GREC: a global platform for gadolinium retention data
GREC: a global platform for gadolinium retention data
We need to develop and maintain a global web-based platform for data backup and analysis and clarify criticisms about safety of GBCAs.
We need to develop and maintain a global web-based platform for data backup and analysis and clarify criticisms about safety of GBCAs. Read more
Why this project needs sharing effort?
Millions of MRI scans are performed every year to image patients, healthy people or volunteers with the advantage to explore anatomy without exposure to ionizing radiation. Gadolinium, chelated in a complex, is used in about 60% of the MRI scans to allow better delineation of anatomy and, eventually, lesions in patients.
Two years ago, my research group in Italy and a group in Japan described changes in MRI images of the brain of patients after multiple injections of linear gadolinium-based contrast agents (GBCAs). Research has since then developed, with several retrospective studies conducted across the world on small samples of patients, using different types of GBCA, both agents with linear and macrocyclic chelates.
Regulatory agencies in Europe (European Medicine Agency, EMA) and USA (Food and Drug Administration, FDA) asked researchers to investigate this topic. Data collection and/or methodology of available studies are flawed by several limitations: for example retrospective design, selection bias, lack of randomization, small sample sizes, lack of good control populations, lack of longitudinal data, and mixed exposure to different GBCAs (both linear and macrocyclic), lumping together all linear and macrocyclic gadolinium-based agents as if they all act similarly within each “class” (despite a growing body of evidence that this is not the case). Meta-analysis or systematic reviews for guidelines are currently not feasible because of the large differences in methodology used by different institutions.
If you or someone of your relatives or friends has received a gadolinium contrast agent you should not worry because these compounds are basically safe and a large amount of data from post-authorization studies is available that supports excellent safety of all GBCA compounds.
However, there are open questions because some patients are reporting symptoms and are allegedly relating these symptoms to exposure to gadolinium compounds.
What are the open questions?
We want to understand which form of gadolinium is responsible for the imaging findings
We want to discover if exposure to gadolinium may be associated with a clinical syndrome and may pose some persons at risk to develop symptoms in their skin, bones, and articulations.
We want to understand if neurological function disturbances are related to gadolinium retention in the brain.
We want to identify potential risk factors that may help to identify patients at increased risk after exposure to GBCAs and prevent any toxicity.
How do we realize the project?
The mission of a global strategy of cooperation is to create a big data web-based infrastructure on large populations exposed to GBCAs, where local inhomogeneous retrospectively collected data are made available for big data mining. In addition, homogeneous prospective data with harmonized protocols can be obtained to give answers to open questions. The infrastructure will play as a multicenter MR image and clinical data repository and GBCA and demographic registry. The systematic and harmonized collection of data on exposure to GBCA type and amount, demographic variables, MR imaging techniques and measures, clinical symptoms, and neuropsychological testing would need to be launched. In addition, bio-banking repositories of tissue samples would allow centralized chemical, biochemical, and genetic analyses.
Work in Progress
A continuously growing research network has been established and called Gadolinium Retention Evaluation Consortium (GREC). The aim of this network is to join forces of preclinical research laboratories, clinical research groups, contrast media manufacturers, MRI manufacturers, and specialists in epidemiology and guidelines in the field of contrast media safety.
Carlo C. Quattrocchi is a MD PhD, leading Diagnostic Imaging at Università Campus Bio-Medico di Roma, Italy. He coordinated with Aart J. van der Molen (Leiden University Medical Center, Netherlands) the first kick-off meeting on November 4 to 6th in Naples in 2016, under the patronage of European and Italian scientific societies. A unique environment was created with the purpose of sharing information, updates and ideas on the issue of retention and / or deposits of gadolinium in patients given intravenous doses of GBCAs.
Alexander Radbruch from Heidelberg (Germany), Joana and Miguel Ramalho from Lisbon (Portugal), Alex Rovira from Barcelona (Spain), Peter Aspelin from Stockholm (Sweden) and Silvio Aime from Turin (Italy) were some of the clinical scientists attending, gave a substantial contribution to the success of the meeting and helped us to focus on the next steps of research. The representatives of contrast media industry (Bayer Healthcare, Bracco Imaging, GE Healthcare, and Guerbet) sponsored the first kick-off meeting and preclinical scientists from all companies gave their active contribution during scientific sessions.
The intense discussion encouraged the exchange of expert opinions to share the state of knowledge on tissue retention of gadolinium and discuss methodological approaches that could sensitively reduce inhomogeneity of data and results among research groups. Methods of data sharing, harmonization and integration between the different institutions in Europe were discussed. It was highlighted that the involvement of the central nervous system as a site of gadolinium retention must be considered in a more integrated and interdisciplinary view that should consider mechanisms of gadolinium retention in other sites such as bone, skin and liver.
As a first step, the European Group invited scientific consultants from the MRI manufacturers and has established a Task Force of clinical and preclinical specialists to develop uniform terminology in defining the symptoms recently attributed to the administration of GBCAs and to develop guidelines to standardize preclinical and clinical research methodologies. In addition, the Task Force has initiated the development of a MR phantom in order to normalize the results from different centers throughout Europe and use a common reference to compare the different GBCAs available today.
What happens if the project is funded?
Funding calls are available from international entities but the preparation of proposals is time-consuming and the pipeline to receive funding usually requires 12 to 24 months. In the meantime, we are using gadolinium contrast agents only focusing on renal function, the only variable that is actually known to affect excretion of gadolinium species from the body.
A Kickstart fund is needed to work with information technology and bring the website platform to life. Also, phantom studies will be funded to harmonize research across the different institutions involved in the world. The time expectation for first results is 12 months. In the meantime, other initiatives will be undertaken to allow success and continuation of the project until a sufficient body of evidence is available.
The proposed project will represent an organizational model to monitor drug compounds safety in the post-marketing surveillance phase. Post-marketing drug surveillance for adverse drug events has typically relied upon spontaneous reporting. Recently, regulatory agencies have turned their attention to more pre-emptive approaches that use existing data for surveillance. When an adverse drug event is reported, as it is in the case of the widely used GBCAs, spontaneous reporting and single institution datasets may be flawed by conflicts of interest, such that the service to the community and the real clinical burden is difficult to estimate. The infrastructure proposed by this project could be of reference for the future of post-marketing surveillance of new commercially available drug compounds.
If we do not reach the pledged amount, we will lose the opportunity to tailor the use of GBCAs on the basis of evidence-based practice guidelines regarding long-term retention in humans.
Risks and challenges
- Challenge of existing data-sharing policies: Administrative challenges or challenges in honoring ethical obligations to patients involved in clinical trials may be encountered. Software tools will be tailored at each site with the consequence that sharing will only involve anonymized alpha-numerical data rather than metadata enriched Digital Imaging and Communication in Medicine, DICOM files.
- The platform is not able to interact with Radiological Informative Systems (RIS) and/or with Picture Archiving and Communication Systems (PACS) in single institutions: the pre-requisites of each site will be checked to adapt database design, implementation and data source analysis.
- Challenges to protocol harmonization are based on different institutional policies of Institutional Review Boards: consent will be requested for data sharing in this project and evaluated on institution-by-institution basis, according to national restrictions laws.
- (60 days)