CONTROLLED-RELEASE END GOAL IS CLINICAL OUTCOME, NOT INFREQUENT DOSING

CONTROLLED-RELEASE END GOAL IS CLINICAL OUTCOME, NOT INFREQUENT DOSING, FDA Commissioner David Kessler said in a recent speech to the Controlled Release Society in Washington, D.C. Kessler said that drug developers "should always think in terms of clinical outcomes: demonstrated, rigorously established in Washington, D.C. [and] documented improvements in patient care." He cautioned: "Steady blood levels and fewer doses, of course, are not ends in and of themselves." The commissioner raised the issue of the appropriateness of controlled-release drugs in certain situations. Equating improved compliance with changing dosing from four-a-day to two-times-daily is "not a given for all drug or all dosage forms," Kessler said. He added: "Whether reducing the dose from twice-a-day to once-a- day improves compliance is less certain, and for some products, particularly those with long half-lives, controlled-release may make no sense at all." Kessler leveled criticism at the motives for some new controlled-release drug formulations. "There's no denying that controlled-release products can increase convenience," Kessler acknowledged, "but what seems to be driving several -- many -- corporate decisions . . . to develop controlled-release products, however, is not convenience or compliance, but economics." In addition to less frequent dosing, another possible endpoint of controlled-release drug therapy is the reduction of the "peak- to-trough difference in drug levels over time," which would potentially avoid "blood level-related adverse effects," Kessler said. "Surprisingly," he noted, "few attempts have been made to document this, even though it would seem to represent real clinical and real commercial advantage." The reason, Kessler suggested, could be that "perhaps this benefit would not occur with once-daily dosing but only twice-daily dosing, and the increased dosing frequency, in our once-daily-fixated world, is too big a down side." FDA looks at three "fundamental characteristics" of controlled-release drug formulations in submissions, Kessler said: "good controlled release"; a "reasonably flat curve for drug concentration over time"; and a "form that permits maintenance of absorption at a therapeutic level." For oral formulations, the agency looks for controlled-release drugs that "avoid the food effect," he said. A company is "likely to end up with a viable product" if the formulation meets these criteria, Kessler said. One problem the agency has encountered in its review of controlled-release drug applications "more often than one would expect" is that "the controlled-release product demonstrates worse control than the immediate-release form," Kessler said. He noted that some controlled release products utilize a larger loading dose "that can lead to real trouble if too much is released too soon." Other reasons why FDA reviewers have "turned back" applications include lack of "appropriate clinical populations" in pharmacokinetic studies for the controlled release formulation; "new issues" not encountered with the immediate-release version of a product; and inadequate validation of controlled release methods, Kessler said. "New issues" examples include physical dependence as seen in studies of the fentanyl patch (Janssen's Duragesic), and tolerance discovered with use of nitroglycerin patches. One deficiency noted "occasionally" is "inadequate efforts to correlate blood levels of drug over time with clinical outcomes," Kessler added. "With controlled-release products, [the agency has] a special interest in the rate-controlling material," the commissioner said. FDA has "basic questions: what is the stability, what does it degrade into." Kessler added: "These are complicated matters, I recognize, that raise difficult issues. Reproducing some of these materials is difficult, because their production and manufacture is quite imprecise in many cases. It's particularly difficult to control product of polymers," he told the group.