OBJECTIVES: Indication expansion is a commonly utilized strategy to maximize return on investment for novel pharmaceuticals. As orphan drug designation can confer pricing, reimbursement and funding benefits, such indications can provide attractive targets for launch or follow-on indications. We aim to understand how expansions into or out of orphan indications affect a product’s total pricing and reimbursement opportunity. METHODS: Centering our research on orphan indications, we explored three potential scenarios that could be reached when expanding a products indication (from highest to lowest frequency of occurrence): 1) Orphan (current) to Orphan (indication expansion); 2) Non-Orphan (current) to Orphan (indication expansion); and 30 Orphan (current) to Non-Orphan (indication expansion). We conducted analogue analysis across a variety of key global markets to understand the implications on pricing and reimbursement for a product moving between these groupings. RESULTS: The analogue analysis indication expansion between orphan indications is relatively common, particularly in oncology. Expansion in this way did not significantly impact product funding or access restrictions, although pricing can be affected by the increased patient population size. Furthermore, regulatory requirements stipulate that a new orphan status application must be submitted for each indication. Under EMA regulations, orphan and non-orphan indications cannot be granted under the same marketing authorization. Although expansions between orphan and non-orphan indications are more common in the US, no examples of expansion from a non-orphan to orphan indication were identified by the authors. CONCLUSIONS: While indication expansion between orphan indications is relatively common, examples of expansion into or out of orphan indications are less frequent due to the regulatory restrictions. Pricing and reimbursement dynamics in all cases are reflective of the trade-offs between price potential and population size across indications.