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DOSAGE CHANGES REQUIRED FOR 8.3% OF NEW MOLECULAR ENTITIES FOLLOWING APPROVAL; FDA PLANS INCLUSION OF PK/PD STUDIES IN CLINICAL GUIDELINES

Executive Summary

Dosage changes were required for 8.3% of new molecular entities, according to interim results of FDA's drug dosage study, Center for Drug Evaluation and Research Director Carl Peck, MD, told an April 24-26 conference in Arlington, Va. The conference, on the integration of pharmacokinetic and pharmacodynamic studies into drug development, was sponsored by the American Association of Pharmaceutical Scientists. The ongoing study, being conducted by the center for drugs, is analyzing changes in dosage of greater than 33% for all NMEs approved from 1980-89. As of April, the center had evaluated 192 NMEs. "We have identified 16 out of 192 drugs that have undergone what we call a significant dosage," Peck said. Nine of the 16 required decreases in dose. Of those, seven were determined to need dosage changes only after the discovery of side effects. For two of the 16 drugs, doses were increased. The remaining five drugs required changes in dosing intervals. The center director remarked that while it is "good news" that only a small proportion of drugs required changes in dosing, "on the other hand this is a significant number expected to rise throughout the next five or seven years." Noting that the median time from first approval to label change is three years and as long as six years, Peck said that "the story will not be in really until 1995 or 1996." Midazolam (Roche's Versed), zidovudine (Burroughs Wellcome's Retrovir), buprenorphine (Norwich Eaton's Buprenex) and alprazolam (Upjohn's Xanax), were cited by Peck as surveyed drugs that required major dosage changes. A slower tapering level for alprazolam, Peck noted, "was motivated by data that suggested that rapid tapering resulted in an excess of drug withdrawal seizures." Peck suggested that "the efficiency of drug development may be impaired by suboptimal dosage identification during [early] drug development." Pharmacokinetic and pharmacodynamic studies early in development, even in preclinical trials, could assist in determining optimal dose, Peck asserted. Such studies also could be useful in identifying the minimal effective dose of a drug, Peck said. "The current drug development paradigm for dose selection typically identifies a dose for marketing that is on the high side," Peck noted. Long favorite subjects of the center director, expanded PK/PD studies, as well as toxicokinetic studies, are swiftly moving toward becoming requirements for all new drug development in the form of guidelines. Industry has traditionally opposed such extensive studies because of the perceived high cost of conducting them. The key points from presentations at the AAPS conference will be compiled into a report, which will be available in a few months. "FDA will extract from that that which they would like to put into their guidelines," FDA Office of Research Resources Deputy Director Jerome Skelly, PhD, commented. Peck said that report's recommendations will be incorporated into "a new issue of the general clinical guidelines," following the requisite proposal and public comment period. The extent of inclusion of such studies in the guidelines, however, will be determined by the parameters of the report. "We have not assembled you this week to proclaim by fiat that PK/PD/TK will be integrated into development: only you can do that," Peck told the pharmaceutical scientists. "We should only embrace what is practically achievable," he added. "Dr. [Robert] Temple and I have committed to each other to press along on that this summer given that we have the report of this conference as a blueprint," Peck said. Concerning preclinical PK/PD studies, Peck noted that "there is a fairly mature effort now . . . under the leadership" of Office of Drug Evaluation I & II Nonclinical Pharmacology/Toxicology Coordinator Judi Weissinger, PhD. She will "bring forth for public comment in the not too distant future a set of draft guidelines that would provide guidance for the application of these techniques in addition to other techniques in the preclinical area," Peck said. Advantages of conducting early PK/PD studies, Peck noted, include a potentially shortened drug development process and earlier access for patients; fewer, more persuasive trials for NDA submission; and a decrease in the costs of drug development. Peck observed that NDAs often include many inconclusive trials, which failed because of the selection of a wrong drug dose. "Decreasing the number of failed clinical trials should decrease development time and should decrease development cost," Peck contended. Leslie Benet, PhD, University of California at San Francisco, who will co-author the AAPS conference report, cited as the most important pharmacokinetic parameters in order of importance: clearance; effective concentration; extent of availability; fraction of available dose excreted unchanged; blood to plasma concentration ratio; extent of protein binding; and rate of availability. Office of Generic Drugs Director Roger Williams, MD suggested that pharmacodynamic studies also might apply to demonstrations of bioequivalence for nonsystemically absorbed generic drugs. "When you are in this setting when you can't measure blood levels . . . a pharmacodynamic study is going to be the most efficient way to document bioequivalence in an in vivo situation." Williams proposed that "if you can define a nice pharmacodynamic parameter, you may be able to establish bioequivalence in small numbers of patients." He added that FDA is "going to try to challenge that hypothesis with metered dose inhalers."
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