MBI's FS069 FDA clearance tabled by lawsuitThe regulatory review process for ultrasound contrast agents has ground to a halt following a U.S. District Court ruling on April 21. The court order culminates a controversy over whether FS069, an agent
MBI's FS069 FDA clearance tabled by lawsuit
The regulatory review process for ultrasound contrast agents has ground to a halt following a U.S. District Court ruling on April 21.
The court order culminates a controversy over whether FS069, an agent from Molecular Biosystems, should be reviewed as a drug in the Food and Drug Administration's Center for Drug Evaluation and Review (CDER), where contrast agents have historically been regulated. FS069 and its predecessor, Albunex, have been reviewed as devices in the FDA's Center for Devices and Radiological Health (CDRH).
Albunex received FDA clearance in February 1995 following four years of review by the CDRH and is the only ultrasound contrast agent available for sale in the U.S. The San Diego-based company's second-generation FS069 agent was recommended for approval without conditions by the FDA's Radiology Device Advisory panel on Feb. 24.
The belief that clearance was imminent triggered lawsuits by Bracco Diagnostics, DuPont Merck Pharmaceutical and its partner ImaRx, and Sonus Pharmaceuticals, who had all filed citizen's petitions with the FDA asking the agency to eliminate the disparity in the regulation of contrast agents and what they believe was unjustified preferential treatment.
Under the preliminary injunction issued by U.S. District Court Judge Paul Friedman, the FDA is enjoined from continuing any approval or review procedures on FS069's premarket approval (PMA) application until 10 days after the FDA has resolved the merits of the citizen's petitions filed by the companies. The FDA has 180 days to respond to a citizen's petition; Bracco was the first to file in December.
In response to a motion from MBI, Friedman ruled that the FDA is also enjoined from continuing any approval or review procedures on the plaintiffs' agents, which are in varying stages of the regulatory process.
Of the companies that filed citizen's petitions with the FDA, the furthest along is EchoGen, from Sonus Pharmaceuticals. A June 30 meeting of the Medical Imaging Advisory Committee has been scheduled to review EchoGen's NDA for approval of both cardiology and radiology indications.
Bracco Diagnostics submitted its investigational new drug (IND) application for its BR-1 agent in December 1994, and clinical trials began in April 1996. ImaRx submitted its IND application for DMP-115 (formerly MRX-115) in August 1995. The agent was licensed to DuPont Merck Pharmaceutical in November 1995.
Differences in review? The substantial difference between review processes for NDAs and PMAs make it critical for the FDA to review all ultrasound contrast agents in the same fashion, said Christopher Cannon, vice president and general counsel for Bracco of Princeton, NJ.
"The distinction that the FDA made by accepting the Albunex product and FS069 as devices was an arbitrary and capricious action," Cannon said.
The agency is also acting contrary to its own opinion on the regulation of contrast agents, Cannon said. In January 1982, the FDA issued a proposed rule that states that the "agency has determined that all radiologic contrast media, including barium enema kits, are to be regulated as drugs...and not as devices." If not repudiated by the FDA, the proposed rule constitutes a binding advisory opinion on the agency, according to court documents.
Supporters of MBI's position that its agents can be reviewed as devices point to the Federal Food, Drug, and Cosmetic Act, which defines a device as, among other things, something that "does not achieve its primary intended purpose through chemical action within or on the body... and which is not dependent upon being metabolized for the achievement of its primary intended purposes."
As neither agent relies on the metabolism of the body to perform functions, they both meet the FDA's test criteria to be regulated as a device, said Peter Faur, director of corporate communications for Mallinckrodt. Mallinckrodt, of St. Louis, distributes Albunex and will also market FS069.
"In the case of both Albunex and FS069, the substance is injected into the body fully formed, fully ready to work, and in no way depending on the metabolism of the body," Faur said. "It's analogous to basically putting a catheter into the body and taking a catheter out."
Further, claims that Albunex and FS069 as devices have not been subject to the kind of rigorous standards required for NDAs are inaccurate, said Bobba Venkatadri, MBI's president and COO. Representatives of the CDER have participated throughout the review process of FS069, he said.
"We have done good-quality science that will stand up to other drugs or devices," Venkatadri said. "There are no shortcuts here."
Allegations in court documents that Albunex was regulated as a device because it may have initially included instrumentation to be used by physicians to prepare the drug are also not true. Albunex and FS069 have always been produced at MBI's manufacturing facility, said Steve Keane, MBI's director of investor relations and business development.
Regulating all ultrasound contrast agents as drugs, however, would allow for better comparisons between agents, said Alex Zisson, a senior analyst at Hambrecht & Quist in New York City.
"When it comes down to follow-up studies and advertising claims, it would make more sense if they were all regulated as drugs," Zisson said.
One contrast agent vendor has taken pains to stay out of the fray, however. Alliance Pharmaceutical of San Diego issued a press release following the court ruling, announcing that it was not party to the lawsuits filed against the FDA. The company also did not file a citizen's petition with the FDA. As a result, development of its Imagent US agent is not affected by the order, according to the company. Imagent US has recently completed phase II clinical trials.