open access: Why Do Phase III Clinical Trials in Oncology Fail so Often?

Why Do Phase III Clinical Trials in Oncology Fail so Often?

 "Achieving success in the development of a cancer drug continues to be challenging. Given the increasing costs (1) and the small number of drugs that gain regulatory approval (2), it is crucial to understand these failures. In this issue of the Journal, Gan et al. (3) reviewed 235 recently published phase III randomized clinical trials (RCTs). They report that 62% of the trials did not achieve results with statistical significance. Trying to explain the high failure rate, they note the actual magnitude of benefit achieved in a clinical trial (designated B) is nearly always less than what was predicted at the time the trial was designed (designated δ) and conclude, “investigators consistently make overly-optimistic assumptions regarding treatment benefits when designing RCTs.”

But really should we be surprised that phase III trials, the venue for detecting “small” differences, so often disappoint? Almost by definition, phase III studies are designed to detect small differences (4,5). The problem is that small has given way to “marginal” as outcomes have fallen below our already modest expectations. And who or what is to blame? Are investigators really overly optimistic regarding experimental therapies and, as the authors suggest, responsible for the large number of negative studies? Although we agree that optimism regarding clinical benefit may lead to an underpowered trial, we disagree that optimistic investigators are those we should blame. We would ask, how do Gan et al. (3) define optimism? Where do they place the line between an optimistic and a realistic expectation?.........