Methods and Designs of Modern Breast Cancer Confirmatory Trials

SIMPLE SUMMARY: The benefit–risk assessments of new drugs for breast cancer (BC) face several challenges, as all stakeholders do not agree on the evidence bar required for market authorization, and by the fragmentation of breast cancer diagnosis. In this study, we describe the methods and designs of breast cancer confirmatory trials published between 2001 and 2020. We found that the quality of the evidence supporting new breast cancer drugs was improving over time, but that patient-relevant endpoints such as survival and quality of life remained unfrequently used as primary endpoints. ABSTRACT: Background: The benefit–risk assessments of new drugs for breast cancer (BC) face several challenges, as all stakeholders do not agree on the evidence bar required for market authorization, and by the fragmentation of breast cancer diagnosis. The aim of this study was to describe the changes in methods and designs of breast cancer confirmatory trials. Methods: All phase III randomized trials published between 2001 and 2020 and assessing systemic BC therapies were included. Trials’ main characteristics, endpoints, and statistical methods were collected using a standardized data extraction form. Results: A total of 347 randomized controlled trials (RCTs) met the inclusion criteria. While most older trials (79%) included all subtypes of breast cancer, most recent trials populations were limited to one large intrinsic BC subgroup (69%). The use of gatekeeping testing strategies increased dramatically from 9% to 71%. The use of overall survival (OS) as an endpoint in the trials increased over time, but its use as a primary endpoint remained infrequent. The inclusion of OS testing in a hierarchical sequence in case of positive testing of a tumor-centered or composite endpoint appeared to have become the new standard. Conclusion: Our findings indicate some improvements in the quality of the evidence-base supporting new breast cancer drugs. The rigorous assessment of patient-relevant endpoints has increased over time, but this improvement is mainly related to the analysis of OS as a secondary endpoint analyzed in a hierarchical sequence.