• 3/5/2005
  • FDA Advisory Committee (www.fdaadvisorycommittee.com)

Advanced Magnetics’ Combidex safety and efficacy data are insufficient for approval of a broad indication in metastatic lymph node detection, FDA’s Oncologic Drugs Advisory Committee concluded. The committee voted 15 to 4 that the data presented by Advance Magnetics do not support approval of the proposed Combidex indication.

Advanced Magnetics is seeking an indication for Combidex (ferumoxtran-10) in the “differentiation of metastatic and non-metastatic lymph nodes in patients with confirmed primary cancer who are at risk for lymph node metastases.”

“I really wanted to vote for this drug today,” committee member Otis Brawley (Emory University) said, but the safety and efficacy of Combidex is “not proven.” Committee member Michael Perry (University of Missouri) agreed, saying that he is “not yet convinced that it is effective.”

The committee’s major concerns involved design and analysis of the pivotal Combidex trials. Committee member Gregory Reaman (Children’s National Medical Center) said that Combidex is one of the “most exciting agents we have had the opportunity to review”; however, the “data are some of the least satisfactory in study design.”

In theory, lymph node imaging could obviate the need for biopsies. However, FDA pointed out in its briefing materials for the meeting that the agent’s near 20% false negative rate means that Combidex-enhanced magnetic resonance imaging cannot be used to replace biopsy.

The size of the studies and the number of lymph nodes included in the primary efficacy analysis for Combidex were too small to support approval of the broad indication Advanced Magnetics is seeking, many committee members agreed.

The pivotal trials included 152 patients imaged with Combidex in a U.S. study and 181 patients from three European studies.

Only 74% of the nodes visualized by site investigators were correlated to pathology results in the U.S. study, which was a requirement for the primary efficacy analysis. The correlation for European studies was even lower, ranging from 10% to 62%.

Several committee members suggested that since the largest group of patients in the trials had head and neck cancer, a narrower indication in this cancer patient group might be more appropriate for Combidex. However, the committee was not asked to vote on a narrower indication.

Other committee members were concerned about the lack of data in pediatric patients since Combidex would likely be used in that group. Pediatric patients are more susceptible to anaphylactoid reactions, Combidex’ major side effect, committee members pointed out.

The user fee deadline for Combidex is March 30. Advanced Magnetics received an “approvable” letter for Combidex in June 2000 that requested at least one additional robust study for approval. Advanced Magnetics resubmitted the NDA with additional data in September 2004.

Combidex consists of iron oxide nanoparticles and was granted a priority review. Cytogen holds exclusive U.S. licensing and marketing rights to Combidex for all uses