Success Rate and Possible Causes of Failures of Phase 3 Clinical Trials in Patients with Breast Cancer: A Systematic Review

Abstract

Background: Besides the high unmet medical needs of cancer patients, the success rate of phase 3 clinical trials in this disease area is relatively low compared with other disease areas. Breast cancer is the most frequently diagnosed cancer among women. The incidence of breast cancer has increased, representing a major health problem worldwide. Objectives: This systematic review aimed to investigate the success rate of phase 3 clinical trials in patients with breast cancer according to primary endpoints and to identify possible causes of failures to meet these endpoints. Methods: We performed an online database search of phase 3 clinical trials in patients with breast cancer in articles published from January 2011 to June 2017, and identified “positive” (met the primary endpoint) and “negative” (failed to meet the primary endpoint) trials. The success rates were sorted by primary endpoints. Possible causes of failures to meet the primary endpoints were investigated by assessing the accuracy of pre-trial estimates. Results: We identified 113 trials, consisting of 39 positive and 74 negative trials (overall success rate: 35%). Most of the primary endpoints (77%) were progression-related or recurrence-related. The success rates of trials assessing progression-related and recurrence-related endpoints were 39% and 17%, respectively. Progression-related and recurrence-related endpoints in the control arm showed significant improvement, compared with pre-trial estimates, which were associated with negative results. Conclusions: The accuracy of pre-trial estimates critically influenced the success rate of phase 3 clinical trials in breast cancer patients. Although these trials need to be designed to retain the reproducibility of pre-trial estimates, the changes in diagnostic measurement and/or standard therapy from the time of study planning could provide a potential risk of underestimation of pre-trial estimates in the control arm.