FDA Panel Calls for Warning Labels on Gadolinium

Deborah Brauser

September 11, 2017

The Medical Imaging Drugs Advisory Committee (MIDAC) of the US Food and Drug Administration (FDA) voted 13 to 1 on Friday, with 1 abstention, for recommending adding a warning to labels about gadolinium retention for gadolinium-based contrast agents (GBCAs) used during MRI.

The new labels would warn that gadolinium may be retained in various organs, including the brain, after use of these agents — with linear GBCAs having a greater risk than macrocyclic agents. The warning would also note a greater risk in specific patient populations, including children and pregnant women.

During the all-day meeting, the committee heard from industry representatives, researchers, patients and patient advocacy groups, and even the actor Chuck Norris and his wife. 

Although the members of MIDAC overwhelmingly concluded there was not enough evidence to show a causal relationship between adverse symptoms and gadolinium retention, they still voiced concerns.

"A lack of evidence is not evidence of safety," said Sonia Hernandez-Diaz, MD, Harvard TH Chan School of Public Health, Boston, Massachusetts.

"Regardless of the data we don't have, we should consider how these agents are being used, when they should be used, and their appropriate dose," said Peter Herscovitch, MD, acting chair of the committee and director of the PET Department at the National Institutes of Health (NIH).

"Also, there was a lot of focus on the brain today, but we need to look inside and outside of the brain, which may require a large population study. And we need to develop more in vitro data for humans and animal models," he summarized.

Ongoing Review

There are currently 6 linear and 3 macrocyclic GBCAs approved by the FDA. In July 2015, the FDA issued a Drug Safety Communication about its ongoing review of potential risks in patients who underwent four or more contrast MRI scans.

The FDA had previously asked that a label change be added to three of the linear agents, noting a gadolinium retention risk in patients with preexisting kidney failure. This population is also at risk for the painful skin disease nephrogenic systemic fibrosis (NSF).

The 2015 communication noted that recent studies suggested that gadolinium could remain in the brain of those even with normal kidney function. Although no related adverse events had been identified, the agency recommended that the agents should be used only when the information they provide is necessary. 

In May 2017, the FDA reported that a new review showed that gadolinium is retained in organs, but no new adverse events were uncovered. Still, it stated that retention is greater for linear over macrocyclic GBCs and assessments are continuing as to whether reports of NSF in patients with normal kidney function are related to gadolinium retention.

In July 2017, the European Medicines Agency (EMA) followed recommendations from their Pharmacovigilance Risk Assessment Committee and Committee for Medicinal Products for Human Use to restrict use of the intravenous linear agents gadoxetic acid and gadobenic acid, as well as gadopentetic acid given intra-articularly. The EMA recommended the suspension of all other linear products.

Gena and Chuck Norris Speak Up

During the often emotional Open Public session during Friday's MIDAC meeting, a letter was read from Chuck Norris and his wife Gena. They had planned to attend the day's events, but problems from the aftermath of Hurricane Harvey prevented travel from their home in Texas.

In a statement read by a representative, Mrs Norris reported that she has been "suffering under gadolinium deposition disease."

She underwent three MRIs with contrast agents during an 8-day period "for a fairly routine medical condition." Three days later, she started experiencing burning sensations, violent tremors, and brain confusion "as if I've suffered concussion." After many clinical visits all over the country and the world, she was told in China that her gadolinium levels "were off the charts."

"My heart breaks for those who don't have the financial means they need. We will continue to use our platform to raise awareness about the dangers of gadolinium," she said.

Another patient told of having normal renal function when undergoing MRI with GBCA agents after a minor accident. Within a week, she developed seizures, tremors, intense burning, and temporary paralysis. More than 11 years later, she still has health problems, including muscle weakness, cognitive dysfunction, and chronic pain.

"Why is it so difficult to consider that if retained gadolinium can cause NSF in renal patients, that it could wreak havoc in normal patients?" she asked.

"If you still believe clinical evidence is needed, spare the animal. Study me and study others like me," she said, adding that the FDA should suspend use of GBCA until all questions have been answered.

On the Other Hand…

Scott Reeder, PhD, professor of radiology at the University of Wisconsin, Madison, and representing the International Society for Medical Resonance in Medicine and the Society of Computed Body Tomography and Magnetic Resonance, said he was there to fight against the "potential overreaction" to gadolinium retention.  

"I'm also here to ensure that the life-saving benefits of gadolinium-based contrast agents are fairly represented," said Dr Reeder.

