Rapacuronium: Premarket Drug Evaluation Can Be Very Effective for the Identification of Drug Risks

To the Editor: In response to Dr. Schulman’s comments in the editorial “Rapacuronium Redux”(1), in which the issue regarding the risk of injury as a result of bronchospasm was discussed, the following might be considered. Premarket drug evaluation can be very effective for the identification of drug risks and for subsequent appropriate management of such risks. It is a fact that when an application for marketing approval is submitted for a new chemical entity, and when no postmarketing data from any country are available, drug regulators must perform a risk-benefit assessment from submitted premarket data only. This assessment should establish that the benefits outweigh the risks in the context of proposed conditions of use before the drug is approved. In 1999, the U.S. Food and Drug Administration (FDA), contingent on postmarketing commitments, approved rapacuronium (Raplon; Organon, Inc., West Orange, NJ). The publicly available FDA Approval Letter of August 18, 1999 (2), reveals these commitments to have included the conduct of clinical pharmacokinetic and safety studies; bronchospasm was not addressed in the Approval Letter. The premarketing data submitted by the manufacturer in the U.S. New Drug Application (NDA) for rapacuronium are now publicly available in the FDA review documents posted on the FDA web site (3,4); I highlight portions of the safety data in this letter. The manufacturer reported a 4.4% incidence rate (25 of 564 patients) of bronchospasm with rapacuronium treatment in premarket clinical trials in the NDA in U.S. clinical trials and a 4.2% (31/736 subjects) incidence rate in non-U.S. clinical trials, whereas the incidence rate of bronchospasm with succinylcholine treatment in these premarket clinical trials reported in the NDA was 1.1% (2 of 177 subjects) in U.S. clinical trials and 2.8% (9 of 322 subjects) in non-U.S. clinical trials. Thus, head-to-head comparative studies of rapacuronium with succinylcholine provided in the original premarketing submission showed that the incidence of respiratory compromise with rapacuronium, including bronchospasm, was markedly more frequent than that for succinylcholine. Additional premarket data from the 120-day Safety Update Reports provided by the manufacturer during NDA review revealed even higher incidence rates for rapacuronium of respiratory adverse events, including bronchospasm (4). Moreover, comparison of these incidence rates with safety data for marketed, other nondepolarizing neuromuscular relaxants of the aminosteroid class (5) or other classes (6), data that were publicly available at the time, indicate that bronchospasm events associated with rapacuronium use in premarket clinical trials occurred with much greater frequency than that observed with these already-marketed drugs (less than 1%). In general, in regulatory premarket evaluation, factors such as the following contribute to the weight of evidence: safety issues, especially when identified in relatively small premarket databases, which can include issues of relative safety in the context of approved therapies; efficacy issues, which can include issues of relative efficacy in the context of approved therapies; and issues concerning the needs and expectations of the clinical health care community for new drugs that are both safe and effective in the proposed context of use. In early 2001, the U.S. manufacturer of rapacuronium voluntarily discontinued marketing of the drug in the United States after the emergence of reports of U.S. deaths and other serious adverse events related to bronchospasm that were associated with the drug’s use. At that time, a spokesperson for the manufacturer indicated to a leading U.S. newspaper that the company was also withdrawing its applications to market rapacuronium in other countries (7). There has been a dearth of other public announcements regarding rapacuronium’s marketing status in countries other than the United States or regulatory decisions, if taken, in other countries in which submissions were filed for rapacuronium marketing approval. Like other scientific research endeavors, premarket drug evaluation is best served through processes that allow for multiple, independent assessments. Robyn Lim, PhD

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