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Panel decides contrast imaging agent did not demonstrate noninferiority
FDA panel determined that the risk-to-benefit ratio of AI-700 was not sufficient to receive agency approval.
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The Cardiovascular and Renal Drugs Advisory Committee voted not to recommend the new drug application of a contrast imaging agent for use in patients being evaluated for ischemia and coronary artery disease.
The panel decided by a vote of 16-1 not to recommend the echocardiographic contrast agent AI-700 (Imagify, Acusphere) for use in patients with stable angina being evaluated for inducible ischemia and for the detection of CAD based on the assessment of wall motion and myocardial perfusion. AI-700 is an injectable suspension of perflubutane polymer microspheres intended to help stratify patients for referral for coronary angiography, according to FDA documents.
The clinical program for AI-700 consisted of 11 studies in which the researchers enrolled 1,241 patients who had received either AI-700 or placebo. Results of two of the studies, according to some of the panelists, raised concerns about the efficacy of the imaging agent. Results from one phase-3 study, known as AI-700-32 and which included 321 patients, failed to demonstrate adequate sensitivity when compared with single-photon emission computed tomography. Results from AI-700-33, another efficacy study in which the researchers enrolled 457 patients, suggested that AI-700 failed to meet its specificity endpoint.
Panelists made their concerns known about what they felt were critical issues regarding the design of the trials and some of the subsequent results generated from them.
“The panel questions not if there is added value but whether or not we have enough information to state that there is added value of this contrast agent to standard,” panel chairman Robert Harrington, MD, director of the Duke University Clinical Research Institute, said at the committee meeting in Silver Spring, Md. “The group appears troubled by the consistency between the studies; the definition of truth varies between the studies and is problematic, and the studies fail on some of the endpoints of specificity and sensitivity.”
Conclusions based on statistical data generated from the studies whose designs were altered also raised questions. In one case, a phase-3 study was modified at the request of the FDA so that SPECT data from the coronary angiography study were collected and used as a comparator rather than the sponsor definition of truth from a previous study. The appropriateness of the inferiority margin, which was 0.83, was another concern for several panelists.
“I was influenced by the concerns and statistical considerations regarding whether or not we have really proven true comparability with the existing standard,” A. Michael Lincoff, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine, said at the meeting. “I believe that SPECT is an appropriate standard, but I am not convinced that the existing data prove noninferiority to that standard.” – by Eric Raible