Single-Arm Clinical Trials as Pivotal Evidence for Cancer Drug Approval: A Retrospective Cohort Study of Centralized European Marketing Authorizations Between 2010 and 2019.

The traditional drug development paradigm, consisting of sequential phases and randomized studies, has been challenged in oncology and hemato-oncology. In the regulatory context, a number of new products have been authorized based on nonrandomized efficacy and safety data. We retrospectively analyzed the European public assessment reports for anticancer treatments authorized between 2010 and 2019 to describe the data behind such approvals. Twenty-two initial marketing authorizations, mainly conditional, were identified. Fifty percent of the products had an orphan indication, and 77% had received previous scientific advice. Conclusions of clinical benefit were based on tumor responses, ranging between 15.8 and 88%. Our data shows that single-arm clinical studies leading to positive regulatory outcomes share common methodological approaches and end points, mostly comparing the overall response rate with a fixed success threshold as the primary analysis. The clinical indications in these approvals are clustered in late-line settings, hematological malignancies, and lung cancer. Our findings underline the need to reflect on the current practice, the methodological aspects, and end points in single-arm studies, and develop specific regulatory guidance on nonrandomized and novel study designs.