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?.........
