SILVER SPRING, Md. -- An FDA advisory committee voted 13-1, with one abstention, to recommend a new warning for gadolinium-based contrast agents (GBCAs) used in magnetic resonance imaging on Friday.
Specifically, the FDA's Medical Imaging Drugs Advisory Committee recommended that prescribing information should include "a warning for retention for all GBCAs with greater retention of all or some of the linear GBCAs compared to the macrocyclics in certain organs including the brain," and that "risk minimization steps" be taken for certain patient populations.
The FDA made a minor distinction between macrocyclic and linear GBCAs, noting the higher stability of the macrocyclics may cause them to "wash out" of the body; but the agency stressed that both agents leave behind deposits of gadolinium.
Agency leadership asked the committee for advice on how to weigh recent findings of gadolinium retention in the brain and other organs, and how to minimize potential risks moving forward.
Virtually all committee members agreed that the evidence of retention in patients, to date, doesn't indicate a definitive causal relationship with an array of symptoms reported in the FDA's database and medical literature, beyond previously identified concerns for kidney patients (current labeling already includes a boxed warning and contraindications for this population).
In 2007, researchers uncovered a link between GBCAs and nephrogenic systemic fibrosis (NSF) -- a debilitating condition, that impacts the skin, muscles and internal organs and is sometimes fatal -- in kidney patients, however more recent evidence suggests patients without impaired renal function also show deposits of gadolinium in their central nervous system and throughout the body. As recently as June, researchers reported that gadolinium deposits were found in patients with normal brains -- previously intracranial abnormalities were seen as responsible for the agents clinging to neural tissues.
Still, members voted unanimously to recommend the FDA consider requiring industry conduct more research to help the agency determine if regulatory action "including withdrawal of approval and restriction of indicated populations" is necessary.
Jeffrey Brent, MD, PhD, of the University of Pennsylvania, who backed the new warning, described the latest evidence of problems in patients without a serious renal condition as "anecdotal data." However, "there clearly is concern and people need to know."
"[P]eople need to know," said Alicia Toledano, ScD, president of Biostatistics Consulting LLC, from Kensington, Md., and the single "no" vote. She said the warning was not strong enough and would never be seen by most patients.
During the meeting, some macrocyclic makers sought to emphasize differences in the chemical structure between their products and linear contrast agents, which may lead to greater retention of linear products;while linear contrast agent manufacturers underscored that retention occurs with both classes, differences in retention are slight, and the threshold for toxicity is unclear.
In public testimony, Sharon Williams and Hubbs Grimm, who run , a support group for people who believe they have gadolinium toxicity. Williams and Grimm argued that if people without renal issues are also retaining gadolinium, it follow that they might have NSF-like symptoms.
"It makes no sense to think that there are only two options: NSF or nothing at all," Williams said.
Sammy Almashat, MD, MPH, a research associate for the consumer group Public Citizen, argued that if they knew the evidence regarding the differences between the two classes of contrast agents, "virtually all patients" would choose the macrocyclics. He, like Brent and Vaughan, argued for adopting the the . That agency suspended certain GBCAs in July.
Concerns about gadolinium toxicity emerged over a decade ago, after some patients with renal failure developed Nephrogenic Systemic Fibrosis (NSF) and a link was found between the "debilitating" condition and GBCA used in MRIs.
In 2010, the FDA adopted safety label changes including a contraindication for patients with renal insufficiency, strengthened a boxed warning and precautions recommending limiting or "allow[ing] clearance" between doses, and screening vulnerable populations.
Then, in July 2015, the FDA issued a Drug Safety communication that noted reports of retention of gadolinium in the brain after the use of GBCAs, which underscored the increased retention with linear GBCAs compared to macrocyclic GBCAs.
In that communication the FDA urged physicians to to "clinical circumstances in which the additional information provided by the contrast is necessary," also urging them to reassess the necessity of repetitive contrast MRIs in established treatment protocols.
In 2016, manufacturer Optimark, requested label changes to include mention that "retention may be greater with linear GBCAs than macrocyclic GBCAs."
On the FDA further updated its recommendation to say,"All GBCAs may be associated with some gadolinium retention in the brain and other body tissues. However, because we identified no evidence to date that gadolinium retention in the brain from any of the GBCAs, including GBCAs associated with higher retention of gadolinium, is harmful, restricting GBCA use is not warranted at this time."
As part of the Friday meeting, FDA officials asked panel members to suggest future directions for research, a hint that the agency may impose more requirements on manufacturers. Members recommended patient registries and epidemiological and animal studies.