OBJECTIVES:  As of mid-2016, the 1983 U.S. Orphan Drug Act (ODA) has facilitated the approval of more than 400 innovative medicines for the treatment of small patient groups with high unmet need. This pathway has been suggested as being a new industry product strategy to capitalize on regulatory and pricing benefits. In order to understand the actual level of innovation and therapeutic value present amongst orphan drug FDA approvals, a comprehensive review of novel orphan designated therapies in the past decade was conducted. METHODS: A review of all orphan-designated drug approvals spanning the period 2006–2016 in the FDA’s Orphan Drug Product designation database identified 294 orphan designation approvals. A comprehensive data compilation of NDA and BLA approvals granted by CDER and CBER for the same period was then conducted, yielding 1,118 and 174 marketing approvals, respectively. Following data cleanup, 136 orphan designations were identified as being associated with CDER (112/1,118, or 10%) and CBER (24/174, or 14%) NME approvals. RESULTS:  While the majority of approvals were associated with high therapeutic utility, 18 approvals (13%) for arguably less innovative products, such as ancillary treatments, radiopharmaceutical agents, and diagnostic assays. Excluding these products from the final sample (N=118), less than half of novel orphan designated approvals had been for biologics (41%). Oncology was the top therapeutic area (42%), with the majority of therapies targeting hematologic malignancies (58%), melanoma (14%), and NSCLC (12%). Despite the growing discussion over gene therapies and targeted treatments, only 7% of all agents mentioned the use of diagnostic testing or specific mutations in their labels. CONCLUSIONS:  The analysis identified only a minority “non-innovative” products suggesting that the ODA pathway is supporting overall the launch of products with the intended profile targeting rare diseases with high unmet need.