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BRISTOL-MYERS SQUIBB STADOL AND ASTRA DALGAN "ABUSE POTENTIAL" POST-MARKETING STUDIES RECOMMENDED BY FDA ADVISORY CMTE. IN LIEU OF SCHEDULING

Executive Summary

FDA's Drug Abuse Advisory Committee endorsed the use of post- marketing studies in lieu of scheduling to determine the "abuse potential" of Bristol-Myers Squibb's Stadol and Astra's Dalgan mixed agonist/antagonist opioid analgesics at its Feb. 4 meeting. The panel supported Astra's plans for post-marketing surveillance of Dalgan (dezocine) and suggested that BMS adopt a similar approach for studying the abuse potential of a proposed nasal delivery form of Stadol (butorphanol) for which an NDA is pending. The committee acknowledged that while both drugs have been known to cause physical dependence, neither appears a likely candidate for widespread substance abuse. BMS has discussed the issue of Stadol's abuse potential numerous times with FDA groups over the years since its approval in 1978. The drug has been before the Drug Abuse Advisory Committee seven times, but the FDA panel has never recommended that Stadol's abuse potential merited scheduling of the drug. Stadol, a potent pain reliever for the treatment of post- operative and chronic pain, has been on the market in I.V. form for more than 13 years and, the committee noted, has shown only "limited addictive potential." Of the over 64 mil. I.V. doses of Stadol prescribed since its introduction, only 59 cases of abuse have been reported to government-sponsored programs. FDA Pilot Drug Evaluation staff Senior Scientist Mike Klein, PhD, conceded that "we have nothing approaching a public health problem here" and called nasal Stadol a product with "good advantages." However, Klein still voiced concern about potential abuse problems that might result from increased outpatient use of Stadol once it becomes available in a nasal form. "We do have some cases of abuse -- 59 cases," Klein said, "the new dosage form concerns me." BMS' NDA for transnasal Stadol is now being "actively" reviewed by FDA, Klein noted. The NDA for nasal Stadol was filed by BMS in April 1989 for the treatment of migraine, which afflicts approximately 12% of the world's population. To address FDA's concerns about the the increased dangers of Stadol in a nasal delivery form, the committee recommended that the product be approved as an unscheduled drug but be carefully monitored through post-marketing studies tracking the drug's distribution and the incidence of Stadol abuse reported to regional rehabilitation programs. The committee's interest in post-marketing studies dates back to December 1989, when FDA approved Dalgan on the condition that the drug's sponsor, Wyeth-Ayerst, conduct extensive Phase IV studies measuring the incidence of Dalgan abuse during the first three years of marketing. In June 1990, Wyeth-Ayerst licensed Dalgan to Astra, transferring responsibility for designing the appropriate post-marketing programs. Astra VP Medical Affairs Nigel Rulewski, MD, reported the company's progress with the project to date. Rulewski told the committee that since assuming ownership of the drug Astra has met several times with FDA and has hired an outside consultant to design the best possible post-marketing surveillance program. The full extent of the drug's market penetration is not yet known, Rulewski said, noting that only about 360,000 doses of Dalgan have been distributed to date. For the moment, Astra has decided to focus its efforts on tracking abuse potential among health care professionals, Rulewski said. This segment of the population is easily monitored, and the drug's I.V. administration makes it unlikely that large segments of the general public will have access to it, Rulewski explained. Astra consultant Mitchell Balter, MD, Tufts University Medical School, is expected to begin contacting "physicians' programs and the anesthetic teaching community . . . [plus] anyone else we can think of to call . . . in an effort to determine what kinds of information can be made available by studying these populations," Rulewski reported. The company is postponing a more ambitious study suggested by FDA in 1990 that would have involved comparing Dalgan's abuse potential to those of other mixed agonist/antagonists ("The Pink Sheet" June 11, 1990, T&G-6). "We are all agreed [that] nothing like this has ever been done before and new methodologies will have to be evolved to enable us to compare addictive potential," Rulewski said. "At this this stage we still do not know what the questions are." The five manufacturers of mixed agonist/antagonists -- DuPont (Nubain), Sterling (Talwin), Norwich Eaton (Buprenex), BMS and Astra -- have all agreed to participate in such a study, Rulewski said. "We're very happy to do it," he commented after the meeting, "but the parameters for measuring addictive potential need to be [established]." National Institute of Drug Abuse representative James Cooper, MD, reported that his agency is "following FDA's lead" and has engaged in several interagency discussions of a comparative trial, but has "not yet advanced to actually designing a study." Despite the tentative nature of Astra's proposals, the committee concluded that the firm's plans "sounded reasonable" and "laudable." Committee Chairman Theodore Cicero, MD, Washington University School of Medicine, instructed Astra to proceed with its plans while maintaining regular contact with FDA and the committee. Astra said it expects to continue meeting with the agency every six months to discuss the progress of the studies. FDA Pilot Drug Evaluation staff Medical Officer Curtis Wright, MD, viewed the two recommendations for post-marketing studies as part of broader effort to devise means for regulating and monitoring new addictive drugs and new dosage forms that represent only questionable threats to public health. "If we're not going to schedule everything to the hilt," Wright argued, "we have to have some methods of our own to measure abuse potential."
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