Clinical laboratories are receiving an increasing number of requests to perform routine testing on a wide range of body fluid types—other than serum, plasma, or urine—that assay manufacturers have not validated. Often times the lab approves these requests without appreciating the unique requirements of this type of testing. Labs have analyzed these off-label specimen types for years, and they have played an important role in diagnosing and managing a variety of diseases. But the patient safety risks were not fully realized until recently, and additional regulatory requirements are adding a new layer of complexity.
Clinical laboratories may now find themselves asking if continuing to provide this service is worth the extra effort required to maintain regulatory compliance. However, despite the difficulties of off-label body fluid testing, it remains a powerful clinical tool when used appropriately and the risks are recognized and reduced. In addition to ensuring that the test performance characteristics are adequate for the intended use, laboratories also can improve patient safety by engaging with the clinical team to improve appropriate test utilization and result interpretation.
What Are Off-Label Body Fluids?
Off-label body fluids refer to any fluid type other than those cited by the manufacturer of a Food and Drug Administration (FDA)-cleared method in the “Intended Use” portion of a product insert (1). They are not derived from blood or urine and include cerebrospinal fluid (CSF), serous fluids (pleural, peritoneal, and pericardial), synovial fluid, and drainage and dialysis fluids, among others. The pathological accumulation of these body fluids occurs due either to increased production or reduced rate of absorption. Each fluid type has a unique composition and generally is considered to be an irreplaceable specimen since collection is often invasive.
What Are Some of the Challenges Associated With Off-Label Body Fluid Testing?
Until recently, off-label body fluid testing could be performed without as many of the rigorous safeguards that typically apply to other in vitro diagnostics. Regulatory agencies only recently began to appreciate the unique nature of each body fluid type and the impact that these variations in chemical composition (proteins, electrolytes, lipids, pH, etc.) can have on assay performance. Now laboratories are required to evaluate and document the performance characteristics of each fluid type to ensure that it is adequate for the intended use.
Although some of the general rules for serum and urine specimens can be applied, numerous challenges exist when validating these off-label specimen types, such as gathering enough rare samples, verifying a wider range of analyte concentrations, finding an alternate method for comparison, and determining reference intervals—despite the fact that healthy subjects do not donate body fluids requiring invasive collections.
Other challenges include a lack of matrix-matched quality control materials, information regarding specimen stability, and pertinent scientific literature sources for establishing reference ranges and clinical utility. Laboratories must critically analyze the limited published studies available because they may not be transferable to the lab’s testing protocols and patient populations.
Is There Guidance Available for Off-Label Body Fluid Testing?
There is limited guidance for clinical laboratories. Although it is now mandatory to evaluate these modified tests, the extent of the validation is at the discretion of the laboratory director. The College of American Pathologists (CAP) checklists are a good resource for ensuring the right documentation for compliance. The most recent versions of the checklists have incorporated regulatory requirements on implementing procedures, method validation, and reporting results.
Other valuable resources are the Clinical and Laboratory Science Institute guidelines developed through the consensus process for the analysis of body fluids (2, 3). These documents deal with the clinical utility of analyte measurements in the majority of fluid types. They also provide guidance to clinical laboratories on result reporting, interpretation, and analytical variables affecting measurement of body fluids. A more recently published review article by Block and Algeciras-Schimnich provides a helpful supplement for serous fluids in particular (4).
How Can Laboratories Reduce Risk?
To reduce the risks associated with off-label body fluid testing, laboratories should start by evaluating their current test ordering patterns and volumes. They should perform a thorough review to separate tests with known clinical utility as described in the literature from those without. Tests that do not provide results used to influence patient management or add value to the clinical context in which they are ordered should be discontinued. To better serve physicians and patients, laboratories should focus their efforts on validating the most prevalent fluid types and tests with known clinical utility. Depending on the size of the laboratory and the level of staffing, it may be more practical to send low volume or perhaps even all off-label body fluid test orders to a reference laboratory.
Laboratories might also consider implementing an approval processes for handling body fluid requests for those with limited or questionable utility or those not yet fully validated. The Mayo Clinic process requires laboratory director approval, and we have recently implemented a similar process at University Hospitals Case Medical Center involving our residents (5). We have validated more than 15 standard chemistry tests for use with a variety of off-label specimen types. For non-validated body fluid test orders, the on-call resident is charged with reviewing the patient medical record and contacting the clinical team, if necessary, to determine why the test is being ordered and how the team intends to interpret the results. If the clinical utility is apparent, we verify the accuracy of the assay by performing dilution experiments to rule out matrix effects. If the dilution study results meet our criteria, the resident approves release of the result. Our testing approval process has been successful, and surprisingly, caused very little pushback, which is similar to Mayo Clinic’s experience.
Clinical laboratories must be mindful of potential safety issues in all aspects of the total testing process. It is our duty as laboratory professionals to encourage appropriate testing of off-label body fluids, to ensure that the results reported are analytically sound, and to provide proper result interpretation guidance—just as we would for blood, serum, or urine.
By optimizing the test menu to include only clinically useful tests with appropriate interpretive information, laboratories will reduce the risks associated with off-label testing while providing physicians with the necessary information for faster diagnosis and treatment of complicated cases.
1. Wians FH. To test or not to test? Opening Pandora’s Box. Lab Medicine 2004;35:707.
2. Clinical and Laboratory Standards Institute (CLSI). Analysis of body fluids in clinical chemistry; Approved guideline. CLSI document C49-A. 2007.
3. Clinical and Laboratory Standards Institute (CLSI). Body fluids analysis for cellular composition; Approved guideline. CLSI document H56-A. 2006.
4. Block DR, Algeciras-Schimnich A. Body fluid analysis: Clinical utility and applicability of published studies to guide interpretation of today’s laboratory testing in serous fluids. Crit Rev Clin Lab Sci 2013;50:107–124.
5. Block D. Body fluid testing in the clinical laboratory: Are you ready for your next CAP inspection? https://www.aacc.org/community/national-academy-of-clinical-biochemistry/scientific-shorts/2012/body-fluid-testing-in-the-clinical-laboratory-are-you-ready-for-your-next-cap-inspection.aspx (Accessed August 2015).
CLN's Patient Safety Focus is sponsored by ARUP Laboratories