On the design of the Phase III drug trial. The example of rheumatoid arthritis

No new drug can be marketed in the United States unless a favorable risk-benefit ratio has been demonstrated to the satisfaction of the Food and Drug Administration. Inspection of the fashion in which this is accomplished with reference to rheumatoid arthritis reveals shortcomings in form and substance. Ten issues of design are isolated and options discussed. One design suggested, as a compromise, is 2 20-center trials to supplant late Phase II and Phase III trials. At each center a single investigator evaluates at least a 10-subject, highly selected cohort over 6 months in a 2-drug or a 2-drug plus placebo double-blind format. The active drug versus active drug component of the program will be pivotal in analysis. Advantages include expedience, lower cost, effective detection of short-term stratum-specific toxicity and of investigator bias, and absence of compromise in beta error. With such data and with emphasis on the beta error, the risk-benefit judgment will be more meaningful. Formalized Phase IV monitoring is proposed to detect infrequent or delayed toxicities.