Clinical trial barriers in neurostimulation for pediatric drug-resistant epilepsy.

OBJECTIVE

The NeuroPace responsive neurostimulation (RNS) System effectively treats focal drug-resistant epilepsy (DRE) in adults but lacks pediatric regulatory approval. Despite effective off-label pediatric use, systemic device-trial challenges have impeded label expansion. The prospective RESPONSE Study (NCT04839601), evaluating RNS in children with focal DRE, terminated prematurely after enrolling nine of 200 planned participants. We aimed to identify barriers to pediatric device-trial participation and evaluate whether anticipated ethical concerns about insurance-based access disparities materialized in practice.

METHODS

We conducted a mixed-methods study: a multi-site cross-sectional survey of barriers to RESPONSE participation, and a retrospective single-site case study at Massachusetts General Hospital (MGH) analyzing insurance distribution against state benchmarks in 96 RNS patients (73 adults and 23 pediatric), with denial rates and time to first reimbursement in a 62-patient subset (2020-2025).

RESULTS

Survey respondents comprised 8 of 9 RESPONSE sites plus MGH (which declined): 2 active, 6 withdrawn, and 1 declined. Study-design and enrolment feasibility were the dominant barriers (89%), followed by financial (44%), resource (33%), ethical (22%), and regulatory concerns (11%). The narrow eligible population reflected a mismatch between regulatory-aligned criteria (≤ 2 seizure-onset zones; exclusion of generalized or multifocal epilepsy; ages 12-17) and the heterogeneous presentations of real-world pediatric DRE, limiting recruitment. Insurance distributions did not differ from statewide benchmarks (p = .13) or between pre- and post-evaluation periods (p = .15). Denial occurred in 2/26 off-label pediatric (7.7%) and 1/36 focal adult (2.8%) RNS indications, all upheld on appeal and resolved by institutional subsidy; time to reimbursement did not differ (p = .31).

SIGNIFICANCE: The RESPONSE Study's premature termination reflected systemic barriers to pediatric device trials rather than isolated site failures. Anticipated insurance-based access disparities did not materialize locally. Advancing pediatric neuromodulation will require practice-aligned protocol design, alternative evidence pathways including registry-based real-world evidence, and leadership from well-resourced centers in collaborative evidence generation.