Silver Spring, MD - The FDA may have a smoother ride the next time it considers whether to approve the marketing of an ultrasound contrast agent, now that its Cardiovascular and Renal Drugs Advisory Committee has provided guidance on how to carry out the supporting clinical trials.

Meeting on June 24, 2008, the panel applied lessons learned from a recent debate between the FDA and the cardiology community on the safety of two such agents in recommending that such supporting trials be randomized or at least observational and prospective, large enough to reliably show any risks, conducted both before and after any approval, and designed to show they do more than make nice pictures.

The two contrast agents considered were perflutren lipid microspheres injectable suspension (Definity, Lantheus Medical Imaging) and perflutren protein-type A microspheres for injection (Optison, General Electric).

As reported by heartwire last month, the FDA replaced the sharp warnings and contraindications it had recently imposed on the agents' labeling, language based on complications seen in their fairly small clinical trials, with less restrictive words after an outcry by clinicians who said the agency had misinterpreted the safety data.

Maybe it doesn't have to be that a better image leads to lower mortality, but that a better image might lead to a better strategy.

The advisory panel wasn't asked to further address those warnings but to consider any future trials of similar agents, observed R Dwaine Rieves, deputy director of medical imaging and hematology products at the FDA's Center for Drug Evaluation and Research. Moreover, he told heartwire, its recommendations don't directly apply to Definity and Optison.

"For the existing products, the companies are largely on track, because we just approved a labeling change that came with postmarketing requirements, and they are actually engaged in doing them now," Rieves said.

The FDA had asked the panel for advice on future trials probably to make things easier next time, according to the panel's chair, Dr William R Hiatt (University of Colorado, Denver). "I think the intention of the FDA was that with several imaging agents [expected to] come before them, they felt that starting out this way would allow everyone to hear what the issues are without targeting a particular [development] program. And then when a particular program comes forward, the issues will already be on the table," he said to heartwire.

The panel also confronted the question of appropriate end points for the premarket and postmarket studies. Hiatt said it felt strongly that "just making a better image wasn't good enough and that it would like to see a better image lead to a better outcome."

But, he added, "we toyed with the idea that maybe it doesn't have to be that a better image leads to lower mortality, but that a better image might lead to a better strategy. With cardiac ultrasound, maybe that strategy is better utilization of cardiac catheterization." What if using the contrast agent led to fewer catheterizations in patients who don't have significant coronary disease? "That would be an example of an outcome we might ask a development program to achieve."