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FDA committee examines use, safety of contrast agents
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The Cardiovascular and Renal Drugs Advisory Committee of the FDA met with industry representatives to discuss safety and efficacy issues surrounding the use of ultrasound contrast agents. The committee concentrated on two agents the FDA previously approved for use in the United States, Optison (perflutren protein-type A microspheres, GE Healthcare) and Definity (perflutren lipid microspheres, Lantheus Medical Imaging), as well as SonoVue (sulfur hexafluoride microspheres, Bracco Diagnostics, Inc.), which has been approved in Europe. The committee was not convened to vote on approval or to revoke the agents.
“We are not focusing on any specific contrast agent, and we are not seeking recommendations for any specific regulatory action,” said Duane Reeves, MD, director of medical imaging and hematology products division at the FDA, said during the meeting.
One of the prominent issues discussed was the design of clinical and prospective trials to assess safety and toxicity of the agents. Testing the agents in animal models, according to Robert Hamlin, DVM, PhD, professor of veterinary medicine at Ohio State University College of Veterinary Medicine, made extrapolating certain information, like toxicity data, to humans more complicated.
“The ‘best’ surrogate can be identified best by regulatory agencies that, by experience, have identified [the surrogate] as predicting with highest sensitivity and specificity, the likelihood of a toxic reaction in man,” Hamlin said.
Another topic the committee discussed was the design of prospective and observational trials to assess safety and efficacy of the agents both before and after FDA approval. Of particular concern was the use of the agents in certain high-risk patients with underlying comorbidities. Although no specific trial designs were formulated, the need for additional safety data in all phases of contrast agent development was stressed.
“If properly designed prospective observational studies could be incorporated into the development program, with appropriate propensity and other statistical controls, they might in fact be quite informative,” William Hiatt, MD, professor of medicine at the University of Colorado and chair of the committee, said. “I would not stop there, because if an observational study detects a signal of concern, this does not define cause and effect. – by Eric Raible