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Executive Summary

Bristol-Myers will send a "Dear Doctor" letter warning of ddI-associated pancreatitis to all physicians involved in the distribution of the AIDS drug under the ongoing expanded access program "in the very near future," the company said. The letter, which will also be sent to investigators participating in the clinical trials, is expected to advise physicians that pancreatitis is a known side effect of ddI and alert them to the symptoms. FDA will have to approve the letter, which will be the company's fourth "dear doctor" communication to physicians involved in the ddI expanded access program since the company began distribution of the drug last fall. In addition, FDA said it has asked the company "to review and update" the patient informed consent forms. To date, six deaths from pancreatitis have occurred in the combined ddI clinical and expanded access patient populations, which total over 8,000 patients. Health officials have expressed concern that serious side effects early in the expanded access program's existence, such as the pancreatitis episodes, would dampen enthusiasm for the expanded access program. According to Bristol-Myers, a total of 44 cases of pancreatitis (including the six patients who died) have been observed in the clinical trials and reported from the expanded access program. Of the deaths, five of the patients were receiving the drug under the expanded access program and one patient was enrolled in a clinical trial. A Bristol-Myers spokesperson cautioned that the pancreatitis deaths may be related to dose or duration of use with ddI as well as other factors, including concomitant therapies. As of March 2, Bristol-Myers and the National Institutes of Health had enrolled 7,545 patients in the expanded access arms of the ddI clinical study program. That total includes 6,311 patients in the Treatment IND arm and an additional 1,234 patients in the open label arm of the expanded access program. Over 700 patients have been enrolled in the three clinical trial protocols for ddI. Since the program started last fall, 290 patients enrolled in the expanded access arms of the ddI trial have died, most from AIDS or complications stemming from the disease. There have been two deaths in the clinical trial protocols. * In a statement on the ddI adverse reactions, FDA said it has asked the company "to provide in depth informatio on these adverse reactions as soon as possible." FDA said it will work with investigators and Bristol-Myers Squibb to "assess these data to determine if dosage, concurrent therapies or other factors may contribute to the onset or severity of pancreatitis in some patients, and to identify any adjustments needed to make the ongoing protocols as safe as possible." Speaking at the Institute of Medicine's "Roundtable for the Development of Drugs and Vaccines against AIDS" on March 12, University of Washington AIDS researcher Lawrence Corey, MD, reported that about 400 new patients are currently entering the expanded access arms of the ddI program each week. This compares to approximately 45 new enrollees a week in the clinical trial arms of the program "for essentially a ten-to-one ratio," Corey pointed out. Corey indicated that patient accrual in one of the three protocols of the ddI clinical trials appears to have been hurt by the expanded access program. "The effect is greatest at the present on protocol 117, which most of us thought would be the first definitive clinical trial of ddI," Corey said. "This trial appears to be accruing at a much slower rate than anticipated, and apparently, at present, will take over a year or more to accrue the stated number of patients." Protocol 117 is a comparison trial with AZT in patients with AIDS or severe ARC who have been on AZT for more than 12 months. As of March 2, 362 patients have enrolled in the study, or approximately 22% of the target study population of 750. Both the clinical trials and the expanded access program "appear to be proceeding," Corey observed. He stressed that "it is unlikely that in a clinical trial program that needs to enroll 2,400 patients as expeditiously as possible, that enrollment of 8,000 with the expanded access program is not going to affect some of these trials." Protocol 116 of the ddI trials, an AZT comparison trial in patients recently diagnosed with AIDS and ARC, has enrolled approximately 23% (342) of the target study population of 1,500. About 57% of the target population (205 out of 360 patients) of a third trial -- a dose-escalating study of ddI in patients intolerant to AZT --had been enrolled as of March 2. The enrollment figures for the three protocols average out to an enrollment rate of 27% of the total target population for the ddI Phase II study program. Commenting on the use of Treatment IND protocols for AIDS drugs, FDA Office of Drug Evaluation I Director Robert Temple, MD, noted that such programs are "not supposed to mess up drug development, and so far it hasn't." He added: "Even the early bad news on ddI, with sluggish entry into the controlled trials, [is] considerably better now." Temple suggested that the reports of pancreatitis with ddI indicate that the current system of making investigational drugs available is working. "The system is supposed to collect some safety information," Temple pointed out. "The answers on that are not all in, but it is possible that recent reports about ddI that you've seen in [the newspapers] tell you [that] physicians under these circumstances will report serious adverse reactions, and that this may contribute to a better understanding of the drug." Speaking at the IoM meeting, Bristol-Myers Squibb Exec VP-Research Jerome Birnbaum noted that physicians in the ddI program "have to report adverse reactions with their monthly reports." Corey pointed out that there will be inevitable pressure to gather efficacy and toxicity data from "parallel track" protocols. The unpublished proposed regulations for parallel track do "not give responsibility to measuring the experiment of parallel track to anybody, nor any funding to look at that aspect," he noted (see story below). The investigator said that "from a policy point of view that that needs to be built into the policy." However, Corey stressed that collecting data from expanded access programs is complicated by different demographic and economic characteristics among patients in the expanded access program and those in the trials. While ddI is distributed free of charge in the expanded access programs, patients must pay physician and laboratory charges. On the other hand, patient participation in the clinical trials is free. Corey estimated that most of the enrollees in the expanded access program "will probably be those who can afford to have private medical care."

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