FDA resolves ultrasound imbroglio, will regulate contrast agents as drugs

Will decision slow Optison's progress?

A gamble by Sonus Pharmaceuticals and several other developers of ultrasound contrast agents paid off last week with a decision by the Food and Drug Administration that all products intended for use in diagnostic ultrasound must be reviewed by the agency as drugs.

The decision could delay the commercial release of Optison (formerly FS069), an ultrasound contrast agent developed by Molecular Biosystems, which appeared in April to be just days or weeks away from final FDA approval. Optison had received a unanimous recommendation for approval from an FDA device advisory panel in February, but a lawsuit filed by several competitors of the San Diego company put the review process on hold (SCAN 4/30/97).

The lawsuit asked a U.S. District Court in Washington, DC, to halt review of Optison until the FDA answered citizen's petitions filed by the four plaintiffs: Sonus, Bracco, ImaRx, and ImaRx marketing partner Du Pont Merck. On July 28, FDA Deputy Commissioner Dr. Michael Friedman provided that reply.

"The ultrasound contrast agents at issue in this proceeding should be brought within the same regulatory scheme," Friedman wrote in a written opinion explaining the ruling. "The agency will regulate these products as 'drugs' and 'new drugs' and will assign primary oversight responsibility to the Center for Drug Evaluation and Research (CDER)."

The decision was made for administrative efficiency and to ensure that the agency continues to apply similar standards to this class of products, according to Friedman. A source at the FDA stated that agency officials could not comment on the decision until the pending lawsuit is over, and the two sides are expected in court Aug. 4. At press time, executives at Sonus and Molecular Biosystems were not available for comment.

The way now appears clear for the FDA to begin again to review EchoGen, the ultrasound contrast agent developed by Sonus of Bothell, WA. Both reviews were halted by court order when the judge reviewing the lawsuit enjoined the FDA from reviewing ultrasound contrast agents associated with any of the principals in the case. Sonus had been scheduled for an FDA advisory panel this summer, but that was dropped when the lawsuit forced the FDA to shut down its review process. It now appears likely that an advisory panel will meet before the end of the year, and a decision could be made by the FDA regarding EchoGen soon after.

The future for Optison is not so easy to predict. The application for market approval must now be shifted from one group of FDA reviewers to another. Friedman provided some hope, however, that this transition from device to drug review will have only a minimal effect on Molecular Biosystems and its Optison product. Concern about the impact of the FDA's decision caused MBI's stock to whipsaw in the days following the announcement. It fell from nearly $10 a share to $8.31 on July 29, then regained nearly all the lost ground the next day. It closed at $9.25 on July 31.

The premarket approval application (PMA) made by the company to the FDA's Center for Devices and Radiology Health has been deemed a submitted and filed new drug application (NDA). Acceptance of this NDA is a strong indication that MBI will probably not have to collect additional clinical data.

Additionally, the FDA has decided that the effective date of submission for the NDA will be Oct. 17, 1996, the date on which the PMA was filed. This provides the company with a high-priority ranking for completion of the review. And while CDER will review the application according to criteria for new drug products, the center will not repeat the review of portions of the PMA that have already been substantially examined.

"CDER will be able to rely, as appropriate, on the extensive analyses already done by CDRH, the comments and recommendations of the Feb. 24, 1997, advisory panel, and any conclusions already reached by CDRH officials regarding the data and information in the PMA," Friedman wrote.

There are, however, several questions that remain unanswered. Optison must follow good manufacturing practices developed for drugs. But the company's supplier of perfluoropropane, the gas enclosed in the microspheres of Optison, currently meets GMPs developed for devices. This might not be a serious problem for MBI, however. Friedman noted that because perfluoropropane has been approved for intraocular use, the company should be able to locate a supplier of the gas for Optison capable of meeting drug GMP requirements.

The decision by the FDA will also affect the company's first ultrasound contrast agent, Albunex, but only minimally. Although this product will be regulated in the future as a drug, the sale of the product will not be impacted. Friedman noted in his response that Albunex is an approved and marketed product and that its manufacture already meets GMP rules for drugs.

"The agency has determined that Albunex, and the approved supplement for Albunex, will continue to be marketed under the existing PMA," Friedman wrote.

The PMA and all pending and approved supplements and investigational device exemptions will be transferred, however, to CDER, which will work with the company to convert these to a format compatible with new drug applications.

Friedman and the FDA hope to avoid any further confusion between the drug and device centers within the agency, at least as they pertain to ultrasound contrast. Friedman noted that all future applications for microbubble- and microsphere-based ultrasound contrast agents must be filed with CDER, while pending IDEs will be transferred to CDER.