Manufacturers could be
required to conduct new studies
·
b By Shannon Firth, Washington Correspondent, MedPage Today
September 11, 2017
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 The LightHouse Project, 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 European Medicines Agency's approach.
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 limit the use of such agents 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 May 22, 2017, 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.
TAGS: MedPage Today, Shannon Firth, MRI, gadolinium, FDA
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