Table 4.

Agency and Regulator Responses to Submission of Pivotal Single-Arm Trial

Feature of reviewer response to submission	N (%)—FDA (N = 20)	N (%)—EMA (N = 17)
Rare disease or gene therapy with inability to recruit placebo	18 (90)	15 (88)
Not rare disease but perceived inability to recruit placebo	2 (10)	1 (5.8)
Objective primary endpoint*	18 (90)	15 (88)
Large expected effect size in primary endpoint	9 (45)	3 (18)
SoC is a device/ surgical procedure/need different procedures for intervention & control	0 (0)	2 (12)
Condition has established natural history without spontaneous improvement	18 (90)	15 (88)
Severe condition with no effective therapies for control/limited SoC options	16 (80)	12 (71)
Intervention could not be masked but could have been randomized e.g., open label parallel or randomized assignment	1 (5)	0 (0)
Intervention requires complex safety assessment or active comparator for safety contextualization	0 (0)	0 (0)
Regulator perception of need to enroll placebo	0 (0)	0 (0)

*Objectivity of endpoint either explicitly noted by regulator or verified by authors as implicit