and class III representing highest risk.  Overall, the proposed framework phases in the new system over a nine-year period, during which laboratories will be allowed to continue offering their current menus of LDTs, pending review of those tests by FDA. 

Once a final guideline is issued, the first year of the phase-in period would be devoted to establishing requirements for pre-market approval (that is, FDA approval prior to offering or marketing a specific LDT) of the highest risk (a subset of class III) tests, including tests that are designed to mimic currently approved companion diagnostics (tests FDA-approved specifically for determining eligibility for treatment with specific medications or biologic agents). 

The next four years would involve phasing in pre-market review requirements for remaining high risk (class III tests), the list of which would be defined within two years of the final published guidance.  The final four years of the phase-in period would be dedicated to establishing pre-market review requirements for intermediate risk (class II) tests. 

The lowest risk (class I) LDTs (including so-called “traditional” LDTs) would be subject essentially to the current system of enforcement discretion, with the exception that laboratories will have to register each test with FDA, and each lab will be subject to adverse event reporting requirements, even for class I LDTs.

There are many logistical details to be worked out in the framework guideline with respect to intended use, clinical validation, quality systems design, and other factors as they relate to LDTs.  As one example, FDA needs to determine the level of evidence required to establish clinical validity of a given LDT.  In the FDA approval process for other medical devices, generally manufacturers either need to provide data from formal clinical trials, or they need to obtain clearance by demonstrating equivalence with existing approved devices (the so-called 510(k) process). 

In contrast, it is possible that FDA would allow for a less stringent demonstration of clinical validity (for example, references to existing medical literature) in the clinical validation of certain LDTs.

FDA-Sponsored Dialogue 

In my role as president of the American Society for Clinical Pathology, I had the privilege of taking part in an FDA-sponsored workshop on regulation of LDTs in Bethesda this January.  The conference brought together many leaders from many non-profit and for-profit organizations, as well as patient advocacy groups. 

Panel discussions focused on

1. Components of a test and LDT labeling considerations,
2. Clinical validity and intended use,
3. Categories for continued enforcement discretion,
4. Notification and adverse event reporting,
5. Public process for classification and prioritization, and
6. Quality systems regulation. 

Opinions varied widely among the workshop participants—from full support of the proposed framework; to opinions agreeing in spirit to policies that would protect patient safety, but with caveats warning against policies that would jeopardize medical innovation in clinical laboratories; to opinions that laboratories are not manufacturers and LDTs are not medical devices, and therefore FDA lacks jurisdiction in the matter entirely. 

Discussions were vigorous, thoughtful, and thorough, and often focused on where to draw the line between the manufacture of medical devices and the practice of medicine with respect to LDTs. 

Webcasts and transcripts of the workshop are available on line at http://www.fda.gov/MedicalDevices/NewsEvents/WorkshopsConferences/ucm423537.htm.

Quality and Compliance

As an esoteric testing laboratory, Warde is keeping careful track of the emerging dialogue in the regulation of LDTs.  FDA has not yet issued a final guidance document, but we look forward to navigating the complex waters of LDT regulation so as to provide seamless and high quality testing for our clients and co-tenants.  Rest assured, we will always maintain the highest standards of quality and compliance as we meet your clinical laboratory testing needs.