Overrunning and underrunning in sequential clinical trials.

In a sequential (or group sequential) clinical trial the fulfillment of some pre-specified stopping rule will cause recruitment to be terminated. However, for various reasons, data on patients treated according to protocol may continue to accumulate for some time afterward. This phenomenon is called overrunning. On the other hand, a sequential clinical trial might be abandoned before the stopping rule has been fulfilled. This is called underrunning. In both of these situations the procedure for validly analyzing the study is unclear. In this paper we first review the arguments for sequential methodology and the practical way in which it can be integrated with normal clinical trial conduct. Turning next to the special situations of overrunning and underrunning, the conditions under which a valid analysis is possible are identified, and a method of analysis based on the frequentist philosophy is presented. The likelihood of first gaining and then losing significance due to overrunning and its consequences are examined. Examples based on experience with real studies are presented.