<p>Due to great unmet medical needs, orphan drug development is a common issue of high priority for policymakers, industry leaders, researchers and patients worldwide. The establishment of a harmonized support system is the way forward to address the dilemma facing rare diseases (RDs). This study pioneers the proposal of a framework and dimensions of support systems affecting orphan drug development, covering legal (political and legal basis), technical (regulatory guidance and acceleration), motivational (economic incentives and innovation returns) and logistical (fundamental infrastructure) factors. This study, based on the framework, shows that the conditions for orphan drug development above are basically developed in the US, the EU and China. Additionally, China lags behind in terms of economic incentives and fundamental infrastructure. Continuous improvements in pricing and reimbursement, as well as the acceleration of real-world data (RWD) database and biobank repository integration, are expected in China. Based on these findings from the three study regions, action plans with three strategies (national plans and strategies, a patient-centered health system, global governance and collaborations) and eleven actions are suggested for strengthening synergies between initiatives and stakeholders to satisfy the medical needs of RD patients and families. This study can provide a reference not only for orphan drug development in the three study regions but also for all other countries worldwide, especially for those with a late start in addressing RDs.</p>