OBJECTIVES This study reviews health technology assessments (HTAs) performed under the NICE (UK) highly specialised technology (HST) program, compared with assessments conducted by HAS (France), G-BA (Germany), PBAC (Australia), and CADTH (Canada). METHODS The SIRIUS Orphan Drug Database includes details of HST assessments made by NICE and corresponding assessments from HAS, G-BA, PBAC, and CADTH. HTA decisions and factors affecting decision-making were compared across HTA organisations using the Database. RESULTS As of 8^th January 2019, NICE published guidance/final evaluation determinations for ten HSTs, of which eight were recommended. Focussing on the most recently published guidance, NICE recommended burosumab for X-linked hypophosphataemia in children/young people (1-17 years). Afamelanotide for erythropoietic protoporphyria was initially not recommended by NICE, who criticised small benefits in clinical trials, and high cost-effectiveness estimates. However, this decision was appealed, and the assessment is ongoing. Assessments for HSTs have been completed by HAS (seven; all recommended, ASMR ranged from II to V), G-BA (eight; all with extent of added benefit unquantifiable or above), PBAC (five; three recommended), and CADTH (six; five recommended). G-BA stated that the extent of added benefit was unquantifiable for burosumab and afamelanotide. Neither drug has been assessed by HAS, PBAC, or CADTH. PBAC has published the fewest assessments and positive recommendations, criticising insufficient trial data to support claims of clinical non-inferiority, preventing acceptance of cost-minimisation analyses. However, technologies may be eligible for special consideration following an initial negative PBAC decision, under the Life Saving Drugs Program (LSDP). CONCLUSIONS The NICE HST program has led to recommendation of drugs for very rare diseases by increasing the cost-effectiveness threshold. In France and Germany, clinical uncertainty has led to low clinical benefit assessment ratings. In Australia the LSDP has been introduced to aid access to these technologies. The standard CADTH HTA process recognises exceptional cases of uncertain clinical or cost-effectiveness evidence.