Increased reliability of laboratory tests through pre-analytical standards
Prof. Dr. rer. nat. Karl-Friedrich Becker
With the kind permission of the Rechts der Isar Hospital of the Technical University of Munich. This article first appeared in German in its December 2015 Newsletter.
Inadequate attention has been paid to date to the quality of biospecimens for molecular tests in diagnostics and research. New European Standards have now been drafted with the assistance of Prof. Karl-Friedrich Becker of the Institute of Pathology of the Technical University of Munich and were published by the European Standards Body CEN last October (http://standards.cen.eu). These will contribute to more reliable results in laboratories in the future.
Millions of biological samples are investigated in laboratories around the world every day. The results of such analyses of just a few milliliters of blood or very small tissue samples will often have a substantial bearing on the further treatment of a patient. For example, tumor cells of certain types of cancer have increased quantities of protein molecules – so-called receptors – on their surface. These receptors modulate growth signals that enable the cancer cells to divide more rapidly. Some modern anti-cancer drugs inhibit those proteins and therefore slow down the spread of the disease. Such drugs may only be prescribed, however, if the receptors are shown to be present on the surface of the tumor cells of the tissue sample in very high quantities. Otherwise the drugs will not be effective. Some blood and/or tissue samples are stored in biobanks for analysis at a later date. Specimens stored in biobanks and the corresponding clinical data are used by researchers in academic and industrial labs to develop new medicines or improve diagnostic methods. There have been very considerable advances in analytical methods for molecular studies in recent years, bringing benefits for patients. The tests are now much more precise and less susceptible to external influences, with very few deviations. However, there is still room for improvement. As Prof. Karl-Friedrich Becker, Head of the Laboratory for Experimental Pathology, explains: "Although the advances in the molecular tests have been enormous in terms of their sensitivity, throughput, accuracy and reliability, the quality of the biological samples derived for testing, for example blood or tissue samples, has been neglected." There were no international standards covering the steps before the test itself – the pre-analytical phase. It is estimated that approximately 68% of the problems encountered in lab tests in hospitals are due to a failure to follow the correct pre-analytical procedures. In addition, many pre-clinical research results are not reproducible, leading to financial losses of billions of dollars. Experts are agreed that the quality of blood, tissue and other specimens for clinics and research laboratories can only be improved through the use of international standards. The researchers working in association with Prof. Becker have successfully integrated the results of their research into the standards.
How are national and international standards developed?
Standards are drafted by subject experts on behalf of national standards bodies such as the German Institute for Standardization (DIN), the European CEN and CENELEC, and the International Organization for Standardization (ISO). The subject experts reach agreement on the wording of each standard, taking into account the latest technology and procedures. Prof. Becker is a member of the Medicine Working Committee NA 063-03-03 AA "Quality management in medical laboratories" of DIN. He is furthermore a member and project leader of the European Committee for Standardization (CEN) TC140 "In vitro diagnostic medical devices" and the Technical Committee TC212 "Clinical laboratory testing and in vitro diagnostic test systems" of ISO. The derivation of biospecimens for in vitro diagnostics and their storage in biobanks for use in academic and industrial labs is a complex process, requiring co-ordination of input from various sources, such as physicians, surgical staff, pathologists, lab personnel, biologists and IT specialists. The influence of the procedures to which the tissue is subject, such as its removal from the patient, transport, fixing and storage, on the integrity, stability and expression of biomarkers has been inadequately researched. Once the impact of sample derivation and preparation parameters on the outcome of biomarker determination are known, then such impact can be minimized, so that better biomarkers can be developed in future and more reliable results derived for the patients.
Success of the Munich Leading-Edge Cluster m4
The Munich Leading-Edge Cluster m4 "Personalized Medicine" (www.m4.de) and the European SPIDIA project (www.spidia.eu) have collated experimental data to identify the critical steps of specimen derivation. Personnel carrying out tests in in vitro diagnostic labs or in clinical research labs at present do not generally know how a sample has been treated before it reaches them. The researchers working with Prof. Becker have demonstrated that analytes such as proteins and phosphoproteins can undergo changes before stabilization of the tissue samples. Not all proteins and phosphoproteins in every patient and in each organ studied react in the same way. These and other findings formed the basis for the drafting of the European Standards that have been published by CEN. These are of relevance to a number of parties, including in vitro labs, the customers of such labs, the developers and manufacturers of in vitro diagnostics, molecular pathology labs, organizations active in biomedical research, biobanks and the regulatory authorities. ISO has since declared the improvement of specimen quality to be a global aim. Prof. Becker is now the Project Leader for two out of eight ISO standards on pre-analysis that are scheduled for publication in 2017. Prof. Becker bears responsibility, together with others, in work package 3 for the drafting of the QM Manual that will be published in summer 2016 for the German Biobank Node.