The use of surrogate outcomes in health technology assessment (HTA) is increasing and methods for validating surrogate relationships have been published. However, these may not be fully applicable to ultra-rare diseases due to challenges such as scarcity of evidence and heterogenous populations. This study reviews and summarizes the use of surrogate outcomes and committee's considerations in the evaluations within the National Institute for Health and Care Excellence's (NICE) Highly Specialised Technology (HST) programme, which was established in 2013 in response to the challenges associated with the assessment of ultra-rare diseases.

All HST evaluation documents published before November 2020 were reviewed. Data extracted included surrogate outcomes used, rationales, the committee's considerations on the validity and generalizability of the surrogate relationships, related uncertainties, and other factors considered in decision-making.

Seven out of the eighteen published HST topics used surrogate outcomes. The rationale for most of the surrogate relationships focused on biological plausibility. Common concerns raised by the committee included the generalizability of the surrogate relationship to the condition of interest, the lack of validation, and inability to prove or quantify the magnitude of benefits associated with the surrogate relationships. In some topics, other aspects of the evidence and clinical/patient expert's opinions were also considered by the committee.

The use of surrogate outcomes is common in NICE HST evaluations and the challenges in supporting surrogate relationships with more than biological plausibility are recognized. However, our review indicates that, the committee considers more than just biological plausibility and will take into account other related factors.