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FDA VACCINES ADVISORY COMMITTEE, IMREG NEED MORE TIME TO EXAMINE ISSUES REGARDING IMREG-1 TREATMENT IND REQUEST; FDA, FIRM DISAGREE ON AIDS DEFINITION

Executive Summary

FDA's Vaccines & Related Biological Products Advisory Committee deferred a recommendation on Imreg's Treatment IND for Imreg-1 at its Nov. 18 meeting. The committee requested more time to further examine FDA's analysis of the Imreg-1 clinical data, and to review the company's response to the agency. The committee agreed with committee member Duard Walker, MD, University of Wisconsin Medical School, who said the panel did not "have the material data here to" make an informed recommendation on the anti-AIDS biologic. Furthermore, "I think we have to see the rebuttal" by Imreg. Imreg similarly requested the opportunity to review the FDA analysis and consult case report forms to prepare a rebuttal before the advisory committee made its recommendation. The advisory committee meeting was called on less than a week's notice to help FDA resolve its difficulties with the Imreg submission. Referring to analyses of the Imreg-1 data presented at the meeting by two FDA reviewers, Imreg Chairman Arthur Gottlieb, MD, said the firm has "seen a limited number of these analyses. We have not seen virtually all of the presentation [by FDA reviewer David Katzenstein, MD] until today." The presentation by Katzenstein entailed an analysis that contradicted Imreg's interpretation of the eight-center, placebo-controlled study, which is the basis for Imreg's Treatment IND application for ARC patients. The FDA reviewer maintained that the data do not provide evidence of a difference between Imreg-1 and placebo in reducing the progression of AIDS-related complex (ARC) to AIDS. Gottlieb maintained that an advisory committee meeting was "an inappropriate forum to raise this kind of issue at this time, particularly since we have not had the opportunity to consider these points. We have to go back to case records" to prepare a rebuttal with documentation, he said. Without the company's ability to "respond adequately" to the FDA presentation "for the benefit of the agency and the committee," such a presentation "serves no constructive purpose" and it would be "unfair" to base a judgment of the drug on such a presentation. Key problems for the agency included randomization of ARC patients entering the trial and whether the study endpoints were met. The ratio of treated patients to placebo patients was two-to-one overall, Katzenstein noted. However, he said, "there was some concern" that there were proportionally more patients with higher CD4 cell counts in the treatment group. The public meeting made clear that the company and FDA are having difficulty reaching an agreement on a fundamental definition of what constitutes AIDS. Discussing study subject judged to have progressed to AIDS, Katzenstein pointed to both a treatment patient and a placebo patient included in the study with peripheral neuropathy. Katzenstein argued that the condition "is not mentioned anywhere in the CDC [Centers for Disease Control] definition of AIDS." He took issue with Imreg's determination that several other placebo patients had developed AIDS. Katzenstein noted the endpoints involved tracheobronchial candida "based on a patient with severe oral candidiasis"; wasting syndrome unaccompanied by diarrhea or fever, "which has to be there in order to meet the CDC's criteria for wasting syndrome"; encephalopathy, noted in a patient for which "there was no supporting MRI or CSF data and no indication that the patient was clinically encephalopathic"; and a case of Kaposi's sarcoma developed after the study. "I don't think [these endpoints] represent AIDS," the FDAer maintained. The analysis also focused on patients who completed the study with CD4 cell counts of less than 250. Three of 16 treated patients, compared to six of 15 placebo patients, developed AIDS. The difference is "not significant," Katzenstein asserted. Gottlieb complained that the focus of the analysis on a CD4 cell count of 250 seems to be "a figure just taken out of the air." Why not reanalyze the data with cell counts of 290 or 300? he asked, adding: "Is it appropriate" to subject study findings "to a post hoc analysis?" The advisory committee was convened to expedite a resolution to questions concerning the Imreg data. FDA recently extended its 30-day regulatory deadline for responding to a Treatment IND request; the new deadline expires on Dec. 4. Committee Chairman Marshall Horwitz, MD, Baylor College of Medicine, asked whether the committee was "working under a restraint to make a decision today, or do we have the time to ask for the answers?" FDA Deputy Director for Biological Evaluation & Research Gerald Quinnan, MD, replied that the agency "would be interested in hearing any questions or additional information that might clarify the picture." However, he noted FDA's concern that it "not be penalized, so to speak" for not acting within the regulatory 30-day deadline for responding to Treatment INDs. Quinnan also hinted at the external pressure on the agency to quickly review applications for AIDS therapies. "There is a certain amount of urgency in settling this," he said. "The claim has been made in public now for many months that this product is effective" in preventing AIDS, Quinnan noted. "We're here now with a [different] analysis of the data to examine whether or not that claim holds up. The agency would like to see the matter resolved as quickly as possible in the public view." On the other hand, he added, "we're not here trying to force a decision that cannot be appropriately made." Quinnan opened the meeting by explaining that in reviewing the Imreg data supporting the Treatment IND request, the committee was also to consider whether a clinical hold on the treatment protocol might be appropriate. He listed for the committee FDA's reservations about the Imreg submission. The agency conducted its analysis after seeing that Imreg's submission included endpoints for "patients who were not dropped from the study," Quinnan said. "There were other patients who were enrolled in the study and dropped for a variety of reasons, such as patients who were started on AZT during the study because of declining CD4 cell numbers. Those patients are not included in the database, they're not counted as endpoints, they aren't counted as anything," he said. Rather than "present additional analyses of that sort to" the committee, Quinnan said the agency decided to prepare "the type of analysis Dr. Katzenstein presented at the end, where he showed the number of AIDS cases among patients enrolled in the study. When you do that you wind up with even distribution between the [treatment and placebo] groups." Horwitz asked the company whether it would feel "comfortable going on to the next phase" of Treatment IND distribution in light of the doubts cast by FDA upon the prospects for ultimate approval. The Gottliebs replied: "Yes, absolutely."
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