OBJECTIVES: Pharmaceutical products facing imminent patent expiration historically have taken steps, such as an enhancement in formulation, to minimize the impact of generic competitors. We sought to understand and identify successful non-price-related strategies leveraged by manufacturers to mitigate sales erosion due to generic entry in the orphan disease space. METHODS: A database of 240 orphan disease pharmaceutical therapies marketed from 1999–2009 were identified.  An attribute based sequenced screening protocol was repeated, eliminating non-relevant products, providing a list of qualified analogs experiencing generic entry and delivery device innovation.  To isolate and interpret the effect of mitigation strategies on sales erosion due to generic entry, products were analyzed assessing historical pricing, sales data,  and market and product shaping activities  ASP pricing data was obtained from CMS, while sales data was extracted from publicly available SEC reports. RESULTS: Of the 240 orphan drugs, multiple  screenings resulted in three therapies qualifying  for analysis. An additional three non-orphan disease analogs were incorporated to further assess the function and impact of device innovation as a mitigating strategy.  Multiple strategies were identified as successful in maintaining a majority market share over generic entry.  The most impactful were: improved patient convenience, manifesting as less frequent dosing schedules;  proactively transitioning patients to a new, less frequent dose ahead of generic entry, thereby inhibiting patient drop-off to a less convenient generic; and innovative delivery devices that improve provider and Payer management.   Additional strategies utilized included advertising to encourage brand loyalty; patient support activities; and lobbying from thought leaders to influence the treatment paradigm. CONCLUSIONS: Less frequent dosing schedules provide strong incentives for patients’ preference, and have historically been successful in preventing or mitigating sales erosion due to generic entry within the orphan disease area.  Manufacturers may consider the development of a longer acting formulation as a viable mitigation tactic.