Trial Termination and Drug Misclassification in Sequential Adaptive Clinical Trials

Abstract

Sequential adaptive clinical trials allow for early termination of drug testing at interim analysis points if the evidence suggests that the candidate drug or therapy is effective (stopping for benefit) or that the drug will not demonstrate to be better than existing therapies (stopping for futility). Early stopping allows the trial sponsor to mitigate investment risks on ineffective drugs and to shorten the development timeline of effective drugs, thus reducing costs and expediting patients’ access to these new therapies. However, this new flexibility may translate into a higher risk of deriving incorrect conclusions from the trial in the form of false positives or false negatives. The authors examine the causes and implications of wrongly terminating the development of an effective drug, which may lead to unrecoverable expenses and unfulfilled patient needs. The authors find that the risk of deriving incorrect conclusions from the trial increases with the number of interim analyses performed throughout its course. The insight for management: Contrary to the literature’s focus on false positives, false negatives can be more likely; thus, whenever the drug’s characteristics and the targeted disease permit, aggressive trial designs should be chosen over conservative ones to detect small but beneficial treatment differences.