Adverse drug reactions: significant cost to society
It is estimated that 197 000 deaths per year in the EU are caused by adverse drug reactions and that the total cost to society in the EU is €79 million. Among the side effects most challenging to drug developers and prescribers alike are drug-induced injuries to the kidney, liver and vascular system. By bringing together pharmaceutical companies, academic centres, and SMEs, SAFE-T has made a significant contribution to detecting such adverse reactions as early and accurately as possible during drug development, through the extensive characterisation of new markers in patients’ blood and/or urine (biomarkers). As well as having great potential to improve drug safety, these biomarkers could in the future also be applied to non-drug related diseases of the liver, kidney, and vascular system.
Letters of support from regulatory agencies
The project generated a vast amount of data on 105 initial biomarker candidates, of which more than 20 showed promising performance. The data on some of these biomarkers has been submitted to the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) and the agencies recently issued letters of support. The letters of support indicate that the new biomarkers have the potential for use in drug development, and that additional exploration and data generation is warranted. As such, the letters are designed to encourage scientists to collect additional data from nonclinical and exploratory clinical trials.
Other achievements: biobank and database
While the characterisation of the biomarkers is the most significant project achievement, SAFE-T also contributed to the field in other ways:
- The team defined and published a scientific strategy for the qualification of biomarkers, which will help improve the efficacy of future qualification efforts.
- The project created a biobank with serum, plasma and urine samples from more than 11 000 patients across 19 different populations. The biobank can now be used by other researchers for the qualification of additional safety biomarker candidates.
- The project set up a database with comprehensive data on 105 new biomarkers. The database will support further research on drug-induced kidney, liver and vascular injuries.
Achievements & News
The US Food and Drug Administration (FDA) issued a Letter of Support for five new liver safety biological markers investigated by IMI's SAFE-T project in collaboration with the Critical Path Institute’s Predictive Safety Testing Consortium (PSTC), opening the way for their clinical qualification in the future.### Liver safety biomarkers are proteins that can be measured in human blood. Higher levels of these biomarkers in patients diagnosed with drug-induced liver injury (DILI) could indicate a risk for progression towards liver failure, which may result in death or the need for liver transplantation. The FDA granted the Letter of Support to encourage the use of the new biomarkers in both nonclinical and exploratory clinical studies. With this milestone, in-depth research can continue on the qualification of the new biomarkers for use in clinical trials. ‘The success of the SAFE-T/PSTC collaboration nicely demonstrates the benefits of working together across public private partnerships on a global scale. Shared scientific enthusiasm, persistence, and team-spirit were the key foundation for this achievement,’ said Michael Merz, SAFE-T project coordinator. The SAFE-T project was set up to develop improved tools for prediction, detection, and monitoring of drug-induced injuries to the kidney, the liver, and the vascular system, using markers in patients’ blood and/or urine. The ultimate goal is to identify for each of the three organ toxicities a set of biomarkers that are more specific, more sensitive and more predictive than currently available ones, and to gain regulatory acceptance for routine use of these biomarkers in drug development.
IMI’s SAFE-T project and the Predictive Safety Testing Consortium (PSTC) managed by the Critical Path Institute (C-Path) have formalised their collaboration through a legal agreement which will enable them to share research and regulatory strategies.###
Both PSTC and SAFE-T are working on the development of new biomarkers to improve our ability to predict, diagnose, and monitor drug-induced injury to the liver, kidney, and vascular system. SAFE-T and PSTC have already been collaborating informally for some time. Increased collaboration between the two research consortia will be mutually beneficial and improve results for both projects. In particular, this agreement defines the framework for enhanced collaboration and exchange of information.
Benefits resulting from the collaboration between SAFE-T and PSTC will include reducing the cost of research while boosting efficiency; maximising the strengths of both projects; increasing communication with regulatory bodies and the projects’ scientific influence; the creation of a dataset with wide dissemination possibilities, and higher chances of the application of safer biomarkers.
• Read the press release
• Find out more about IMI’s SAFE-T project
IMI project SAFE-T has devised a simple strategy that is able to identify patients with drug-induced liver injury before serious damage has occurred.### Writing in the journal PLoS ONE, the project team points out that 1 in 100 hospitalised patients experience liver injury as a result of an adverse drug reaction, but many cases are missed, especially in non-hepatology departments. The SAFE-T scientists used a common indicator of liver damage, namely alanine aminotransferase (ALT) levels. Using the SAFE-T strategy, all patients with ALT levels three times higher than the top end of the ‘normal’ range were referred to an experienced hepatologist. The SAFE-T strategy was compared to the hospital’s standard strategy, in which non-hepatologists refer suspected cases of drug induced liver injury (DILI) to experts. The results show that the SAFE-T strategy is much more sensitive, picking up 12 times more cases than the standard strategy and detecting cases of DILI while they are still in the earlier stages. ‘These results therefore strongly suggest that the centralized [SAFE-T] method could prevent very severe complications,’ the researchers write.
