OBJECTIVES: With an increasing number of orphan disease (OD) drugs in development, the objective of the current study is to assess launch pricing trends of orphan drugs in the U.S.  From this pricing assessment, implications and effects of increasing orphan drug prices on US managed care payer access is discussed.  METHODS: Non-cancer OD approvals between 2003 and 2012 were extracted from the FDA Orphan Products database. Oncology and acute indications were excluded due to the confounders of acute and chronic treatments.  Wholesale acquisition cost drug prices were collected from Medispan-PriceRx for product launch year.  Annualized drug costs were calculated using the product label and consistent assumptions on weight-based dosing. Drug costs were adjusted to 2012 dollars using the CPI. RESULTS: From 2003-2012, 33 ODs gaining U.S. market approval were included in the present analysis, with 30% of the drugs approved in 2011 and 2012. Launch pricing trends indicate that average launch price of ODs has increased 107% to $276,471/year during the examined time period.  In 2012, 4 of 6 new ODs were priced between $294,000 and $295,000.   CONCLUSIONS: The OD approvals and prices have grown substantially since 2003, accelerating in the last two years.  The historically open US payer policy towards ODs must be reconsidered for sustainability.  Expansion of the covered population will increase the traditionally modest payer OD economic burden, accelerated by new treatments.  Payers must prepare by creating OD policy that identifies the most appropriate patients through collaboration with thought leaders and manufacturers.  Payer investment should be made in patient management programs to ensure clinical benefit is delivered.  The OD regulatory mechanism encourages manufacturers to invest modestly in clinical development and assign ultra-premium prices.  Manufacturers may be challenged by payers and regulatory authorities to develop evidence describing the burden of illness and justifying the payer investment.