OBJECTIVES: Access to orphan drugs is often inconsistent, and is hindered by difficulties in demonstrating value in HTA appraisals due to the small patient populations and insufficient data. To inform future submissions, we examined the trends and key decision drivers that resulted in a submission being rejected across five HTA agencies. METHODS: The Orphanet database was searched for orphan drugs with a marketing authorisation between 2002 and 2014. To assume a certain level of competition, awareness and commercial potential, rare diseases for which two or more orphan drugs were available were selected. Decisions from five HTA agencies were considered: AWMSG (Wales), CADTH (Canada), NICE (England), PBAC (Australia), and SMC (Scotland). Assessments that resulted in a rejection were examined for key decision drivers, and for trends and variation by disease type. RESULTS: A total of 28 licensed orphan drugs were available for the treatment of eight rare diseases. The number of orphan drugs assessed, and rejection rates, varied by HTA agency; PBAC and SMC had the lowest rejection rates (4/18; 22% and 6/22; 27%, respectively), while NICE had the highest rejection rate with 40% (4/10). Uncertainties regarding clinical efficacy, and concerns over the robustness of economic evidence were the key decision drivers that led to a rejection. Examination of data by disease type indicated a trend towards higher rejection rates for diseases with a higher prevalence rate. CONCLUSIONS: The proportion of rejected submissions varied by HTA agency, particularly within the HTA bodies in the UK, highlighting inconsistencies in decision-making. An association between prevalence rate and the proportion of rejected submissions was found, with lower rates of disease prevalence correlating with higher acceptance rates. This is most likely due to the lower budget impact incurred in smaller patient populations.