Knowledge management is key to the success of many IMI projects, and the tranSMART system is proving a popular tool for this. TranSMART is a translational medicine platform based on open source software and data that was originally developed by Johnson & Johnson for its own projects.### However, it quickly became clear that the system could be extremely useful for other groups. Today, tranSMART is used by research consortia on both sides of the Atlantic. The first IMI project to use tranSMART was U-BIOPRED, which is using it to collate data on asthma and chronic obstructive pulmonary disease (COPD) from four different companies, for example. Eventually, U-BIOPRED partners will be able to access the data and use it to test new hypotheses. Other ongoing projects that are implementing or about to implement tranSMART are OncoTrack, SAFE-T and BT Cure; some of the 3rd Call projects are also planning to use the system. Looking to the future, the 4th Call topic eTRIKS (European Translational Information & Knowledge Management Services) will support efforts to take tranSMART to the next level.
The IMI project SAFE-T has enrolled the first patients into 4 major studies that aim to boost scientists’ ability to determine whether or not a potential drug will be toxic to the kidney.### Drug-induced kidney injury is a serious problem in drug development and the treatment of patients. All too often, currently-used tests only detect kidney damage when it is already irreversible. The new SAFE-T studies aim to assess the potential of biological markers (biomarkers) that could allow doctors and researchers to detect kidney damage while it is still in the early stages. People participating in the studies include patients treated with medicines known to be toxic to the kidney; people with kidney diseases; and kidney transplant recipients who take immunosuppressant drugs that could be harmful to the kidney. According to the team, putting together studies of this scale would not have been possible without intense interdisciplinary and cross-institutional collaboration. The first results from the studies are expected in six to nine months. In addition to drug-induced kidney injury, SAFE-T researchers are also working on improving tests to pick up on drug-induced liver and vascular problems. Large-scale studies in these areas have also been initiated by the consortium.
SAFE-T project generates promising clues for detection of drug-induced injuries
SAFE-T was among the first IMI projects which started in 2009. Seven years later, the project came to a close, having achieved most of its objectives and made significant progress in developing improved tools for the prediction, detection, and monitoring of drug-induced injuries to the kidney, liver, and vascular system. ### In an interview with the IMI Programme Office, project coordinator Michael Merz of Novartis, and scientific coordinator Thomas Joos of the Natural and Medical Institute at the University of Tübingen (NMI), share their thoughts on the project’s successes. ‘We have generated a lot of data on new biomarkers – molecules that we can measure in the blood or urine – that allow us to detect drug side-effects earlier and more accurately than has been feasible in the past,’ said Merz. ‘In addition to helping detect drug-related injuries, these biomarkers will also help improve diagnosis and monitoring in chronic disease patients. They will help clinicians make better decisions on specific treatment alternatives and other things, such as when to stop treatment. I think there will be lots of benefits to patients across a large variety of different diseases.’
- Read the full interview
- Find out more about the project's achievements in the project factsheet
- Visit the project website
ParticipantsShow participants on map
- Almirall SA, Barcelona, Spain
- Amgen, Brussels, Belgium
- Astrazeneca AB, Södertälje, Sweden
- Bayer Pharma AG, Berlin, Germany
- Boehringer Ingelheim Internationalgmbh, Ingelheim, Germany
- Eli Lilly And Company LTD, Basingstoke, United Kingdom
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
- Novartis Pharma AG, Basel, Switzerland
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
- Takeda Development Centre Europe LTD, London, United Kingdom
Universities, research organisations, public bodies, non-profit groups
- Assistance Publique Hopitaux De Paris, Paris, France
- Charite - Universitaetsmedizin Berlin, Berlin, Germany
- Consorci Institut Català De Ciències Cardiovasculars, Barcelona, Spain
- Naturwissenschaftliches Und Medizinisches Institut An Der Universitaet Tuebingen, Reutlingen, Germany
- The Foundation For Medical Research Infrastructural Development And Health Services Next To The Medical Center Tel Aviv, Tel Aviv, Israel
- The University Of Liverpool, Liverpool, United Kingdom
- Universidad De Malaga, Malaga, Spain
- Universitaet Leipzig, Leipzig, Germany
- Universitaetsklinikum Aachen, Aachen, Germany
- University College Dublin, National University Of Ireland, Dublin, Dublin, Ireland
Small and medium-sized enterprises (SMEs)
- EKF Diagnostics Limited, Trinity Technology and Enterprise Centre, Ireland
- Edi Experimentelle Und Diagnostische Immunologie GMBH, Reutlingen, Germany
- Firalis, Huningue, France
- Interface Europe, Bruxelles, Belgium
|Name||EU funding in €|
|Assistance Publique Hopitaux De Paris||2 039 152|
|Charite - Universitaetsmedizin Berlin||1 300 441|
|Consorci Institut Català De Ciències Cardiovasculars||1 555 875|
|Edi Experimentelle Und Diagnostische Immunologie GMBH||351 776|
|EKF Diagnostics Limited||789 510|
|Firalis||2 570 752|
|Interface Europe||684 646|
|Naturwissenschaftliches Und Medizinisches Institut An Der Universitaet Tuebingen||2 623 800|
|The Foundation For Medical Research Infrastructural Development And Health Services Next To The Medical Center Tel Aviv||1 299 126|
|The University Of Liverpool||129 159|
|Universidad De Malaga||115 104|
|Universitaet Leipzig||191 280|
|Universitaetsklinikum Aachen||196 900|
|University College Dublin, National University Of Ireland, Dublin||54 450|
|Total Cost||13 901 971|