FDA perspective on ultrasound contrast agents safety and development

Regulatory actions through 2007-2008 demonstrate FDA's response to multiple reports of sudden death and severe cardiopulmonary reactions temporally related to the administration of Ultrasound Contrast Agents (UCA). Certain animal data showed similar adverse effects at a clinically relevant dose. The products labels were changed to include the boxed warning encouraging healthcare providers to assess patients for contraindications and to monitor patients with pulmonary hypertension or unstable cardiac conditions. To further characterize risks, the manufacturers agreed to perform postmarketing studies in the outpatient setting, a retrospective study in the critically ill and a pulmonary hemodynamic study. Over 2008 FDA held two Advisory Committees to discuss UCA. The first in June, 2008, dealt with the issues of safety particularly relating to the rare cardiovascular reactions which had lead to the boxed warnings and the interpretation of pre-clinical data from various species. The Advisory Committee discussed the difficulty of characterizing safety in a study of a single arm design (all patients receiving the test UCA), particularly in patients with serious co-morbidities. The Advisory Committee emphasized the need for premarket prospective randomized studies in high risk populations who are likely to receive the product and also for large sample size post-marketing observational studies. Additionally the Advisory Committee re-confirmed the importance of pre-clinical data when obtained from a relevant species. The second Advisory Committee held in December, 2008 evaluated the possible approval of AI-700, a new UCA, with the proposed indication being the detection of coronary artery disease based on the assessment of myocardial perfusion and wall motion. The targeted population was patients with stable chest pain being evaluated for inducible ischemia. The Advisory Committee's finding of an unacceptable risk:benefit profile was based on the safety data as well as variations in diagnostic performance in the registration studies and failure to demonstrate the added value of AI-700 to non-contrast echocardiography. The major safety concerns related to the occurrence of hypotension following administration of the product. The process for UCA development from conception, pre-clinical studies, and early safety trials through registration trials leading to licensure should be evident to all stakeholders. The FDA website contains relevant recommendations from our Gui