Single‐Arm Clinical Trials as Pivotal Evidence for Cancer Drug Approval: a Retrospective Cohort Study of Centralised European Marketing Authorizations between 2010‐2019

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 non-randomized efficacy and safety data. We retrospectively analysed the European public assessment reports for anti-cancer treatments authorized between 2010 and 2019 to describe the data behind such approvals. Twenty two (22) initial marketing authorizations, mainly conditional, were identified. Fifty (50)% of the products had an orphan indication, and 77% had received previous scientific advice. Conclusions of clinical benefit were based on tumour responses, ranging between 15.8-88%. 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 non-randomized and novel study designs.