Real-World Data as External Controls for Single-Arm Trials: Role in Regulatory and Health Technology Assessments

OBJECTIVES:

Single-arm trial (SAT) data are increasingly reviewed by regulatory and Health Technology Assessment (HTA) agencies. External comparators (ECs) are used to contextualize SAT data. We analyzed SAT-based submissions using Real World Data (RWD) as ECs to evaluate the role in respective regulatory and HTA assessments.

METHODS:

Final reports published by 8 HTA agencies between 2015-2020 were screened to identify pivotal SAT-based submissions with RWD as ECs. For respective products, FDA and EMA reports were also reviewed.

RESULTS:

Of 50 SAT-based marketing authorizations, 18 products with 21 indications were identified for which RWD were included in 85 HTA submissions. RWD were used for marketing authorization in 57% (11/21) of indications. In situations where RWD were included in regulatory submissions, RWD were also submitted for HTA in 98% (56/57) of cases, albeit not necessarily using the exact same evidence package. In fact, additional RWD were submitted particularly to G-BA, HAS, and NICE. The overall HTA agency acceptance rate was 57% (32/56). In situations where RWD were not included in regulatory submissions, RWD were still submitted for HTA in 63% (31/49) of cases with an acceptance rate of 23% (7/31).

The overall acceptance rate of SAT-based HTA submissions with RWD as ECs ranged between different agencies, from 13% (PBAC) to 87% (NICE).

For pediatric indications, 59% (23/39) of indirect treatment comparisons (ITCs) provided to the agencies were accepted, in contrast to 35% (16/46) for adult indications.

CONCLUSIONS:

HTA agencies were more willing to accept RWD as ECs for SATs when RWD were also submitted to regulatory agencies, albeit the overall evidence package might differ. Difference in regulatory vs HTA evidence package was most pronounced with G-BA, HAS and NICE. For pediatric indications, higher acceptance rates for RWD were detected.