ABSTRACT
Phase II clinical trials represent the first introduction of new drugs into patients that have the disease under the study. These are relatively small trials, and typically there is no determination of sample size for these trials from the point of view of statistical power (see Section 4.4.6). The purpose of Phase II is to identify the doses and the frequency of dosing that should be used in Phase III clinical trials of efficacy. Phase III clinical trials are therefore viewed as confirmatory, pivotal proof-of-efficacy trials-to confirm that the doses and frequency of dosing determined from Phase II are in fact effective. Prior to the IND=NDA rewrite in the mid-to-late 1980s, pharmaceutical
companies did not do much in the way of determining in any optimal sense dose and frequency of dosing in the Phase II program that should be used in the Phase III program. The FDA regulations at that time permitted a pharmaceutical company to produce only two adequate and well-controlled trials at some dose and frequency of dosing, both of which demonstrated effectiveness of the compound to satisfy U.S. regulatory efficacy requirements. The IND and NDA rewrite of the mid-1980s introduced for the first time the dose comparison or clinical dose-response trial. One impact of the IND=NDA rewrite legislation [1], which became effective June 17, 1987, was to serve notice to the pharmaceutical industry that they had to do a better job at identifying dose regimens for drugs to be marketed. It is widely held that Dr. Bob Temple at the FDA was of the opinion that the doses of drugs on the market prior to the IND=NDA rewrite were generally too high. This position is understandable in the absence of regulation requiring evidence of clinical dose response. Presented in this chapter is a novel application of using response surface
methodology (RSM) [2] for identifying dose and frequency of dosing from a Phase II clinical trial of stress test-induced angina. By identifying dose and frequency of dosing it is meant that a dose-by-frequency region is
determined such that in this region onset of angina would be expected to be delayed at least 30% (defined as clinically of interest) above baseline. Prior to the application, an overview of RSM including the full quadratic model is presented.
