HOW FRAGILE ARE THE CLINICAL TRIALS SUPPORTING APPROVAL OF NOVEL ANTICANCER MEDICINES

A new article by Joseph C Del Paggio and Professor Ian F Tannock, recently published in The Lancet Oncology, raises a question of the fragility of phase 3, randomized, controlled trials supporting anticancer drugs that were approved by the FDA in the 5-year interval between 2014 and 2018. This was a retrospective analysis of 36 trials based on the calculation of the so-called fragility index of trial results, defined as the minimum number of changes from non-events to events resulting in loss of statistical significance. 

Only 17 (47%) trials met the inclusion criteria and were included in the fragility index analysis. The median fragility index was 2, which means that a median of two events was required to change the results of the endpoint analysis from significant to non-significant. The fragility index was 2 or less, or 1% or less of the total sample size, in nine (53%) of 17 trials. In five (29%) of 17 trials, the number of patients lost to follow-up exceeded the fragility index. 

The authors concluded that many phase 3 randomized controlled trials supporting FDA-approved anticancer drugs have a low fragility index, challenging confidence for concluding their superiority over control treatments. Although not a measure of effect, the fragility index might provide an additional means of assessing the robustness of clinical trial data.