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NEUROMUSCULAR BLOCKING DRUGS: FDA FORMING SUBCOMMITTEE

Executive Summary

NEUROMUSCULAR BLOCKING DRUGS: FDA FORMING SUBCOMMITTEE to develop guidelines for preclinical and clinical development of the anesthetic drugs. Neuromuscular blocking drugs are used to produce skeletal muscle relaxation during surgery. Formation of the subcommittee was recommended by the FDA Advisory Committee on Anesthetic and Life Support Drugs at its April 19 meeting. The guidelines subcommittee is currently being organized under the direction of outgoing advisory committee chairman Ronald Miller, MD, of the University of California-San Francisco, and may include outside experts and industry representatives as well as members of the advisory committee. No timetable has been set for when the subcommittee will meet or when official formulation of guidelines will begin. Burroughs Wellcome and Organon, which both have licensed neuromuscular blocking agents and are developing follow-ups, have each submitted recommendations to FDA for the proposed guidelines. The Burroughs Wellcome submission includes suggestions on preclinical testing, while Organon's comments are restricted to clinicals in humans. Burroughs Wellcome has marketed the neuromuscular blocking drug Tracrium (atracurium) since 1983 and in 1989 filed an NDA for a new agent, Nuromax (doxacurium). The company also has completed clinicals on a third agent in the family, mivacurium. Organon markets Norcuron (vercuronium), first approved in 1984, and has an NDA pending for its second generation blocker, Arduad (pipercurium). Burrough's suggestions for preclinical requirements include I.V. and subcutaneous toxicity studies in two species, teratology studies in rabbits and rats, in vitro study of the test formulation's interactions with other anesthetics likely to be given at the same time, and cesarian section studies in dogs or cats if the test drug is likely to be used in human cesarian procedures. Burroughs Wellcome's proposal also raises the question of the relevance of animal studies for mutagenicity and carcinogenicity in testing anesthestic agents, since these tests are "intended to simulate chronic (years to lifetime) exposure...Skeletal muscle relaxants are administered infrequently over an individual's lifetime and thus the significance of mutagenicity and carcinogenicity testing results is of questionable clinical significance." In its comments on human testing, Burroughs Wellcome suggests that new neuromuscular blockers be tested in approximately 1,000-1,500 patients, 800-1,000 of them in Phase III, for an NDA filing. Phase I should begin with dose-response studies in healthy volunteers and move to safety and dosing studies in surgery patients, including separate studies in renal failure, hepatic failure and elderly surgical patients, the company recommends. Organon and Burroughs Wellcome both propose Phase II and III studies in a wide variety of surgery patients and clinical settings to establish dose-response relations for magnitude, onset and duration of neuromuscular blockade, as well as reversability of neuromuscular blockade and recovery time under different anesthetic conditions. However, Organon recommends clinical testing in approximately 750 subjects and, in a departure from Burroughs Wellcome's proposal, would move directly to study in a surgical population in Phase I studies. Discussion by FDA representatives and advisory committee members at the April 19 meeting appeared to favor Burroughs Wellcome's suggestion of early testing in healthy volunteers, especially as a means of gathering pharmacokinetic and pharmacodynamic data. Specifically, the committee noted that testing in healthy volunteers would allow more invasive testing of pharmacokinetic/pharmacodynamic paramaters than is practical with recovering surgery patients. The committee also expressed interest in seeing more accurate assays developed for the class of drugs; in insuring that such drugs are tested in women of childbearing age, in whom the agents are likely to be used; and compiling a list of unlabeled uses for which current neuromuscular blockers are employed.
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