The current gold standard across most regulators, including the New York State Department of Health Oncology guidelines, ISO 15189 and CLIA guidelines, are focused on use of patient specimens for verification and validation activities. Is the availability and reproducibility of alternative reference materials improved to the point that other reference material sources could be considered? Hannah Murfet of Horizon Discovery evaluates the potential of cell line derived reference materials.
The use of reference materials, whether derived from patient specimens or otherwise is clear for demonstrating validity across the clinical supply chain. From drug discovery to detection mechanisms to the clinical laboratory, reference materials are essential to determine key performance characteristics such as reproducibility and sensitivity. Patient derived samples often have the limitation of a supply limit. With a lack of sustainability comes a lack of a permanent benchmark, and as patient derived reference materials are depleted, an alternative may be hard to source, introducing further variability and uncertainty.
Through limited availability and distribution, use of patient specimens introduces variability between hospitals and even the same hospital within a period of time. Cell line based reference materials can be produced from immortalised line that are sustainable and able to be modified to meet the clinical need through targeted genetic engineering, giving the potential to represent even the clinically rare patient specimens. Developments in genetic engineering and use of similar matrices to patient specimens allow greater potential for cell line reference material used for pre-analytical aspects of the workflow such as extraction and sample preparation.
Cell line derived reference materials can represent much closer models to patient specimens through the format matrices, such as FFPE or on-slide reference materials. Other reference material providers are emerging for new technologies such synthetic constructs, however further work is required to determine acceptable use of these for validation. Meanwhile valuable efforts such as the Genome in a Bottle Consortium aim to characterise human genome sequences for reference materials through repeated testing and community distribution. In spite of this, there is still a perception over a lack of available reference materials, including those available for proficiency testing of genetic tests (Congressional Research Service).
There is no doubt that reference materials are required for developing the essential case for clinical utility and validity across the clinical supply chain. Development in the matrices such as FFPE or even serum substrates may further enhance the patient relevance of cell line derived materials to a point where they may be seen as equivalent. Availability of defined cell line based from genetic engineering can improve the availability of reference materials, so perhaps it is time to review the focus on patient specimens. Perhaps it is time to consider the utility of cell-line derived reference materials and their value proposition of long term sustainability in validation and verification in the clinical supply chain.