IMREG FILES FOR IMREG-1 TREATMENT IND; FDA RESPONSE COULD BE IMMINENT, WEIGHING POSITIVE RESULTS v. QUESTIONS RAISED IN INSPECTIONS OF CLINICAL RECORDS

Imreg has filed an application to distribute its anti-AIDS biologic product, Imreg-1, under a Treatment IND. FDA's response to the application could come quickly. Imreg reportedly filed the application in early October; FDA is under pressure to meet its 30-day deadline for responding to requests for Treatment IND status. On the other hand, the agency's response need not constitute only approval or rejection; FDA might give a noncommittal answer or request more data. If a Treatment IND for Imreg-1 is approved, the start-up biotechnology firm is expected to take advantage of the Treatment IND regulation's cost recovery provisions. In that case, Imreg-1 would become the third product distributed under a Treatment IND for which the sponsor charges patients. The Parkinson's disease therapy Eldapryl (selegilene) is sold to patients by Somerset Labs, and the Massachusetts Department of Public Health is charging for cytomegalovirus immunoglobulin, used in kidney transplant patients. The agency's decisionmaking process will involve science, art, and politics. Commissioner Young recently referred to the public pressure for the development and approval of AIDS therapies. In remarks prepared for an Oct. 24 speech in Los Angeles to the Interscience Conference on Antimicrobial Agents and Chemotherapy, Young said "physicians fully recognize the desperateness that AIDS patients feel, and I have recently met with the leaders of a number of AIDS groups prior to the recent demonstration at FDA headquarters." Young told the conference that "excellence in study design" is needed, along with "more emphasis on the quality of the actual conduct of major clinical trials," including "close adherence to the protocol in terms of entrance criteria, randomization . . . ]and[ the need to keep careful and accurate records throughout the study." The need for careful recordkeeping "deserves special emphasis," Young explained. "Prior to the marketing approval of new drugs," he noted, "FDA inspectors conduct an on-site audit of the major studies and of clinical investigators to make sure that the raw data in the patients' medical records are consistent with the information sent to FDA." Imreg also addressed the scientific conference, presenting an update of information from its clinical trials of Imreg-1. The company reviewed data on survival to endpoint previously presented at a conference in Stockholm ("The Pink Sheet" June 20, T&G-2) and also discussed data on immunological function and symptoms. Imreg's ICAAC presentation reiterated the company's presentation in Stockholm on the five-fold improvement in the drug group in terms of halting progression to AIDS by ARC patients. In reviewing Imreg's Treatment IND application, FDA will consider the company's answers to questions raised by agency inspections of the clinical records from at least two of the study centers. A preliminary report of an FDA inspection of the records of the Eisenhower Medical Center in California notes that the study's "protocol was not followed with respect to subject selection" of 26 patients, who were ineligible under one or more of three criteria. In an Oct. 21 form FD-483 inspection report, FDA inspector Ronald Koller said that although inclusion criteria required T4 cell counts of 100-400 mm, "20 subjects had T4 cell numbers greater than 400 and three ]of those[ had T4 cell counts greater than 600." The FDA report provides subject identification numbers for only 19 patients. In addition, "eight subjects had T4+/T8+ ratios of greater than 0.7" even though eligibility criteria required subjects to have ratios of 0.7 or less, Koller reported, and three patients had none of the seven constitutional symptoms listed in the study protocol. The investigator's list of adverse observations does not constitute a formal FDA evaluation. Imreg and the clinical investigator Milan Fiala, MD, will be given opportunities to respond to the three-page report. The company also received a six-page report on an inspection of clinical records from its New Orleans study center. ]EDITORS' NOTE: Imreg discussed patient selection and randomization in a letter to a single stockholder, not in a general mailing to investors, as indicated in a previous story in "The Pink Sheet." The same story incorrectly reported that the FD-483 from the inspection of the New Orleans center states that Imreg did not have certain IRB approval records on file; the 483 states that clinical investigator Kenneth Combs, MD, did not have IRB approval records on file ("The Pink Sheet" Oct. 31, p. 6).[ The California inspection report states that clinical investigator Fiala "did not have a copy of the HIV test results for" for 41 study subjects. Keller further reported a "lack of signed informed consents for" eight patients. "Corrections and alteration in data made throughout the case report forms are not always initialed and dated by the person who made them per the protocol," the report continues. "Entries in the investigator's original copy of the case report form are not always the same as they are on the copy submitted to FDA," the report states. Koller listed eight discrepancies as "examples." An "Eligibility Checklist" for one study subject is incomplete in that boxes are not checked to indicate the patient's "helper/suppressor ratio, absolute number of OK T4 cells, skin test energy, ]and whether[ informed written consent ]was[ obtained." The inspector reported that Imreg-1 accountability records were "inadequate" in that records of receipt were "incomplete." Receipt records were "not available for all lots of the test article shipped to the clinical investigator," the report states. "The receipt records do not record the receiving date." The "Drug Dispensing Log" was also incomplete in that the subject "study number is not recorded," the date of vial return to Imreg is not recorded, and "the disposition of vials used by Dr. Cone is not recorded." In addition, the log offers no "explanation of what happened to" four three-dose vials from which fewer than three doses were taken, nor does it explain why four doses are recorded as having been taken from each of six vials and five doses from another vial. Discrepancies and other adverse findings listed in an FD-483 report are considered initial observations rather than final evaluations by FDA. It could be anticipated that a start-up biotechnology firm like Imreg, which has no prior experience in developing drugs and shepherding them through the regulatory maze, would confront difficulties during the inspection process. The company contends that the various observations cited in FDA's inspection reports are either "incorrect," "misleading," or can be readily explained. Furthermore, it is reportedly not unusual for up to 5%-10% of patients enrolled in clinical trials to be ineligible under the inclusion criteria. If the California inspection report proves correct, more than two dozen patients from only one center of an eight-center, 158-subject trial will be ruled ineligible. FDA will have to determine whether such factors have an impact on the evaluation of the trial.