OBJECTIVES

: Despite that randomized clinical trials (RCTs) are the gold standard for drug evaluation, in some cases (e.g. small populations, ethical concerns) options for controlled trials are limited and regulatory decisions have to be made based on single-arm trials (SATs). Due to the lack of control arm in such studies, clinical benefits of a therapy compared to the natural disease course could be uncertain. The study objective was to analyse US Food and Drug Administration (FDA) approach to SATs used as the key evidence for regulatory approvals.

METHODS

: The sample of drugs approved based on SAT by the FDA was identified using the list of drugs identified in the European Medicines Agency database evaluated based on SAT in the agency in years 2010-2018. Information and comments pertaining to the robustness of SATs were extracted from FDA regulatory documents.

RESULTS

: In total 23 drugs were analysed. Most common rationale for accepting SATs were rarity of the disease, lack or other treatment options, and life-threatening condition. In the absence of control arm, various approaches for results interpretation were used including historical results for other treatments, natural history control cohorts, assessment of subjects before and after intervention or predefining a treatment goal (e.g. response rate). Subgroup analyses were often applied to identify patients most likely to benefit from the drug. Limitations of SATs were mentioned for over 70% of reviewed cases. FDA highlighted that some outcomes (such as time-to-event data, patient-reported and safety outcomes) cannot be adequately evaluated in such trials. Confirmatory trials or post-marketing requirements were requested for almost all cases.

CONCLUSIONS

Considering rapid emergence of innovative treatments for rare diseases, it is likely that SATs will be increasingly a part of FDA submissions. Any methodological issues with SAT should be well balanced against feasibility of conducting a RCT or the level of unmet medical needs.