Table 5.

Agency and Regulator Responses to ECA (Includes Critiques of Any Non-baseline Controlled Pivotal Single-Arm Trial)

Feature of comparator/external control	N (%)—FDA	N (%)—EMA
Benchmark: Single arm trial bench-marked to aggregate (not patient-level) results	5 (25)	1 (5)
Data access: Patient level data not accessible by regulator or 3rd party data, ownership limits regulators QA or inspections;	3 (15)	0 (0)
Endpoint selection: Subjective, imaging, or biomarker endpoints without good reliability studies or time to event endpoint	6 (30)	2 (11)
Timing: ECA not contemporaneous to trial	9 (45)	0 (0)
Setting: ECA not generated among geographically representative populations and/ or similar practice setting as single arm trial	3 (15)	0 (0)
Baseline covariates: ECA and trial arms not balanced on baseline covariates; comparable inclusion/exclusion criteria cannot be applied to both arms	6 (30)	2 (12)
Disease status: cannot provide a clinical alternative at a similar point in the disease progression as the single arm trial	5 (25)	5 (29)
Outcome measurement: risk of outcome ascertainment bias in the comparator	4 (20)	0 (0)
Other Data quality issues	8 (30)	4 (24)