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Executive Summary

FDA's review of Imreg's application for Treatment IND distribution of the anti-AIDS drug Imreg-1 has been extended 30 days while FDA continues to evaluate the application. In a Nov. 4 statement, Imreg said it "was notified by FDA" that the agency "was requesting another 30 days to reach a decision on this matter, owing to the fact that review of the large dataset submitted by the company had not been completed." Treatment IND regulations require FDA to respond to an application within 30 days of submission. The Treatment IND request for Imreg-1 was filed Oct. 4; a 30-day extension of FDA's regulatory review time would stretch to Dec. 4. Imreg indicated that it was preparing to proceed with expanded distribution as the 30-day waiting period for a Treatment IND application "passed without notification to the contrary." According to the company's statement, Imreg "planned to proceed with implementation of its Treatment IND protocol" before FDA asked for the extension. The company plans to charge those patients receiving Imreg-1 if the Treatment IND application is approved. Imreg said it "intends to request that FDA grant it permission to recover costs in connection with the Treatment IND." Approximately 70 patients currently are taking Imreg-1, and Imreg said those patients will continue to receive the drug at no charge during the extended period of FDA's review of the Treatment IND. Imreg noted that "more than 70 patients" who had participated in the company's multicenter randomized, placebo-controlled trial "have continued, with FDA's consent, to receive" the drug since the study concluded in March. Citing the high cost of the drug's development, Imreg said that it cannot afford to continue to provide the drug free of charge for an indefinite period. "Owing to the costs of production, quality control, and clinical monitoring required, the company is not in a position, in the absence of a Treatment IND with cost recovery, to continue to provide the drug indefinitely to these particular patients," Imreg said. Nevertheless, "the company has decided to continue to provide drug to these patients for the additional 30-day period which FDA has requested for further consideration of the company's Treatment IND proposal." FDA reportedly is preparing for announcements during the week of Nov. 14 of the release of two drugs with AIDS indications. The products are expected to involve approvals of an NDA and a Treatment IND. NDAs have been pending for some time for alpha interferon (Schering-Plough's Intron-4 and Roche's Roferon-A); for use in treating Kaposi's sarcoma, a form of cancer often developed in AIDS patients. Candidates for Treatment IND approval include Syntex' Cytovene (ganciclovir). Syntex has been providing the antiviral free-of-charge of AIDS patients under a "compassionate IND" for the treatment of cytomegalovrius (CMV) infections of the eye, an orphan indication. Although Syntex is not known to have applied for a Treatment IND, that process would allow the company to recover costs of supplying the drug while FDA works through the large amount of data from "open" trials in the Cytovene NDA. Imreg-1 is another of the likely candidates for the imminent Treatment IND expanded use. The FDA inspection activity at the firm since late summer is a sign of the agency's active review of Imreg's application. In a Nov. 8 press release, Imreg expressed confidence in its ability to answer any FDA questions arising during the agency's review of the application. Imreg President A. Arthur Gottlieb, MD, pointed out that the company had collected extensive patient records as part of the trials. "Over 28,000 pages of patient records and thousands of individual data items were collected" during the clinical trials, Gottlieb said. Putting the task of filing an FDA application into perspective, he said "we would expect some questions to arise" in the process of collecting the large amount of material. However, he declared, "we expect to answer these questions satisfactorily." FDA has been circumspect in its review of Imreg-1. The agency has said it expedited the inspection process for three reasons: it anticipated the Treatment IND request, Imreg-1 is an AIDS therapy, and the company publicly announced preliminary results indicating a positive benefit. FDA has conducted inspections of clinical records from at least two of the eight study centers and the company's manufacturing procedures ("The Pink Sheet" Nov. 7, p. 17 and Aug. 22, p. 5). Imreg questioned published reports about FDA investigations relating to its application for FDA approval. The company noted articles in the trade press and the New Orleans Times-Picayune that cited record-keeping concerns and suggested "that patient rejection protocol was not followed in several instances." In response to such articles, the firm declared: "Any suggestion that the integrity of the dataset from the trial has been compromised, or that records have been improperly altered, is completely without foundation and is an affort to the company, its officer, scientific and clinical monitoring staff, as well as the participating clinical investigators." IMREG COMMENTS ON FDA 483 REPORTS The following five paragraphs were issued by Imreg on Nov. 7 to explain the status of FDA inspections of clinical trial data. The press release has been reproduced by "The Pink Sheet." Imreg, Inc said today that is has received many inquiries concerning FDA 483 Inspection Reports which were issued to two of the clinical investigators who participated in the company's clinical trial of IMREG-1 in ARC/AIDS patients. Articles based on these reports have recently appeared in trade publications and the New Orleans Times-Picayune. These articles allege that the patient selection protocol was not followed in several instances, and cite a number of other record-keeping and procedural issues. The company has had a standing policy against public discussion of FDA-related matters except for material regulatory actions. However, the release of the 483s into the media, and statements about alleged improper record-keeping in the recent articles, have compelled the company to comment on these points. Dr. A. Arthur Gottlieb, Imreg President and Chief Executive Officer, said today, "Any suggestion that the integrity of the dataset from the trial has been compromised, or that records have been improperly altered is completely without foundation, and is an affront to the company, its officers, scientific and clinical monitoring staff, as well as the participating clinical investigators." Dr. Gottlieb further stated, "The recent articles which have appeared in trade publications and the New Orleans Times-Picayune contain several misstatements of fact. For example, statements that Imreg had no record of approval by an Institutional Review Board and that the protocol was not followed with respect to subject selection are simply not correct. Imreg, Inc. had all requisite IRB approvals for the clinical trial, before any patients were enrolled, and filed these IRB approvals with the FDA. All of the patients were selected appropriately. "It is my view that uninformed discussion in the media of points from these FDA 483s, or data from the clinical trials is not appropriate. I believe, as well, that to publish such so-called 'information' without the benefit of a description of all the facts pertinent to a particular item in a given 483 is misleading, borders on the irresponsible, and is a disservice to the reader. This was a complex trial in sick patients that required the collection of a very large amount of data. Over 28,000 pages of patient records, and thousands of individual data items were collected. In such a process, we would expect some questions to arise. We expect to answer these questions satisfactorily. In light of this, it is improper and misleading for anyone to attempt to impugn the integrity of the data, or to malign the clinical investigators who participated in the trial."

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