Fragility Analysis of Phase III Trials Supporting FDA Approval of Anticancer Drugs


Key Points

  • The median fragility index among all trials analyzed was 2.
  • In several trials, the number of patients lost to follow-up was greater than the fragility index.

In an analysis reported in The Lancet Oncology, Del Paggio and Tannock found that many phase III trials supporting U.S. Food and Drug Administration (FDA) approval of anticancer drugs have a low fragility index—a measure of how many people in a study would have had to have a different outcome in order for the findings to become not statistically significant—indicating a lack of robustness in the demonstration of superiority over control treatments.

The analysis included 17 phase III trials resulting in FDA approval of drugs between January 2014 and December 2018. The trials had to be two-arm studies with 1:1 randomization that showed significant positive primary outcome results for a time-to-event outcome in the intention-to-treat population.

As stated by the investigators, “The fragility index was calculated from a two by two contingency table by the iterative addition of an event to the experimental group (defined as the group with the smaller number of events in positive trials) and concomitant subtraction of a nonevent from that same group, thereby maintaining a constant total number of events plus nonevents, until positive significance (defined as P < .05) was lost.”

Fragility Analysis

The median fragility index for the 17 studies was 2 (interquartile range = 0–27); that is, a median of two events was required to change the results of the analysis from significant to nonsignificant. The fragility index was ≤ 2 in nine (53%) of the trials, with the fragility index in these trials being ≤ 1% of the entire sample size. In five trials (29%), the number of patients lost to follow-up was greater than the fragility index.

The investigators concluded, “Many phase III 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.”

Ian F. Tannock, MD, of the Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, is the corresponding author for The Lancet Oncology article.

Disclosure: The investigators reported that there was no funding source for this study. For full disclosures of the study authors, visit

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.