OBJECTIVES: Rare disease treatments (RDTs) often pose challenges to standard appraisal and reimbursement processes. Countries vary in their approaches to appraising RDTs; some use different ‘supplemental’ processes, others use standard processes. This study examines the impacts of these different appraisal processes for two RDTs in selected countries. METHODS: Literature Review and Synthesis. A case study analysis was conducted on countries with different types of appraisal processes. Country selection was based on availability of public health technology assessment (HTA) reports and representative countries with various processes for appraising RDTs. Two contrasting RDTs were chosen according to the criteria rare/ultra-rare treatment, affecting child/adult, and life-threatening/disabling. Information for each country's RDT appraisal was extracted into templates to enable comparison of appraisals across countries, and evaluation of the impact of the different processes in practice. RESULTS: Reports from Belgium, England, France, Germany, U.S., Italy, Netherlands, Norway, Scotland, Sweden and the U.S. were selected for Nusinersen and Voretigene. Characteristics of each country's process were identified, including information related to evidence submitted and committees’ interpretation of it. Uncertainties raised did not vary between the two treatments and did not seem to depend on the type of appraisal process. Additional considerations beyond clinical and cost effectiveness were seen for both drugs. For Nusinersen, more countries with supplemental processes took into account the impact on QoL than countries with standard processes, while for Voretigene, more countries with supplemental processes took into account severity, rarity and unmet need than countries with standard processes. While acceptance of uncertainty and additional considerations existed within both standard and supplemental processes, countries with supplemental processes more often referred to formal criteria for these considerations. CONCLUSIONS: The formal criteria for RDT appraisal within supplemental approaches may make them more appropriate to facilitate consistent decision-making and management of RDT challenges.