Good health care requires reliable measurements of health status and disease markers. The results of such In-Vitro diagnostics measurements need to be comparable between different laboratories, and over time.
The measurement of biomarkers, mainly in blood, is performed in many thousands of hospital laboratories. The results are used to monitor health status, screen for disease, support diagnosis, and monitor the effect of therapies for diseases.
However, various factors like equipment calibration, chemical reactions, testing methods, and patient genetics can affect the accuracy of these results. Without standardisation, comparing test results obtained at different hospitals or in the same hospital over a period of time, is very challenging. This situation is exacerbated by demographics and increased population dynamics.
In order to have comparable laboratory results we need standardisation using reference materials and methods. This need for standardisation and traceability is articulated in the EU Regulation (EU) 2017/746 on in vitro Diagnostic Medical Devices. Thus in Vitro Diagnostics manufacturers can make use of JRC’s standardisation tools in order to comply with the requirements of the regulation.
To create clinical reference materials, the JRC collaborates with the International Federation for Clinical Chemistry and Laboratory Medicine (IFCC), which brings together clinical chemists, expert clinicians and representatives of In Vitro Diagnostic industry. As an independent entity, the JRC facilitates the consensus needed for the broad acceptance of standardisation processes.
Monitoring patients' health status
Biomarkers in human blood are crucial to determine our health status. Essentially these are molecules that indicate whether there is an abnormal process taking place in the patient’s body.
Standardisation of plasma proteins
Plasma proteins constitute different types of proteins that are located in blood plasma, the clear fluid left when red and white blood cells, along with platelets, are taken out of the blood. They have many important functions, such as carrying fats, hormones, vitamins, and minerals throughout the body, and helping the immune system to protect against illness.
A major breakthrough in standardising plasma protein measurements was the JRC’s release of the first stable and reliable reference material certified for 15 proteins in the 1990s. Since then, the JRC has developed and released a range of clinical reference materials for proteins like C-reactive protein and cystatin C. Higher levels of these proteins indicate inflammation and impaired kidney function respectively. A reference material for 12 protein markers (called ERM®-DA470/IFCC) has been produced to ensure continuity in the measurement of the main plasma proteins like albumin, the most abundant protein in human blood plasma, and the antibodies IgG and IgM, proteins made by our immune system to help fight off infections.
Enzymes' measurements
In the same way, the standardisation of catalytic activity concentration measurements of enzymes is a very demanding task in clinical chemistry. Enzymes are routinely measured as biomarkers for liver, kidney, cardiac and other functions. The catalytic activity of an enzyme is a property measured under specific experimental conditions. The JRC produced certified reference materials covering, for example, the measurement of aspartate aminotransferase (measured for the evaluation of the liver function) and creatine kinase (marker for myocardial infarction and muscular dystrophy).
The JRC's reference materials for human plasma proteins and enzymes are the de facto standards that enable laboratories worldwide to use common reference ranges in diagnosis and to compare results between hospitals and over time. The process leading to the standardisation of plasma protein measurements is reviewed in Standardising plasma protein measurements worldwide: a challenging enterprise.
Diagnoses and monitoring of diabetes
The JRC has developed a key certified reference material to accurately measure haemoglobin A1c (HbA1c) levels in the blood. Haemoglobin A1c is a form of haemoglobin, which is the protein in red blood cells that carries oxygen. The amount of HbA1c in the blood reflects the average blood sugar level over the last 2 to 3 months. This measure is key for both diagnosing and monitoring diabetes.
Supporting the early diagnosis and monitoring of neurodegenerative and chronic diseases
Chronic diseases like autoimmune diseases and neurodegenerative diseases are not only devastating for the patients and their families, but also have a major societal cost. The early diagnosis of such diseases is important for the development and implementation of treatments. However, many of these diseases are difficult to diagnose, particularly in early stages. This is where reliable biomarker measurements could make a big difference.
Neurodegenerative diseases
In 2017, the JRC released a certified reference material designed to help the early detection of Alzheimer’s disease. It will serve to set the accuracy of instruments or equipment used to measure the levels of amyloid-β 1-42, a biomarker for Alzheimer's disease found in cerebrospinal fluid. Early diagnosis is key in the fight against this neurodegenerative disease. Clinical results have shown that a combination of biomarkers amyloid-β 1-42, tau and phospho-tau have a promising potential to be used in early diagnosis.
Autoimmune diseases
Vasculitis
The JRC has developed two certified reference materials for the diagnosis of small vessel-associated vasculitis, a rare and inflammatory blood vessel disease with symptoms that can vary widely. These materials are critical for ensuring accurate and consistent measurements of specific autoantibodies across different test assays used in clinical laboratories, regardless of the methodology employed.
Coeliac disease
Currently, the JRC is developing a certified reference material for coeliac disease, a chronic immune disorder triggered by gluten ingestion. This will be the very first control material for this disease.
Worldwide first certified reference materials for monitoring of leukaemia
Chronic myelogenous leukaemia (CML) is a cancer of the white blood cells. In the EU, about 6 200 new patients per year are diagnosed and CML mainly affects adults. CML can been treated with targeted therapy drugs but regular monitoring of the CML patient is needed to ensure optimal treatment.
The JRC has developed a set of certified reference materials for the calibration of BCR-ABL1 measurements, a fusion gene associated with CML. This new set is an essential tool to correctly assess the response to leukaemia treatment and to facilitate early detection of patient relapse.
Early detection of a genetic blood disease
The JRC produced in 2024 two certified reference materials for the early detection of Beta-thalassemia, a genetic disorder that leads to lower haemoglobin production and can cause severe anaemia. If not treated, the most serious cases of beta-thalassemia can result in death or require lifelong blood transfusions. Carriers and those with the disease typically have elevated levels of a form of haemoglobin known as HbA2.
The availability of these new reference materials can help couples planning to have children and take informed decisions about prenatal or preimplantation genetic testing to ensure a healthy baby.
