FDA delivers blow to blood pool agent MS-325

The FDA announced on Jan. 14 that it would approve the MR blood pool imaging agent MS-325, but only if Epix Medical completed additional clinical studies that demonstrate efficacy.

Berlex, the U.S. arm of contrast giant Schering, has been waiting since October for the final go-ahead to launch MS-325. The FDA was to have completed its review last fall but extended the deadline to January.

The reasons for the delay were exactly the same as the ones stipulated in the action letter the FDA issued in October. The agency notified Epix then that it had two concerns.

First, the methods for acquiring noncontrast-enhanced images were not standardized. These images were supposed to establish a baseline against which the contrast-enhanced images could be compared. The lack of standardization raised questions in FDA reviewers' minds about the validity of the results.

Second, the agency was concerned about the number of uninterpretable scans. Again, this related to the noncontrast-enhanced imaging methods. The FDA questioned whether the high rate of uninterpretable scans might have artificially exaggerated the benefit of MS-325.

In both instances, Epix responded to the FDA's concerns with new analyses, but the FDA found the data wanting.

There is a reason why nobody does unenhanced MRA - because it doesn't work, said Dr. William Bradley, Jr., radiology chair at the University of California, San Diego.

"How can the FDA complain about the slight differences in technique when as a class unenhanced MRA is inferior to contrast-enhanced MRA?" he said.

The whole advantage of MS-325 is that it stays vascular for an hour. The first pass should be identical to any other agent, he said.

The FDA has changed the rules of the game, said Dr. E. Kent Yucel, who helped design the trials and is now a consultant for Epix.

"The studies were structured - with FDA approval - to meet specific goals," he said. "After the goals were met, the agency decided it wanted other data."

The protocols and standards for noncontrast body MRA vary from place to place, said Yucel, chief of radiology at Boston VA Healthcare System. Therefore, he and colleagues allowed the investigators in the trial to optimize the time-of-flight scans to their equipment and their preferred parameters. Hence, no standardization.

Regarding the high number of uninterpretable images, Yucel said they did an intent to treat analysis, which means that every image - whether interpretable or not - got entered into the analysis. If an image was uninterpretable, it was called wrong. There was no guesswork. That was the standard of reference for both noncontrast- and contrast-enhanced MRA.

"We felt these provisions would result in a better study," he said. "And the FDA at the time apparently felt the same."

People should be concerned that the FDA is not facilitating the development of these products within the U.S., Yucel said. There is a good chance that one or more agents could be approved in Europe before they are available here.

For more information from the Diagnostic Imaging archives:

Blood pool contrast extends MRA's ability

MR equipment, protocols adapt to take advantage of contrast

Bolus chasing improves peripheral MR angiography