Bioequivalence Trials, Intersection-union Tests, and Equivalence Conndence Sets

The bioequivalence problem is of practical importance because the approval of most generic drugs in the United States and the European Community (EC) requires the establishment of bioequivalence between the name brand drug and the proposed generic version. The problem is theoretically interesting because it has been recognized as one for which the desired inference, instead of the usual signiicant diierence, is practical equivalence. The concept of intersection-union tests will be shown to clarify, simplify, and unify bioequivalence testing. A test more powerful than the one currently speciied by the FDA and EC guidelines will be derived. The claim that the bioequivalence problem deened in terms of the ratio of parameters is more diicult than the problem deened in terms of the diierence of parameters will be refuted. The misconception that size-bioequivalence tests generally correspond to 100(1?2)% conndence sets will be shown to lead to incorrect statistical practices, and should be abandoned. Techniques for constructing 100(1?)% conndence sets that correspond to size-bioequivalence tests will be described. Finally, multiparameter bioequivalence problems will be discussed. 1 Bioequivalence Problem Two diierent drugs or formulations of the same drug are called bioequivalent if they are absorbed into the blood and become available at the drug action site at about the same rate and concentration. Bioequivalence is usually studied by administering dosages to subjects and measuring concentration of the drug in the blood just before and at set times after the administration. These data are then used to determine if the drugs are absorbed at the same rate. The determination of bioequivalence is very important in the pharmaceutical industry because regulatory agencies allow a generic drug to be marketed if its manufacturer can demonstrate that the generic product is bioequivalent to the brand-name product. The assumption is that bioequivalent drugs will provide the same therapeutic eeect. If the generic drug manufacturer can demonstrate bioequivalence, it does not need to perform 1