Randomized Phase II Trials: Inevitable or Inadvisable?

Abstract

Phase II trials remain a critical step in drug development. They are conducted “to evaluate the effectiveness of a drug for a particular tumor type and to further determine the common short-term side effects.” Given the low eventual success rate of oncology drugs entering clinical trials, it is vital that these trials efficiently screen out inactive drugs. Maximizing their positive and negative predictive values allows for a more efficient drug development process as fewer inactive drugs will progress to phase III trials, the most expensive phase of development. It has been proposed that drug development could be made more efficient through greater use of randomized phase II (RP-II) trials. Although there are a number of designs for such trials, most (approximately 90%) are two-armed studies. The use of RP-II trials is already increasing, although definitive data do not yet exist to show that the increased expenditure and patient numbers required translate into greater efficiency. This article discusses the merits of single-arm phase II (SA-II) trials versus RP-II trials (specifically, comparator trials in which patients are randomly assigned between experimental and standard therapy arms) in a debate format. Initially, Grothey and Sargent will present the merits of using RP-II trials, while Siu, Moore, Pond, and Gan will present the merits of SA-II trials. Thereafter, each team will rebut the arguments of the other. Lastly, we will conclude with a consensus statement identifying points of agreement about the appropriate use of these trial designs.