In vitro diagnostic tests must typically be reviewed and cleared for clinical use based on safety and effectiveness criteria by the US Food and Drug Administration (FDA).2 Some new tests may be cleared by demonstrating equivalence to existing assays, a process known colloquially as the 510k. Assays without a “predicate” must go through the more rigorous premarket approval process to demonstrate their safety, analytic, and clinical effectiveness. The FDA approval and clearance process plays a key role in ensuring that laboratories have access to a consistent and reproducible stream of reagents and instruments that ensures accuracy in clinical diagnostics and therapeutics. It is important to note, however, that not all FDA-cleared tests are perfect (1) and that such tests do not exist for every necessary clinical indication or all patient populations. Practitioners of laboratory medicine are uniquely qualified to address such gaps through development, proper validation, and implementation of laboratory-developed tests (LDTs).
Pediatrics is an area where there are many unmet laboratory testing needs. Pediatric practitioners like myself must carefully adopt FDA-cleared methods. The vast majority of these methods are cleared for indications in adult populations. However, none of the assays on the chemistry, hematology, and coagulation systems used in my laboratory carry specific indications for pediatric patients. Do these assays perform adequately with samples from neonates, toddlers, or adolescents? Not always. Automated drug screening immunoassays, for example, do not effectively detect illicit substances in neonates. The likelihood of false-positive results necessitates confirmatory testing that may not be available before patient discharge. False-negative results are also common (2) because infant urine samples are often very dilute and already contain low concentrations of maternally transmitted substances. The solution deployed at St. Louis Children's Hospital is a laboratory-developed LC-MS/MS broad-spectrum, high-sensitivity, drug-screening assay performed around the clock in lieu of immunoassay screening.
LDTs also fill large gaps in the diagnosis of rare disorders where there are no FDA-cleared or approved methods. Some of these are complicated mass spectrometric methods that detect a broad spectrum of metabolites useful in the diagnosis and follow-up care of babies with inborn errors of metabolism. Rapid, accurate diagnosis of these disorders is critical to saving lives and preserving physical and intellectual development. Other LDTs are not particularly high-tech, such as the measurement of chloride concentration in sweat, which is still the gold standard for the diagnosis of cystic fibrosis. LDTs such as these are demanding to develop, validate, and maintain along guidelines dictated by CLIA and the College of American Pathologists (CAP). These efforts go largely unrecognized by the public and the parents and families of affected children. However, they make a huge difference to physicians charged with the care of these often-fragile patients.
Two recent personal experiences precipitated in large part by the proposed FDA guidance on LDTs (3) illustrate the damaging impact of the mere threat of new regulatory enforcement. In one instance, our institution ordered, paid for, and received new chloride titrators to replace a 25-year-old version of the same instrument that was beginning to fail excessively. The day after the shipment arrived, we were asked to return the devices by the distributor, who cited the lack of FDA-cleared indications for the instrument. In a second instance, an instrument manufacturer blocked purchase of an additional blood coagulation device similar to others already in our laboratory, citing a lack of specific pediatric approval by the FDA. These issues presently remain unresolved, but our ability to support well-established clinical practice has already been negatively affected.
Is this our future-state? Will all of our equipment need specific pediatric approval? If so, will we need specific approval for premature babies, term babies, or toddlers? In the absence of such approval, how will we take care of pediatric and other vulnerable and unique patient populations? Having worked in industrial research and development, I am equally sympathetic to the burdens new regulations will bring to manufacturers. During my time in research and development, a very wise scientist once told me at the conclusion of an exasperating product launch that our efforts were limited. “We can build ingenious, robust reagent systems and fully characterize them,” he said, “but at some point, we have to turn them over to smart, experienced people to use and take care of patients.” Clinical laboratorians are those “smart people” who translate these tools into the clinic. Although we understand that regulatory bodies are charged with assuring safe and efficacious testing for the US population, without the ability to modify, validate, and offer niche-specific LDTs, our hands are needlessly tied, and patient care suffers.
↵2 Nonstandard abbreviations:
- Food and Drug Administration
- laboratory-developed test.
Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form.
Employment or Leadership: D.J. Dietzen, JALM, AACC.
Consultant or Advisory Role: None declared.
Stock Ownership: None declared.
Honoraria: None declared.
Research Funding: None declared.
Expert Testimony: None declared.
Patents: None declared.
- Received April 25, 2016.
- Accepted May 4, 2016.
- © 2016 by American Association for Clinical Chemistry