CONTROLLED RELEASE DRUG FORMULATIONS WITH INDIRECT THERAPEUTIC EFFECT, POTENTIAL FOR IRREVERISIBILE TOXICITY, SHOULD BE SUPPORTED BY CLINICALS

Clinical studies for controlled release formulations are preferable in at least four situations, according to preliminary guidelines released by FDA on Sept. 5. The guidelines were issued as a report on the September 1985 workshop on controlled release dosage forms sponsored by FDA, the Drug Information Association, the Academy of Pharmaceutical Sciences and the American Society for Clinical Pharmacology & Therapeutics. Authors of the guidelines include FDA Biopharmaceutics Div. Director Jerome Skelly, PhD, and Office of Drug Research & Review Director Robert Temple, MD. Describing the purpose of the report, the authors state that it is "an initial attempt to develop guidelines for the design, conduction, and evaluation of studies of controlled release pharmaceutical dosage forms. No attempt has been made to achieve completeness, and it has been written with the recognition that it can and should be improved." The need for clinical trial information on a controlled release formulation is "a fundamental question in developing a controlled release product," the report notes. According to the guidelines, clinical studies will probably be necessary where: (1) "therapeutic effect is indirect"; (2) "irreversible toxicity can occur"; (3) "peak to trough differences of the immediate release form are very large"; or (4) "there is any other reasonable uncertainty concerning the relationship between plasma concentration and therapeutic and adverse effects." For a controlled release oral dosage form of a marketed immediate release drug for which an extensive base of pharmacodynamic-pharmacokinetic data exist, the report identifies two types of pharmacokinetic studies that may constitute the sole basis for approval: (a) single dose, three-way crossover with three treatment regimens; and (b) multiple dose steady-state studies.