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IMREG-1 CLINICAL TRIAL REVIEW NOTES INSTANCES WHERE PATIENT SELECTION PROTOCOL "WAS NOT FOLLOWED"; FDA INSPECTION RAISES RECORDKEEPING QUESTIONS

Executive Summary

Records of the study of Imreg's Imreg-1 experimental AIDS drug have raised FDA questions at FDA about adherence to the patient selection protocol. A Sept. 16 form FD-483 inspection report issued to Imreg by FDA investigator Henry Sanchez states that "the protocol was not followed with respect to subject selection" in several instances. The report recapped a two-month review of Imreg's clinical records by FDA. FD-483 reports recount an investigator's initial view of adverse observations; the report is not an official agency position. The significance of the inspector's observations is not clear. The company will be given an opportunity to provide its perspective on the observations before FDA develops a final evaluation. Investigator Sanchez reported, for example, that two patients were included even though they did not meet eligibility requirements regarding their T4+/T8+ ratios. Three were included despite having T4+ cell counts outside the requisite range, and one patient had "none" of the "constitutional symptoms listed in the protocol." The report recounts a second inspection of Imreg by FDA. An earlier inspection report focused on the manufacture of Imreg-1 ("The Pink Sheet" Aug. 22, p. 5). The agency has said it is expediting its inspections because Imreg-1 is an AIDS therapy that may be subject to a Treatment IND application. In a letter to stockholders dated Oct. 19, Imreg President and Scientific Director A. Arthur Gottlieb, MD, maintained that the study's patient selection and randomization procedures were appropriate. Questions about patient eligibility criteria and selection "have been very carefully addressed by ourselves and independent consultants," Gottlieb wrote. "It is our view that the data from the trial indicate that the patients were appropriately selected and that they were comparable within the treated and placebo groups," Gottlieb said. The letter adds that Imreg submitted 28,000 pages of patient case records to FDA and has "been responding to questions put to us by the agency about the data and the case records." The six-page list of observations by the FDA investigator from Imreg's clinical records contains numerous comments on recordkeeping. For example, Sanchez observed: "Corrections and alterations in data made throughout the case report forms are not initialed and dated by the person who made them." The report lists several discrepancies with regard to the records for 11 patients. Regarding "subject 1301," the inspector observed that records as to when the patient left the study appear to have been altered. The report observes that an Aug. 27, 1987 pathology report indicates the patient "developed esophageal candidiasis during the study." Data regarding the candidiasis and "the 'off study summary' were altered on the investigator's copy of the case report forms," Sanchez reported. "The 'off study summary' originally indicated that the subject completed the study on Oct. 7, 1987," the report continues. "It was altered to indicate that an endpoint was reached and the subject was off the study on Aug. 26, 1987, yet the case report forms extend through Sept. 23, 1987, and the drug dispensing log indicates that the subject received his final dose . . . on Sept. 9, 1987. The FDA copies of the case report forms were not similarly altered." Additionally, an incorrect "helper/suppressor ratio" is indicated in subject 1301's "eligibility checklist." The checklist also "indicates that the subject is not a male, but he is." The investigator's files for subject 1305 did not contain a "copy of the HIV test results," the report continues. Additionally, "the entries in the 'Other Concurrent Therapy' section" of the patient's case report form "are not the same on the investigator's copy . . . as they are on the copy submitted to FDA." Records of the drug administered to the patient do not agree, the report said. For example, "the vial number from which the test drug was drawn" for administration to subject 1305 on July 23, 1987, during week 14 of the study, is recorded differently in the investigator's records, FDA's records, and the drug dispensing log, Sanchez observed. Twelve entries in the "Other Concurrent Therapy" section of subject 1312's case report form "are not the same on the investigator's copy . . . as they are on the copy submitted to FDA." The documents also differ at seven different points in the "Other Skin Lesions" section, the report states. "Generalized papular rash" is recorded on the investigator's copy, but the FDA copy "either lists nothing or shows that observation scratched out." Sanchez cited three documents pertaining to subject 1304's pretreatment condition which were altered and recorded differently on the investigator copies. For example, the agency's copy of the Eligibility Checklist for the patient "indicates the subject had +CMV ]cytomegalovirus[, but the investigator's copy shows the entry scratched out and the work 'error' written beside it. The change is not signed or dated," the report states. Other observations in the 483 raise procedural concerns about the trial. For example, Sanchez reported that the drug "was administered by and sections of the case report forms were completed by a person who was not employed by or under the direct supervision of the clinical investigator." Imreg had no record of initial approval by an Institutional Review Board for the conduct of the investigation, the report states. Furthermore, protocol modifications "were not submitted to the IRB for review and approval." Neither were protocol and consent forms for an open-label continuation study submitted, the report states. In fact, Imreg "continues to administer the test article without IRB review," Sanchez reported. The report suggests that patient consent forms were doctored. Six patients did not sign consent forms at the same time as the clinical investigator, Sanchez observed. Furthermore, he reported, "this observation was noted on July 22, 1988 during a review of the consent forms. When the same consent forms were reviewed again on July 26, 1988, they were signed by the investigator and backdated to the date when the subject had signed them." Sanchez reported that Imreg-1 "was not stored under conditions specified in the protocol." In addition, he said, "drug accountability records are incomplete." A drug dispensing log indicated that only one or two doses were drawn from several three-dose vials, the inspector noted. "The reason for the missing doses was either not explained or was explained as 'not enough' or 'vial empty.'" Furthermore, in at least four instances, the drug dispensing log did not agree with indications on individual vials and on case report forms as to which patients received which dose and when.
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