Rare diseases provide a perplexing problem for reimbursement agencies. Orphan drug development is often incentivized by government entities.  Despite these incentives, reimbursement at a viable level is not assured, and recent efforts by reimbursement bodies are changing the reimbursement paradigm substantially.  Value-based pricing agreements, which link the price of the drug to the value achieved, is one such effort. However, demonstrating value for an orphan drug remains challenging.  To better understand the potential value and therefore pricing of orphan drugs, we developed a comprehensive model to evaluate the pricing, economics, reimbursement, and market strategy (PERMS) specifically for these drugs. The interactive simulation model was developed to combine evidence on development costs, cost-effectiveness, treatment pathways, improvements in quality of life, and market share. The PERMS model was designed to evolve alongside the drug development process, incorporating new parameters and data as they become known. Extensive sensitivity analyses are performed to highlight the substantial uncertainty in disease prevalence and costs of the diseases. An interactive interface is developed for users to examine how changes in model input values affect outcomes of interest.  In this presentation, we will describe the primary elements of the PERMS model, demonstrate how the results may vary across subpopulations and illustrate the potential value of new drugs. Concepts will be illustrated through the use of real-world examples such as graft-versus-host disease (GVHD); a major complication of stem cell or bone marrow transplantation that has significant prognostic implications in the setting of a rare resource. This presentation will illustrate how a holistic view through simulation modeling can be useful and informative for understanding disease burden and potential reimbursement levels and making a decision to proceed to the next phase of drug development.