Changes to primary endpoints of phase 3 cancer trials may be common and underreported, according to research published in JAMA Network Open.
In an analysis of more than 750 cancer trials, nearly 20% had their primary endpoints changed, and about 70% of those changes were not reported in the trial manuscripts.
In addition, trials with primary endpoint changes were more likely to have a positive primary endpoint.
For this study, researchers evaluated publicly available data for completed phase 3 randomized cancer trials registered in ClinicalTrials.gov from inception through February 2020.
The researchers used 3 methods to determine if the trials had primary endpoint changes. They assessed the history of tracked changes in ClinicalTrials.gov, self-reported changes noted in published manuscripts about the studies, and changes reported within all available versions of protocol documents.
Of the 755 trials evaluated, 145 (19.2%) had primary endpoint changes found by at least 1 of the 3 detection methods.
Some trials had multiple types of primary endpoint changes. The most frequent changes were:
- At least 1 primary endpoint was reported as a secondary endpoint (33.8%)
- The definition of the primary endpoint changed (32.4%)
- A secondary endpoint became the primary endpoint (30.3%)
- At least 1 primary endpoint was omitted in publications (18.6%)
- A new primary endpoint was introduced in the manuscript (17.2%).
There was significant variability in rates of primary endpoint changes via each method of detection (P <.001). The highest rate of primary endpoint changes was detected in published protocols (27.7%), followed by ClinicalTrials.gov (15.9%) and articles (5.7%).
Of the 145 trials with primary endpoint changes, 102 (70.3%) did not have the changes disclosed within the published manuscript. There were no trials in which the primary endpoint changes were detected exclusively in publications.
Multivariable analysis revealed that primary endpoint changes were associated with trial positivity, which was defined as meeting a prespecified threshold for a positive primary endpoint (odds ratio, 1.86; 95% CI, 1.25-2.82; P =.003).
Based on these findings, the researchers concluded that journal policies should be revised to require trialists to publish and report primary endpoint changes within the article and to provide protocols with multiple versions.
Disclosures: Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of disclosures.
Florez MA, Jaoude JA, Patel RR, et al. Incidence of primary end point changes among active cancer phase 3 randomized clinical trials. JAMA Netw Open. Published online May 17, 2023. doi:10.1001/jamanetworkopen.2023.13819