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Executive Summary

NEUROMUSCULAR BLOCKING DRUGS' REPRODUCTIVE RISK DATA is of interest to FDA, but the agency has not decided whether to draw up formal guidelines on testing the anesthetics for teratogenic potential, according to discussion at a July 20 meeting of FDA's Anesthetic and Life Support Drugs subcommittee on neuromuscular blocking drugs. The subcommittee specifically discussed reproductive risks to women who undergo surgery during pregnancy and might be treated with neuromuscular blocking agents, a class of anesthetics used to produce skeletal muscle relaxation. In discussing the need for more data on the drugs' effects in pregnant women, FDA's John Harter, director of the Pilot Drug Evaluation Staff, indicated the value of such information, pointing out that "if there are differences [in reproductive risks] between the agents you might use, you might choose one over another." However, after expert presentations to the committee, Harter noted that preclinical animal studies for neuromuscular blockers are often very expensive, difficult to conduct and may not produce significant data. "The kind of studies where you're going to have a lot of animals are probably not feasible," for the anesthetics, Harter said, also adding that in human epidemiologic studies of the drugs the "power to pick up things that don't happen very often is not very high." The subcommittee's discussions indicated to him, Harter said, that FDA may have to settle for data that is not ideal. "What you're really going to have to ask is, with the effort we're willing to put into it, or think ought to be put into it...what's feasible to be done?" The presentations to the panel focused principally on whether expanded preclinical animal tests of reproductive risks should be required for approval of future versions of the drugs. Subcommittee member David Beckman, PhD, E.I. Du Pont Institute, noted that for the neuromuscular blockers "an animal model cannot be extrapolated with any certainty to humans," in part because of the difficulty of putting animals on mechanical ventilation, which high dosages of the drugs require. If "full blown" animal reproductive studies of neuromuscular blockers were required by FDA, Beckman recommended that they include rat studies in "a minimum of two generations, with two litters per generation and teratology tests on the second generation" with "histological evaluation of adult tissue...and pilot studies to determine the appropriate dosages." The studies should test the effects of exposure "at all stages of pregnancy," Beckman indicated. He noted that the drugs can be administered to rats "for a short period at a relatively high dose requiring ventilation" to reproduce the conditions under which the drugs are used in humans, but that the process is "very labor intensive and expensive." A recently published epidemiological study conducted by subcommittee member Richard Mazze, MD, VA Medical Center, Palo Alto, and researchers at Lind University, Sweden, "did not show an increase in congenital abnormalities in the offspring of women operated on for non-obstetrical causes during pregnancy," Mazze told the committee. The study examined the records on 5,405 pregnant women who had surgery during pregnancy and received anesthesia, including neuromuscular blockers. FDA announced it would consider developing guidelines specifically for the testing and development of neuromuscular blockers at the April 19 meeting of the Anesthetic and Life Support Drugs Advisory Committee ("The Pink Sheet" May 14, T&G-4). Two companies that have approved neuromuscular blockers and new versions of the drugs in research, Burroughs Wellcome and Organon, have submitted suggestions on potential guidelines to FDA. Burroughs Wellcome markets the neuromuscular blocker Tracrium (atracurium) and filed an NDA in 1989 for Neuromax (doxacurium). Organon's approved blocker is Norcuron (vercuronium); the firm has an NDA pending for its second generation blocker, Arduad (pipercurium).

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