International medical experts filed a Citizen Petition with the U.S. FDA urging the federal agency to remove boxed warnings from ultrasound contrast agents (UCAs) based on current highly favorable safety data and clinical experience.
According to the International Contrast Ultrasound Society (ICUS), UCAs are radiation-free diagnostic imaging agents that enhance the clarity and reliability of front-line ultrasound scans and often reduce the need for more expensive downstream testing.
The Citizen Petition cited studies showing that UCAs are extremely safe and ultimately improve patient care, reduce overall health care costs, speed up the time to diagnosis and reduce the length of hospital stays. UCAs are liquid suspensions of tiny gas-filled microbubbles that are injected into a patient’s arm vein during the ultrasound exam. As the UCA flows through the bloodstream, it reflects ultrasound waves in real time, helping physicians more accurately diagnose medical conditions and monitor therapy.
According to the petition filed with the FDA, UCAs present no known risk of kidney or liver damage and are expelled from the body within minutes. In addition, patients do not require sedation during the contrast-enhanced ultrasound (CEUS) exam. Three UCAs are currently approved for use in the United States, including Definity (Lantheus Medical Imaging), Lumason (Bracco), and Optison (GE Healthcare).
“The risk-benefit ratio for UCA use has dramatically changed since 2007, when the FDA first mandated the black box,” says cardiologist Mike Main, MD, of Saint Luke’s Mid-America Heart Institute in Kansas City, Mo, a vice president of ICUS, and the principal author of recent studies examining the safety of UCAs. “Scientific data now consistently show that UCAs are extremely safe, and their benefits have been extended as a result of newly approved applications and use in larger patient populations.”
ICUS represents cardiologists, radiologists, and other physicians and imaging professionals in approximately 60 countries. The organization’s board recently voted to formally request FDA action on the black box warning.
“The boxed warnings are appropriate only as an indicator of the very highest level risk associated with FDA-approved products,” says Steven Feinstein, MD, a cardiologist and professor of medicine at Rush University Medical Center in Chicago and ICUS Co-President. “This extreme level of risk is simply not presented by the use of UCAs, and ICUS is deeply concerned that the current boxed warnings unduly deter the use of UCAs when medically indicated, to the detriment of our patients.”
UCAs are approved in the United States for cardiac and liver imaging in adults, and were recently also approved for use in children. But throughout Europe, Canada, Asia and Brazil UCAs are safely and routinely used to pinpoint cancers elsewhere in the body, monitor chronic gastrointestinal diseases, detect vascular disease, as well as diagnose heart disease and other serious medical conditions.
“The United States is actually behind the rest of the world when it comes to using contrast-enhanced ultrasound,” says Stephanie Wilson, MD, ICUS Co-President and Clinical Professor of Radiology at the University of Calgary. CEUS is very patient friendly, extremely reliable and easy to use, she adds.
The Petition notes that the FDA has steadily responded to the mounting evidence of safety and efficacy by downgrading package insert contraindications three times since 2007 and removing a 30-minute monitoring requirement for patients with pulmonary hypertension or unstable cardiopulmonary conditions. More recently, the FDA approved new indications for use in additional patient populations.
According to the petition, “The (published scientific) evidence more clearly supports a warning in the ‘warnings and precautions’ section, as the potential adverse reactions (namely, a serious allergic or anaphylactoid reaction or CARPA reaction) do not occur frequently enough to rise to the boxed warning standard.”
Adds ICUS’ Main, “Now, with even more published research and clinical experience demonstrating the very strong safety profile and efficacy of UCAs, together with expanded UCA indications and patient populations for whom CEUS is clinically appropriate, it is time to remove the “black box” entirely.”