PHARMACOKINETIC/PHARMACODYNAMIC STUDIES IN PHASE II COULD LESSEN PHASE III REQUIREMENTS, FDA's PECK SUGGESTS; MERCK's ABRAMS CITES PRACTICAL DIFFICULTIES

Pharmacokinetic and pharmacodynamic studies in early Phase II, by providing "circumstantial" evidence of efficacy, can reduce the burden of proving efficacy in Phase III, FDA Center for Drug Evaluation and Research Director Carl Peck, MD, suggested at a Dec. 7 seminar for FDA staff. "Convincing kinetic and dynamic studies in early Phase II, it seems to me, could provide circumstantial evidence for effectiveness by establishing unequivocal activity or action of the drug, thereby laying the groundwork for a different [efficacy] standard," Peck said. For example, he explained, "we could talk about a one-tailed test [in Phase III], rather than a two-tailed test." FDA could incorporate pharmacokinetic/pharmacodynamic data "formally into the kind of comparative evidence that we ordinarily require when we assume that we don't know whether the drug even works and, therefore, apply a high-sample-size, two-tailed hypothesis test," he added. Peck suggested the use of pharmacokinetic and pharmacodynamic studies for efficacy data as part of a broader recommendation that such studies be used more often in the early development phases of a drug. More extensive use of such studies, he predicted, could lead to identification of the optimum dosage regimen for Phase III investigations. Currently, Peck asserted, "pharmacokinetic and pharmacodynamic studies are not optimally integrated into drug development and drug regulation. The consequences of this are a sometimes inefficient drug development history, and more importantly, the dosages of new drugs at the time of first marketing may be far from optimal." Peck illustrated the point with references to a number of products that have had their dosages reduced after being introduced to the marketplace, including: midazolam, cimetidine, vancomycin, hydrochlorothiazide, cyclosporine, propranolol, metronidazole and miconazole. Peck attributed the limited use of the studies, in part, to a lack of guidance from FDA. "I believe we can probably do better, because I think for new drugs our advice in kinetics and dynamics is somewhat scanty and somewhat vague," he said. Optimizing the dose of a drug before beginning the central clinical trials should result in "a decrease in the number and complexity of clinical trials, which in the past have wasted much time and resource in dose finding," Peck said. Addressing the practical difficulties in Peck's proposal, Merck Executive Director of Scientific Development William Abrams, MD, who has been working at FDA part-time since April as head of the Office of Professional Development, pointed out that waiting for the results of kinetic studies before initiating Phase III studies can put sponsors at a competitive disadvantage. "One realizes that with a pharmacokinetic or bioequivalence study or any study that involves assays and evaluations, there's an enormous amount of time that's involved," Abrams said. "If these are early in the drug development process in a very competitive environment, it's rather difficult for sponsors to sit still until all the samples are in, analyzed, and the results are available, before making some interim kind of judgment on whether or not to go ahead, and whether the dose is appropriate and so forth." Responding, Peck said he was not endorsing "a charge to demand kinetic and dynamic studies and that nothing move forward until those are completed and analyzed and their implications are fully appreciated." Where moving forward quickly is a priority, he said, "I guess I would suggest that there be some middle ground... where studies can proceed while analysis from a previous study is underway, with an opportunity to make an adjustment if something very impactful is discovered from the last study."