OBJECTIVES: The number of pediatric orphan drugs (PODs) launching have increased. The marketing authorization and HTA evaluations for many PODs has been based on data from single-arm trials. This study aims to explore HTA agencies´ willingness to provide access to PODs with evidence from single arm trials, given their preference for randomized control trials.

METHODS: PODs approved by EMA and Health Canada between 2006-2022 were identified in the EPAR database or searching Health Canada website. PODs approved based on a single-arm trial were selected. HTA reports for the selected PODs were retrieved for four HTA agencies (i.e., NICE, HAS, CADTH, and TLV).

RESULTS: A total of 19 PODs were identified, four approvals were based on data from single-arm trials. Nine corresponding HTA submissions were identified (4 NICE, 3 HAS, 2 CADTH). All PODs received positive recommendations across the HTA agencies, five with restriction. The use of single-arm trials and subsequent lack of comparator arm resulted in a paucity of data that was criticized, but was not perceived as a critical barrier to access due to manufacturers´ detailed justification for the trial design based on ethical principles of conducting pediatric human research, the extremely high unmet need, and the poor prognosis for children. In the absence of trial comparators, all submissions included an indirect comparison (MAIC or naïve) versus SoC or a natural history cohort to demonstrate comparative value, which were associated with methodological weaknesses.

CONCLUSIONS: Single-arm trials for PODs can be accepted as a source of clinical evidence under extenuating ethical and medical circumstances. Acceptance will depend on manufacturers´ detailed justification and identification of alternative strategies to prove comparative value. Early payer and scientific engagement can help define the perceived level of unmet need and likelihood of reimbursement based on clinical evidence with varying levels of robustness.