Limitations of dose tolerance studies on predictability for phase III.

Phases I, II and III of the development of a new drug are briefly described. The limitations of dose tolerance studies in Phase I are considered in relation to their predictive value for Phase III. Limitations on predictability may arise because of differences between Phase I and Phase III in both study population and study design. The study population in Phase I, in contrast with Phase III, is usually numerically small, male, young, of average size, healthy, asymptomatic and free from other medication. The Phase III population may be of different nationality or race. Phase I studies are always of short duration. Drug administration is usually in the morning and may be accompanied by more restrictions on diet, smoking and alcohol intake than in Phase III trials. The implications of these differences in study population and design are discussed. The predictive value of dose tolerance studies for Phase III can be substantial, provided that the results are interpreted sensibly. However, the tolerance studies should perhaps be regarded mainly as an essential preliminary to single and multiple dose kinetic, dynamic and interaction studies; the combined experience of these trials should have much greater predictive power for Phase III than dose tolerance studies alone.