Protocol design considerations that relate to demonstrating the safety and effectiveness of chemopreventive agents.

As with other drugs, applications for marketing approval of new chemopreventive agents in the United States must include data from adequate and well-controlled clinical trials that demonstrate effectiveness and safety for the intended use. Knowledge of a drug's pharmacologic actions and metabolism may benefit protocol design, by identifying the patient populations and dosing schedules associated with a favorable risk/benefit profile. With availability of appropriate preclinical data, including standard assessments of an agent's toxicology, effects on reproductive performance, and genotoxicity, initial Phase I studies of 1-3 months may be performed in normal volunteers or an appropriate higher risk population. For chronic dosing studies of longer duration, preclinical toxicology studies of longer duration are relevant. Enrollment in chemoprevention studies should be directed toward individuals at sufficient risk of developing cancer so that potential benefit may counterbalance the unpredictable and possibly serious adverse effects that may be observed with prolonged administration of a study drug. Phase I and II studies with clinical dosing lasting up to 12 months often afford opportunities to assess drug effect on surrogate endpoint biomarkers that may correlate with endpoints of clinical effectiveness. Phase III and late phase II chemopreventive investigations should routinely utilize a prospective, randomized study design (double-masked and placebo-controlled, when possible). To support marketing approval, there must be evidence that a chemopreventive agent significantly delays or prevents the occurrence of malignancy, with acceptable safety. In some circumstances, modulation of a surrogate marker may provide a basis for marketing approval, before more definitive endpoint data become available. However, the acceptability of a surrogate depends on the nature and quality of the data supporting its predictive value. Given the considerations of large study size, long duration, and high cost that may hamper development of potential agents, studies designed to examine the predictive value of surrogate endpoint biomarkers are of great importance to the future development of chemoprevention research.