Elizabeth Morris, MD, head of breast imaging at Memorial Sloan Kettering Cancer Center, New York City, and past president of the Society of Breast Imaging, said that the agent was "absolutely essential" for detecting breast cancer in some women, especially those who are at high risk for the disease. "It can bring up cancers that aren't otherwise seen," she said. "People often ask: Why can't you do it without gadolinium? Because it does not work. Picking up early detection can save lives."

Although her center has performed almost 100,000 exams with gadolinium, "anecdotally we do not have any reports of any adverse effects."

Still, she noted that because their patients do not undergo brain MRI, she supports prospective trials looking further into all of this.

Jeffrey Brent, MD, PhD, Division of Clinical Pharmacology and Toxicology, University of Pennsylvania, Philadelphia, said that, so far, adverse reports have all been anecdotal, "which doesn't really help us. We need to take a cautious approach and we really need scientific data."

Safety Plan Vote

At the end of the day-long meeting, committee members were asked to vote on whether they agreed with the FDA's plan to include a warning for all GBCAs, along with a warning that all or some of the linear versions may have greater retention than macrocyclics in certain organs.

"Words matter and these were well chosen," said Michael Weisman, MD, Cedars-Sinai Medical Center and the University of California, Los Angeles, who was among the majority "yes" votes.

"It's appropriate to state that there may be differences among these agents that need to be explored and…that risk strategies need to be looked at more carefully," said Dr Weisman.

"In spite of the lack of evidence, there is obvious concern in the medical community and industry and patient populations. I think it's important that information be put out there with regard to gadolinium retention," agreed Dr Herscovitch.

The lone "no" vote was cast by Alicia Toledano, ScD, president of Biostatistics Consulting, Kensington, Maryland. She said that the FDA's plan doesn't go far enough.

"It's hard to dismiss an anecdotal report when you are the anecdote. When a patient is finally tested and found to have gadolinium retention, there's no FDA-approved antidote. So what does the patient do?" asked Dr Toledano.

"I voted no because as beautiful as the wording is, I do not believe it is sufficient."

The one abstaining vote came from Sean Hennessy, PhD, PharmD. "I think the decision of whether or not linear agents should remain available is a risk-benefit decision, but we did not have that decision in a 1-day meeting," he said.

"The EMA considered other risks, including hypersensitivity and the benefits of better images with one class compared to the others. Their conclusion…was that the linears shouldn't be available except under special circumstances, but we haven't had that deliberation," said Dr Hennessy.

Interestingly, two committee members suggested during the postvote discussion that an asterisk be placed beside their yes votes.

"I voted yes but wish I could've voted for the EMA proposal. This was the next best thing," said William Vaughan, consultant in Falls Church, Virginia, and the meeting's acting consumer representative.

Because he said the FDA should withdraw these products, he agreed that an asterisk should be included with his yes. Dr Brent also asked for the addition.

More Studies Needed

The committee also voted on whether the FDA should require more studies from manufacturers to "inform our decisions about the need for further regulatory actions including withdrawal of approval and restriction of indicated populations." The results showed unanimous agreement for that plan.

"This is a serious question that needs to be investigated and is an important public health problem," said Dr Brent. "We want to understand [these agents'] upsides but also their downsides so that we can adjust to them."

"At this time there does not appear to be sufficient evidence to implicate one specific agent or class of agents," said Karen Furie, MD, neurologist-in-chief at Rhode Island Hospital, Providence, but she added that more research is definitely needed.

"There is no question that gadolinium MR saves lives, and I use it every day," said Kimberly Applegate, MD, division chief of pediatric radiology, University of Kentucky at Lexington. "However, we do have a lot of uncertainty in the current state about what its effects are in terms of risk. So we need to continue to collect data and review it just like any scientist, and we have to be open-minded about what we are going to find out."

She added that "we don't want to necessarily ban" these agents, but instead should educate patients about the potential risks. "If it's your family member, what do you want to have happen to them? That is the whole 'image gently' belief. We want to continue to use these agents to save lives but let's do it the best way we can."

During presentations earlier in the day, several industry representatives noted that their companies would support label changes and "enhancements" for the GBCA class.

In a postmeeting statement, Guerbet said it is "strongly committed" to ensuring that contrast-enhanced MRIs remain available to physicians. However, "evidence supports precautionary measures primarily with respect to linear agents."

"As recent evidence has raised the possibility that repeated use of linear agents might lead to a much higher propensity for gadolinium deposits in tissue, the risk mitigation measure Guerbet proposed to the FDA is to comply with the [NIH] approach, and to use linear GBCAs only in cases where there is no alternative," noted the company.

It adds that it supports taking precautions for patients who will need multiple injections during their lifetime, as well as children and those with renal impairment. "We also support using contrast agents at the lowest diagnostic dose."

The company, which makes a macrocyclic product, reported that it will be phasing out its linear agent.

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