Quality control has long been one of the top priorities for clinical laboratory teams. From high-level checks to ensure the quality of lab-generated results to the specific control materials used to verify the consistency of each testing protocol, every effort is made to guarantee the best results for patient care. But now more than ever, quality controls — specifically the control materials used to assess test reliability — are in the spotlight with the new final rule on laboratory-developed tests from the U.S. Food & Drug Administration set to be phased in this year. Barring any changes to the rule or its rollout, this May, labs will need to begin complying with a host of reporting and quality system requirements.
One of the most effective and dependable ways to achieve compliance with these requirements is to incorporate the highest-quality external reference controls as part of a lab’s quality control framework. While there is a broad range of control materials available, there is also quite a range in their reliability, accessibility, and performance.
For clinical lab teams, it’s worth taking a close look at the features of various control materials and considering which ones best meet their specific needs. This will be a mandatory step if the FDA rule is phased in as expected, but even if it gets delayed or adjusted, the right selection of reference controls will still be important in helping lab professionals generate high-confidence results from the patient samples they receive. Having independent control materials with known reference values makes it possible to properly measure and contextualize clinical tests, ensuring that tests perform as they should, day in and day out. In addition, high-quality reference materials are important for validating new tests and workflows as well as for training laboratory scientists and technicians.
Commonly used controls
Throughout the clinical test workflow, lab members may use a few different controls for ensuring optimal test performance. For example, there are positive controls designed to generate positive results no matter what, and negative controls that should always produce negative results. These basic controls can be used at many points in a test workflow and serve as a valuable quality check for the results generated by the analytical test process.
Other types of controls are designed to assess the reliability of the overall testing process rather than individual test results. Internal controls go through the same testing workflow as the patient sample to provide a quality check on the entire assay. External controls, by contrast, are processed separately, following the same workflow but independent from the patient sample to verify the overall method. For the best view of test validity and performance, both internal and external controls are used together. The earlier that controls can be introduced — even as early as sample collection when appropriate — the more confidence laboratory operators can have in the end results of the testing process.
While there are many commercially available control options, lab professionals often opt for the one that seems most readily available and affordable: residual patient samples left over after a positive test. In the infectious disease realm, these controls introduce a degree of risk that may not be acceptable in all clinical labs. Residual samples, immortalized cell lines created from patient samples, and attenuated viral strains that are also go-to control materials put operators at risk of infection, particularly for highly contagious pathogens. Relying on patient sample materials also means that the supply of necessary controls is unpredictable. For more reliable workflows, labs should have a steadier supply of control materials.
For other types of tests, such as DNA-based molecular diagnostics for oncology or rare genetic diseases, it can be challenging to find a native, easily accessible source of controls that accurately mirror DNA mutations of interest.
Whatever control type is selected by a clinical lab team has to be accessible — not just for running tests on patient samples, but also for the test validation and operator training protocols that are important for overall laboratory quality. For all of these reasons, commercial sources of control materials may prove to be a better fit for most clinical labs than residual patient samples.
Synthetic molecular controls
For optimal results across a number of testing applications, laboratory professionals may find that synthetic molecular controls best fit the bill. Unlike patient sample remnants, they are readily available from vendors and can be stocked to meet surges in demand for testing, such as during a severe respiratory infection season.
While using synthetic controls for tests of real-life patient samples might seem counterintuitive, these controls can be carefully designed to match key attributes of native samples and can be detected in any type of sample matrix. Importantly, synthetic molecular controls can match the biology of pathogens without being infectious, offering a safer alternative to residual patient samples.
Synthetic controls undergo rigorous manufacturing techniques in well-controlled environments to ensure consistency from one lot to the next. As a result, they are ideally suited to cross-harmonization studies conducted at multiple laboratories to benchmark testing results across locations. Another advantage of synthetic controls is their ability to be customized quickly, allowing them to be used even for emerging infectious diseases or novel genetic mutation testing.
Certain synthetic controls have an added feature that allows them to better mimic native biological analytes and to withstand harsh processes in the testing workflow. These “armored” controls are encapsulated and surrounded by a protein layer that protects the inner control from degradation in a variety of biological matrices. This layer of protection means that armored controls are stable enough to be used in any part of the testing protocol, riding alongside the patient sample for a carefully controlled, system-level assessment of the full workflow from start to finish. These controls are broadly compatible with molecular testing assays.
When evaluating third-party sources of synthetic molecular controls, looking for a few key features beyond armoring can help to ensure optimal outcomes. For example, check to see if any of a manufacturer’s control materials have been included in FDA-reviewed in vitro diagnostic tests. Controls that are included in FDA-cleared assays clearly perform well and provide external validation of the manufacturer’s approach to quality control. In addition, look into the method a manufacturer uses to quantify its own materials; this is important for ensuring that a set concentration value of a control matches the concentration in a patient sample. The use of advanced methods such as digital PCR is a good indicator that a manufacturer is as quality-focused as its clinical laboratory customers.
What’s next?
It is difficult to know how the FDA final rule about laboratory-developed tests will play out, with the ongoing legal challenges and a new government administration creating some level of uncertainty. But no matter how things proceed, the well-known clinical laboratory commitment to quality will not change. Evaluating each lab’s selection and use of control materials is an important step that any clinical lab team can take today to ensure that they are ready for whatever compliance requirements are coming their way and that they are generating the highest-confidence results for their patients.
