On September 8th, the Medical Imaging Drugs Advisory Committee (MIDAC) discussed the potential risk of systemic gadolinium retention, especially in the brain, in patients receiving gadolinium-based contrast agents (GBCAs) used for magnetic resonance imaging (MRI) diagnostic procedures. This was a multi-sponsor meeting, which included Bayer Healthcare, Bracco Diagnostics, GE Healthcare, and Guerbet. The meeting began with the FDA presentation and industry presentations, which were then followed by the open public session and committee discussion, which included two voting questions.
The purpose of this meeting was to discuss the safety risk of gadolinium retention. Gadolinium is a rare earth element with fluorescent properties. The free ion of gadolinium is toxic to mammals but when the element is chelated, the compound is far less toxic. Therefore, chelated gadolinium can be used as a contrasting agent during MRI diagnostic procedures. Additionally, GBCAs are currently available in two structural forms, linear and macrocyclic. Linear GBCAs house gadolinium in an “open chain” form, whereas macrocyclic GBCAs contain gadolinium within a more stable, cage-like structure. Dissociation of gadolinium is known to be more prevalent with linear GBCAs, when compared to macrocyclic GBCAs. Dissociation of the gadolinium ion can potentially lead to retention of free gadolinium within the body, which may lead to adverse events (AEs).
Gadolinium retention, according to the FDA, is the persistence of gadolinium for a longer time than would be predicted from the acute time course of gadolinium leaving in the urine and feces. The FDA presented data relating to AEs associated with GBCAs from their AE Reporting System (FAERS) and medical literature review. In this review, the FDA found a total of 139 cases of gadolinium retention, the majority of which occurred in the US. The FDA identified that the patients’ AEs were typically associated with certain clinical categories, such as pain syndromes, neurological symptoms, skin conditions, and musculoskeletal pain. However, the FDA determined that the heterogeneity of clinically reported AEs makes interpretation challenging and concluded that an association between clinical AEs and GBCA exposure cannot currently be determined. The FDA also highlighted the need for epidemiologic studies to be conducted, to address the current concerns surrounding gadolinium retention.
The sponsors’ presentations similarly addressed past label enhancements for GBCAs, which effectively addressed past safety observations related to GBCA stability in patients with renal impairment. Additionally, the sponsors presented data from their GBCA-based research programs, which highlighted efforts to further evaluate the effects of gadolinium presence in certain tissues throughout the body, especially the brain. Bayer Healthcare also provided insight to research conducted within their own pharmacovigilance database, relative to presence of gadolinium in the brain, which yielded no confirmation of adverse health effects associated with gadolinium retention. However, Bayer did identify 40 reports which noted persistent or elevated levels of gadolinium within the blood, hair, skin, nails, and urine. Bayer noted that these reports are being further investigated with a targeted questionnaire. The sponsors concluded that continued cooperation with FDA, non-clinical, and epidemiological research are necessary for further identifying and understanding gadolinium retention and its potential affects on the well-being of patients.
The FDA then presented the committee with several discussion questions, as well as two voting questions. The committee discussed the need for additional research to further assess the risks of gadolinium retention and factors which may predispose patients to increased risk of gadolinium retention. The committee also discussed the FAERS database findings, which were presented by the FDA. The committee concluded that there is insufficient data available to draw a causal relationship between gadolinium retention and reported symptoms. Additionally, the committee discussed the idea of long-term epidemiological studies in patients exposed to different GBCAs, as well as potential study designs for pre-clinical trials to be conducted in animal models. Lastly, the committee was presented with two voting questions. The first asked for their support in issuing a warning for retention for all GBCAs, with greater retention of all or some of the linear GBCAs compared to the macrocyclic GBCAs in certain organs, such as the brain; recommended risk minimization steps for certain patient populations. The vote resulted in a positive 13 (Yes)-1 (No)-1(Abstention) outcome, favoring the FDA’s plan. The second voting question suggested that FDA may request additional studies, based on current ongoing pre-clinical and clinical studies, which will drive further regulatory actions including withdrawal of approval and restriction of indicated populations. The vote resulted in a unanimous positive outcome, favoring the FDA’s plan.
Innovative Science Solutions (ISS) was proud to assist in providing regulatory insight and knowledge to Bayer Healthcare and Guerbet throughout the FDA Advisory Committee Meeting process. ISS has almost two decades of experience in developing regulatory strategies including support for FDA Advisory Committee meetings. We are involved in more FDA AdComms per year than even the largest pharmaceutical companies. For more information on how ISS can help you prepare for your next meeting, contact firstname.lastname@example.org.