Evolving trial design standards and miscommunication with the review division tripped up Acusphere's effort to bring Imagify to market, signaling to competitors in the space that FDA is raising the bar on contrast imaging agents.

Inconsistent efficacy, safety signals and unconvincing diagnostic value also sunk Imagify Dec. 10, as the Cardiovascular and Renal Drugs Advisory Committee voted 16-1 with one abstention that the totality of data did not provide sufficient benefit to patients with chest pain to justify the use of the product as a screening tool to stratify patients for referral to coronary arteriography.

During a contentious panel meeting, Acusphere admitted the primary endpoint selection for Phase III was never formally discussed with FDA. The firm also lashed out at the agency for their recommendation of a midstream modification to the trial design.

For their part, FDA contended that the standards were clear, and the burden of proof of value is on the sponsor. "In general," said Division of Medical Imaging and Hematology Products Director Dwaine Rieves, "one anticipates that the contrast agent will add diagnostic value over the non-contrast agent in order to justify exposure to the contrast agent's safety risk."

June Panel Discussion "Very Applicable"

Acusphere submitted the NDA for Imagify (perflubutane polymer microspheres) in June, the same month FDA convened the Cardio-Renal panel to review safety issues for similar products. The agency had received over 200 warnings on severe cardiopulmonary adverse events and added "black box" warnings to the labeling of similar contrast agents in October 2007, and requested the panel discuss the future of the class.

The committee emphasized the need for pre-market, prospective, randomized studies in intended populations to thoroughly evaluate safety, Rieves said. "This perspective is particularly notable because imaging studies have over the last many years predominantly been single-arm studies, including [Imagify's] studies."

Acusphere submitted two pivotal trials in support of the NDA, 32 and 33. The open-label, single-arm crossover studies evaluated whether Imagify was non-inferior in over 1,000 patients experiencing chest pain in a stress echocardiogram compared to a single-photon emission computed tomography test.

The efficacy data from the two trials were inconsistent, further complicating analysis of value (¹ Also see "Acusphere Reports Mixed Top-Line Phase III Results For Imagify" - Pink Sheet, 1 May, 2007.). Both studies met the accuracy endpoint, but study 32 showed specificity (the true negative rate) but not sensitivity (the true positive rate). Study 33 showed sensitivity but not specificity.

[Editor's note: Further coverage of the Imagify panel meeting, including trial design issues and safety problems, will appear in future issues.]

FDA also criticized the supporting exploratory studies, particularly one in which Acusphere compared Imagify to placebo. The difference was marginal, said reviewer Sheldon Kress, suggesting Imagify had no added benefit over placebo. "These findings raise questions as to the added value of Imagify compared to the results that could be obtained without the use of Imagify."

Future Of Imagify, Acusphere Up In The Air

The panel proposed a number of issues for the company to consider in future additional trials, like establishing a better-defined non-inferiority margin based on evidence (rather than estimates from literature); rethinking the primary endpoint; clarifying the truth standards; including some aspect of randomization in a trial; and building a larger safety database comprised of a broader population by including patients with co-morbidities.

Any additional trials also will have to overcome the cardiovascular safety signals seen in the trials.

Acusphere, whose stock has plummeted since FDA briefing documents were posted, will likely have to request funding from its partners, Cephalon and Nycomed, before the user fee date in February, and before they could undertake additional clinical trials (see ² Also see "Acusphere Left Unstable By FDA Panel Review; CEO Turns Ire On Panelists" - Pink Sheet, 15 December, 2008.).

- Becky Jungbauer (r.jungbauer@elsevier.com)

Acusphere Future Up In Air After Imagify Fails Before Advisory Panel

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