OBJECTIVES:  More than 500 orphan products are in the pipeline. These include precision therapies, novel therapies and gene therapies representing the hope of first time treatments and potential cures. We sought to understand approval success rates and failure reasons that may lead to opportunities for HEOR evidence. METHODS:  We conducted a targeted review of peer reviewed and grey literature to identify studies to evaluate trends in orphan drug designations, FDA approvals and Complete Response Letters (CRL). RESULTS:  Since inception of the Orphan Drug Act of 1983, FDA approved 500 products to treat rare conditions. Over 200 orphan drugs were approved in the past decade. In 2015, 50% of new molecular entities (NME) were for rare diseases. This same year, Office of Orphan Product Development received 440 orphan status applications, granted 355, designated 20% as breakthrough status, granted 34% fast track status, and approved 21 NMEs. Not all orphan drug applications are approved despite recognition of unmet medical need in conditions such as, Idiopathic Pulmonary Fibrosis, Huntington’s disease, and Fabry disease. CPLs denote product approval and designate failures. In the latter, clear descriptions of evidence required to adequately demonstrate patient benefit is provided. Our study identified the following evidence shortcomings: need for additional efficacy/safety data requiring new phase 3 trials; lack of response reliability; lack of evidence demonstrating patient benefits; inability to achieve sustained thresholds of clinical benefit, and failure to demonstrate expected outcomes. Products utilizing biomarkers and surrogate endpoints not well characterized or linked to clinical response also failed. CONCLUSIONS:  Outcomes Researchers are well poised to develop much needed RWE that considers the heterogeneity in rare conditions to demonstrate patient benefit. Analyzing PROs by individual domains may provide a clearer picture of initial and durable patient response. Modeling and simulation may accommodate for limited patient populations and augment evidence.