SEQUENTIAL CLINICAL-TRIALS IN EMERGENCY-MEDICINE

In a traditional clinical trial, a fixed number of patients are evaluated before the data are analyzed. This has the disadvantage that more patients may be enrolled than are necessary to achieve a statistically significant result. Sequential statistical techniques provide a method for the analysis of clinical trials so that a reliable result is obtained with a minimum number of patients. In a sequential trial, the data are analyzed after each patient's outcome is known, and the trial is halted as soon as treatment efficacy or lack thereof is demonstrated. This study was undertaken to confirm the advantages of sequential statistical techniques over conventional fixed-sample-size statistical techniques for the analysis of clinical trials. Using sequential techniques, we conducted computer simulations of two fixed-sample-size clinical studies from the literature - a trial of hepatitis B vaccine in homosexual men (N Engl J Med 1980;303:833-841) and a trial of the pneumatic antishock garment in hypotensive patients with penetrating abdominal trauma (Ann Emerg Med 1987;16:653-658). In the trial simulations, patients were randomly assigned to the control and test groups, their outcomes were determined randomly according to the frequency of outcomes observed in the actual studies, and the simulated sequential studies were continued until conclusions were reached. Thousands of possible realizations of each trial were simulated; thus, the distribution of required patient numbers was determined. The risks of type I and type II errors were set at 0.05. A sequential trial sufficiently sensitive to detect a vaccine-induced reduction in hepatitis B of 50% would have required a median of 150 patients to complete the follow-up to terminate and demonstrate efficacy given the observed vaccine efficacy of 92%. The actual hepatitis B vaccine study included 1,083 patients. Given the same lack of efficacy seen in the original trial, a sequential study designed to detect a 50% reduction in mortality with use of the pneumatic antishock garment would have required a median of 102 patients and demonstrated lack of efficacy. The actual study included 201 patients. A disadvantage of sequential trials in that while the number of required patients is reduced, the estimated magnitude of the treatment effect is slightly less accurate than that of conventional fixed-sample-size trials. The theoretical properties of sequential trials are confirmed by our simulations and make this trial design advantageous for many clinical trials in emergency medicine. © 1990 American College of Emergency Physicians.