FDA committees evaluate recent safety data on contrast agents

Issue: June 2011

Members of the Cardiovascular and Renal Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee met today to interpret and discuss safety data for the two approved ultrasound contrast agents, Definity and Optison, as well as the investigational agent SonoVue. The FDA was not seeking advice on a vote to approve or revoke any of the agents but a discussion on current labeling.

The Cardiovascular and Renal Drugs Advisory Committee (CRDAC) had previously gathered in 2008 to examine efficacy and safety issues of those three agents.

According to background provided by the FDA, despite the appearance of a low overall adverse event rate with ultrasound contrast agents, serious adverse events and even fatalities still persist with all three agents. Although the organization noted the difficulty in distinguishing adverse events related to ultrasound contrast agents from concomitant medications and complications due to underlying comorbidities, it also said there is reason to believe ultrasound contrast agents play a contributory role.

In today’s meeting, both the CRDAC and the Drug Safety and Risk Management Advisory Committee convened at the request of the FDA to discuss in detail the safety data that have come to light in the 3 years since the meeting.

During the morning session, industry members from Lantheus Medical Imaging (Definity), GE Healthcare (Optison) and Bracco Diagnostics (SonoVue) presented post-marketing results on the safety studies performed on their respective agents. All of the studies presented showed minimal risk for serious adverse events related to usage of the agents, while also being consistent with the data presented at the previous meeting. As a result, both GE and Lantheus requested changes to the black box warnings, which they said are a barrier to use. The requested changes were either to remove the black lines or remove the warning completely.

Responding to this concern, Allan Coukell, BScPharm, director of medical safety, the Pew Health Group, Washington DC, said during the meeting, “It does seem there was a dip in use [of contrast agents] after the black box warning, but it’s come back up. It also seems clear that these agents are going to be used in ever-expanding settings by more and more people using them for the first time. So it seems to me that you would want them to know there is this [risk for a] rare but potentially very serious event.”

This led to one of the main issues discussed in the afternoon portion of the meeting which was the extent to which the new safety information presented justified modification of the boxed warnings. A consensus was not reached among members.

“The most positive thing I’ve heard today is of the impact of the black box warnings, in that it actually did something, maybe, which is unusual compared to drugs,” said Brian Strom, MD, MPH, chair and professor of biostatistics and epidemiology, University of Pennsylvania, Philadelphia. “But it’s important to keep in mind that black box warnings do not prohibit use. They are simply a way to clarify the risk/benefit balance. We are also in a climate now when more and more black box warnings are being added. Clearly, if you look at now, as opposed to five years ago, there is a lot more of them. To take it away now sends a clear message that we’ve seen data that changes the risk/benefit from what it was before seeing the data, and we haven’t. We’re all very clear on that. So if we haven’t seen anything to change it, it would send a really bad message that these agents are safer than we thought.”

However, Henry Black, MD, clinical professor of medicine, New York University School of Medicine, New York, was still not convinced there was a need for the warning and questioned why the black boxes were even added in the first place.

“It’s like an inflation creep, a grade creep. That’s why there are more black box warnings and why their impact becomes less and less; because they are not used appropriately,” he said. “I wasn’t at the 2008 meeting, [but the labeling’s] already been softened and there isn’t anything here. And I think it has an impact based on what we saw. I don’t think it’s going to affect things very much except in the legal environment we’re in where risk management to a hospital’s lease is so important that they are not going to go against this for obvious reasons that I think we ought to take this away.” – by Brian Ellis

Disclosures: Drs. Black, Coukell, and Storm report no relevant financial disclosures. Dr. Coukell's comments are his own and are not representative of the Pew Health Group.

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